These are representative sample records from related to your search topic.
For comprehensive and current results, perform a real-time search at

Protein kinase C activation inhibits eosinophil degranulation through stimulation of intracellular cAMP production  

PubMed Central

The mechanism of inhibition of eosinophil degranulation by protein kinase C (PKC) was investigated in complement C5a (C5a)-stimulated degranulation of highly purified human eosinophils using the specific PKC activator – phorbol 12-myristate 13-acetate (PMA). C5a-induced release of eosinophil peroxidase and eosinophil cationic protein was potently inhibited in a concentration-dependent manner by PMA (IC50: 3 and 5 nM, respectively). The inhibition by PMA, but not histamine, was significantly reversed by the specific, but isoform nonselective, PKC inhibitor Ro 31-8220 (1 ?M). In the presence of phosphodiesterase inhibitor rolipram (5 ?M), PMA stimulated a pronounced concentration-dependent increase in intracellular cAMP, with a potency 400 times that of histamine (EC50: 55 nM vs 22.5 ?M). The inactive PMA analogue, 4?-PMA, had no such effect. The cAMP production by PMA, but not histamine, was significantly reversed by Ro 31-8220 (1 ?M) and the selective inhibitor of the novel PKC?, rottlerin (1–3 ?M), but not the selective inhibitor of the classical PKC isoforms, Gö 6976 (0.01–0.1 ?M). Western blot analysis revealed the presence of six PKC isoforms (?, ?I, ?II, ?, ? and ?) in isolated eosinophils. Chelation of internal or external calcium had no effect on PMA-induced cAMP response, but abolished that induced by histamine. There was a good correlation between increase in intracellular cAMP and inhibition of degranulation. These results show, for the first time, that in human eosinophils, PMA, via activation of PKC? isoform, can stimulate cAMP production, and that this may be the basis for its potent anti-degranulatory effect. PMID:15504748

Ezeamuzie, Charles I; Taslim, Najla



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

SciTech Connect

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

Nishikawa, Hirofumi; Kitani, Seiichi, E-mail:



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

PubMed Central

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

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



Saucerneol F, a New Lignan Isolated from Saururus chinensis, Attenuates Degranulation via Phospholipase C? 1 Inhibition and Eicosanoid Generation by Suppressing MAP Kinases in Mast Cells  

PubMed Central

During our on-going studies to identify bioactive compounds in medicinal herbs, we found that saucerneol F (SF), a naturally occurring sesquilignan isolated from Saururus chinensis (S. chinensis), showed in vitro anti-inflammatory activity. In this study, we examined the effects of SF on the generation of 5-lipoxygenase (5-LO) dependent leukotriene C4 (LTC4), cyclooxygenase-2 (COX-2) dependent prostaglandin D2 (PGD2), and on phospholipase C?1 (PLC?1)-mediated degranulation in SCF-induced mouse bone marrow-derived mast cells (BMMCs). SF inhibited eicosanoid (PGD2 and LTC4) generation and degranulation dose-dependently. To identify the molecular mechanisms underlying the inhibition of eicosanoid generation and degranulation by SF, we examined the effects of SF on the phosphorylation of PLC?1, intracellular Ca2+ influx, the translocation of cytosolic phospholipase A2 (cPLA2) and 5-LO, and on the phosphorylation of MAP kinases (MAPKs). SF was found to reduce intracellular Ca2+ influx by inhibiting PLC?1 phosphorylation and suppressing the nuclear translocations of cPLA2 and 5-LO via the phosphorylations of MAPKs, including extracellular signal-regulated protein kinase-1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Taken together, these results suggest that SF may be useful for regulating mast cell-mediated inflammatory responses by inhibiting degranulation and eicosanoid generation. PMID:24009845

Lu, Yue; Son, Jong-Keun; Chang, Hyeun Wook



Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  


The aim of this study was to determine whether hydroxytyrosol and oleuropein, the major phenols found in olives and olive oil, inhibit mast cell activation induced by immune and non-immune pathways. Purified peritoneal mast cells were preincubated in the presence of test compounds (hydroxytyrosol or oleuropein), before incubation with concanavalin A, compound 48/80 or calcium ionophore A23187. Dose-response and time-dependence studies were carried out. Comparative studies with sodium cromoglycate, a classical mast cell stabilizer, were also made. After incubation the supernatants and pellets were used to determine the ?-hexosaminidase content by colorimetric reaction. The percentage of ?-hexosaminidase release in each tube was calculated and taken as a measure of mast cell activation. Other samples of cell pellets were used for cell viability studies by the trypan blue dye exclusion test, or fixed for light and electron microscopy. Biochemical and morphological findings of the present study showed for the first time that hydroxytyrosol and oleuropein inhibit mast cell degranulation induced by both immune and non-immune pathways. These results suggest that olive phenols, particularly hydroxytyrosol and oleuropein, may provide insights into the development of useful tools for the prevention and treatment of mast cell-mediated disorders. PMID:25007967

Persia, Fabio Andrés; Mariani, María Laura; Fogal, Teresa Hilda; Penissi, Alicia Beatriz



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

PubMed Central

The aggregation of high-affinity immunoglobulin E (IgE) receptors (Fc?RI) on mast cells is a critical event in the initiation of an allergic reaction. Coengagement of Fc?RI with immunoglobulin G (IgG) low-affinity receptor Fc?RIIB/CD32 inhibits degranulation and the release of inflammatory mediators from mast cells and has therefore been proposed as a new therapeutic approach for the treatment of allergies. In this study, we investigated whether Fc?RIIB, besides inhibiting degranulation, negatively regulates other signalling pathways downstream of Fc?RI. For this, we determined the phosphorylation and/or expression of proteins involved in the regulation of mast-cell apoptosis. Coaggregation led to an attenuation of Akt phosphorylation but did not inhibit phosphorylation of transcription factor Foxo3a or its proapoptotic target, Bim. Similarly, Fc?RI-dependent expression of the prosurvival gene A1 was not affected by coaggregation. Our data demonstrate that coengagement of Fc?RI and Fc?RIIB inhibits degranulation but not the signalling pathways regulating Bcl-2 family members Bim and A1. PMID:20525153



Blockage by SP600125 of Fcepsilon receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3-kinase signalling pathway.  


SP600125 is used as a specific inhibitor of c-Jun N-terminal kinase (JNK). We initially aimed to examine physiological roles of JNK in mast cells that play a central role in inflammatory and immediate allergic responses. We found that Fc receptor for IgE (FcepsilonRI)-induced degranulation (serotonin release) and cytokine gene expression [interleukin (IL)-6, tumour necrosis factor-alpha and IL-13] in bone marrow-derived mast cells, were almost completely inhibited by SP600125. However, the time course of FcepsilonRI-induced JNK activation did not correlate with that of serotonin release. Furthermore, FcepsilonRI-induced degranulation and cytokine gene expression were not impaired in a JNK activator, MKK7-deficient mast cells, in which JNK activation was lost. These results indicate that the inhibitory effects by SP600125 are not due to impaired JNK activation. Instead, we found that SP600125 markedly inhibited the FcepsilonRI-induced activation of phosphatidylinositol 3-kinase (PI3K) and Akt, the same as a PI3K inhibitor, wortmannin. Finally, we found that SP600125 specifically inhibits delta form of p110 catalytic subunit (p110delta) of PI3K. Thus, SP600125 exerts its influence on mast cell functions by inhibiting the kinase activity of PI3K, but not JNK. PMID:19106158

Tanemura, Shuhei; Momose, Haruka; Shimizu, Nao; Kitagawa, Daiju; Seo, Jungwon; Yamasaki, Tokiwa; Nakagawa, Kentaro; Kajiho, Hiroaki; Penninger, Josef M; Katada, Toshiaki; Nishina, Hiroshi



PUVA Treatment for Alopecia areata  

Microsoft Academic Search

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

A. Karaduman



Neisserial porins inhibit human neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but prime the neutrophils to increase their oxidative burst.  

PubMed Central

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 1 and 3 and gonococcal outer membrane protein 1B (P1B). The neisserial porins inhibited human neutrophil chemoattractant-induced actin polymerization and degranulation of both primary and secondary granules. The neutrophil expression of immunoglobulin G (IgG) Fc receptors II (Fc gamma RII; CDw32) and III (Fc gamma RIII; CD16), as well as the activation-dependent downregulation of Fc gamma RIII, were reduced by the meningococcal and gonococcal porins. The neisserial porins impaired the upregulation of complement receptors 1 (CD35) and 3 (CD11b) and inhibited the phagocytic capacity of neutrophils, as evaluated by the uptake of meningococci (strain 44/76) in the presence of patient serum containing known amounts of IgG against meningococcal porins. The porins also primed neutrophils to increase their intracellular hydrogen peroxide production in response to FMLP, whereas no such priming was observed if the neutrophil protein kinase C was stimulated directly with phorbol myristate acetate. The neisserial porins influenced neutrophil functions in a time- and concentration-dependent manner. The meningococcal class 1 outer membrane protein and the gonococcal P1B tended to alter neutrophil functions more than the meningococcal class 3 protein. Thus, the neisserial porins inhibited human neutrophil actin polymerization, degranulation, opsonin receptor expression, and phagocytosis but primed the neutrophils to increase their oxidative burst. It remains to be determined whether these in vitro observations reflect mechanisms that may be of importance for the interaction between neutrophils and Neisseria species in vivo. PMID:7806353

Bjerknes, R; Guttormsen, H K; Solberg, C O; Wetzler, L M



Nicotine Inhibits Fc?RI-induced Cysteinyl Leukotrienes and Cytokine Production without Affecting Mast Cell Degranulation Through Alpha7/Alpha9/Alpha10-nicotinic Receptors1  

PubMed Central

Smokers are less likely to develop some inflammatory and allergic diseases. In Brown-Norway rats, nicotine inhibits several parameters of allergic asthma including the production of Th2 cytokines and the cysteinyl leukotriene LTC4. Cysteinyl leukotrienes are primarily produced by mast cells, and these cells play a central role in allergic asthma. Mast cells express a high affinity receptor for IgE (Fc?RI). Following its cross-linking, cells degranulate and release preformed inflammatory mediators (early phase), and synthesize and secrete cytokines/chemokines and leukotrienes (late phase). The mechanism by which nicotine modulates mast cell activation is unclear. Using ?-bungarotoxin binding, qPCR, and PCR product sequencing, we show that the rat mast/basophil cell line RBL-2H3 express nicotinic acetylcholine receptors (nAChRs) ?7, ?9, and ?10, and exposure to exceedingly low concentrations of nicotine (nanomolar), but not the biologically inactive metabolite cotinine for ?8h suppressed the late phase (leukotriene/cytokine production) but not degranulation (histamine and hexosaminidase release). These effects were unrelated to those of nicotine on intracellular free calcium concentration but causally associated with the inhibition of cPLA2 activity and PI3K/ERK/NF-?B pathway, including phosphorylation of Akt and ERK, and nuclear translocation of NF-?B. The suppressive effect of nicotine on the late-phase response was blocked by the ?7/?9-nAChRs antagonist methyllycaconitine and ?-bungarotoxin, and by siRNA knockdown of ?7, ?9, or ?10 nAChRs, suggesting a functional interaction between ?7, ?9, and ?10 nAChRs that might explain the response of RBL to nanomolar concentrations of nicotine. This “hybrid” receptor might serve as a target for novel anti-allergic/asthmatic therapies. PMID:20505147

Mishra, Neerad C.; Rir-sima-ah, Jules; Boyd, R. Thomas; Singh, Shashi P.; Gundavarapu, Sravanthi; Langley, Raymond J.; Razani-Boroujerdi, Seddigheh; Sopori, Mohan L



Cardiovascular stress of photochemotherapy (PUVA)  

SciTech Connect

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

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



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

SciTech Connect

The presynaptically active snake venom neurotoxin ..beta..-bungarotoxin (..beta..-Butx) is known to affect neurotransmitter release by binding to a subtype of voltage-activated K/sup +/ channels. Here the authors show that mast cell degranulating (MCD) peptide from bee venom inhibits the binding of /sup 125/I-labeled ..beta..-Butx to chick and rat brain membranes with apparent K/sub i/ values of 180 nM and 1100 nM, respectively. The mechanisms of inhibition of MCD peptide is noncompetitive, as is inhibition of /sup 125/I-..beta..-Butx binding by the protease inhibitor homologue from mamba venom, toxin I. ..beta..-Butx and its binding antagonists thus bind to different sites of the same membrane protein. Removal of Ca/sup 2 +/ by ethylene glycol bis(..beta..-aminoethyl ether)-N,N,N',N'-tetraacetic acid inhibits the binding of /sup 125/I-..beta..-Butx by lowering its affinity to brain membranes.

Schmidt, R.R.; Betz, H.; Rehm, H.



Effects of PUVA on the eye  

SciTech Connect

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

Backman, H.A.



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

PubMed Central

Background There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression. Objectives We investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity. Methods We used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity. Results We showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-?-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxic metabolite(s). Conclusion Our data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity. PMID:24086543

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



Mathematical model of laser PUVA psoriasis treatment  

NASA Astrophysics Data System (ADS)

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

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



Photochemotherapy of psoriasis (PUVA) without specialized equipment.  


High intensity long ultraviolet light (UV-A) systems along with oral methoxsalen (8-methoxypsoralen [8-MOP]) have been dramatically successful in clearing long-standing psoriasis. Since this equipment is beyond the reach of many dermatologists, we have examined alternate ways of achieving the benefits of PUVA photochemotherapy. A total of 24 patients with psoriasis have been treated with ordinary fluorescent blacklights in a conventional Zimmerman cabinet. Fourteen patients' conditions (58%) were cleared completely and the conditions of three (12%) were more than 80% improved. We used higher doses of 8-MOP, starting with 50 mg, and increased the dosage further in 15 cases. In five instances, 80-mg levels were given. With certain modifications, it may be possible to attain satisfactory therapeutic results with ordinary equipment. Higher doses of 8-MOP may be necessary to compensate for the lower irradiance light source in some instances. However, wide-spread use of PUVA therapy cannot be recommended at this time until the long-term effects of this treatment become known. PMID:629574

Petrozzi, J W; Kligman, A M



Cyclin-dependent kinase 5 regulates degranulation in human eosinophils.  


Degranulation from eosinophils in response to secretagogue stimulation is a regulated process that involves exocytosis of granule proteins through specific signalling pathways. One potential pathway is dependent on cyclin-dependent kinase 5 (Cdk5) and its effector molecules, p35 and p39, which play a central role in neuronal cell exocytosis by phosphorylating Munc18, a regulator of SNARE binding. Emerging evidence suggests a role for Cdk5 in exocytosis in immune cells, although its role in eosinophils is not known. We sought to examine the expression of Cdk5 and its activators in human eosinophils, and to assess the role of Cdk5 in eosinophil degranulation. We used freshly isolated human eosinophils and analysed the expression of Cdk5, p35, p39 and Munc18c by Western blot, RT-PCR, flow cytometry and immunoprecipitation. Cdk5 kinase activity was determined following eosinophil activation. Cdk5 inhibitors were used (roscovitine, AT7519 and small interfering RNA) to determine its role in eosinophil peroxidase (EPX) secretion. Cdk5 was expressed in association with Munc18c, p35 and p39, and phosphorylated following human eosinophil activation with eotaxin/CCL11, platelet-activating factor, and secretory IgA-Sepharose. Cdk5 inhibitors (roscovitine, AT7519) reduced EPX release when cells were stimulated by PMA or secretory IgA. In assays using small interfering RNA knock-down of Cdk5 expression in human eosinophils, we observed inhibition of EPX release. Our findings suggest that in activated eosinophils, Cdk5 is phosphorylated and binds to Munc18c, resulting in Munc18c release from syntaxin-4, allowing SNARE binding and vesicle fusion, with subsequent eosinophil degranulation. Our work identifies a novel role for Cdk5 in eosinophil mediator release by agonist-induced degranulation. PMID:25346443

Odemuyiwa, Solomon O; Ilarraza, Ramses; Davoine, Francis; Logan, Michael R; Shayeganpour, Anooshirvan; Wu, Yingqi; Majaesic, Carina; Adamko, Darryl J; Moqbel, Redwan; Lacy, Paige



Microvascular leakage of plasma proteins after PUVA and UVA  

SciTech Connect

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

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



Trivalent Antigens for Degranulation of Mast Cells  

PubMed Central

Degranulation of basophils and mast cells, releasing histamine, plays a central role in allergic reactions. Degranulation is a response to cell surface receptor aggregation caused by association of receptors with antibodies bound to multivalent antigens. Tools used in studying this process have included small-molecule divalent antigens, but they suffer from weak signaling due to small aggregate size. We have prepared trivalent antigens that allow formation of larger aggregates and potent responses from mast cells. PMID:17691795

Posner, Richard G.; Geng, Dianliang; Haymore, Seth; Bogert, James; Pecht, Israel; Licht, Arie; Savage, Paul B.



Upregulation of heme oxygenase-1 by degranulation in rat basophilic leukemia cells.  


Heme oxygenase (HO)-1, which is a rate-limiting enzyme involved in the catabolism of heme, is upregulated by a variety of stresses including oxidative stresses and inflammatory cytokines, in many cell types. Recent studies have suggested that upregulation of HO-1 might provide cytoprotection and immunomodulatory functions in addition to its obvious role in heme metabolism. In this study, we examined whether HO-1 was upregulated following degranulation in mast cells that initiate vigorous immunity reactions. To trigger degranulation, rat basophilic leukemia (RBL)-2H3 cells were passively sensitized using an antiserum collected from ovalbumin (OA) immunized-Brown Norway rats, and the cells were stimulated by treatment with OA. Degranulation was confirmed by measuring the release of beta-hexosaminidase. HO-1 mRNA and presence of HO-1 protein were detected using Northern blot and Western blot analyses, respectively. The effect of the antioxidant N-acetyl-L-cysteine (NAC) on HO-1 expression was also tested. HO-1 mRNA transiently increased at 1--2 h after RBL-2H3 cells were stimulated to degranulate. Its mRNA increases were dependent on the extent of degranulation. Following the upregulation of HO-1 mRNA, HO-1 protein was also increased. We also detected intracellular production of reactive oxygen species following degranulation in RBL-2H3 cells. NAC attenuated the HO-1 expression in a dose-dependent manner. This is the first report to reveal induction of both HO-1 mRNA and protein by degranulation in RBL-2H3 cells. We showed that NAC inhibited HO-1 upregulation. These results suggest that oxidative stress in activated RBL-2H3 cells results in the upregulation of HO-1. PMID:17329835

Yasui, Yumiko; Sasao, Emiko; Sakata, Masaru; Matsui, Nobuaki; Fukuishi, Nobuyuki; Akagi, Reiko; Akagi, Masaaki



Antiangiogenic effect of methotrexate and PUVA on psoriasis.  


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

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



PUVA: A Monte Carlo code for intra-articular PUVA treatment of arthritis  

SciTech Connect

Current rheumatoid arthritis treatments are only partially successful. Intra-articular psoralen-ultraviolet light (PUVA) phototherapy appears to be a new and valid alternative. Ultraviolet laser light (UVA) delivered in the knee joint through a fiber optic is used in combination with 8-methoxypsoralen (8-MOP), a light-sensitive chemical administered orally. A few hours after ingestion, the psoralen has diffused in all body cells. Once activated by UVA light, it binds to biological molecules, inhabiting cell division and ultimately causing local control of the arthritis. The magnitude of the response is proportional to the number of photoproducts delivered to tissues (i.e., the number of absorbed photons): the PUVA treatment will only be effective if a sufficient and relatively uniform dose is delivered to the diseased synovial tissues, while sparing other tissues such as cartilage. An application is being developed, based on analog Monte Carlo methods, to predict photon densities in tissues and the minimum number of intra-articular catheter positions necessary to ensure proper treatment of the diseased zone. Other interesting aspects of the problem deal with the compexity of the joint geometry, the physics of light scattering in tissues (a relatively new field of research that is not fully understood because of the variety of tissues and tissue components), and, finally, the need to include optic laws (reflection and refraction) at interfaces.

Descalle, M.A.; Laing, T.J.; Martin, W.R. [Univ. of Michigan, Ann Arbor, MI (United States)



Mathematical modeling for laser PUVA treatment of psoriasis  

NASA Astrophysics Data System (ADS)

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.

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



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


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

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



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

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),

Marcin Rozalski; Magdalena Boncler; Jacek Golanski; Cezary Watala



Effect of fruits of Opuntia elatior Mill on mast cell degranulation  

PubMed Central

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.

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



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


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

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



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

PubMed Central

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

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



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

Microsoft Academic Search

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

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



Accidental PUVA burns, vitiligo and atopic diathesis resulting in prurigo nodularis: a logical but undocumented rarity.  


Vitiligo is a dreaded disease in India due to its social and cultural consequences. PUVA and PUVAsol are the main treatment modalities for vitiligo vulgaris. To the best of our knowledge, this is the first case of accidental PUVA burns eventuating in prurigo nodularis lesions to be reported in a female patient who was undergoing home PUVA therapy. The itch is so prominent and disabling that the focus of the patient has shifted from treating her vitiligo to ameliorating the pruritus. PMID:23197209

Verma, Shyam Bhanushankar; Wollina, Uwe



Accidental PUVA burns, vitiligo and atopic diathesis resulting in prurigo nodularis: a logical but undocumented rarity*  

PubMed Central

Vitiligo is a dreaded disease in India due to its social and cultural consequences. PUVA and PUVAsol are the main treatment modalities for vitiligo vulgaris. To the best of our knowledge, this is the first case of accidental PUVA burns eventuating in prurigo nodularis lesions to be reported in a female patient who was undergoing home PUVA therapy. The itch is so prominent and disabling that the focus of the patient has shifted from treating her vitiligo to ameliorating the pruritus. PMID:23197209

Verma, Shyam Bhanushankar; Wollina, Uwe



Cytokine expression in psoriatic skin lesions during PUVA therapy  

Microsoft Academic Search

To determine whether an improvement in skin lesions as a result of PUVA therapy may be correlated with changes in cytokine\\u000a patterns, RT-PCR amplification was used to compare the levels of IL-2, IL-6, IL-8, IL-10, TNF-? and IFN-? cytokine mRNA expression\\u000a in serial biopsies from three chronic plaque psoriatic patients. In each case, 3-mm punch biopsies were taken from lesional

Angeli K. Olaniran; Barbara S. Baker; David G. Paige; Jennifer J. Garioch; Anne V. Powles; Lionel Fry



Negative control of mast cell degranulation and the anaphylactic response by the phosphatase lipin1  

PubMed Central

Summary Mast cells play a critical role in the pathogenesis of allergic diseases. How mast cell function is regulated is still not well understood. Both phosphatidic acid (PA) and diacylglycerol (DAG) are important second messengers involved in mast cell activation. Lipin1 is a phosphatidate phosphatase that hydrolyzes PA to produce DAG. The role of lipin1 in mast cell function has been unknown. In this report, we show that lipin1 is an important and selective inhibitor of mast cell degranulation. Lipin1 deficiency enhanced Fc?RI-mediated ?-hexosaminidase and prostaglandin D2 release from mast cells in vitro and exacerbated the passive systemic anaphylaxis reaction in vivo. However, Lipin1 deficiency did not exert obvious effects on IL-6 or TNF-? production following Fc?RI engagement. Fc?RI-induced PKC and SNAP-23 phosphorylation was augmented in the lipin1-deficient mast cells. Moreover, inhibition of PKC activity reduced SNAP-23 phosphorylation and mast cell degranulation in lipin1 deficient mast cells. Together, our findings suggest that lipin1 may negatively control mast cell degranulation and anaphylactic response through inhibiting the PKC-SNAP-23 pathway. PMID:23065777

Shin, Jinwook; Zhang, Ping; Wang, Shang; Wu, Jinhong; Guan, Ziqiang; Zhong, Xiao-Ping



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

Microsoft Academic Search

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

Robert S. Stern; Rudee Lange



Therapy of psoriasis with retinoid plus PUVA: Clinical and histologic data  

Microsoft Academic Search

In a group of 40 patients suffering from wide-spread psoriasis oral administration of a retinoid (Ro 10-9359) was followed by PUVA therapy. The clearance rate was increased by 30% as compared to PUVA alone. Except for cheilitis no side effects were seen. Histological analysis in 20 patients before, during and after therapy revealed an intensification of psoriatic tissue changes after

G. Heidbreder; E. Christophers



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

PubMed Central

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

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



siRNA Screen for Phosphatases Involved in IgE-mediated Mast Cell Degranulation  

PubMed Central

Mast cells play pivotal roles in the initiation of the allergic response. To gain an understanding on the functions played by phosphatases in IgE-mediated mast cell activation, a siRNA library that targets all mouse phosphatase genes was screened in a mouse mast cell line, MMC-1. Out of 198 targets, 10 enhanced and 7 inhibited high affinity IgE receptor (Fc?RI) induced degranulation. For 7 of the strongest hits, four different siRNAs per target were tested, and at least 2 out of the 4 single siRNA per target had similar effects as the pool suggesting that these were true hits. Bone marrow derived mast cells from normal mice further validated these results for six definite positive targets. The mechanism of the reduced mast cell degranulation due to calcineurin B deficiency was investigated. Calcineurin B deficiency reduced the phosphorylation of MAP kinases and the phosphorylation of PKD/PKC? and PKC?, which are involved in Fc?RI signaling. The screen therefore, has identified several new molecules that are critical for Fc?RI-induced degranulation. Regulating the function of these proteins may be potential targets for the treatment of allergic inflammation. The result also indicates that the system used is efficient for searching molecules implicated in complex receptor-induced signaling. PMID:20483767

Zhang, Juan; Mendoza, Mary; Guiraldelli, Michel; Barbu, Emilia Alina; Siraganian, Reuben P.



Deciphering the syntax of cytotoxic lymphocyte degranulation.  


In the killer lymphocyte, the targeted delivery of perforin- and granzyme-containing cytotoxic granules to the immunological synapse is crucial for the eradication of pathogen-infected or transformed targets. This process is achieved through a tightly controlled and highly efficient granule exocytosis pathway. Mutations in the granule trafficking proteins Munc13-4, syntaxin 11, Munc18-2 or Rab27 leads to a fatal lapse of immune surveillance and can be manifested as haemophagocytic lymphohistiocytosis in humans. Elucidation of the role of these proteins in exocytic trafficking is pivotal for our understanding of their role in health and disease. In this issue of the European Journal of Immunology, D'Orlando et al. [Eur. J. Immunol. 2013. 43: 194-208] make an important step in this direction, as they generate and characterise syntaxin 11 deficient mice. Herein, we discuss the role of syntaxin-11 in soluble NSF (N-ethylmaleimide sensitive fusion) attachment protein receptors complex formation leading to cytotoxic lymphocyte degranulation and its importance in maintaining immune homeostasis. PMID:23322694

Lopez, Jamie A; Voskoboinik, Ilia



Silver nanoparticle-induced degranulation observed with quantitative phase microscopy  

NASA Astrophysics Data System (ADS)

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

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



Human Umbilical Cord Blood Mesenchymal Stem Cell-Derived PGE2 and TGF-?1 Alleviate Atopic Dermatitis by Reducing Mast Cell Degranulation.  


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. Stem Cells 2015;33:1254-1266. PMID:25522163

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



PUVA treatment of alopecia areata partialis, totalis and universalis: audit of 10 years' experience at St John's Institute of Dermatology.  


Our 10-year experience with PUVA treatment for alopecia areata, partialis, totalis and universalis was retrospectively reviewed using charts and follow-up questionnaires for 70 patients at St John's Institute of Dermatology. In all cases, several previous therapies were judged to be unsatisfactory prior to starting PUVA, and many cases were already deemed clinically refractory prior to referral for PUVA. If cases of vellus hair growth are excluded, and those who lost their PUVA-induced regrowth rapidly on follow-up, the effective success rate was at best 6.3% for alopecia areata partialis, 12.5% for alopecia areata totalis and 13.3% for alopecia areata universalis. We affirm that PUVA is generally not an effective treatment for alopecia areata. PMID:8547044

Taylor, C R; Hawk, J L



Therapy of psoriasis with retinoid plus PUVA: clinical and histologic data.  


In a group of 40 patients suffering from wide-spread psoriasis oral administration of a retinoid (Ro 10-9359) was followed by PUVA therapy. The clearance rate was increased by 30% as compared to PUVA alone. Except for cheilitis no side effects were seen. Histological analysis in 20 patients before, during and after therapy revealed an intensification of psoriatic tissue changes after retinoid treatment. Loss of corneal layers, massive exoserosis, and neutrophil migration were prominent features. Mitotic counts were not increased by the pretreatment. The increased susceptibility of diseased skin to PUVA as produced by this drug appears to be based on several factors related to the tissue changes revealed by histology. PMID:464650

Heidbreder, G; Christophers, E



The tetraspanin CD63 is required for efficient IgE-mediated mast cell degranulation and anaphylaxis1  

PubMed Central

Mast cell activation through the high affinity IgE receptor Fc?RI leads to the release of mediators involved in immediate-type allergic reactions. While antibodies against the tetraspanins CD63 and CD81 inhibit Fc?RI-induced mast cell degranulation, the intrinsic role of these molecules in Fc?RI-induced mast cell activation is unknown. In mast cells, CD63 is expressed at the cell surface and in lysosomes (particularly secretory lysosomes that contain allergic mediators). Here, we investigated the role of CD63 in mast cells using a CD63 knockout mouse model. CD63-deficiency did not affect in vivo mast cell numbers and tissue distribution. Bone-marrow-derived mast cells (BMMC) developed normally in the absence of CD63 protein. However, CD63-deficient BMMC showed a significant decrease in Fc?RI-mediated degranulation, but not PMA/ionomycin-induced degranulation, as shown by ?-hexosaminidase release assays. The secretion of TNF-?, which is both released from granules and synthesized de novo upon mast cell activation, was also decreased. IL-6 secretion, and production of the lipid mediator leukotriene C4 were unaffected. There were no ultrastructural differences in granule content and morphology, late endosomal/lysosomal marker expression, Fc?RI-induced global tyrosine phosphorylation, and Akt phosphorylation. Finally, local reconstitution in genetically mast cell-deficient Kitw/w-v mice was unaffected by the absence of CD63. However, the sites reconstituted with CD63-deficient mast cells developed significantly attenuated cutaneous anaphylactic reactions. These findings demonstrate that the absence of CD63 results in a significant decrease of mast cell degranulation, which translates into a reduction of acute allergic reactions in vivo, thus identifying CD63 as an important component of allergic inflammation. PMID:23945142

Kraft, Stefan; Jouvin, Marie-Hélène; Kulkarni, Nitin; Kissing, Sandra; Morgan, Ellen S.; Dvorak, Ann M.; Schröder, Bernd; Saftig, Paul; Kinet, Jean-Pierre



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

NASA Astrophysics Data System (ADS)

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

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



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

PubMed Central

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

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



SNARE complex-mediated degranulation in mast cells  

PubMed Central

Mast cell function and dysregulation is important in the development and progression of allergic and autoimmune disease. Identifying novel proteins involved in mast cell function and disease progression is the first step in the design of new therapeutic strategies. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a family of proteins demonstrated to mediate the transport and fusion of secretory vesicles to the membrane in mast cells, leading to the subsequent release of the vesicle cargo through an exocytotic mechanism. The functional role[s] of specific SNARE family member complexes in mast cell degranulation has not been fully elucidated. Here, we review recent and historical data on the expression, formation and localization of various SNARE proteins and their complexes in murine and human mast cells. We summarize the functional data identifying the key SNARE family members that appear to participate in mast cell degranulation. Furthermore, we discuss the utilization of RNA interference (RNAi) methods to validate SNARE function and the use of siRNA as a therapeutic approach to the treatment of inflammatory disease. These studies provide an overview of the specific SNARE proteins and complexes that serve as novel targets for the development of new therapies to treat allergic and autoimmune disease. PMID:21880114

Woska, Joseph R; Gillespie, Marc E



Methoxychlor enhances degranulation of murine mast cells by regulating Fc?RI-mediated signal transduction.  


Abstract Methoxychlor, an organochlorine insecticide developed to replace DDT (dichlorodiphenyltrichloroethane), has been reported to induce mast cell degranulation and to enhance IgE-mediated allergic responses. However, the mechanisms underlying these effects are not clear. To clarify potential mechanisms, the effects of methoxychlor on degranulation of mast cells were examined. Degranulation responses were evaluated using RBL-2H3 cells and mouse bone marrow-derived mast cells with either the antigen-induced or calcium ionophore-induced stimulation. Phosphorylation of enzymes related to signaling events associated with mast cell degranulation was analyzed by immunoblotting. Effects on vascular permeability in the passive cutaneous anaphylaxis reaction were evaluated following oral administration of methoxychlor to BALB/c mice. The results indicated that methoxychlor caused increased mast cell degranulation in the presence of antigen, whereas it had no effect on calcium ionophore-induced degranulation of RBL-2H3 cells. Immunoblot analyses demonstrated that the phosphorylation level of phosphoinositide 3-kinase (which plays a central role in mast cell signaling) was increased by methoxychlor during antigen-induced degranulation. In addition, methoxychlor activated the signaling pathway via the high-affinity IgE receptor by inducing phosphorylation of Syk and PLC?1/2, which transfer the signal for degranulation downstream. Lastly, oral administration of methoxychlor exhibited a tendency to promote vascular permeability in passive cutaneous anaphylaxis model mice. Taken together, the results here suggested that methoxychlor enhanced degranulation through Fc?RI-mediated signaling and promoted allergenic symptoms involved in mast cell degranulation. PMID:25418051

Yasunaga, Sho; Nishi, Kosuke; Nishimoto, Sogo; Sugahara, Takuya



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

SciTech Connect

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

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



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

Microsoft Academic Search

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

Anders Bredberg



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

SciTech Connect

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

Bredberg, A.



[Phagocytic activity of polymorphonuclear cells in patients with psoriasis vulgaris from the aspect of PUVA therapy].  


The authors present results of examining phagocytotic activity of polymorphonuclear (PMN) granulocytes in patients with psoriasis vulgaris from the aspect of applied PUVA-therapy. 100 patients with psoriasis vulgaris were examined and divided into three groups, 20 patients with acute exanthematous form of the disease, 16 patients with chronic stationary form of the disease, and 64 patients with acute phase of the chronic form of the disease. 50 healthy persons made up the control group. Phagocytotic activity of neutrophils was examined by opsonization test, a modified method by Brandt. Phagocytotic index was expressed as a number of ingested particles of yeast germs in 100 PMN. Polymorphonuclears of patients were examined in the autologous and control serum of healthy people. Values of immunoglobulin IgM and IgG as well as values of complement C3 were examined in all patients using the method of laser nephelometry (Behring). All mentioned parameters were determined prior to and after PUVA therapy which was conducted by apparatus: PUVA 4000 and 6001. Results of examination show that the phagocytotic activity of PMN in patients with psoriasis vulgaris is normal and that it does not depend on how skin disorders are spread, on the strength of infiltration, exudation, the length of duration and course of the disease, as well as on applied PUVA-therapy. Reduced phagocytotic activity of PMN was determined only in individual cases, that is in 5 patients not depending on the applied therapy. In one patient hypoimmunoglobulinemia IgM as a probable cause of disturbed phagocytosis was established while in the remaining 4 patients causes of reduced phagocytosis remained unknown. PMID:7739462

Poljacki, M; Suboti?, M; Budakov, M; Jovanovi?, M; Duran, V; Matovi?, L



E-prostanoid 2 receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling  

PubMed Central

The experimental administration of PGE2 for the treatment of asthma dampens clinical symptoms, and similar efficacy has been found in dust mite-induced hypersensitivity reactions in animal models. Here, we investigate the mechanism by which PGE2 mediates suppression of MC degranulation. We find that the effect of PGE2 on Fc?RI-dependent MC degranulation varies from activating to suppressing, depending on the relative ratio of EP2 to EP3 expression on these cells with suppression evident only in cells having increased EP2 to EP3 expression. Consistent with a role for EP2 in suppressing MC responses in vitro, we found that a selective EP2 agonist, Butaprost, inhibited MC-mediated Fc?RI-induced immediate hypersensitivity in a model of PCA. EP2 engagement on MCs increased cAMP production and inhibited Fc?RI-mediated calcium influx. In addition, it also decreased the extent of Fc?RI-induced Fyn kinase activity, leading to decreased phosphorylation of key signaling molecules such as Gab2 and Akt. Treatment with an antagonist of cAMP or shRNA down-regulation of PKA (the principal intracellular target of cAMP) reversed the EP2-mediated inhibitory effect on MC degranulation and restored calcium influx and phosphorylation of Akt. Collectively, the findings demonstrate that EP2 suppresses the Fyn-mediated signals that are central to Fc?RI-dependent MC degranulation, suggesting that engagement of the EP2 on MCs may be beneficial in dampening allergic responses. PMID:22859831

Serra-Pages, Mariona; Olivera, Ana; Torres, Rosa; Picado, César; de Mora, Fernando; Rivera, Juan



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

NASA Astrophysics Data System (ADS)

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

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



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

SciTech Connect

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

Ham, Hwa-Yong [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)] [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Hong, Chang-Won, E-mail: [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: [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)



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

PubMed Central

Inhaled and intravenously administered adenosine induces mast cell-mediated (histamine-dependent) bronchospasm in asthmatics without causing urticaria. A differential response to adenosine by human lung and skin mast cells is shown: low concentrations potentiate Fc?RI-induced degranulation of human lung mast cells but not that of skin mast cells. Human lung mast cells were found to express ~3-fold more A3AR mRNA than skin mast cells, suggesting the involvement of the Gi-linked A3AR. Indeed, the adenosine-induced potentiation was sensitive to inhibition by pertussis toxin, and, furthermore, could be induced with an A3AR-specific agonist. This study reveals a previously unrecognized disparity in the response to adenosine by primary human mast cells from lung and skin that might explain why adenosine induces a pulmonary but not dermatologic allergy-like response in vivo. In addition, we identify the A3AR as a potentiating receptor of Fc?RI-induced degranulation, thereby implicating it in the in vivo bronchoconstrictive response to adenosine in asthmatics. PMID:21437670

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



Down-Regulation of MicroRNA-223 Promotes Degranulation via the PI3K/Akt Pathway by Targeting IGF-1R in Mast Cells  

PubMed Central

Background Mast cells play a central role in allergic and inflammatory disorders by inducing degranulation and inflammatory mediator release. Recent reports have shown that miRNAs play an important role in inflammatory response regulation. Therefore, the role of miR-223 in mast cells was investigated. Methods The expression of miR-223 was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) in immunoglobulin E (IgE)-mediated mast cells. After successful miR-223 inhibition by transfection, degranulation was detected in IgE-mediated mast cells. The phosphorylation of I?B-? and Akt were examined using western blotting. NF-?B was tested using electrophoretic mobility shift assay. PI3K-inhibitor (LY294002) was used to investigate whether the PI3K/Akt pathway was essential for mast cell activation. The TargetScan database and a luciferase reporter system were used to identify whether insulin-like growth factor 1 receptor (IGF-1R) is a direct target of miR-223. Results MiR-223 expression was up-regulated in IgE-mediated mast cells, whereas its down-regulation promoted mast cell degranulation. Levels of I?B-? and Akt phosphorylation as well as NF-?B were increased in miR-223 inhibitor cells. LY294002 could block the PI3K/Akt signaling pathway and rescue the promotion caused by suppressing miR-223 in mast cells. IGF-1R was identified as a direct target of miR-223. Conclusions These findings suggest that down-regulation of miR-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PMID:25875646

Xu, Hong; Zhou, Hui; Yang, Qian-Yuan; Liu, Feng; Zhou, Guo-Ping



Anti type I allergic property of Japanese butterbur extract and its mast cell degranulation inhibitory ingredients.  


Pollenosis is a disease that affects 1 in 10 of the Japanese population. During the season of cedar pollen dispersal, many patients suffer from symptoms such as sniffling, sternutation, and itching of the eyes. Japanese butterbur is a popular vegetable and is one of the few domestic vegetables in Japan. The anti type I allergic effects of an aqueous ethanol extract from aerial parts of Japanese butterbur (JBE) were evaluated in rats and RBL-2H3 mast cells. In the passive cutaneous anaphylaxis reaction in rats, a single oral treatment of JBE (1000 mg/kg) was found to suppress the reaction. In IgE-sensitized RBL-2H3 cells, JBE (10-100 microg/mL) inhibited beta-hexosaminidase release, leukotriene C(4)/D(4)/E(4) synthesis, and TNF-alpha production. Moreover, a high concentration of JBE (1000 microg/mL) suppressed smooth muscle constriction induced by histamine (10 microM) and leukotriene D(4) (10 nM) in a guinea pig trachea strip. The search for components in JBE with an inhibitory activity on mast cell degranulation was guided by inhibition of beta-hexsosaminidase release. Two eremophilane-type sesquiterpenes, six polyphenolic compounds, and two triterpene glycosides were isolated. Of these compounds, fukinolic acid, a principal polyphenol constituent, showed potent inhibitory activity (IC(50) value = 2.1 microg/mL). Consequently, On the basis of its inhibition of mast cell activation and direct smooth muscle reaction induced by released mediators, JBE was found to suppress the type I allergic reaction. PMID:16608208

Shimoda, Hiroshi; Tanaka, Junji; Yamada, Emi; Morikawa, Toshio; Kasajima, Naoki; Yoshikawa, Masayuki



Degranulation of acinar cells in von Ebner's gland of the rat.  


We investigated the effect of sympathetic agonists, parasympathetic muscarinic agonists and substance P on depletion of secretory granules in acinar cells of rat von Ebner's gland. Drugs were injected intraperitoneally at several different concentrations. Antagonists were given 15 minutes before injection of the agonist, and the extent of depletion of secretory granules in glandular acini was calculated using a computerized color image analyzer. The specific alpha 2-sympathetic agonist clonidine and the beta 1-sympathetic agonist dobutamine produced a depletion of secretory granules. When combined with injections of the alpha 2-sympathetic antagonist yohimbine and the beta 1-sympathetic antagonist acebutolol, depletion of secretory granules was blocked. The parasympathetic muscarinic agonist carbachol also produced a depletion of secretory granules. QNB blocked the depletion caused by carbachol, while atropine partially inhibited depletion. The specific M1-muscarinic agonist McN-A-343 caused some depletion, although there was no significant differences between it and the control. Complete depletion of the secretory granules was achieved by carbachol stimulation superimposed on substance P stimulation. We concluded that the activation of the sympathetic alpha 2- and beta 1-receptors, as well as the M2 (M2 beta)-muscarinic and substance P receptors, results in degranulation of acinar cells in von Ebner's gland of the rat. PMID:1725993

Ueba, H; Uchihashi, K



Mast cell degranulation – a mechanism for the anti-arrhythmic effect of endothelin-1?  

PubMed Central

Background and purpose: The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. Experimental approach: Male Sprague-Dawley rats received either ET-1 (1.6 nmol·kg?1) in the presence or absence of disodium cromoglycate (DSCG; 20 mg·kg?1·h?1) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 µg·kg?1) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. Key results: ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. Conclusions and implications: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation. PMID:19422371

Walsh, SK; Kane, KA; Wainwright, CL



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

NASA Astrophysics Data System (ADS)

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.

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



Singlet oxygen generation in PUVA therapy studied using electronic structure calculations  

NASA Astrophysics Data System (ADS)

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

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



Influence of physicochemical properties of silver nanoparticles on mast cell activation and degranulation.  


Silver nanoparticles (AgNPs) are increasingly being incorporated into products for their antimicrobial properties. This has resulted in increased human exposures and the possibility of adverse health effects. Mast cells orchestrate allergic immune responses through degranulation and release of pre-formed mediators. Little data exists on understanding interactions of AgNPs with mast cells and the properties that influence activation and degranulation. Using bone marrow-derived mast cells and AgNPs of varying physicochemical properties we tested the hypothesis that AgNP physicochemical properties influence mast cell degranulation and osteopontin production. AgNPs evaluated included spherical 20 nm and 110 nm suspended in either polyvinylpyrrolidone (PVP) or citrate, Ag plates suspended in PVP of diameters between 40–60 nm or 100–130 nm, and Ag nanowires suspended in PVP with thicknesses <100 nm and length up to 2 ?m. Mast cell responses were found to be dependent on the physicochemical properties of the AgNP. Further, we determined a role for scavenger receptor B1 in AgNP-induced mast cell responses. Mast cell degranulation was not dependent on AgNP dissolution but was prevented by tyrosine kinase inhibitor pretreatment. This study suggests that exposure to AgNPs may elicit adverse mast cell responses that could contribute to the initiation or exacerbation of allergic disease. PMID:25458489

Aldossari, Abdullah A; Shannahan, Jonathan H; Podila, Ramakrishna; Brown, Jared M



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

Microsoft Academic Search

In the last decade, there has been renewed interest in biologically active peptides in fields like allergy, autoimmune diseases and antibiotic therapy. Mast cell degranulating peptides mimic G-protein receptors, showing different activity levels even among homologous peptides. Another important feature is their ability to interact directly with membrane phospholipids, in a fast and concentration-dependent way. The mechanism of action of

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



Replication study concerning the effects of homeopathic dilutions of histamine on human basophil degranulation in vitro  

Microsoft Academic Search

Summary Background: Various investigators have observed significant effects of highly diluted histamine on human basophil degranulation in vitro, compared to corresponding water controls. However, active and inactive dilution levels differed in most studies. Objective: We aimed to reproduce former studies with flow-cytometry usingrig or- ously controlled experimental conditions to minimise confoundingfactors. Methods: In seven independent experiments, basophils of the same

Adrian G. Guggisberg; Stephan M. Baumgartner; Cornelia M. Tschoppb; Peter Heusser



Phosphorylation of SNAP-23 by I?B Kinase 2 Regulates Mast Cell Degranulation  

PubMed Central

SUMMARY Mast cells are known to play a pivotal role in allergic diseases. Cross-linking of the high-affinity receptor for IgE (Fc?RI) leads to degranulation and allergic inflammation; however, the regulatory mechanisms of IgE-dependent exocytosis remain unknown. We show here that I?B kinase (IKK) 2 in mast cells plays critical roles in IgE-mediated anaphylaxis in vivo, and IgE-mediated degranulation in vitro, in an NF-kB-independent manner. Upon Fc?RI stimulation, IKK2 phosphorylates SNAP-23, the target membrane soluble N-ethylmaleimide-sensitive fusion factor attachment protein receptor (SNARE), and ectopic expression of a phosphomimetic mutant of SNAP-23 partially rescued the impaired IgE-mediated degranulation in IKK2-deficient mast cells. These results suggest that IKK2 phosphorylation of SNAP-23 leads to degranulation and anaphylactic reactions. While this reaction is NF-kB-independent, we additionally show that IKK2 also regulates late-phase allergic reactions promoted by the release of proinflammatory cytokines in an NF-kB-dependent manner. The findings suggest that IKK2 is a central player in allergic reactions. PMID:18692471

Suzuki, Kotaro; Verma, Inder M.



Bacterial lipopolysaccharide induces endothelial cells to synthesize a degranulating factor for neutrophils  

Microsoft Academic Search

Enzymes and other factors secreted by degranulating neutrophils (polymorphonuclear leukocytes, PMNs) mediate endothelial injury, thrombosis, and vascular remodeling. In bacter- emia and sepsis syndrome and their consequent complications (including acute respiratory distress syndrome and systemic ischemia-reperfusion re- sulting from septic shock), neutrophil degranula- tion is an important mechanism of injury. In related studies, we found that human endothelial cells reg-




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


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

Keskin, Ali Umit




PubMed Central

In vitro degranulation of rat mast cells was studied at different intervals ranging from 10 to 60 sec after adding the histamine liberator, compound 48/80 (0.4 µg/ml, 17°C). The ultrastructural changes were followed by electron microscopy, and parallel assays were made to determine the histamine released. In addition, the extracellular tracers lanthanum and hemoglobin (demonstrated by its peroxidative activity) were applied to mast cells to follow communication of the extracellular space with the cavities formed during degranulation. After a lag period of 10 sec, degranulation started in the most peripherally located granules. The perigranular membrane fused with the plasma membrane, resulting in a pore bridged by a thin diaphragm. This was followed by rupture of the diaphragm and extrusion of the granule matrix (exocytosis). The process advanced towards the cell interior by fusion and opening of the deeper situated granules to the formerly opened granule cavities. At the end of the process, the cell was filled by a system of complicated cavities containing a number of altered granules. Extracellular tracers have shown that these intracellular cavities were in unbroken communication with the extracellular space from the very beginning of their formation. Both lanthanum and hemoglobin were found to be adsorbed to the limiting membrane of the cavities and bound to altered mast cell granules. In contrast, no tracer substance was present in nondegranulating mast cells. Degranulation of mast cells by compound 48/80 is regarded as a sequential exocytosis, a process similar to that described for some exocrine gland cells. All the "intracellular" cavities, formed by degranulation, were shown to communicate with the extracellular space; consequently, granules lying in these cavities must be considered as biologically extracellular. The present findings support the view that histamine is released from the granule matrix by the extracellular ionic milieu. PMID:4107023

Röhlich, Pál; Anderson, Per; Uvnäs, Börje



Staphylococcus ?-toxin promotes mouse allergic skin disease by inducing mast cell degranulation  

PubMed Central

Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15 to 30% of children and ~5% of adults in industrialized countries1. Although the pathogenesis of AD is not fully understood, the disease is mediated by an abnormal immunoglobulin E (IgE) immune response in the setting of skin barrier dysfunction2. Mast cells (MCs) contribute to IgE-mediated allergic disorders including AD3. Upon activation, MCs release their membrane-bound cytosolic granules leading to the release of multiple molecules that are important in the pathogenesis of AD and host defense4. More than 90% of AD patients are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbor the pathogen5. Several Staphylococcal exotoxins (SEs) can act as superantigens and/or antigens in models of AD6. However, the role of these SEs in disease pathogenesis remains unclear. Here, we report that culture supernatants of S. aureus contain potent MC degranulation activity. Biochemical analysis identified ?-toxin as the MC degranulation-inducing factor produced by S. aureus. MC degranulation induced by ?-toxin depended on phosphoinositide 3-kinase (PI3K) and calcium (Ca2+) influx, but unlike that mediated by IgE crosslinking, it did not require the spleen tyrosine kinase (Syk). In addition, IgE enhanced ?-toxin-induced MC degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from AD patients produced high levels of ?-toxin. Importantly, skin colonization with S. aureus, but not a mutant deficient in ?-toxin, promoted IgE and IL-4 production, as well as inflammatory skin disease. Furthermore, enhancement of IgE production and dermatitis by ?-toxin was abrogated in KitW-sh/W-sh MC-deficient mice and restored by MC reconstitution. These studies identify ?-toxin as a potent inducer of MC degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease. PMID:24172897

Nakamura, Yuumi; Oscherwitz, Jon; Cease, Kemp B.; Chan, Susana M.; Muñoz-Planillo, Raul; Hasegawa, Mizuho; Villaruz, Amer E.; Cheung, Gordon Y. C.; McGavin, Martin J.; Travers, Jeffrey B.; Otto, Michael; Inohara, Naohiro; Núñez, Gabriel



Vesicle associated membrane protein (VAMP)-7 and VAMP-8, but not VAMP-2 or VAMP-3, are required for activation-induced degranulation of mature human mast cells.  


Mediator release from mast cells (MC) is a crucial step in allergic and non-allergic inflammatory disorders. However, the final events in response to activation leading to membrane fusion and thereby facilitating degranulation have hitherto not been analyzed in human MC. Soluble N-ethyl-maleimide-sensitive factor attachment protein receptors (SNARE) represent a highly conserved family of proteins that have been shown to mediate intracellular membrane fusion events. Here, we show that mature MC isolated from human intestinal tissue express soluble N-ethylmaleide sensitive factor attachment protein (SNAP)-23, Syntaxin (STX)-1B, STX-2, STX-3, STX-4, and STX-6 but not SNAP-25. Furthermore, we found that primary human MC express substantial amounts of vesicle associated membrane protein (VAMP)-3, VAMP-7 and VAMP-8 and, in contrast to previous reports about rodent MC, only low levels of VAMP-2. Furthermore, VAMP-7 and VAMP-8 were found to translocate to the plasma membrane and interact with SNAP-23 and STX-4 upon activation. Inhibition of SNAP-23, STX-4, VAMP-7 or VAMP-8, but not VAMP-2 or VAMP-3, resulted in a markedly reduced high-affinity IgE receptor-mediated histamine release. In summary, our data show that mature human MC express a specific pattern of SNARE and that VAMP-7 and VAMP-8, but not VAMP-2, are required for rapid degranulation. PMID:18253931

Sander, Leif E; Frank, Simon P C; Bolat, Seza; Blank, Ulrich; Galli, Thierry; Bigalke, Hans; Bischoff, Stephan C; Lorentz, Axel



c-kit receptor signaling through its phosphatidylinositide-3'-kinase-binding site and protein kinase C: role in mast cell enhancement of degranulation, adhesion, and membrane ruffling.  

PubMed Central

In bone marrow-derived mast cells (BMMCs), the Kit receptor tyrosine kinase mediates diverse responses including proliferation, survival, chemotaxis, migration, differentiation, and adhesion to extracellular matrix. In connective tissue mast cells, a role for Kit in the secretion of inflammatory mediators has been demonstrated as well. We recently demonstrated a role for phosphatidylinositide-3' (PI 3)-kinase in Kit-ligand (KL)-induced adhesion of BMMCs to fibronectin. Herein, we investigated the mechanism by which Kit mediates enhancement of Fc epsilon RI-mediated degranulation, cytoskeletal rearrangements, and adhesion in BMMCs. Wsh/Wsh BMMCs lacking endogenous Kit expression, were transduced to express normal and mutant Kit receptors containing Tyr-->Phe substitution at residues 719 and 821. Although the normal Kit receptor fully restored KL-induced responses in Wsh/Wsh BMMCs, Kit gamma 719F, which fails to bind and activate PI 3-kinase, failed to potentiate degranulation and is impaired in mediating membrane ruffling and actin assembly. Inhibition of PI 3-kinase with wortmannin or LY294002 also inhibited secretory enhancement and cytoskeletal rearrangements mediated by Kit. In contrast, secretory enhancement and adhesion stimulated directly through protein kinase C (PKC) do not require PI 3-kinase. Calphostin C, an inhibitor of PKC, blocked Kit-mediated adhesion to fibronectin, secretory enhancement, membrane ruffling, and filamentous actin assembly. Although cytochalasin D inhibited Kit-mediated filamentous actin assembly and membrane ruffling, secretory enhancement and adhesion to fibronectin were not affected by this drug. Therefore, Kit-mediated cytoskeletal rearrangements that are dependent on actin polymerization can be uncoupled from the Kit-mediated secretory and adhesive responses. Our results implicate receptor-proximal PI 3-kinase activation and activation of a PKC isoform in Kit-mediated secretory enhancement, adhesion, and cytoskeletal reorganization. Images PMID:9168474

Vosseller, K; Stella, G; Yee, N S; Besmer, P



Role of Complement Activation and Mast Cell Degranulation in the Pathogenesis of Rapid Intestinal Ischemia\\/Reperfusion Injury in Rats  

Microsoft Academic Search

The aim of this study is to define the putative role of complement activation and mucosal mast cell (MMC) degranulation in the pathogenesis of rapid ischemia-reperfusion (I\\/R) injury. We prepared complement activity-depleted rats by the administration of the anti-complementary agent K-76COONa. To assess the role of MMC degranulation, we used the MMC stabilizer MAR-99 and genetically mast cell-deficient Ws\\/Ws rats.

Akira Andoh; Yoshihide Fujiyama; Yoshio Araki; Toshio Kimura; Tomoyuki Tsujikawa; Tadao Bamba



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

PubMed Central

Pulmonary mast cells (PMC) are important components of the inflammatory process in equine allergic lung diseases such as heaves. Very little, however, is known of the degranulation kinetics of these cells and thus, their pathophysiologic role remains largely speculative. The purpose of this study was to develop a repeatable protocol for in vitro equine PMC degranulation. Five mature horses (sex: 2 M, 3 F; age: 8.8 +/- 6.5 y), historically free of pulmonary disease and normal on clinical respiratory examination, arterial blood gas analysis, pulmonary mechanics testing and histamine inhalation challenge, were studied. Bronchoalveolar lavage was performed on 4 separate occasions, at least 2 d apart, in a different lung lobe on each occasion. The lavage fluid was concentrated by centrifugation. Cells were resuspended in modified HEPES/Tyrode, assessed for viability by Trypan blue exclusion, and PMC concentration determined. Cell inocula containing 30,000 PMC were incubated with 10(-8) to 6 x 10(-5) M A23187. Cells were then separated by centrifugation and histamine release (HR) was determined by fluorometric assay. The procedure was readily performed and yielded sufficient PMC for 30 to 60 inocula per lavage. Maximal HR (34.4 +/- 16.1%) was obtained with 10(-5) M A23187. The degranulation process was largely complete by 20 min but cell lysis was negligible. The challenge was repeatable within horse and produced a mean coefficient of variability of 23.0% following 20 min incubation with 10(-5) M A23187. We conclude that equine PMC degranulation can be repeatably performed in vitro and speculate that this protocol may be useful in further studies on the pathophysiology and treatment of equine allergic lung diseases. PMID:9553713

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



Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses.  


Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions. PMID:15778496

Forssell, Johan; Sideras, Pascalis; Eriksson, Christina; Malm-Erjefält, Monika; Rydell-Törmänen, Kristina; Ericsson, Per-Olof; Erjefält, Jonas S



Mast Cells Express 11?-hydroxysteroid Dehydrogenase Type 1: A Role in Restraining Mast Cell Degranulation  

PubMed Central

Mast cells are key initiators of allergic, anaphylactic and inflammatory reactions, producing mediators that affect vascular permeability, angiogenesis and fibrosis. Glucocorticoid pharmacotherapy reduces mast cell number, maturation and activation but effects at physiological levels are unknown. Within cells, glucocorticoid concentration is modulated by the 11?-hydroxysteroid dehydrogenases (11?-HSDs). Here we show expression and activity of 11?-HSD1, but not 11?-HSD2, in mouse mast cells with 11?-HSD activity only in the keto-reductase direction, regenerating active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone). Mast cells from 11?-HSD1-deficient mice show ultrastructural evidence of increased activation, including piecemeal degranulation and have a reduced threshold for IgG immune complex-induced mast cell degranulation. Consistent with reduced intracellular glucocorticoid action in mast cells, levels of carboxypeptidase A3 mRNA, a glucocorticoid-inducible mast cell-specific transcript, are lower in peritoneal cells from 11?-HSD1-deficient than control mice. These findings suggest that 11?-HSD1-generated glucocorticoids may tonically restrain mast cell degranulation, potentially influencing allergic, anaphylactic and inflammatory responses. PMID:23349944

Coutinho, Agnes E.; Brown, Jeremy K.; Yang, Fu; Brownstein, David G.; Gray, Mohini; Seckl, Jonathan R.; Savill, John S.; Chapman, Karen E.



Immature DC isolated after co-culture with PUVA-treated peripheral blood mononuclear cells downregulate graft-versus-host reactions in the human skin explant model.  


Graft-versus-host disease (GvHD) remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) is a potent immunomodulatory treatment option for GvHD. In contrast to conventional immunosuppressants, ECP is considered not to increase relapse and infection rates resulting from generalised immunosuppression. ECP involves the mechanical separation of 5-10% of patient peripheral blood mononuclear cells, which are then exposed to psoralen and UVA light (PUVA) before they are returned to the patient. ECP has been shown to induce apoptosis in various cell types, in particular lymphocytes. Several studies describe downregulation of pro-inflammatory cytokines as well as promotion of peripheral tolerance through enhanced production of T regulatory cells in the course of ECP-treatment. Modulation of antigen-presenting cells such as dendritic cells (DC) by PUVA-treated lymphocytes might be implicated in these regulatory processes. We evaluated the impact of PUVA-treated lymphocytes on immature DC and further demonstrated the functional capacity of such modified DC to modulate GVH reactions using a well-established human skin-explant model of GvHD. Addition of immature DC isolated after co-culture with PUVA-treated but not untreated MLR cells significantly downregulated skin-GvH reactions (p=0.023, Mann-Whitney-Test). IFN-gamma levels were non-significantly decreased in MLR and skin supernatants. We observed a non-significant increase in PD-L1 expression in iDC after co-culture with PUVA-treated MLR cells whereas expression levels of IDO and ILT-3 were not affected. We conclude that iDC modulated by PUVA-induced apoptotic cells potently downregulate allogeneic immune responses possibly through PD-L1- dependent signaling. PMID:23363467

Holtick, Udo; Wang, Xiao N; Marshall, Scott R; Scheid, Christof; von Bergwelt-Baildon, Michael; Dickinson, Anne M



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

NASA Astrophysics Data System (ADS)

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

Diffey, Brian



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

PubMed Central

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

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



The use of fractal dimension and lacunarity in the characterization of mast cell degranulation in rainbow trout (Onchorhynchus mykiss).  


Fractal analysis is a reliable method for describing, summarizing object complexity and heterogeneity and has been widely used in biology and medicine to deal with scale, size and shape management problems. The aim of present survey was to use fractal analysis as a complexity measure to characterize mast cells (MCs) degranulation in a rainbow trout ex vivo model (isolated organ bath). Compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine with formaldehyde, was adopted as MCs degranulation agent in trout intestinal strips. Fractal dimension (D), as a measure of complexity, 'roughness' and lacunarity (?), as a measure of rotational and translational invariance, heterogeneity, in other words, of the texture, were compared in MCs images taken from intestinal strips before and after compound 48/80 addition to evaluate if and how they were affected by degranulation. Such measures were also adopted to evaluate their discrimination efficacy between compound 48/80 degranulated group and not degranulated group and the results were compared with previously reported data obtained with conventional texture analysis (image histogram, run-length matrix, co-occurrence matrix, autoregressive model, wavelet transform) on the same experimental material. Outlines, skeletons and original greyscale images were fractal analysed to evaluate possible significant differences in the measures values according to the analysed feature. In particular, and considering outline and skeleton as analysed features, fractal dimensions from compound 48/80 treated intestinal strips were significantly higher than the corresponding untreated ones (paired t and Wilcoxon test, p < 0.05), whereas corresponding lacunarity values were significantly lower (paired Wilcoxon test, p < 0.05) but only for outline as analysed feature. Outlines roughness increase is consistent with an increased granular mediators interface, favourable for their biological action; while lacunarity (image heterogeneity) reduction is consistent with the biological informative content decrease, due to granule content depletion. In spite of the significant differences in fractal dimension and lacunarity values registered according to the analysed feature (greyscale obtained values were, on average, lower than those obtained from outlines and skeletons; General Linear Model, p < 0.01), the discrimination power between not degranulated and degranulated MCs was, on average, the same and fully comparable with previously performed texture analysis on the same experimental material (outline and skeleton misclassification error, 20% [two false negative cases]; greyscale misclassification error, 30% [two false negative cases and one false positive case]). Fractal analysis proved to be a reliable and objective method for the characterization of MCs degranulation. PMID:25087582

Manera, M; Dezfuli, B S; Borreca, C; Giari, L



Pyk2 is required for neutrophil degranulation and host defense responses to bacterial infection  

PubMed Central

The appropriate regulation of neutrophil activation is critical for maintaining host defense and limiting inflammation. Neutrophils (PMNs) express a number of cytoplasmic tyrosine kinases that regulate signaling pathways leading to activation. One of the most highly expressed, but least studied, kinases in PMNs is proline rich kinase 2 (Pyk2). By analogy to the related FAK kinase, Pyk2 has been implicated in regulating PMN adhesion and migration, however its physiologic function has yet to be described. Using pyk2?/? mice, we found that this kinase was required for integrin-mediated degranulation responses, but was not involved in adhesion-induced cell spreading or activation of superoxide production. Pyk2-deficient PMNs also manifested reduced migration on fibrinogen-coated surfaces. The absence of Pyk2 resulted in a severe reduction in paxillin and Vav phosphorylation following integrin ligation, which likely accounts for the poor degranulation and cell migration. Pyk2?/? mice were unable to efficiently clear infection with Staphylococcus aureus in a skin abscess model due in part to poor release of granule contents at the site of infection. However, Pyk2-deficient PMNs responded normally to soluble agonists, demonstrating that this kinase functions mainly in the integrin pathway. These data demonstrate the unrealized physiologic role of this kinase in regulating adhesion-mediated release of PMN granule contents. PMID:21187437

Kamen, Lynn A.; Schlessinger, Joseph; Lowell, Clifford A.



Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage.  


Cytotoxic lymphocytes are important for immune responses against viral infections and cancer. They are able to kill target cells through the release of cytotoxic granules (CGs) without being harmed in the process. Because the lysosomal-associated membrane proteins (LAMPs) appear on the cell surface after CG exocytosis, we hypothesized that some of these proteins might be involved in transiently protecting cytotoxic lymphocytes from self-destruction. Intracellular expression of CD107a/LAMP-1, and to a lesser extent that of CD107b/LAMP-2, correlated with lymphocyte CG content. Engineered surface expression of CD107a/LAMP-1, but not of CD107b/LAMP-2, reduced the granule-mediated killing of transfected target cells. This was dependent on glycosylation of the CD107a/LAMP-1 hinge. Moreover, surface expression of CD107a/LAMP-1 reduced binding of perforin to cells. Importantly, knockdown of CD107a/LAMP-1 in primary human natural killer (NK) cells and deficiency of CD107a/LAMP-1 in mice resulted in increased NK cell apoptosis upon target cell-induced degranulation. Thus, our data support a novel role of CD107a/LAMP-1 in the protection of NK cells from degranulation-associated suicide, which may represent a general mechanism to transiently limit self-destruction by cytotoxic lymphocytes upon target cell killing. PMID:23847195

Cohnen, André; Chiang, Samuel C; Stojanovic, Ana; Schmidt, Hendrik; Claus, Maren; Saftig, Paul; Janßen, Ottmar; Cerwenka, Adelheid; Bryceson, Yenan T; Watzl, Carsten



Treatment with recombinant tissue plasminogen activator (r-TPA) induces neutrophil degranulation in vitro via defined pathways.  


Thrombolysis is recommended for reperfusion following acute ischemic stroke (AIS), but its effects on stroke-associated injury remain to be clarified. Here, we investigated the effects of recombinant tissue plasminogen activator (r-tPA) on neutrophil pathophysiology in vitro and in a case-control study with AIS patients submitted (n=60) or not (n=30) to thrombolysis. Patients underwent radiological and clinical examination as well as blood sampling at admission and after 1, 7 and 90days. In vitro, 30-min incubation with 0.1-1mg/ml r-tPA induced neutrophil degranulation in different substrate cultures. Pre-incubation with kinase inhibitors and Western blot documented that degranulation was associated with activation of PI3K/Akt and ERK1/2 pathways in Teflon dishes and PI3K/Akt in polystyrene. In thrombolysed patients, a peak of neutrophil degranulation products (matrix metalloproteinase [MMP]-9, MMP-8, neutrophil elastase and myeloperoxidase), was shown during the first hours from drug administration. This was accompanied by serum augmentation of protective tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. An increased rate of haemorrhagic transformations on day 1 after AIS was shown in thrombolysed patients as compared to non-thrombolysed controls. In conclusion, r-tPA treatment was associated with in vitro neutrophil degranulation, indicating these cells as potential determinants in early haemorrhagic complications after thrombolysis in AIS patients. PMID:25530154

Carbone, Federico; Vuilleumier, Nicolas; Bertolotto, Maria; Burger, Fabienne; Galan, Katia; Roversi, Gloria; Tamborino, Carmine; Casetta, Ilaria; Seraceni, Silva; Trentini, Alessandro; Dallegri, Franco; da Silva, Analina Raquel; Pende, Aldo; Artom, Nathan; Mach, François; Coen, Matteo; Fainardi, Enrico; Montecucco, Fabrizio



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


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

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



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

PubMed Central

Widespread experience indicates that application of suboptimal concentrations of stimulating ligands (secretagogues) to secretory cells elicits submaximal extents of secretion. Similarly, for permeabilized secretory cells, the extent of secretion is related to the concentration of applied intracellular effectors. We investigated the relationship between the extent of secretion from mast cells (assessed as the release of hexosaminidase) and the degranulation (exocytosis) responses of individual cells. For permeabilized mast cells stimulated by the effector combination Ca2+ plus GTP-gamma-S and for intact cells stimulated by the Ca2+ ionophore ionomycin, we found that exocytosis has the characteristics of an all-or-none process at the level of the individual cells. With a suboptimal stimulus, the population comprised only totally degranulated cells and fully replete cells. In contrast, a suboptimal concentration of compound 48/80 applied to intact cells induced a partial degree of degranulation. This was determined by observing the morphological changes accompanying degranulation by light and electron microscopy and also as a reduction in the intensity of light scattered at 90 degrees, indicative of a change in the cell-refractive index. These results may be explained by the existence of a threshold sensitivity to the combined effectors that is set at the level of individual cells and not at the granule level. We used flow cytometry to establish the relationship between the extent of degranulation in individual rat peritoneal mast cells and the extent of secretion in the population (measured as the percentage release of total hexosaminidase). For comparison, secretion was also elicited by applying the Ca2+ ionophore ionomycin or compound 48/80 to intact cells. For permeabilized cells and also for intact cells stimulated with the ionophore, levels of stimulation that generate partial secretion gave rise to bimodal frequency distributions of 90 degrees light scatter. In contrast, a partial stimulus to secretion by compound 48/80 resulted in a single population of partially degranulated cells, the degree of degranulation varying across the cell population. The difference between the all-or-none responses of the permeabilized or ionophore-treated cells and the graded responses of cells activated by compound 48/80 is likely to stem from differences in the effective calcium stimulus. Whereas cell stimulated with receptor-directed agonists can undergo transient and localized Ca2+ changes, a homogeneous and persistent stimulus is sensed at every potential exocytotic site in the permeabilized cells. PMID:8227127



Impaired neutrophil killing in a patient with defective degranulation of myeloperoxidase.  


A case of recurrent, superficial abscesses in an 18 year old girl, is described. Staphylococcus aureus was the pathogen most often implicated and on several occasions the abscesses required surgical drainage. Defects in humoral immunity, neutrophil chemotaxis or opsonophagocytosis were not observed. However, her neutrophil's ability to kill ingested S. aureus in vitro was impaired. This was associated with impaired luminol-dependent chemiluminescence in response to stimulation by either latex beads, or the chemotactic peptide FMLP plus cytochalasin B. Oxygen uptake and superoxide anion production were normal but release of myeloperoxidase by this patient's neutrophils occurred more slowly and to a lower extent than in control cells. These data suggest that the recurrent infections and diminished in vitro neutrophil bactericidal activity observed in this patient are associated with impaired degranulation of myeloperoxidase. PMID:2845090

Edwards, S W; Hart, C A; Davies, J M; Pattison, J; Hughes, V; Sills, J A



Fibrinogen binding is independent of an increase in intracellular calcium concentration in thrombin degranulated platelets.  


In a suspension of thrombin degranulated platelets (TDP), ADP and epinephrine can induce platelet aggregation, whereas the synthetic agonist of the thromboxane/endoperoxide receptor U46619 causes only shape change. However, U46619 can enhance platelet aggregation induced by ADP and epinephrine. In this paper, we have measured fibrinogen binding in relation to phospholipase C (PLC) activation and calcium mobilization in TDP activates by ADP, epinephrine and U46619. ADP caused fibrinogen binding in TDP but neither activated PLC nor caused a calcium mobilization. The requirement for ADP in inducing exposure of fibrinogen binding sites was not absolute since the combination of epinephrine and U46619 produced an increase in fibrinogen binding. U46619 caused significant PLC activation and cytosolic calcium release but not fibrinogen binding. These results suggest that in TDP the exposure of fibrinogen binding sites, after agonist activation, is independent of both PLC activation and calcium mobilization. PMID:7792747

Pulcinelli, F M; Daniel, J L; Riondino, S; Gazzaniga, P P; Salganicoff, L



Dengue vascular leakage is augmented by mast cell degranulation mediated by immunoglobulin Fc? receptors  

PubMed Central

Dengue virus (DENV) is the most significant human arboviral pathogen and causes ?400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC activation are correlated with disease severity in human DENV patients (St John et al., 2013b). A major risk factor for developing severe dengue is secondary infection with a heterologous serotype. The dominant theory explaining increased severity during secondary DENV infection is that cross-reactive but non-neutralizing antibodies promote uptake of virus and allow enhanced replication. Here, we define another mechanism, dependent on Fc?R-mediated enhanced degranulation responses by MCs. Antibody-dependent mast cell activation constitutes a novel mechanism to explain enhanced vascular leakage during secondary DENV infection. DOI:

Syenina, Ayesa; Jagaraj, Cyril J; Aman, Siti AB; Sridharan, Aishwarya; St John, Ashley L



Degranulation and abnormal bactericidal function of granulocytes procured by reversible adhesion to nylon wool.  


Granylocyte bactericidal capacity, chemotaxis, hexose monophosphate shung activity (before and after phagocytic stimulus), and quantitative nitroblue tetrazolium reduction and enzyme content were examined in cells obtained by filtration leukaphresis (FL) and continuous-flow centrifugation (CFC). A decrease in the bactericidal efficiency of FL-produced cells compared to that of both normal and CFC-procured granulocytes was found; the decrease was 17% with a cell-to-bacteria ratio of 5:1, and 55% with a 1:1 ratio. Moreover, FL-acquired cells were often vacuolated and consistently contained less acid phosphatase and beta-glucuronidase than did normal granulocytes. When normal cells were incubated for 1-2 hr with nylon wool, 30% of the total acid phosphatase and beta-glucuronidase was released, with no evidence of cell death, thus suggesting degranulation. Similar results were obtained with glass, cotton, or polysulfone plastic fibers. Electron microscopic and peroxidase cytochemical studies of the adherence of normal granulocytes to nylon fibers were also carried out. After 30 min of incubation, cell-to-fiber attachment and cellular aggregation had occurred, although the cells per se appeared normal. After 60 and 120 min, other changes became apparent: (1) a decrease in the amount of cytoplasmic granules; (2) large, intracytoplasmic vaculoles; and (3) extracellular peroxidase on fiber surfaces. We conclude that granulocytes obtained by adherence to nylon fibers show both morphological and biochemical evidence of degranulation and diminished bactericidal capacity, and that these abnormalities may be causally related to decreased granulocyte survival in transfusion recipients. PMID:947403

Klock, J C; Bainton, D F



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

Microsoft Academic Search

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

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



Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells  

PubMed Central

MC degranulation requires the influx of calcium from the extracellular environment. Orai1/STIM1 is essential to MC SOCE, as shown in rat peritoneal MCs, the rat MC lines (RBL-2H3), or in Orai1 null embryo liver-derived, cultured MCs. However, minimal information exists about the role of other calcium channels expressed on these cells. Here, we demonstrate that the nonselective TRPC1 participates in Fc?RI-mediated calcium entry in mouse BMMCs. We found that Fyn null MCs, which have an impaired degranulation response, expressed reduced levels of TRPC1, had normal depletion of intracellular calcium stores but an impaired calcium influx, and failed to depolymerize cortical F-actin (a key step for granule-plasma membrane fusion). Partial RNAi silencing of TRPC1 expression in WT MCs (to the level of Fyn null MCs) mimicked the Fyn null defect in calcium influx, cortical F-actin depolymerization, and MC degranulation. Ectopic expression of Fyn or TRPC1 in Fyn null MCs restored calcium responses and cortical F-actin depolymerization and increased MC degranulation. Together with our findings that expression of Orai1 is not altered in Fyn null MCs, our findings suggest that TRPC1 participates in calcium influx and other key events required for MC degranulation. This demonstrates that in addition to a role described previously for Orai1 in promoting MC degranulation, nonselective cation channels participate in promoting the exocytotic response. PMID:20571036

Suzuki, Ryo; Liu, Xibao; Olivera, Ana; Aguiniga, Lizath; Yamashita, Yumi; Blank, Ulrich; Ambudkar, Indu; Rivera, Juan



Degranulation of Mast Cells in the Trachea and Bronchi of the Rat following Stimulation of the Vagus Nerve  

Microsoft Academic Search

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-?m 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

J. A. Kiernan



A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy  

PubMed Central

Studies have endeavored to reconcile whether dysfunction of neutrophils in people with cystic fibrosis (CF) is a result of the genetic defect or is secondary due to infection and inflammation. In this study, we illustrate that disrupted function of the CF transmembrane conductance regulator (CFTR), such as that which occurs in patients with ?F508 and/or G551D mutations, correlates with impaired degranulation of antimicrobial proteins. We demonstrate that CF blood neutrophils release less secondary and tertiary granule components compared with control cells and that activation of the low-molecular-mass GTP-binding protein Rab27a, involved in the regulation of granule trafficking, is defective. The mechanism leading to impaired degranulation involves altered ion homeostasis caused by defective CFTR function with increased cytosolic levels of chloride and sodium, yet decreased magnesium measured in CF neutrophils. Decreased magnesium concentration in vivo and in vitro resulted in significantly decreased levels of GTP-bound Rab27a. Treatment of G551D patients with the ion channel potentiator ivacaftor resulted in normalized neutrophil cytosolic ion levels and activation of Rab27a, thereby leading to increased degranulation and bacterial killing. Our results confirm that intrinsic alterations of circulating neutrophils from patients with CF are corrected by ivacaftor, thus illustrating additional clinical benefits for CFTR modulator therapy. PMID:24934256

Pohl, Kerstin; Hayes, Elaine; Keenan, Joanne; Henry, Michael; Meleady, Paula; Molloy, Kevin; Jundi, Bakr; Bergin, David A.; McCarthy, Cormac; McElvaney, Oliver J.; White, Michelle M.; Clynes, Martin; McElvaney, Noel G.



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


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

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



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


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. PMID:24689187

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



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

USGS Publications Warehouse

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

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



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


The above article published in Medicinski Glasnik online on 26 June 2014 by the Medical Association of Zenica-Doboj Canton ( 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

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



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

PubMed Central

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

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



A method to prepare degranulated human platelets: use for studies of platelet aggregation and ca(2+) mobilization.  


A method for the preparation of a suspension of thrombin-degranulated human platelets is described. Two peptides (RGDS and GPRP) are used to prevent fibrinogen binding and consequent aggregation, and to prevent fibrin polymerization during thrombin activation. A mixture of creatine phosphokinase and creatine phosphate is used to remove ADP. Hirudin and TAMe are used to neutralize thrombin after the platelets have been activated. [(14)C] Serotonin and PF4 release and electron microscopy demonstrate that the preparation is completely degranulated. After all inhibitors are removed and fibrinogen added, the preparation aggregates rapidly to a mixture of agonists composed of ADP, epinephrine and the synthetic analog of prostaglandin H(2)/thromboxane A(2), U46619. ADP and epinephrine when added individually are both able to induce a clearly detectable aggregation, while U46619 induces only a shape change. The preparation is also suitable for intracellular Ca(2+) studies and we find that the mixture of agonists produces an increase in the intracellular calcium concentration to about 1 µM. PMID:21043844

Pulcinelli, F M; Daniel, J L; Riondino, S; Gazzaniga, P P; Russo, M A; Salganicoff, L



UDP-glucose acting at P2Y14 receptors is a mediator of mast cell degranulation  

PubMed Central

UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y14 receptor. RBL-2H3 mast cells endogenously express a P2Y14 receptor at which UDPG mediates degranulation as indicated by ?-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (diphosphoric acid 1-?-D-glucopyranosyl ester 2-(2-thiouridin-5’’-yl) ester), caused a substantial calcium transient in RBL-2H3 cells, which was blocked by pertussis toxin, indicating the presence of the Gi-coupled P2Y14 receptor, supported also by quantitative detection of abundant mRNA. Expression of the closely related P2Y6 receptor was over 100 times lower than the P2Y14 receptor, and the P2Y6 agonist 3-phenacyl-UDP was inactive in RBL-2H3 cells. P2Y14 receptor agonists also induced [35S]GTP?S binding to RBL-2H3 cell membranes, and phosphorylation of ERK1/2, P38 and JNK. UDPG and MRS2690 concentration-dependently enhanced HEX release with EC50 values of 1150 ± 320 and 103 ± 18 nM, respectively. The enhancement was completely blocked by pertussis toxin and significantly diminished by P2Y14 receptor-specific siRNA. Thus, mast cells express an endogenous P2Y14 receptor, which mediates Gi-dependent degranulation and is therefore a potential novel therapeutic target for allergic conditions. PMID:19896471

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



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

SciTech Connect

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

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



ADP-ribose/TRPM2-mediated Ca2+ signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells  

PubMed Central

Natural killer (NK) cells are essential for immunosurveillance against transformed cells. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel gated by ADP-ribose (ADPR). However, the role of TRPM2-mediated Ca2+ signaling in the antitumor response of NK cells has not been explored. Here, we show that ADPR-mediated Ca2+ 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 Ca2+ 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 Ca2+ signaling system involved in the antitumor activity of NK cells. PMID:25879940

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



Helicobacter pylori Outer Membrane Vesicle Proteins Induce Human Eosinophil Degranulation via a ?2 Integrin CD11/CD18- and ICAM-1-Dependent Mechanism  

PubMed Central

Eosinophil cationic protein (ECP), a cytotoxic protein contained in eosinophils granules, can contribute to various inflammatory responses. Although Helicobacter pylori infection increases infiltration of eosinophils, the mechanisms of eosinophil degranulation by H. pylori infection are largely unknown. The goal of this study was to investigate the role of H. pylori outer membrane vesicles (OMVs) in modulating eosinophil degranulation. We found that eosinophils treated with H. pylori OMVs released significantly more ECP compared with untreated controls. In addition, eosinophils cocultured with OMV-preexposed primary gastric epithelial cells exhibited significantly increased ECP release. Similarly, eosinophils cocultured with culture supernatant (CM) from primary gastric epithelial cells exposed to OMVs (OMV-CM) released significantly higher amounts of ECP compared with eosinophils cocultured with CM from unexposed control cells. Furthermore, OMVs and OMV-CM both induced the upregulation of ICAM-1 on gastric epithelial cells and ?2 integrin CD11b on eosinophils. In addition, both transduction of ICAM-1 shRNA into gastric epithelial cells and treatment with neutralizing mAbs to CD18 significantly decreased OMV-mediated or OMV-CM-mediated release of ECP. These results suggest that the eosinophil degranulation response to H. pylori OMVs occurs via a mechanism that is dependent on both ?2 integrin CD11/CD18 and ICAM-1.

Ko, Su Hyuk; Jeon, Jong Ik; Kim, Young-Jeon; Yoon, Ho Joo; Kim, Hyeyoung; Kim, Nayoung; Kim, Joo Sung; Kim, Jung Mogg



Differential induction of nitric oxide, degranulation, and oxidative burst activities in response to microbial agonist stimulations in monocytes and heterophils from young commercial turkeys.  


The toll-like receptors (TLRs) recognize microbial pathogens and pathogen-associated molecular patterns and trigger inflammatory immune responses to control the infection. Here, we examined functional innate immune responses to Salmonella enteritidis (SE, live or formalin-killed) and various TLR agonists including lipoteichoic acid (LTA) and peptidoglycan (PGN) from Staphylococcus aureus and synthetic lipoprotein Pam3CSK4 (PAM), poly I:C (synthetic double-stranded RNA analog), lipopolysaccharide (LPS) from S. enteritidis, flagellin (FGN) from S. typhimurium, loxoribine (LOX) and R837 (synthetic anti-viral compounds), and CpG oligodeoxydinucleotide (CpG ODN)by measuring antimicrobial activities including oxidative burst and degranulation in heterophils and nitric oxide production in peripheral blood monocytes. Our results demonstrate differential nitric oxide responses to TLR agonists in turkey monocytes. LTA and CpG ODN were the most potent stimuli for nitric oxide induction followed by PAM, poly I:C, and LPS, whereas FGN, PGN, LOX, R837, and control ODN stimulated little or no nitric oxide production. Live SE stimulated significantly less NO production than formalin-killed SE (FKSE). Although FKSE induced significant degranulation and oxidative burst, most TLR agonists stimulate little oxidative burst and degranulation responses in turkey heterophils. PMID:18304649

He, Haiqi; Genovese, Kenneth J; Swaggerty, Christina L; Nisbet, David J; Kogut, Michael H



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

PubMed Central

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

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



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


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

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



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

PubMed Central

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

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



Herbex-kid Inhibits Immediate Hypersensitivity Reactions in Mice and Rats  

PubMed Central

Herbex-kid (HK), a polyherbal formulation was evaluated in various experimental allergic models of Type I hypersensitivity reactions. Compound 48/80 (C 48/80) has been shown to induce rat mesentery mast cell degranulation and HK (1.07, 10.75 and 107.5?mg?ml?1) inhibited the mast cell degranulation in a dose dependent manner. HK (1.07, 10.75 and 107.5?mg?kg?1; p.o.) showed dose-dependent protection against C 48/80 induced systemic anaphylaxis in male Balb/C mice. In active anaphylaxis model, male Wistar rats orally administered with 10.75 and 107.5?mg?kg?1 of HK showed significant (P?degranulation, while in passive anaphylaxis model, only at 107.5?mg?kg?1 showed significant (P?degranulation. HK at all dose levels was able to significantly decrease the time spent in nasal rubbing in Wistar rats sensitized to ovalbumin, while only at 107.5?mg?kg?1 it showed significant (P?inhibition in histamine induced contraction in guinea pig ileum. From the above findings we conclude that the HK possesses antiallergic activity mediated by reducing of the release mediators from mast cells and also by 5-HT antagonism without the involvement of histamine (H1) receptors. PMID:18830458

Prasad, Rawal; Jogge, Nanjan Mulla; Bhojraj, Suresh; Emerson, Solomon F.; Prabakar, S.



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

Microsoft Academic Search

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

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



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

PubMed Central

Background Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment. Methodology/Principal Findings Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor ? (TNF?), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. Conclusions/Significance We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself. PMID:23936562

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



Altered expression of degranulation-related genes in CD8+ T cells in human T lymphotropic virus type I infection.  


Human T lymphotropic virus type I (HTLV-1) is the etiological agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD8+ T cells may contribute to the protection or development of HAM/TSP. In this study we used SAGE methodology to screen for differentially expressed genes in CD8+ T cells isolated from HTLV-1 asymptomatic carriers (HAC) and from HAM/TSP patients to identify genes involved in HAM/TSP development. SAGE analysis was conducted by pooling samples according to clinical status. The comparison of gene expression profiles between HAC and HAM/TSP libraries identified 285 differentially expressed tags. We focus on cytotoxicity and cytokine-related genes due to their potential biological role in HTLV-1 infection. Our results showed that patients with HAM/TSP have high expression levels of degranulation-related genes, namely GZMH and PRF1, and of the cytoskeletal adaptor PXN. We found that GZMB and ZAP70 were overexpressed in HTLV-infected patients compared to the noninfected group. We also detected that CCL5 was higher in the HAM/TSP group compared to the HAC and CT groups. Our findings showed that CD8+ T cells of HAM/TSP patients have an inflammatory and active profile. PXN and ZAP70 overexpression in HTLV-1-infected patients was described for the first time here and reinforces this concept. However, although active and abundant, CD8+ T cells are not able to completely eliminate infected cells and prevent the development of HAM/TSP and, moreover, these cells might contribute to the pathogenesis of the disease by migrating to the central nervous system (CNS). These results should be further tested with biological functional assays to increase our understanding on the role of these molecules in the development of HTLV-1-related diseases. PMID:23301858

Malta, Tathiane M; Silva, Israel T; Pinheiro, Daniel G; Santos, Anemarie R D; Pinto, Mariana T; Panepucci, Rodrigo A; Takayanagui, Osvaldo M; Tanaka, Yuetsu; Covas, Dimas T; Kashima, Simone



Catestatin, a neuroendocrine antimicrobial peptide, induces human mast cell migration, degranulation and production of cytokines and chemokines  

PubMed Central

Catestatin, a neuroendocrine peptide with effects on human autonomic function, has recently been found to be a cutaneous antimicrobial peptide. Human catestatin exhibits three single nucleotide polymorphisms: Gly364Ser, Pro370Leu and Arg374Gln. Given reports indicating that antimicrobial peptides and neuropeptides induce mast cell activation, we postulated that catestatin might stimulate numerous functions of human mast cells, thereby participating in the regulation of skin inflammatory responses. Catestatin and its naturally occurring variants caused the human mast cell line LAD2 and peripheral blood-derived mast cells to migrate, degranulate and release leukotriene C4 and prostaglandins D2 and E2. Moreover, catestatins increased intracellular Ca2+ mobilization in mast cells, and induced the production of pro-inflammatory cytokines/chemokines such as granulocyte–macrophage colony-stimulating factor, monocyte chemotactic protein-1/CCL2, macrophage inflammatory protein-1?/CCL3 and macrophage inflammatory protein-1?/CCL4. Our evaluation of possible cellular mechanisms suggested that G-proteins, phospholipase C and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) are involved in catestatin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G-protein inhibitor), U-73122 (phospholipase C inhibitor) and U0126 (ERK inhibitor), respectively. We also found that human mast cells express the ?7 subunit of the nicotinic acetylcholine receptor at both the mRNA and protein levels. Given that silencing the ?7 receptor mRNA and an ?7-specific inhibitor did not affect catestatin-mediated activation of mast cells, however, we concluded that this receptor is not likely to be functional in human mast cell stimulation by catestatins. Our finding that the neuroendocrine antimicrobial peptide catestatin activates human mast cells suggests that this peptide might have immunomodulatory functions, and provides a new link between neuroendocrine and cutaneous immune systems. PMID:21214543

Aung, Gyi; Niyonsaba, François; Ushio, Hiroko; Kajiwara, Naoki; Saito, Hirohisa; Ikeda, Shigaku; Ogawa, Hideoki; Okumura, Ko



Angiopoietin1 Inhibits Mast Cell Activation and Protects against Anaphylaxis  

PubMed Central

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

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



Angiopoietin1 inhibits mast cell activation and protects against anaphylaxis.  


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

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



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

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

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



Antiallergic and antiasthmatic effects of a novel enhydrazinone ester (CEE-1): inhibition of activation of both mast cells and eosinophils.  


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

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



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

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



Inhibition of the antigen-induced activation of rodent mast cells by putative Janus kinase 3 inhibitors WHI-P131 and WHI-P154 in a Janus kinase 3-independent manner  

PubMed Central

We analyzed the effects of the Janus kinase 3 (Jak3)-specific inhibitor WHI-P131 (4-(4?-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline) and the Jak3/Syk inhibitor WHI-P154 (4-(3?-bromo-4?-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline) on the antigen-induced activation of mast cells. In the rat mast cell line RBL-2H3, both WHI-P131 and WHI-P154 inhibited the antigen-induced degranulation and phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK and c-Jun N-terminal kinase (JNK). The phosphorylation of Gab2, Akt and Vav was also inhibited by WHI-P131 and WHI-P154, indicating that these inhibitors suppress the activation of phosphatidylinositol 3-kinase (PI3K). In bone marrow-derived mast cells (BMMCs) from Jak3-deficient (Jak3?/?) mice, degranulation and activation of MAPKs were induced by the antigen in almost the same extent as in BMMCs from wild-type mice. In addition, the antigen-induced degranulation and activation of MAPKs were inhibited by WHI-P131 and WHI-P154 in both groups of BMMCs, indicating that these compounds inhibit a certain step except for Jak3. The antigen-induced increase in the activity of Fyn, a probable tyrosine kinase of Gab2, was also inhibited by WHI-P131 and WHI-P154 in RBL-2H3 cells. In BMMCs from Jak3?/? mice, the antigen stimulation induced tyrosine phosphorylation of Fyn, which was inhibited by WHI-P131, as well as in BMMCs from wild-type mice and in RBL-2H3 cells. These findings suggest that Jak3 does not play a significant role in the antigen-induced degranulation and phosphorylation of MAPKs, and that WHI-P131 and WHI-P154 inhibit the PI3K pathway by preventing the antigen-induced activation of Fyn, thus inhibiting the antigen-induced degranulation and phosphorylation of MAPKs in mast cells. PMID:15852029

Linwong, Watchara; Hirasawa, Noriyasu; Aoyama, Suzue; Hamada, Hirofumi; Saito, Takashi; Ohuchi, Kazuo



Estrogen inhibits mast cell chymase release to prevent pressure overload-induced adverse cardiac remodeling.  


Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell (MC) chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized (OVX) rats. Three days before creating the constriction, additional groups of OVX rats began receiving 17?-estradiol, a chymase inhibitor, or a MC stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, MC density and degranulation, and myocardial and plasma chymase levels were assessed 18 days postsurgery. Aortic constriction resulted in ventricular hypertrophy in intact and OVX groups, whereas collagen volume fraction was increased only in OVX rats. Chymase protein content was increased by aortic constriction in the intact and OVX groups, with the magnitude of the increase being greater in OVX rats. MC density and degranulation, plasma chymase levels, and myocardial active transforming growth factor-?1 levels were increased by aortic constriction only in OVX rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, MC density and degranulation, plasma chymase, and myocardial active transforming growth factor-?1, as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction-induced ventricular hypertrophy and collagen volume fraction in the OVX rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects, except for the reduction of chymase content. We conclude that the estrogen-inhibited release of MC chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling. PMID:25403608

Li, Jianping; Jubair, Shaiban; Janicki, Joseph S



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

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

Margherita A. Barracco; Bernard Duvic; Kenneth Söderhäll



Insulin-containing lipogenic stimuli suppress mast cell degranulation potential and up-regulate lipid body biogenesis and eicosanoid secretion in a PPAR?-independent manner  

PubMed Central

Lipid bodies are most studied in adipocytes, where the lipogenic action of insulin initiates their formation. Here, we test the hypothesis that insulin may regulate lipid body content in mast cells and hence, modify their proinflammatory potential. Our data show that insulin causes lipid body accumulation in RBL2H3 and BMMCs. Lipid body accumulation in mast cells is associated with enhanced levels of leukotriene-synthesizing enzymes (LTC4S and 5-LO). Increased basal and antigen-stimulated release of LTC4 is observed in insulin-treated mast cells. Concomitantly, the insulin-containing lipogenic stimulus induces a phenotypic change in mast cells, where this enhancement in leukotriene levels is accompanied by a marked down-regulation in secretory granule content and release in response to stimulus. Mast cells exposed to insulin exhibit altered scatter and fluorescence properties, accumulating in a SSCloFSChi population that exhibits decreased BS staining and degranulation responses and is enriched in NR-positive lipid bodies and eicosanoid synthesis enzymes. Lipid body accumulation in mast cells is mechanistically distinct from the process in adipocytes; for example, it is independent of PPAR? up-regulation and does not involve significant accumulation of conjugated glycerides. Thus, chronic exposure to metabolic stimuli, such as insulin, may be a determinant of the proinflammatory potential of the mast cell. PMID:22706316

Greineisen, William E.; Shimoda, Lori M. N.; Maaetoft-Udsen, Kristina; Turner, Helen



Inhibition of early and late phase allergic reactions by Euphorbia hirta L.  


A 95% ethanol extract from whole aerial parts of Euphorbia hirta (EH A001) showed antihistaminic, antiinflammatory and immunosuppressive properties in various animal models. EH A001 inhibited rat peritoneal mast cell degranulation triggered by compound 48/80. It significantly inhibited dextran-induced rat paw edema. EH A001 prevented eosinophil accumulation and eosinophil peroxidase activity and reduced the protein content in bronchoalveolar lavage fluid (BALF) in a 'mild' model of asthma. Moreover, the CD4/CD8 ratio in peripheral blood was suppressed. EH A001 attenuated the release of interleukin-4 (IL-4) and augmented interferon-gamma (IFN-gamma) in ovalbumin-sensitized mouse splenocytes. The results were compared with the effects of known compounds, ketotifen, cetirizine and cyclophosphamide. These findings demonstrated that Euphorbia hirta possessed significant activity to prevent early and late phase allergic reactions. PMID:16557622

Singh, G D; Kaiser, P; Youssouf, M S; Singh, S; Khajuria, A; Koul, A; Bani, S; Kapahi, B K; Satti, N K; Suri, K A; Johri, R K



In-Cell Intrabody Selection from a Diverse Human Library Identifies C12orf4 Protein as a New Player in Rodent Mast Cell Degranulation  

PubMed Central

The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate the proteome. We describe here an approach based on a large-scale intracellular expression and selection of antibody fragments in eukaryotic cells, so-called intrabodies, and the subsequent identification of their natural target within living cell. Starting from a phenotypic trait, this integrated system allows the identification of new therapeutic targets together with their companion inhibitory intrabody. We applied this system in a model of allergy and inflammation. We first cloned a large and highly diverse intrabody library both in a plasmid and a retroviral eukaryotic expression vector. After transfection in the RBL-2H3 rat basophilic leukemia cell line, we performed seven rounds of selection to isolate cells displaying a defect in Fc?RI-induced degranulation. We used high throughput sequencing to identify intrabody sequences enriched during the course of selection. Only one intrabody was common to both plasmid and retroviral selections, and was used to capture and identify its target from cell extracts. Mass spectrometry analysis identified protein RGD1311164 (C12orf4), with no previously described function. Our data demonstrate that RGD1311164 is a cytoplasmic protein implicated in the early signaling events following Fc?RI-induced cell activation. This work illustrates the strength of the intrabody-based in-cell selection, which allowed the identification of a new player in mast cell activation together with its specific inhibitor intrabody. PMID:25122211

Bec, Nicole; Parez, Vincent; Hahn, Chang S.; Mollevi, Caroline; Parrinello, Hugues; Desvignes, Jean-Pierre; Larroque, Christian; Jupp, Ray; Dariavach, Piona; Martineau, Pierre



Specific inhibition of allogeneic reactions with disodium cromoglycate.  


Milligram amounts of disodium cromoglycate (DSCG) inhibit allogeneic responses in mixed lymphocyte culture (MLC) reactions, but do not affect cell viability or suppress lymphocyte responses to either phytohemagglutinin (PHA) or pokeweed (PKW) mitogens. Preincubation of lymphocytes with DSCG is without effect, indicating that membrane binding is an unlikely explanation for inhibition. The HLA-DR tissue typing of cells in the presence of optimal MLC-inhibitory doses of DSCG is normal suggesting that MLC-reactive lymphocytes are not denied recognition of these antigens. Timed studies demonstrate that DSCG must be present continuously during the induction period, for removal of DSCG after 16 hr culture restores MLC reactivity and addition of the drug after 48 hr is without effect. Both natural killing (NK) and cell mediated lympholysis (CML) assays proceed normally in the presence of optimal MLC-inhibitory concentrations of DSCG; however, CML reactions are eliminated by the addition of drug during cytotoxic T cell priming. Background CML reactivity also disappears when lymphocytes are continuously cocultured in DSCG, implying that such killing cannot be attributed to NK activity. DSCG is said to inhibit allergic reactions by impeding calcium flux across mast cell membranes, thereby preventing degranulation, but other mechanisms are required to explain the selective effects on in vitro lymphocyte reactivity. PMID:6460014

McIntyre, J A; Neerunjun, E D; Faulk, W P



Heme oxygenase-1 inhibits cytokine production by activated mast cells.  


Heme oxygenase-1 (HO-1) is thought to contribute to host defense reactions against various stresses. In addition, recent reports have suggested that HO-1 modulates immunocyte activation and functions. HO-1 suppresses mast cell degranulation, but whether HO-1 suppresses cytokine synthesis as well is not yet known. We examined whether rat HO-1 cDNA transfected rat basophilic leukemia (RBL)-2H3 cells have altered cytokine production in response to stimulation with anti-ovalbumin (OA) serum/OA compared to Mock transfected RBL-2H3 cells. HO-1 inhibited anti-OA serum/OA-induced IL-3 and TNF-alpha production. Inhibition of HO-1 activity by Zn (II) protoporphyrin IX, a specific HO-1 inhibitor, prevented the suppression of TNF-alpha production. The cytokine inhibition by HO-1 was associated with selective suppression of the DNA-binding activity of AP-1 transcription factors. The suppression of mast cell cytokine production by HO-1 may be an important aspect of the processes that lead to resolution of allergic inflammation. PMID:17234154

Yasui, Yumiko; Nakamura, Mao; Onda, Toshihiro; Uehara, Tomohiro; Murata, Saori; Matsui, Nobuaki; Fukuishi, Nobuyuki; Akagi, Reiko; Suematsu, Makoto; Akagi, Masaaki



Comparison of the effect of multi-wavelength light produced by a cluster of semiconductor diodes and of each individual diode on mast cell number and degranulation in intact and injured skin.  


Intact skin and partial thickness wounds in adult male Wistar rats were irradiated by pulsed, monochromatic light of different spectral wavelength peaks simultaneously and the effects on mast cell number and degranulation were assessed. The light was produced by a Biotherapy 3ML (Omega Universal Technologies) device utilizing a 21 semiconductor diode cluster probe emitting 6 different wavelengths in the red and near infrared part of the spectrum simultaneously, only one of the wavelengths (820 nm) being coherent. The duration of treatment was 4 minutes. The average power density, distributed over the surface area of the probe (19.62 cm2) was 45 mW/cm2. The average energy density at the wound site was 10.8 J/cm2. The effect of each of the wavelengths incorporated in the cluster probe was then examined separately. The average power density for each single probe was 120 mW/cm2, except for the 820 nm diode which was 400 mW/cm2. The average energy density was maintained at 10.8 J/cm2 as with the cluster probe. After 2 hours the rats were killed and the skin was removed, processed for light microscopy, and stained with toluidine blue to identify the mast cells. The numbers of the intact and degranulated mast cells were counted in 100 high power fields (i.e., over a total area of 20 mm2) in each irradiated specimen and compared to the sham-irradiated and untreated groups. To avoid bias, the slides examined were coded and evaluated blind. In intact skin, the cluster probe irradiation was followed by a statistically significant increase in the total number of mast cells compared to the sham-irradiated group, but the percentage of the degranulated mast cells was not affected. In the partial thickness wound, the cluster probe irradiation was also followed by a statistically significant increase in the total number of mast cells compared to the sham-irradiated group; however, there was, in addition, a significant increase in the percentage of degranulated mast cells. Concerning the single probes, only the 660, 820, 940, and 950 nm wavelength emitters produced statistically significant increases in both mast cell number and degranulation in partial thickness wounds. However, when intact skin was irradiated with probes emitting these wavelengths, although the total number of mast cells was increased significantly, there was no change in degranulation compared with the sham-irradiated group. The effects observed were less than those of the cluster probe. No significant differences were found between the 870 and 880 nm wavelength-irradiated, sham-irradiated, and untreated groups in either intact or injured skin.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2263155

el Sayed, S O; Dyson, M



Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts.  


Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and synovial hyperplasia leading to progressive joint destruction. Fibroblast-like synoviocytes (FLS) are central components of the aggressive, tumour-like synovial structure termed pannus, which invades the joint space and cartilage. A distinct natural killer (NK) cell subset expressing the inhibitory CD94/NKG2A receptor is present in RA synovial fluid. Little is known about possible cellular interactions between RA-FLS and NK cells. We used cultured RA-FLS and the human NK cell line Nishi, of which the latter expresses an NK receptor repertoire similar to that of NK cells in RA synovial fluid, as an in vitro model system of RA-FLS/NK cell cross-talk. We show that RA-FLS express numerous ligands for both activating and inhibitory NK cell receptors, and stimulate degranulation of Nishi cells. We found that NKG2D, DNAM-1, NKp46 and NKp44 are the key activating receptors involved in Nishi cell degranulation towards RA-FLS. Moreover, blockade of the interaction between CD94/NKG2A and its ligand HLA-E expressed on RA-FLS further enhanced Nishi cell degranulation in co-culture with RA-FLS. Using cultured RA-FLS and the human NK cell line Nishi as an in vitro model system of RA-FLS/NK cell cross-talk, our results suggest that cell-mediated cytotoxicity of RA-FLS may be one mechanism by which NK cells influence local joint inflammation in RA. PMID:24673109

Nielsen, Natasja; Pascal, Veronique; Fasth, Andreas E R; Sundström, Yvonne; Galsgaard, Elisabeth D; Ahern, David; Andersen, Martin; Baslund, Bo; Bartels, Else M; Bliddal, Henning; Feldmann, Marc; Malmström, Vivianne; Berg, Louise; Spee, Pieter; Söderström, Kalle



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)

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.

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



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

PubMed Central

This study examines the relative contributions made by inhibition of mast cell degranulation, reduction of mast cell recruitment and maturation, and lowering the responsiveness of the vasculature to histamine, in the inhibition by glucocorticoids of the weal and flare in human skin. One forearm of healthy human volunteers was treated for 24?h (n=6) or daily for 21 days (n=10) with 0.05% clobetasol propionate. The other arm served as control. Weal and flare responses were elicited by intradermal injection of 20??l of 0.3?mM codeine. The areas of the responses were measured using scanning laser Doppler imaging. Microdialysis was used to assess histamine release. Mast cell numbers and tissue histamine content were assessed in 4-mm punch biopsies. Histamine (20??l of 1??M i.d.) was used to assess the status of the vasculature. No significant effects were seen at 24?h. At 21 days, clobetasol reduced the areas of the codeine-induced weal and flare responses by 59 and 58% respectively (both P=0.006). Mast cell numbers were reduced by 47%, (P=0.014) and total tissue histamine content by 52% (P=0.006). Codeine-induced histamine release was reduced by 44% (P=0.022). The weal, but not the flare, induced by histamine was significantly inhibited (P=0.019). Echography revealed a 15% thinning of the skin by clobetasol. These results demonstrate that reduction of the weal and flare responses to codeine following clobetasol treatment, results primarily from reduced mast cell numbers and tissue histamine content rather than inhibition by corticosteroids of mast cell degranulation. PMID:11156588

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



Damnacanthal inhibits IgE receptor-mediated activation of mast cells.  


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

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



Inhibition by troglitazone of the antigen-induced production of leukotrienes in immunoglobulin E-sensitized RBL-2H3 cells  

PubMed Central

The effect of troglitazone, an anti-diabetic drug with insulin-sensitizing action, on antigen-induced production of leukotriene (LT) B4, C4 and E4 and prostaglandin D2 (PGD2) was examined in dinitrophenol (DNP)-specific immunoglobulin E (IgE)-sensitized RBL-2H3 mast cells following stimulation by the antigen, DNP-conjugated human serum albumin. Levels of LTB4, C4 and E4 and PGD2 in the conditioned medium were enzyme-immunoassayed. Troglitazone inhibited the antigen-induced production of LTB4, C4 and E4 and the potency of the inhibition was comparable to that of zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX) and a clinically used anti-asthmatic drug. Neither troglitazone nor zileuton affected antigen-induced production of PGD2, arachidonic acid release from membrane phospholipids and degranulation. Troglitazone inhibited LTB4 production by the supernatant fraction of RBL-2H3 cell lysate with similar potency to zileuton, suggesting that troglitazone inhibits LT production by direct inhibition of 5-LOX activity. Furthermore, it was shown that troglitazone as well as zileuton inhibited LTB4 production in A23187-stimulated rat peritoneal neutrophils. These findings suggest that troglitazone inhibits antigen-induced LT production in the IgE-sensitized RBL-2H3 cells and A23187-stimulated rat peritoneal neutrophils by direct inhibition of 5-LOX activity. PMID:10694244

Yamashita, Masamichi; Kushihara, Mikie; Hirasawa, Noriyasu; Takasaki, Wataru; Takahagi, Hidekuni; Takayanagi, Motoaki; Ohuchi, Kazuo



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

PubMed Central

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

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



Sanguinarine suppresses IgE induced inflammatory responses through inhibition of type II PtdIns 4-kinase(s).  


The effects of sanguinarine on IgE mediated early signaling mechanisms leading to inflammatory mediators release were investigated. Pretreatment of RBL 2H3 cells with sanguinarine inhibited IgE induced activation of type II PtdIns 4-kinase activity. Concomitant with type II PtdIns 4-kinase inhibition, sanguinarine also inhibited IgE induced degranulation and ? hexosaminidase release in RBL 2H3 cells. In vitro assays showed sanguinarine inhibited type II PtdIns 4-kinase activity in a dose dependent fashion with no effect on PtdIns 3-kinase activity. Fluorescence spectroscopic studies suggested that sanguinarine binds to type II PtdIns 4-kinases ? and ? isoforms with a Kd of 2.4 and 1.8?M, respectively. Kinetic studies showed that sanguinarine competes with PtdIns binding site of type II PtdIns 4-kinase ?. These results suggest that the anti-inflammatory effects of sanguinarine on PtdIns 3-kinase signaling pathway are more likely an indirect effect and emphasize the importance of the cross talk between type II PtdIns 4-kinases and PtdIns 3-kinases. PMID:23899475

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



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


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

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



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

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

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.



Characterization of Ca(2+)-inhibited potassium channels in the LNCaP human prostate cancer cell line.  


Potassium plasma membrane channels have been studied in the LNCaP androgen-sensitive human prostate cancer cell line, derived from a lymph node of a subject with metastatic carcinoma of the prostate. Membrane currents were recorded by the patchclamp technique, using the cell-attached, cell-free and whole-cell mode. A voltage-dependent, non-inactivating potassium channel (delayed rectifier) was the most commonly observed ion channel in LNCaP cells. The slope conductance of K+ channels in a symmetrical 140 mM K+ gradient was 78 pS. In excised inside-out patches, the channel was inhibited by increasing the cytoplasmic Ca2+ concentration (with half-block at 0.5 microM Ca2+) over a wide range of membrane potentials. The K+ channel had a high sensitivity to tetraethylammonium (TEA), that reduced the single channel conductance with Kd of 280 +/- 27 microM. The K+ channel open probability was inhibited by alpha-dendrotoxin (DTX) (with a half-blocking concentration of approximately 5 nM) and mast cell degranulating peptide (MCDP) (with half-blocking concentration of approximately 70 nM) at all membrane potentials and with very slow reversibility. In view of the biophysical and pharmacological properties of K+ channels in LNCaP cells, it is not possible to classify these channels as one of the previously characterized types of voltage- or ligand-gated K+ channels in other cell lines. PMID:10412718

Skryma, R; Van Coppenolle, F; Dufy-Barbe, L; Dufy, B; Prevarskaya, N



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


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

Luo, Chenfang; Yuan, Dongdong; Zhao, Weicheng; Chen, Huixin; Luo, Gangjian; Su, Guangjie; Hei, Ziqing



Inhibition in Multiclass Classification  

Microsoft Academic Search

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

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



Inhibition of selectin binding  


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

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



Inhibition of selectin binding  


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

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



Inhibition of selectin binding  


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

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



Inhibition of experimental angiogenesis by the somatostatin analogue octreotide acetate (SMS 201-995).  


The present study investigates the effect of the somatostatin analogue octreotide acetate (SMS 201-995) on experimental angiogenesis in vitro and in vivo. Octreotide reduced the proliferation of human HUV-EC-C endothelial cells (mean, -45.8% versus controls at 10(-9) M; P < 0.05) as well as the density of the vascular network of the chick chorioallantoic membrane (mean, -35.7% versus controls at 50 microgram; P < 0.05). Furthermore, octreotide significantly inhibited chick chorioallantoic membrane neovascularization by the human MCF-10Aint-2 mammary cells secreting the angiogenic protein FGF-3. The proliferation of endothelial and smooth muscle cells from rat aorta explants on fibronectin was reduced by octreotide 10(-8) M (mean, -32.6% versus controls; P < 0.05), and a similar effect was produced on cells sprouting from explants cultured in fibrin (mean, -52.9% versus controls; P < 0.05). Topical administration of octreotide 10 microgram/day for 6 days inhibited rat cornea neovascularization induced by AgNO3/KNO3 (mean, -50.6% versus controls; P < 0.05). Octreotide 40 microgram/day i.p was tested on angiogenesis in rat mesentery obtained by i.p. injections of compound 48/80, a mast cell degranulating agent, or conditioned medium from MCF-10Aint-2 cells and was able to reduce the extent of neovascularization (mean, -45.6 and -64.1%, respectively, versus controls; P < 0.05). These data provide evidence that octreotide is an inhibitor of experimental angiogenesis in vitro and in vivo. PMID:9815682

Danesi, R; Agen, C; Benelli, U; Paolo, A D; Nardini, D; Bocci, G; Basolo, F; Campagni, A; Tacca, M D



AOP description: Acetylcholinesterase inhibition  

EPA Science Inventory

This adverse outcome pathway (AOP) leverages existing knowledge in the open literature to describe the linkage between inhibition of acetylcholinesterase (AChE) and the subsequent mortality resulting from impacts at cholinergic receptors. The AOP takes a chemical category approa...


Psychotherapy by reciprocal inhibition  

Microsoft Academic Search

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

Joseph Wolpe



Inhibition in Multiclass Classification  

PubMed Central

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

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



Inhibition in multiclass classification.  


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

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



Synergistic inhibition of thrombin-induced platelet aggregation by the novel nitric oxide-donor GEA 3175 and adenosine.  

PubMed Central

1. The influence of the novel nitric oxide-donor GEA 3175 on thrombin- and ionomycin-stimulated human platelets was investigated. The effect of GEA 3175 was compared with that of adenosine, an activator of platelet adenylyl cyclase. 2. GEA 3175 inhibited thrombin-induced secretion of ATP but did not affect aggregation; similar results were obtained with adenosine. 3. Thrombin-stimulated rises in the cytosolic free Ca2+ concentration, [Ca2+]i, were dose-dependently inhibited by GEA 3175 and adenosine. GEA 3175 and adenosine maximally reduced the initial rise in [Ca2+]i by 41% and 35%, respectively. 4. Simultaneous exposure to GEA 3175 and adenosine nearly abolished both the functional responses (i.e. aggregation and degranulation) and the rises in [Ca2+]i in thrombin-stimulated platelets. 5. Aggregation and increases in [Ca2+]i triggered in platelets by the Ca(2+)-ionophore ionomycin were only marginally affected by a combination of GEA 3175 and adenosine. 6. GEA 3175 potently increased the guanosine 3':5'-cyclic monophosphate (cyclic GMP) content in platelets but did not affect adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. Adenosine did not increase either the cyclic AMP or the cyclic GMP levels in platelets. However, adenosine and GEA 3175 combined significantly elevated the platelet cyclic AMP content. 7. The results show that simultaneous exposure to GEA 3175 and adenosine promotes potent anti-aggregatory properties in platelets in vitro. The findings suggest that blockage of the cytosolic Ca(2+)-signal, which is probably mediated by an amplified cyclic nucleotide response, is an important event during the synergistic inhibition of thrombin-induced aggregation. PMID:8864553

Grenegård, M.; Gustafsson, M. C.; Andersson, R. G.; Bengtsson, T.



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

SciTech Connect

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

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



Biochanin A, a Phytoestrogenic Isoflavone with Selective Inhibition of Phosphodiesterase 4, Suppresses Ovalbumin-Induced Airway Hyperresponsiveness  

PubMed Central

The present study investigated the potential of biochanin A, a phytoestrogenic isoflavone of red clover (Triflolium pratense), for use in treating asthma or chronic obstructive pulmonary disease (COPD). Biochanin A (100??mol/kg, orally (p.o.)) significantly attenuated airway resistance (RL), enhanced pause (Penh), and increased lung dynamic compliance (Cdyn) values induced by methacholine (MCh) in sensitized and challenged mice. It also significantly suppressed an increase in the number of total inflammatory cells, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, and tumor necrosis factor (TNF)-? in bronchoalveolar lavage fluid (BALF) of the mice. However, it did not influence interferon (IFN)-? levels. Biochanin A (100??mol/kg, p.o.) also significantly suppressed the total and ovalbumin (OVA)-specific immunoglobulin E (IgE) levels in the serum and BALF, and enhanced the total IgG2a level in the serum of these mice. The PDE4H/PDE4L value of biochanin A was calculated as >35. Biochanin A did not influence xylazine/ketamine-induced anesthesia. Biochanin A (10~30??M) significantly reduced cumulative OVA (10~100??g/mL)-induced contractions in the isolated guinea pig trachealis, suggesting that it inhibits degranulation of mast cells. In conclusion, red clover containing biochanin A has the potential for treating allergic asthma and COPD. PMID:21437195

Ko, Wun-Chang; Lin, Ling-Hung; Shen, Hsin-Yi; Lai, Chi-Yin; Chen, Chien-Ming; Shih, Chung-Hung



Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling.  


IgE-mediated mast cell activation is critical for development of allergic inflammation. We have recently found that selinidin, one of the coumarin derivatives isolated from Angelica keiskei, attenuates mast cell degranulation following engagement of the high-affinity receptor for IgE (Fc epsilonRI) with IgE and antigen. In the present study, we investigated the effects of selinidin on intracellular signaling and mast cell activation employing bone marrow-derived mast cells. Here, we report that selinidin attenuates the release of beta-hexosaminidase, synthesis of leukotriene C4, and production of tumor necrosis factor-alpha without affecting IgE-Fc epsilonRI binding. Furthermore, biochemical analyses of the Fc epsilonRI-mediated signaling pathway demonstrated that selinidin decreases phosphorylation of phospholipase C-gamma1, p38 mitogen-activated protein kinase, and IkappaB-alpha upon FcepsilonRI stimulation. These results suggest that this compound suppresses IgE-mediated mast cell activation by inhibiting multiple steps of FcepsilonRI-dependent signaling pathways and would be beneficial for the prevention of allergic inflammation. PMID:18310907

Kishiro, Sachiko; Nunomura, Satoshi; Nagai, Hisashi; Akihisa, Toshihiro; Ra, Chisei



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

PubMed Central

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

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



Immunization with Hypoallergens of Shrimp Allergen Tropomyosin Inhibits Shrimp Tropomyosin Specific IgE Reactivity  

PubMed Central

Designer proteins deprived of its IgE-binding reactivity are being sought as a regimen for allergen-specific immunotherapy. Although shrimp tropomyosin (Met e 1) has long been identified as the major shellfish allergen, no immunotherapy is currently available. In this study, we aim at identifying the Met e 1 IgE epitopes for construction of hypoallergens and to determine the IgE inhibitory capacity of the hypoallergens. IgE-binding epitopes were defined by three online computational models, ELISA and dot-blot using sera from shrimp allergy patients. Based on the epitope data, two hypoallergenic derivatives were constructed by site-directed mutagenesis (MEM49) and epitope deletion (MED171). Nine regions on Met e 1 were defined as the major IgE-binding epitopes. Both hypoallergens MEM49 and MED171 showed marked reduction in their in vitro reactivity towards IgE from shrimp allergy patients and Met e 1-sensitized mice, as well as considerable decrease in induction of mast cell degranulation as demonstrated in passive cutaneous anaphylaxis assay. Both hypoallergens were able to induce Met e 1-recognizing IgG antibodies in mice, specifically IgG2a antibodies, that strongly inhibited IgE from shrimp allergy subjects and Met e 1-sensitized mice from binding to Met e 1. These results indicate that the two designer hypoallergenic molecules MEM49 and MED171 exhibit desirable preclinical characteristics, including marked reduction in IgE reactivity and allergenicity, as well as ability to induce blocking IgG antibodies. This approach therefore offers promises for development of immunotherapeutic regimen for shrimp tropomyosin allergy. PMID:25365343

Wai, Christine Y. Y.; Leung, Nicki Y. H.; Ho, Marco H. K.; Gershwin, Laurel J.; Shu, Shang An; Leung, Patrick S. C.; Chu, Ka Hou



Heparinase inhibits neovascularization.  

PubMed Central

Neovascularization is associated with the regulation of tissue development, wound healing, and tumor metastasis. A number of studies have focused on the role of heparin-like molecules in neovascularization; however, little is known about the role of heparin-degrading enzymes in neovascularization. We report here that the heparin-degrading enzymes, heparinases I and III, but not heparinase II, inhibited both neovascularization in vivo and proliferation of capillary endothelial cells mediated by basic fibroblast growth factor in vitro. We suggest that the role of heparinases in inhibition of neovascularization is through depletion of heparan sulfate receptors that are critical for growth factor-mediated endothelial cell proliferation and hence neovascularization. The differences in the effects of the three heparinases on neovascularization could be due to different substrate specificities for the enzymes, influencing the availability of specific heparin fragments that modulate heparin-binding cytokines involved in angiogenesis. Images PMID:7509076

Sasisekharan, R; Moses, M A; Nugent, M A; Cooney, C L; Langer, R



Inhibition of Histone Deacetylases  

PubMed Central

Lysine acetylation of histones is one of the major epigenetic regulators of chromatin conformation and gene expression. The dynamic nature of histone acetylation is determined by the counterbalancing activity of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Acetylation of histones is generally associated with open and transcriptionally active chromatin, whereas the activity of HDACs leads to histone deacetylation, condensation of chromatin, and inhibition of transcription. Aberrant silencing of tumor suppressors and other genes has been found in different types of cancer. Abnormal activity of HDACs has been implicated in tumorigenesis and therefore considerable effort has been put into the development of HDAC inhibitors as a means of modifying histone acetylation status and reexpressing aberrantly silenced tumor suppressor genes. This has led to the generation of a number of structurally diverse compounds that can effectively inhibit HDAC activity, thus altering chromatin structure in cancer cells. This unit discusses the methods and recent technological developments with respect to the studies of HDAC inhibition in cancer. PMID:15273406

Huang, Yi; Shaw, Patrick G.; Davidson, Nancy E.



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

SciTech Connect

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

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



Enzyme inhibition by antibodies.  


The interest in the inhibition of enzymes by their specific antibodies stems mainly from the fact that these systems can serve as suitable models in the study of neutralization of biologically active molecules in general. The interaction of enzymes with their specific antibodies generally leads to a reduction in their enzymatic activity. The mechanism of this inhibition is rarely a direct combination of the antibodies with the catalytic site, but is rather due to steric hindrance, namely, barring the access to the active site. In several systems the mechanism of the antibody effect is by conformational changes which it induces on the enzyme. In these cases, the interaction with the antibody may result either in inhibition or in enhancement of the enzymatic activity. In every instance, however, the effect of the antibody is dependent on its narrow specificity, namely, on the regions of the enzyme to which it is directed. The extent of inhibition or enhancement is, therefore, a reflection of the nature and distribution of the various antigenic determinants on the enzyme molecule. Antibodies specific exclusively to defined regions of an enzyme molecule can be prepared. This has been performed for both lysozyme and staphylococcal nuclease by two procedures: a) Selective separation of the relevant antibodies from the anti-enzyme serum by an immunoadsorbent containing a particular immunologically active fragment of the enzyme. b) The use of an isolated antigenic fragment of the enzyme, or a conjugate of it, for immunization. The antibodies thus prepared, specific toward a unique defined region of the lysozyme molecule (residues 60-83, denoted "loop") recognize the structural conformation of the fragment and are reactive with the intact enzyme molecule. Furthermore, a chemically synthesized loop-like derivative was proved immunologically identical with the natural fragment, and when forming a part of a completely synthetic conjugate, elicited conformation-specific antibodies, reactive with native lysozyme. These findings are relevant to the topic of an immunological approach to fertility control from two different viewpoints: In the first place they are informative regarding the specific inhibition by antibodies of sperm enzymes which partake in the fertilization process. Secondly, they encourage the synthetic approach for induction of an immune response toward hormones which are crucial in fertilization or implantation. PMID:47683

Arnon, R



Inhibits of of colon carcinogenesis.  


Disulfiram (tetraethylthiuram disulfide, Antabuse) and sodium diethyldithiocarbamate, when added to the diet, inhibit 1,2-dimethylhydrazine (DMH)-induced neoplasia of the large bowel in female CF1 mice. Ethylene bis(dithiocarbamato)manganese (Maneb) and bis(ethylxanthogen), two pesticides with structural similarities to disulfiram, produce comparable inhibition of DHM. In other work, disulfiram was found to inhibit the carcinogenic effect of azoxymethane (AOM) on the large bowel. Under comparable conditions the inhibition of AOM was considerably less than that obtained with DMH as the carcinogen. The data suggest that disulfiram inhibits DMH metabolism at more than one oxidative step. PMID:200340

Wattenberg, L W; Lam, L K; Fladmoe, A V; Borchert, P



Pharmacological Inhibition of FTO  

PubMed Central

In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity. PMID:25830347

McMurray, Fiona; Demetriades, Marina; Aik, WeiShen; Merkestein, Myrte; Kramer, Holger; Andrew, Daniel S.; Scudamore, Cheryl L.; Hough, Tertius A.; Wells, Sara; Ashcroft, Frances M.; McDonough, Michael A.; Schofield, Christopher J.; Cox, Roger D.



Oxazolidinones Inhibit Cellular Proliferation via Inhibition of Mitochondrial Protein Synthesis  

Microsoft Academic Search

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

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



Lymphoma with large-plaque parapsoriasis treated with PUVA.  


We report on a 78-year-old Japanese woman with a 50-year history of large-plaque parapsoriasis that had evolved into cutaneous T-cell lymphoma. Her large-plaque parapsoriasis had been treated with psoralen plus ultraviolet A for 10 years. Subsequently an isolated nodule appeared on her right lower leg. Prior or concurrent patches or plaques were absent. Histology revealed a diffuse nonepidermotropic infiltrate of large lymphocytes in the dermis, which had enlarged nuclei and prominent nucleoli. A diagnosis of CD30- cutaneous large T-cell lymphoma was made. Following systemic chemotherapy, there was clinical improvement. No evidence of recurrence or systemic lymphoma has subsequently been found. PMID:16048755

Tamagawa, Risa; Katoh, Norito; Shimazaki, Chihiro; Okano, Akira; Yamada, Shinya; Ichihashi, Kaori; Masuda, Koji; Kishimoto, Saburo



Method for decreasing radiation load in puva therapy  

SciTech Connect

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

Wolff, K.



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


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

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



Inhibition of sulfotransferases by xenobiotics.  


The sulfotransferase (SULT) family comprises important phase II conjugation enzymes for the detoxification of xenobiotics and modulation of the activity of physiologically important endobiotics such as thyroid hormones, steroids, and neurotransmitters. SULT enzymes catalyze the transfer of a sulfuryl group, donated by 3'-phosphoadenosine-5'-phosphosulfate (PAPS), to an acceptor substrate that may be a hydroxy group or an amine group in a process originally called sulfation, but more correctly referred to as sulfonation or sulfurylation. SULT activity may be inhibited when humans are exposed to certain xenobiotics including drugs (mefenamic acid, salicylic acid, clomiphene, danazol etc.), dietary chemicals (catechins, food colorants, flavonoids and phytoestrogens etc.), and environmental chemicals (hydroxylated polychlorinated biphenyls, hydroxylated polyhalogenated aromatic hydrocarbons, pentachlorophenol, triclosan and bisphenol A, etc.). Inhibition of individual SULT isoforms may cause adverse effects on human health. For example, hydroxylated polychlorinated biphenyls have been shown to interfere with the transport of thyroid hormones, inhibit estradiol sulfonation, and inhibit thyroid hormone sulfonation, thereby potentially disrupting the thyroid hormone system. Formation of sulfate conjugates of toxic xenobiotics usually decreases their toxicity, so inhibition of this pathway may lead to prolonged exposure to the compounds. Conversely, some sulfate conjugates are chemically reactive, inhibition of their formation may protect from toxicity. This manuscript will review the literature concerning the inhibition of SULTs by xenobiotics including isoform-selective effects, inhibition kinetics and health effects resulting from the inhibition. PMID:16454694

Wang, Li-Quan; James, Margaret O



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

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

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



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.  


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-6(686-936)). BAG-6(686-936) 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-6(686-936) 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-6(686-936) 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

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



Anthrax lethal factor inhibition  

PubMed Central

The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) ?50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit “point of no return” model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax. PMID:15911756

Shoop, W. L.; Xiong, Y.; Wiltsie, J.; Woods, A.; Guo, J.; Pivnichny, J. V.; Felcetto, T.; Michael, B. F.; Bansal, A.; Cummings, R. T.; Cunningham, B. R.; Friedlander, A. M.; Douglas, C. M.; Patel, S. B.; Wisniewski, D.; Scapin, G.; Salowe, S. P.; Zaller, D. M.; Chapman, K. T.; Scolnick, E. M.; Schmatz, D. M.; Bartizal, K.; MacCoss, M.; Hermes, J. D.



Inhibition of cellulases by phenols  

Technology Transfer Automated Retrieval System (TEKTRAN)

The inhibition of enzymes by the end products that they make is a well-known phenomenon. Another form of inhibition is manifested by the decrease in hydrolysis of pretreated cellulosic material as the concentration of solid biomass material increases, even though the ratio of enzyme to cellulose is...


Suppressive effects of Schizandra chinensis Baillon water extract on allergy-related cytokine generation and degranulation in IgE-antigen complex-stimulated RBL-2H3 cells  

PubMed Central

Schizandra chinensis Baillon is a traditional folk medicine plant that is used to treat and prevent several inflammatory diseases and cancer in Korea, but the underlying mechanisms involved in its anti-allergic activity are not fully understood. This study was designed to investigate mechanisms of anti-allergic activity of a Schizandra chinensis Baillon water extract (SCWE) in immunoglobulin E (IgE)-antigen complex-stimulated RBL2H3 cells and to assess whether gastric and intestinal digestion affects the anti-allergic properties of SCWE. Oxidative stress is an important consequence of the allergic inflammatory response. The antioxidant activities of SCWE increased in a concentration-dependent manner. RBL-2H3 cells were sensitized with monoclonal anti-dinitrophenol (DNP) specific IgE, treated with SCWE, and challenged with the antigen DNP-human serum albumin. SCWE inhibited ?-hexosaminidase release and expression of interleukin (IL)-4, IL-13, and tumor necrosis factor-alpha (TNF-?) mRNA and protein in IgE-antigen complex-stimulated RBL2H3 cells. We found that digested SCWE fully maintained its antioxidant activity and anti-allergic activity against the IgE-antigen complex-induced activation of RBL-2H3 cells. SCWE may be useful for preventing allergic diseases, such as asthma. Thus, SCWE could be used as a natural functional ingredient for allergic diseases in the food and/or pharmaceutical industries. PMID:22586497

Chung, Mi Ja; Kim, Jeong-Mi; Lee, Sangchul; Kim, Taewoo; Kim, Daejung; Baek, Jongmi; Kim, Taehyuk; Lee, Jaesung; Kim, Kyoungkon; Yoon, Jin A



Inhibition of Nicotinamide Phosphoribosyltransferase  

PubMed Central

The NAD rescue pathway consists of two enzymatic steps operated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide mononucleotide adenylyltransferases. Recently, the potent Nampt inhibitor FK866 has been identified and evaluated in clinical trials against cancer. Yet, how Nampt inhibition affects NAD contents and bioenergetics is in part obscure. It is also unknown whether NAD rescue takes place in mitochondria, and FK866 alters NAD homeostasis within the organelle. Here, we show that FK866-dependent reduction of the NAD contents is paralleled by a concomitant increase of ATP in various cell types, in keeping with ATP utilization for NAD resynthesis. We also show that poly- and mono(ADP-ribose) transferases rather than Sirt-1 are responsible for NAD depletion in HeLa cells exposed to FK866. Mass spectrometry reveals that the drug distributes in the cytosolic and mitochondrial compartment. However, the cytoplasmic but not the mitochondrial NAD pool is reduced upon acute or chronic exposure to the drug. Accordingly, Nampt does not localize within the organelles and their bioenergetics is not affected by the drug. In the mouse, FK866-dependent reduction of NAD contents in various organs is prevented by inhibitors of poly(ADP-ribose) polymerases or the NAD precursor kynurenine. For the first time, our data indicate that mitochondria lack the canonical NAD rescue pathway, broadening current understanding of cellular bioenergetics. PMID:20724478

Pittelli, Maria; Formentini, Laura; Faraco, Giuseppe; Lapucci, Andrea; Rapizzi, Elena; Cialdai, Francesca; Romano, Giovanni; Moneti, Gloriano; Moroni, Flavio; Chiarugi, Alberto



HIV-1 Vpu Antagonism of Tetherin Inhibits Antibody-Dependent Cellular Cytotoxic Responses by Natural Killer Cells  

PubMed Central

ABSTRACT The type I interferon-inducible factor tetherin retains virus particles on the surfaces of cells infected with vpu-deficient human immunodeficiency virus type 1 (HIV-1). While this mechanism inhibits cell-free viral spread, the immunological implications of tethered virus have not been investigated. We found that surface tetherin expression increased the antibody opsonization of vpu-deficient HIV-infected cells. The absence of Vpu also stimulated NK cell-activating Fc?RIIIa signaling and enhanced NK cell degranulation and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The deletion of vpu in HIV-1-infected primary CD4+ T cells enhanced the levels of antibody binding and Fc receptor signaling mediated by HIV-positive-patient-derived antibodies. The magnitudes of antibody binding and Fc signaling were both highly correlated to the levels of tetherin on the surfaces of infected primary CD4 T cells. The affinity of antibody binding to Fc?RIIIa was also found to be critical in mediating efficient Fc activation. These studies implicate Vpu antagonism of tetherin as an ADCC evasion mechanism that prevents antibody-mediated clearance of virally infected cells. IMPORTANCE The ability of the HIV-1 accessory factor to antagonize tetherin has been considered to primarily function by limiting the spread of virus by preventing the release of cell-free virus. This study supports the hypothesis that a major function of Vpu is to decrease the recognition of infected cells by anti-HIV antibodies at the cell surface, thereby reducing recognition by antibody-dependent clearance by natural killer cells. PMID:24623433

Alvarez, Raymond A.; Hamlin, Rebecca E.; Monroe, Anthony; Moldt, Brian; Hotta, Mathew T.; Rodriguez Caprio, Gabriela; Fierer, Daniel S.; Simon, Viviana



Aluminum inhibits erythropoiesis in vitro.  

PubMed Central

Anemia has been associated with aluminum intoxication in patients on chronic dialysis and in animals. In studies presented here, in vitro human erythroid culture was used to delineate the effects of aluminum on normal hematopoiesis. Aluminum by itself in routine culture, even at very high levels (1,035 ng/ml), did not significantly affect erythroid colony growth. The addition of human transferrin to the culture, however, resulted in a marked dose-dependent inhibition of erythroid, but not myeloid colony growth. At all doses, CFU-E progenitors showed greater inhibition than burst-forming units (BFU-E). Aluminum inhibition was not overcome by increasing the dose of erythropoietin or adding additional burst-promoting activity to the culture. Inhibition by aluminum was directly related to the number of binding sites on transferrin in the culture, and was not observed in the presence of fully iron-saturated transferrin. Images PMID:3384943

Mladenovic, J



Presynaptic inhibition of elicited neurotransmitter release  

Microsoft Academic Search

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

Ling-Gang Wu; Peter Saggau



Remote inhibition of polymer degradation.  

SciTech Connect

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.

Clough, Roger Lee; Celina, Mathias Christopher



Homo Economicus Belief Inhibits Trust  

PubMed Central

As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

Xin, Ziqiang; Liu, Guofang



Action spectra for photosynthetic inhibition  

NASA Technical Reports Server (NTRS)

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

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



Subliminal priming of intentional inhibition.  


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

Parkinson, Jim; Haggard, Patrick



Islam Does Not Inhibit Science.  

ERIC Educational Resources Information Center

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

Shanavas, T. O.



Behavioral Inhibition: Type or Continuum?  

ERIC Educational Resources Information Center

This study investigated whether behavioral inhibition is best conceptualized as a continuous variable or as a distinct typology with two or more subcategories. The following data were gathered on 58 infants at 5, 7, 10, and 13 months of age; physiological functioning (cardiovascular activity and salivary cortisol); emotional expressivity in…

Scholmerich, Axel; And Others


Inhibition of Hsp90 in Streptomyces coelicolor  

E-print Network

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 ...

Wu, Katherine A. (Katherine Ann)



Attentional inhibition mediates inattentional blindness.  


Salient stimuli presented at unattended locations are not always perceived, a phenomenon termed inattentional blindness. We hypothesized that inattentional blindness may be mediated by attentional inhibition. It has been shown that attentional inhibition effects are maximal near an attended location. If our hypothesis is correct, inattentional blindness effects should similarly be maximal near an attended location. During central fixation, participants viewed rapidly presented colored digits at a peripheral location. An unexpected black circle (the critical stimulus) was concurrently presented. Participants were instructed to maintain central fixation and name each color/digit, requiring focused attention to that location. For each participant, the critical stimulus was presented either near to or far from the attended location (at the same eccentricity). In support of our hypothesis, inattentional blindness effects were maximal near the attended location, but only at intermediate task accuracy. PMID:20227894

Thakral, Preston P; Slotnick, Scott D



Survivin Inhibits Apoptosis in Cytotrophoblasts  

Microsoft Academic Search

Survivin, a protein that inhibits apoptosis, is expressed in a variety of tumour cells. We detected survivin-specific mRNA and protein in normal placental tissues, two human choriocarcinoma cell lines (JEG-3 and BeWo), and a trophoblastic cell line (tPA30-1) by reverse transcription-polymerase chain reaction (RT-PCR), Northern blotting, and Western blotting. Immunohistochemically, survivin was localized to normal villous cytotrophoblasts, normal extravillous trophoblasts,

A. Shiozaki; K. Kataoka; M. Fujimura; H. Yuki; M. Sakai; S. Saito



The inhibition of acquired fear  

Microsoft Academic Search

A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is\\u000a at the root of a variety of disorders, among which are phobias, generalized anxiety, and the posttraumatic stress disorder\\u000a (PTSD). The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS\\u000a alone, so that

Iván Izquierdo; Martín Cammarota; Mónica R. M. Vianna; Lía R. M. Bevilaqua



Bifunctional thiosialosides inhibit influenza virus  

PubMed Central

We have synthesized a panel of bivalent S-sialoside analogues, with modifications at the 4 position, as inhibitors of influenza virus. These first generation compounds show IC50 values ranging from low micromolar to high nanomolar in enzyme inhibition and plaque reduction assays with two intact viruses, Influenza H1N1 (A/California/07/2009) and H3N2 (A/Hongkong/8/68). PMID:24374271

Yang, Yang; He, Yun; Li, Xingzhe; Dinh, Hieu



8, 87438771, 2008 Inhibition of ice  

E-print Network

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

Paris-Sud XI, Université de


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


Oxyhemoglobin inhibition of acetylcholinesterase activity.  


The effects of human oxyhemoglobin (HbO2), human methemoglobin (MetHb), and porcine serum albumin (PSA) on the activity of acetylcholinesterase (AChE) isolated from Electrophorus electricus were examined. HbO2 produced a dose-dependent reduction in AChE activity. Fifty percent of activity was obtained at 5 microM HbO2, while 95% inhibition was obtained at 50 microM. In this concentration range MetHb and PSA had little effect on esterase activity. PMID:3725181

Linnik, M D; Lee, T J



Spider stimuli improve response inhibition.  


Anxiety can have positive effects on some aspects of cognition and negative effects on others. The current study investigated whether task-relevant anxiety could improve people's ability to withhold responses in a response inhibition task. Sixty-seven university students completed a modified and an unmodified version of the Sustained Attention to Response Task (SART; Robertson, Manly, Andrade, Baddeley, & Yiend, 1997) and provided subjective measures of arousal and thoughts. Anxiety appeared to improve participants' ability to withhold responses. Further, participants' performance was consistent with a motor response inhibition perspective rather than a mind-wandering perspective of SART commission error performance. Errors of commission were associated with response times (speed-accuracy trade-off) as opposed to task-unrelated thoughts. Task-related thoughts were associated with the speed-accuracy trade-off. Conversely task-unrelated thoughts showed an association with errors of omission, suggesting this SART metric could be an indicator of sustained attention. Further investigation of the role of thoughts in the SART is warranted. PMID:25770464

Wilson, Kyle M; Russell, Paul N; Helton, William S



Isolation and characterization of PhoP homolog in Brucella abortus  

E-print Network

of Brucella in neutrophils has been shown to rely upon the inhibition of degranulation and the oxidative burst (7, 26). Survival in macrophages also relies on the inhibition of phagolysosomal fusion and has been shown to correlate with virulence...

Huang, Xin



Therapeutic effects of immune plasma in foals with experimentally induced Rhodococcus equi pneumonia  

E-print Network

mechanisms of the cell (Zink et al 1987; Hietala and Ardans 1987a). The mechanism of inhibiting phagosome-lysosome fusion remains unexplained; however, it is thought to involve lysosomal degranulation. The inhibition of phagosome-lysosome fusion by R...

Chaffin, Morgan Keith



Well having inhibited microbial growth  


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.

Lee, Brady D.; Dooley, Kirk J.



Stereotype Activation, Inhibition, and Aging  

PubMed Central

This research explored age-related changes in drawing stereotypic inferences during the comprehension of narrative texts. Previous research suggests that declines in inhibitory function can lead older adults to rely more on stereotypes and be more prejudiced than younger adults, even in the face of a desire to be non-prejudiced. In two experiments reported here, younger and older adults read stories that allowed for stereotypic inferences. Older adults were less likely to inhibit stereotypic inferences as measured by recognition measures and lexical decision times. A third control experiment verified that the results of the lexical decision task were not due to a priori response biases for the specific target words. Overall, older adults were more likely to make and maintain stereotypic inferences than younger adults, potentially causing them to be more prejudiced than younger adults. PMID:20161549

Radvansky, Gabriel A.; Copeland, David E.; von Hippel, William



Magnetic Catalysis vs Magnetic Inhibition  

E-print Network

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.

Kenji Fukushima; Yoshimasa Hidaka



The inhibition of caeruloplasmin by cyanide  

PubMed Central

1. The reversible inhibition of the oxidase activity of caeruloplasmin by cyanide was investigated. 2. The kinetics are unusual, being competitive but with the inhibited complex formed only during cycling. 3. Inhibitory concentrations of cyanide are comparable with that of caeruloplasmin. 4. One azide group completely inhibits a caeruloplasmin molecule but two cyanide groups are required. 5. The results suggest that azide binds to a half-reduced or fully reduced conformational isomer of the enzyme whereas cyanide binds to completely reoxidized isomers, and that inhibited complexes contain ligand bridges between copper atoms. PMID:5637370

Speyer, Barbara E.; Curzon, G.




PubMed Central

The effect of cortisone on the sequestration of (a) antibody-coated red cells and (b) incubated red cells was studied in rats. Cortisone administration inhibited the hepatic sequestration of red cells altered by non-immune as well as by immune injury. There was a latent period of 2 days between the institution of cortisone therapy and its first manifest effect on hepatic sequestration. The splenic sequestration of altered red cells was not inhibited by cortisone, and there was no inhibition of the sequestration of hemoglobin by either liver or spleen. It is suggested that steroids may inhibit hepatic sequestration through hemodynamic effects. PMID:14453768

Kaplan, Manuel E.; Jandl, James H.



Pyridoxal phosphate inhibition of platelet function.  


The effect of pyridoxal phosphate (PLP) on human platelet function in vitro was studied. PLP inhibited adenosine diphosphate (ADP)-induced shape change, aggregation, and the potentiation by ADP of arachidonic acid-induced aggregation. This inhibition could easily be reversed by increasing concentrations of ADP or by removing PLP. The addition of sodium borohydride to PLP-treated platelets produced an irreversible inhibition of ADP aggregation. Thus it is possible that PLP inhibited ADP-induced platelet function by forming a Schiff base with platelet-surface amino groups. PLP also produced a partial inhibition of platelet aggregation to epinephrine, arachidonic acid, A23187, and a dose-dependent inhibition of [14C]serotonin release to epinephrine and arachidonic acid. PLP did not inhibit [14C]serotonin release to A23187, nor did it suppress arachidonic acid-induced malondialdehyde production. The conclusion is drawn that the partial inhibition by PLP of platelet aggregation observed to epinephrine, arachidonic acid, and A23187 resulted from PLP's inhibition of the effect of released ADP. PMID:6766674

Kornecki, E; Feinberg, H



Inhibition of brain mitochondrial swelling by idebenone.  


The effects of idebenone on the swelling of rat brain mitochondria were studied. When FeCl3 was added to a mitochondrial suspension, a pronounced mitochondrial swelling occurred accompanied by the production of lipid peroxide; the two phenomena were closely correlated (r = 0.96, p less than 0.01). Idebenone inhibited the mitochondrial swelling and lipid peroxidation in a concentration-dependent manner; the concentration giving 50% inhibition was 37 microM for swelling and 53 microM for lipid peroxidation. Metabolites of idebenone also inhibited the lipid peroxidation. These results suggest that idebenone stabilizes the mitochondrial membrane by inhibiting lipid peroxidation in brain mitochondria. PMID:2669658

Suno, M; Nagaoka, A



Restoring ionotropic inhibition as an analgesic strategy.  


Neuronal inhibition in nociceptive relays of the spinal cord is essential for the proper processing of nociceptive information. In the spinal cord dorsal horn, the activity of synaptic and extrasynaptic GABAA and glycine receptors generates rapid, Cl(-)-dependent neuronal inhibition. A loss of this ionotropic inhibition, particularly through the collapse of the inhibitory Cl(-)-gradient, is a key mechanism by which pathological pain conditions develop. This review summarizes the roles of ionotropic inhibition in the regulation of nociception, and explores recent evidence that the potentiation of GABAA or glycine receptor activity or the enhancement of inhibitory drive can reverse pathological pain. PMID:24080373

Bonin, Robert P; De Koninck, Yves



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

ERIC Educational Resources Information Center

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

Adams, Nena C.; Jarrold, Christopher



Inhibition and Attention Deficit Hyperactivity Disorder  

Microsoft Academic Search

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

Herbert C. Quay



Presynaptic modulation of quadriceps arthrogenic muscle inhibition  

Microsoft Academic Search

Arthrogenic muscle inhibition (AMI) impedes rehabilitation following knee joint injury by preventing activation of the quadriceps. AMI has been attributed to neuronal reflex activity in which altered afferent input originating from the injured joint results in a diminished efferent motor drive to the quadriceps muscles. Beginning to understand the mechanisms responsible for muscle inhibition following joint injury is vital to

Riann M. Palmieri; Arthur Weltman; Jeffrey E. Edwards; James A. Tom; Ethan N. Saliba; Danny J. Mistry; Christopher D. Ingersoll



Mechanisms of Rotenone-induced Proteasome Inhibition  

PubMed Central

The etiology of Parkinson’s disease is unclear but appears to involve mitochondrial dysfunction, proteasome inhibition, and environmental toxins. It has been shown that pesticides, including the complex I inhibitor rotenone, cause proteasome inhibition but the mechanism of rotenone-induced proteasome dysfunction remains largely unknown. In this study, we examined the role of mitochondrial inhibition, oxidative stress, and microtubule dysfunction as potential mediators of rotenone-induced proteasome inhibition. Proteasome activity (26S) was measured in HEK and SK-N-MC cells expressing an EGFP-U degron fusion protein that is selectively degraded by the proteasome. We found that complex I and III inhibition led to the production of peroxides and decreased proteasome activity. We also found that rotenone increased nitric oxide production and nitric oxide and peroxynitrites led to proteasome inhibition. The effects of rotenone were attenuated by anti-oxidants and nitric oxide synthase inhibition. Since rotenone can also inhibit microtubule assembly, we tested a specific MT inhibitor and found it led to proteasome dysfunction. Rotenone also led to a decrease in 20S proteasome activity and 20S proteasome subunit immunoreactivity without a change in subunit mRNA. Together, these data suggest that rotenone-induced decreases in proteasome activity are due to increased degradation of proteasome components secondary to oxidative damage and possibly microtubule dysfunction. PMID:20417232

Chou, Arthur P.; Li, Sharon; Fitzmaurice, Arthur G.; Bronstein, Jeff M.



Hydrogen production from inhibited anaerobic composters  

Microsoft Academic Search

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

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



A Qualitative Approach to Enzyme Inhibition  

ERIC Educational Resources Information Center

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

Waldrop, Grover L.



Optimal Decision Making in Neural Inhibition Models  

ERIC Educational Resources Information Center

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…

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



Interhemispheric inhibition in patients with multiple sclerosis  

Microsoft Academic Search

Objectives: A single focal magnetic stimulus applied to the motor cortex of normal subjects can suppress ongoing voluntary electromyographic activity in ipsilateral small hand muscles. This inhibition is mediated from one motor cortex to the contralateral side via a transcallosal pathway. Methods: We have investigated transcallosal inhibition in 24 patients with definite multiple sclerosis (MS) and in 24 healthy volunteers.

B Boroojerdi; M Hungs; M Mull; R Töpper; J Noth



PARP-1 inhibits glycolysis in ischemic kidneys.  


After ischemic renal injury (IRI), selective damage occurs in the S(3) segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a modification that inhibits its activity. Using in vitro and in vivo models, under hypoxic conditions, we detected poly(ADP-ribosyl)ation and reduced activity of GAPDH; inhibition of PARP-1 activity restored GAPDH activity and ATP levels. Inhibition of GAPDH with iodoacetate exacerbated ATP depletion, cytotoxicity, and necrotic cell death of LLCPK(1) cells subjected to hypoxic conditions, whereas inhibition of PARP-1 activity was cytoprotective. In conclusion, these data indicate that poly(ADP-ribosyl)ation of GAPDH and the subsequent inhibition of anaerobic respiration exacerbate ATP depletion selectively in the proximal tubule after IRI. PMID:19056868

Devalaraja-Narashimha, Kishor; Padanilam, Babu J



Inhibition and Facilitation of Nucleic Acid Amplification  

Microsoft Academic Search

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




Inhibition of Experimental Dental Caries by Antibiotics  

PubMed Central

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

Fitzgerald, Robert J.



Interhemispheric inhibition of the human motor cortex.  

PubMed Central

1. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus over the motor cortex of one hemisphere on the size of EMG responses evoked in the first dorsal interosseous (FDI) muscle by a magnetic test stimulus given over the opposite hemisphere. 2. A single conditioning shock to one hemisphere produced inhibition of the test response evoked from the opposite hemisphere when the conditioning-test interval was 5-6 ms or longer. We shall refer to this as interhemispheric inhibition. However, the minimum latency of inhibition observed using surface EMG responses may have underestimated the true interhemispheric conduction time. Single motor unit studies suggested values 4-7 ms longer than the minimum interval observed with surface EMG. 3. Interhemispheric inhibition was seen when the test muscle was active or relaxed. Increasing the intensity of the conditioning stimulus increased the duration of inhibition: increasing the intensity of the test stimulus reduced the depth of inhibition. 4. The conditioning coil had to be placed on the appropriate area of scalp for inhibition to occur. The effect of the conditioning stimulus was maximal when it was applied over the hand area of motor cortex, and decreased when the stimulus was moved medial or lateral to that point. 5. The inhibitory effect on the test stimulus probably occurred at the level of the cerebral cortex. In contrast to the inhibition of test responses evoked by magnetic test stimuli, test responses evoked in active FDI by a small anodal electric shock were not significantly inhibited by a contralateral magnetic conditioning stimulus. Similarly, H reflexes in relaxed forearm flexor muscles were unaffected by conditioning stimuli to the ipsilateral hemisphere. However, inhibition was observed if the experiment was repeated with the muscles active. PMID:1464843

Ferbert, A; Priori, A; Rothwell, J C; Day, B L; Colebatch, J G; Marsden, C D



Shed syndecan-2 inhibits angiogenesis  

PubMed Central

ABSTRACT Angiogenesis is essential for the development of a normal vasculature, tissue repair and reproduction, and also has roles in the progression of diseases such as cancer and rheumatoid arthritis. The heparan sulphate proteoglycan syndecan-2 is expressed on mesenchymal cells in the vasculature and, like the other members of its family, can be shed from the cell surface resulting in the release of its extracellular core protein. The purpose of this study was to establish whether shed syndecan-2 affects angiogenesis. We demonstrate that shed syndecan-2 regulates angiogenesis by inhibiting endothelial cell migration in human and rodent models and, as a result, reduces tumour growth. Furthermore, our findings show that these effects are mediated by the protein tyrosine phosphatase receptor CD148 (also known as PTPRJ) and this interaction corresponds with a decrease in active ?1 integrin. Collectively, these data demonstrate an unexplored pathway for the regulation of new blood vessel formation and identify syndecan-2 as a therapeutic target in pathologies characterised by angiogenesis. PMID:25179601

De Rossi, Giulia; Evans, Alun R.; Kay, Emma; Woodfin, Abigail; McKay, Tristan R.; Nourshargh, Sussan; Whiteford, James R.



Reduced surround inhibition in musicians  

PubMed Central

To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia. PMID:22543743

Shin, Hae-Won; Kang, Suk Y.; Hallett, Mark



Reduced surround inhibition in musicians.  


To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia. PMID:22543743

Shin, Hae-Won; Kang, Suk Y; Hallett, Mark; Sohn, Young H



Inhibition of platelet aggregation by idebenone and the mechanism of the inhibition.  


The inhibitory effect of 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) on platelet aggregation was studied in rat and human platelets in vitro, and the mechanism of inhibition was examined in rat platelets. Idebenone inhibited the aggregation induced by collagen and thrombin in washed platelets, and by arachidonate and ADP in platelet-rich plasma (PRP). The inhibition was more prominent in collagen- and arachidonate-induced aggregation. In collagen-induced aggregation of human platelets, idebenone was 8-fold more potent than aspirin. In addition, idebenone inhibited prostaglandin synthesis and thromboxane B2 production, and also increased the cyclic AMP content in platelets. However, the concentration of idebenone required to inhibit thromboxane B2 production was much lower than that required to increase cyclic AMP. These results indicate that idebenone inhibits platelet aggregation by inhibiting thromboxane B2 synthesis rather than by increasing cyclic AMP content. PMID:2548448

Suno, M; Terashita, Z; Nagaoka, A



Regulation of Spatial Selectivity by Crossover Inhibition  

PubMed Central

Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or “crossover” inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell’s spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs. PMID:23575830

Cafaro, Jon; Rieke, Fred



Tetherin inhibits prototypic foamy virus release  

PubMed Central

Background Tetherin (also known as BST-2, CD317, and HM1.24) is an interferon- induced protein that blocks the release of a variety of enveloped viruses, such as retroviruses, filoviruses and herpesviruses. However, the relationship between tetherin and foamy viruses has not been clearly demonstrated. Results In this study, we found that tetherin of human, simian, bovine or canine origin inhibits the production of infectious prototypic foamy virus (PFV). The inhibition of PFV by human tetherin is counteracted by human immunodeficiency virus type 1 (HIV-1) Vpu. Furthermore, we generated human tetherin transmembrane domain deletion mutant (delTM), glycosyl phosphatidylinositol (GPI) anchor deletion mutant (delGPI), and dimerization and glycosylation deficient mutants. Compared with wild type tetherin, the delTM and delGPI mutants only moderately inhibited PFV production. In contrast, the dimerization and glycosylation deficient mutants inhibit PFV production as efficiently as the wild type tetherin. Conclusions These results demonstrate that tetherin inhibits the release and infectivity of PFV, and this inhibition is antagonized by HIV-1 Vpu. Both the transmembrane domain and the GPI anchor of tetherin are important for the inhibition of PFV, whereas the dimerization and the glycosylation of tetherin are dispensable. PMID:21529378



Homeostatic Competition between Phasic and Tonic Inhibition*  

PubMed Central

The GABAA receptors are the major inhibitory receptors in the brain and are localized at both synaptic and extrasynaptic membranes. Synaptic GABAA receptors mediate phasic inhibition, whereas extrasynaptic GABAA receptors mediate tonic inhibition. Both phasic and tonic inhibitions regulate neuronal activity, but whether they regulate each other is not very clear. Here, we investigated the functional interaction between synaptic and extrasynaptic GABAA receptors through various molecular manipulations. Overexpression of extrasynaptic ?6?3?-GABAA receptors in mouse hippocampal pyramidal neurons significantly increased tonic currents. Surprisingly, the increase of tonic inhibition was accompanied by a dramatic reduction of the phasic inhibition, suggesting a possible homeostatic regulation of the total inhibition. Overexpressing the ?6 subunit alone induced an up-regulation of ? subunit expression and suppressed phasic inhibition similar to overexpressing the ?6?3? subunits. Interestingly, blocking all GABAA receptors after overexpressing ?6?3? receptors could not restore the synaptic GABAergic transmission, suggesting that receptor activation is not required for the homeostatic interplay. Furthermore, insertion of a gephyrin-binding-site (GBS) into the ?6 and ? subunits recruited ?6GBS?3?GBS receptors to postsynaptic sites but failed to rescue synaptic GABAergic transmission. Thus, it is not the positional effect of extrasynaptic ?6?3? receptors that causes the down-regulation of phasic inhibition. Overexpressing ?5?3?2 subunits similarly reduced synaptic GABAergic transmission. We propose a working model that both synaptic and extrasynaptic GABAA receptors may compete for limited receptor slots on the plasma membrane to maintain a homeostatic range of the total inhibition. PMID:23839941

Wu, Xia; Huang, Lanting; Wu, Zheng; Zhang, Ce; Jiang, Dongyun; Bai, Yuting; Wang, Yun; Chen, Gong



Macrophage migration inhibition test in untreated syphilis.  


Two modifications of macrophage migration inhibition test, one of George and Vaughan and the other one of Svejcar, were performed on a total of 78 cases of untreated syphilis at various stages. As specific antigens were used: Treponema Pallidum ultrasonate and cardiolipin. Inhibition of migration was observed in 87 percent patients with primary syphillis and in all patients with late and late congenital syphilis. After improving and standardisation of the technique of Treponema Pallidum antigen-the migration inhibition test may be recommended as a specific in vitro-test for detection of cell mediated immunity in syphilis. PMID:1090263

Bowszyc, J



Inhibition of lipoxygenase-1 by tetrahydrocurcumin  

Microsoft Academic Search

Tetrahydrocurcumin (THC)—the reduced form of curcumin—is more hydrophilic than its parent compound. It possesses higher stability\\u000a in aqueous medium compared to curcumin. Lipoxygenase (LOX) enzyme is implicated in inflammatory conditions. THC was investigated\\u000a for the inhibition of soy LOX-1. THC-inhibited LOX-1 with an IC50 value of 44.6 ± 0.6 ?M. Kinetics of inhibition revealed mixed linear type with a K\\u000a \\u000a i\\u000a value of

A. H. Sneharani; Sridevi Annapurna Singh; P. Srinivas; A. G. Appu Rao


Inhibition of urinary calculi -- a spectroscopic study  

NASA Astrophysics Data System (ADS)

Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis



Glycerol inhibition of ruminal lipolysis in vitro  

Technology Transfer Automated Retrieval System (TEKTRAN)

Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of...


Myopotential inhibition of unipolar lithium pacemakers.  


The effect of isometric upper extremity exercise on pacemaker function was evaluated in 27 patients who remained pacemaker-dependent during testing. Inhibition was demonstrated in eight (31 percent) of which five were symptomatic. Based on design of the sensing amplifier and return to an all-metal housing in the unipolar lithium pulse generators, myopotential inhibition is being recognized as one cause of symptomatic pacemaker inhibition that is more common than generally appreciated. A method of evaluation and management options for symptomatic patients are discussed. Routine testing of all patients should be performed at the time of a regular office evaluation. If one model pulse generator appears to be particularly prone to myopotential inhibition, this knowledge should be considered in the choice of future pacing systems. PMID:7116965

Levine, P A; Caplan, C H; Klein, M D; Brodsky, S J; Ryan, T J




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...


Retroactive Inhibition of Meaningful Discourse (A Monograph)  

ERIC Educational Resources Information Center

This monograph analyzes theoretical and methodological problems that may have prevented previous research from detecting retroactive inhibition with meaningful discourse and reports on two experiments based on the analysis. (Author/TA)

Anderson, Richard C.; Myrow, David L.



Understanding socially inhibited behaviors in managers.  


The authors' purpose in this study is to define and highlight socially inhibited behaviors among managers, explore the implications of these behaviors for the workplace, identify ways to assist inordinately shy managers, and help staff to understand and relate more effectively when subjected to an inhibited manager. The authors search for the origins of shyness, surveying the various perspectives in personality theory and within the concept of situational causality. PMID:10158870

Austin, M J; Martin, M



Aryl hydrocarbon hydroxylase: induction and inhibition  

E-print Network

in the toxicity of halogenated biphenyls, cimetidine, a relatively non-toxic compound reported to inhibit the activity of microsomal drug metabolizing enzymes, was admin- istered to rats together with 3, 3', 4, 4'-tetrabromobiphenyl, the most potent... of the compounds investigated above. The inhibition observed was not reliably reproducible, so it was not possible to probe the role of increased enzyme activity in the toxicity of these compounds. However, it was noted that no evidence of protection against...

Andres, Janet Lee



Seed extracts inhibiting protein synthesis in vitro.  

PubMed Central

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

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



Quorum sensing inhibition, relevance to periodontics.  


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

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



Inhibited solid propellant composition containing beryllium hydride  

NASA Technical Reports Server (NTRS)

An object of this invention is to provide a composition of beryllium hydride and carboxy-terminated polybutadiene which is stable. Another object of this invention is to provide a method for inhibiting the reactivity of beryllium hydride toward carboxy-terminated polybutadiene. It was found that a small amount of lecithin inhibits the reaction of beryllium hydride with the acid groups in carboxy terminated polybutadiene.

Thompson, W. W. (inventor)



Inhibition of Spirochaeta aurantia chemotaxis by neurotoxins.  


The effects of neurotoxic compounds on the chemotactic response of Spirochaeta aurantia were investigated. In the presence of neurotoxins that affect action potential generation and transmission in excitable eucaryotic cells, D-xylose taxis was inhibited by 69 to 93%. Inhibition of chemotaxis was not due to decreased viability or motility. This study supports the hypothesis that the molecular basis for sensory signal transduction in S. aurantia involves ion fluxes across the cytoplasmic membrane. PMID:6136501

Goulbourne, E A; Greenberg, E P



Chemical Defoliation and Regrowth Inhibition in Cotton.  

E-print Network

of these materials with true defoliants is undesirable. The effect of some of the more promising ma- terials on regrowth is shown in Figure 5. Production of seed cotton was not significantly affected by any of the treatments (Table 6). Even though the seed...Chemical Defoliation and Regrowth Inhibition in Cotton [Blank Page in Original Bulletin] DIGEST Tests were conducted during 1950, 1951 and 1952 on the feasibility of employing growth regulators and other chemicals to inhibit secondary growth...

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



Inflammasome inhibition: putting out the fire.  


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

Netea, Mihai G; Joosten, Leo A B



Quorum Sensing Inhibition, Relevance to Periodontics  

PubMed Central

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

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



Reduction of part-list cuing inhibition  

E-print Network

REDUCTION OF PART-LIST CUING INHIBITION A Thesis by JEFFREY MICHAEL BROWN Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE December 1991 Major... Subject: Psychology REDUCTION OF PART-LIST CUING INHIBITION A Thesis by JEFFREY MICHAEL BROWN Approved as to style and content by: Steven Smith (Chair of Committee) Thomas Ward (Member) Ernest Goetz (Member) Ste 'en rchel (Head of partment...

Brown, Jeffrey Michael



Human milk glycoconjugates that inhibit pathogens.  


Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants. PMID:9927761

Newburg, D S



Grape seed extracts inhibit platelet aggregation by inhibiting protein tyrosine phosphatase.  


Platelets play an important role in various thrombotic diseases, including myocardial infarction. Because red wine consumption is inversely associated with death due to ischemic heart diseases, the effects of grape components on platelet function have been extensively investigated. Grape seed extracts (GSEs) reportedly inhibit platelet aggregation; however, the underlying mechanism has not been elucidated. We discovered that GSEs inhibit platelet aggregation induced by collagen and thrombin-receptor agonist peptide and increase basal levels of tyrosine phosphorylation, which was also observed in the presence of a protein tyrosine phosphatase (PTP) inhibitor. An in vitro phosphatase assay indicated that GSE dose dependently inhibited PTP-1B and Src homology 2 domain-containing phosphatase-1 activity, which positively regulates platelet aggregation. We propose that GSEs inhibit platelet aggregation by inhibiting tyrosine phosphatase activity. Moreover, we showed that GSE ingestion inhibited platelet aggregation in mice without enhancing tail bleeding, implying that GSE supplementation might be beneficial to prevention of thrombotic diseases. PMID:23478570

Jin, Joseph Wuxun; Inoue, Osamu; Suzuki-Inoue, Katsue; Nishikawa, Go; Kawakami, Yoshinori; Hisamoto, Masashi; Okuda, Tohru; Ozaki, Yukio



Activin inhibits telomerase activity in cancer  

SciTech Connect

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

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



Lovastatin inhibits formation of AA amyloid.  


Amyloid A (AA) amyloidosis is a severe complication of many chronic inflammatory disorders, including the hereditary periodic fever syndromes. However, in one of these periodic fever syndromes, the hyper IgD and periodic fever syndrome, amyloidosis is rare despite vigorous, recurring inflammation. This hereditary syndrome is caused by mutations in the gene coding for mevalonate kinase, an enzyme of the isoprenoid pathway. In this study, we used a cell culture system with human monocytes to show that inhibition of the isoprenoid pathway inhibits amyloidogenesis. Inhibition of the isoprenoid pathway by lovastatin resulted in a dose-dependent reduction of amyloid formed [53% at 10 microM (P=0.01)] compared with mononuclear cells that are exposed only to serum AA. The inhibitory effects of lovastatin are reversible by addition of farnesol but not geranylgeraniol. Farnesyl transferase inhibition also inhibited amyloidogenesis. These results implicate that the isoprenoid metabolism could be a potential target for prevention and treatment of AA amyloidosis. PMID:18285405

van der Hilst, J C H; Kluve-Beckerman, B; Bodar, E J; van der Meer, J W M; Drenth, J P H; Simon, A



Ampligen inhibits human herpesvirus-6 in vitro.  


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

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



Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion.  


Ribavirin is a broad-spectrum antiviral drug that is used to treat hepatitis C virus (HCV)-infected patients. The virological response after ribavirin treatment appears to be insufficient to fully explain ribavirin-induced beneficial effects. Angiogenesis plays a pathogenic role in HCV-induced liver damage. Here, we investigated the influence of therapeutic ribavirin concentrations on angiogenesis. Ribavirin inhibited endothelial cell tube formation in vitro and vessel formation in the chick chorioallantoic membrane assay in vivo. Ribavirin inhibits inosine monophosphate dehydrogenase, which causes depletion of cellular GTP and in turn reduction of cellular tetrahydrobiopterin levels. The availability of tetrahydrobiopterin limits NO production by endothelial NO synthase. Ribavirin reduced levels of tetrahydrobiopterin (as revealed by HPLC), NO (as revealed by electron spin resonance spectroscopy), and cGMP (as revealed by RIA) in endothelial cells. Addition of tetrahydrobiopterin or NO prevented ribavirin-induced tube formation inhibition. In conclusion, angiogenesis inhibition by ribavirin has not been described before. This inhibition may contribute to ribavirin-induced pharmacological effects including adverse events. PMID:17135367

Michaelis, Martin; Michaelis, Ruth; Suhan, Tatyana; Schmidt, Helmut; Mohamed, Annisuddin; Doerr, Hans Wilhelm; Cinatl, Jindrich



Thrombin inhibition by cyclic peptides from thrombomodulin.  

PubMed Central

Peptides corresponding to the loop regions of the fourth, fifth, and sixth epidermal growth factor (EGF)-like domains of thrombomodulin (TM) have been synthesized and assayed for thrombin inhibition, as indicated by both inhibition of thrombin-mediated fibrinogen clotting and inhibition of the association of thrombin with TM that results in protein C activation. Peptides from the fifth EGF-like domain showed significant inhibition of fibrinogen clotting and protein C activation, whereas peptides from the fourth and sixth EGF-like domains were weak inhibitors in both assays. Two structural features were important for inhibitory potency of the peptides from the fifth EGF-like domain: cyclization by a disulfide bond and attachment of the "tail" amino acids C-terminal to the disulfide loop. Linear control peptides did not significantly inhibit clotting or protein C activation. The C-terminal loop alone, the "tail" peptide, or a mixture of the two were at least 10-fold less potent inhibitors of clotting or protein C activation. A more constrained peptide analog was designed by deletion of an isoleucine within the C5-C6 disulfide loop, TM52-1 + 5C. This analog was a better inhibitor in both assay systems, having a Ki for protein C activation of 26 microM. PMID:7613475

Lougheed, J. C.; Bowman, C. L.; Meininger, D. P.; Komives, E. A.



Inhibition of bacterial luminescence by cerulenin  

SciTech Connect

Bacterial luminescence is very sensitive to cerulenin, a fungal inhibitor of fatty acid (FA) synthesis. Cerulenin does not inhibit luciferase itself, but rather the synthesis of its aldehyde substrate by FA reductase. The acyl-CoA reductase (58 kDa) component of the Photobacterium phosphoreum FA reductase complex was inhibited by cerulenin in vitro. Similarly, acylation of the corresponding Vibrio harveyi 57 kDa protein with (/sup 3/H)myristic acid was preferentially decreased, while cerulenin had no effect on the activities of luciferase or the acyltransferase (32 kDa) responsible for FA supply to luminescence. Light emission of wild type V. harveyi was less sensitive to cerulenin at 10 (5-fold decrease at 1h) than that of the FA-stimulatable dark mutant M17 (100-fold inhibition), which lacks the 32 kDa acyltransferase. The V. harveyi reductase subunit was also labeled by (/sup 3/H)tetrahydrocerulenin in vivo in M17 but not wild type cells; this labeling could be prevented by preincubating M17 cells with cerulenin or FA. These results suggest that (a) cerulenin specifically and covalently inhibits the reductase component of aldehyde synthesis, and (b) this enzyme is partially protected from inhibition in vivo in the wild type cell.

Byers, D.M.; Wall, L.A.; Meighen, E.A.



Crayfish Tonic Inhibition: Prolonged Modulation of Behavioral Excitability by Classical GABAergic Inhibition  

Microsoft Academic Search

Previous studies have indirectly implicated the two neuro- transmitters 5-HT and GABA in mediating tonic inhibition of the crayfish lateral giant (LG) escape reaction. In this study, pharmacological agents were selectively delivered to re- stricted portions of the abdominal CNS (where LG escape circuitry resides) to assess directly the role of these two transmitters in tonic inhibition. Both 5-HT and

Eric T. Vu; Franklin B. Krasne



Inhibition in Language Switching: What Is Inhibited when Switching between Languages in Naming Tasks?  

ERIC Educational Resources Information Center

When people switch between languages, inhibition of currently irrelevant languages is assumed to occur. The authors examined inhibition of irrelevant languages with a cued language-switching paradigm. A cue indicated in which of 3 languages (German, English, or French) a visual stimulus was to be named. In 2 experiments, the authors found that…

Philipp, Andrea M.; Koch, Iring



The role of (dis)inhibition in creativity: decreased inhibition improves idea generation.  


There is now a large body of evidence showing that many different conditions related to impaired fronto-executive functioning are associated with the enhancement of some types of creativity. In this paper, we pursue the possibility that the central mechanism associated with this effect might be a reduced capacity to exert inhibition. We tested this hypothesis by exhausting the inhibition efficiency through prolonged and intensive practice of either the Simon or the Eriksen Flanker task. Performance on another inhibition task indicated that only the cognitive resources for inhibition of participants facing high inhibition demands were impaired. Subsequent creativity tests revealed that exposure to high inhibition demands led to enhanced fluency in a divergent thinking task (Alternate Uses Task), but no such changes occurred in a convergent task (Remote Associate Task; studies 1a and 1b). The same manipulation also led to a hyper-priming effect for weakly related primes in a Lexical Decision Task (Study 2). Together, these findings suggest that inhibition selectively affects some types of creative processes and that, when resources for inhibition are lacking, the frequency and the originality of ideas was facilitated. PMID:25460384

Radel, Rémi; Davranche, Karen; Fournier, Marion; Dietrich, Arne



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


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

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



Anticancer Alkaloid Lamellarins Inhibit Protein Kinases  

PubMed Central

Lamellarins, a family of hexacyclic pyrrole alkaloids originally isolated from marine invertebrates, display promising anti-tumor activity. They induce apoptotic cell death through multi-target mechanisms, including inhibition of topoisomerase I, interaction with DNA and direct effects on mitochondria. We here report that lamellarins inhibit several protein kinases relevant to cancer such as cyclin-dependent kinases, dual-specificity tyrosine phosphorylation activated kinase 1A, casein kinase 1, glycogen synthase kinase-3 and PIM-1. A good correlation is observed between the effects of lamellarins on protein kinases and their action on cell death, suggesting that inhibition of specific kinases may contribute to the cytotoxicity of lamellarins. Structure/activity relationship suggests several paths for the optimization of lamellarins as kinase inhibitors. PMID:19172192

Baunbæk, Dianne; Trinkler, Nolwenn; Ferandin, Yoan; Lozach, Olivier; Ploypradith, Poonsakdi; Rucirawat, Somsak; Ishibashi, Fumito; Iwao, Masatomo; Meijer, Laurent



Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation  

PubMed Central

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

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



Inhibition of melanogenesis by Xanthium strumarium L.  


Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3? (GSK3?) and ?-catenin. Hence, the influence of X. strumarium stem extract on GSK3? and ?-catenin was further investigated. X. strumarium induced GSK3? phosphorylation (inactivation), but the level of ?-catenin did not change. Moreover, a specific GSK3? inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3? phosphorylation. PMID:22484949

Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok



Mapuche herbal medicine inhibits blood platelet aggregation.  


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

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



Human pregnancy serum inhibits interleukin-2 production.  

PubMed Central

Cell-mediated immunity may be depressed during pregnancy. We used the two way mixed lymphocyte reaction as an in vitro model of cell mediated immunity and studied the effect of pregnancy sera on this system by the amount of tritiated thymidine taken up by activated lymphocytes. We found that: (1) pregnancy sera contain a factor inhibiting the mixed lymphocyte reaction; (2) the inhibition of the mixed lymphocyte reaction induced by sera could be reversed by the addition of the supernatant from allogeneic mixed lymphocyte reaction; (3) pure interleukin-1 could not reverse the inhibitory effect and (4) recombinant interleukin-2 (IL-2) completely reversed the inhibitory effect of pregnancy sera on the mixed lymphocyte reaction. We conclude that a factor (or factors) present in serum from pregnant women is capable of inhibiting the generation of IL-2 during lymphocyte activation. PMID:6239719

Nicholas, N S; Panayi, G S; Nouri, A M



The mechanism whereby growth hormone-release inhibiting hormone (somatostatin) inhibits food stimulated gastric acid secretion in the cat  

Microsoft Academic Search

Growth hormone-release inhibiting hormone (somatostatin) inhibits the gastric acid response to food in concious cats. We have confirmed that this tetradecapeptide blocks the food stimulated gastrin release. However, the inhibition of gastrin release is delayed relative to that of acid secretion, showing that the inhibition of food stimulated acid secretion is by a primary effect on the acid secretory mechanism.

M. Albinus; E. L. Blair; E. R. Grund; J. D. Reed; D. J. Sanders; A. Gomez-Pan; A. V. Schally; G. M. Besser



Inhibition of thyroid peroxidase by dietary flavonoids.  


Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities including antithyroid effects in experimental animals and humans. A structure-activity study of 13 commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of TPO, with IC50 values ranging from 0.6 to 41 microM. Inhibition by the more potent compounds, fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate substrate for iodination. The major product, 6,8-diiodo-biochanin A, was characterized by electrospray mass spectrometry and 1H-NMR. These inhibitory mechanisms for flavonoids are consistent with the antithyroid effects observed in experimental animals and, further, predict differences in hazards for antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of reversible binding inhibitors and alternate substrates would be temporary due to attenuation by metabolism and excretion. The central role of hormonal regulation in growth and proliferation of thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could play a role in the etiology of thyroid cancer. PMID:8924586

Divi, R L; Doerge, D R



The inhibition of monoamine oxidase by esomeprazole.  


Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered. PMID:23677700

Petzer, A; Pienaar, A; Petzer, J P



Experimental studies of inhibited counterflow flames  

NASA Astrophysics Data System (ADS)

An experimental and numerical study was performed to investigate the fundamental mechanisms of chemical inhibition. The first part of this work examined the structure of non-premixed counterflow methane-air flames. Gas samples were taken with a quartz microprobe and analyzed using a gas chromatograph with a thermal conductivity detector. Experimental and detailed numerical results were obtained for an uninhibited flame and flames inhibited by 1.5% CF3Br and 1.5% CF3I added to the oxidizer, all with a strain rate of 150s-1. The experimental data showed a slight shift toward the oxidizer duct above the flame, but showed excellent agreement with the numerical results below the flame in all cases. The inhibiting effect of CF3Br on a non-premixed diluted hydrogen-air flame was also investigated in the counterflowing configuration. Extinction results were obtained for 15%H2/85%N2 and 16%H 2/84%N2 in the fuel stream. The experimental results supported the theory that carbon chemistry does not play a significant role in inhibition by CF3Br. These results were compared with two different numerical models with different inhibition mechanisms. The effect of partially premixing a methane-air counterflow flame on the extinction strain rate was also examined. Premixing the oxidizer flow had a stabilizing effect, premixing the fuel flow had a weak inhibiting effect, and premixing in both flows had a very weak stabilizing effect that was basically the average of the two individual cases. These results were compared with detailed calculations, asymptotic and one-step analysis. The detailed numerical calculations had excellent agreement with the experiments but the asymptotic and one-step analysis predicted incorrect trends for all cases. Tests were also performed to examine the inhibiting effectiveness of alkali metal salts. Experiments were performed with NaHCO3 and KHCO3 with particle sizes of <30 microns and <20 microns, NaBr and KBr with a particle size of 5--25 microns, and silica (SiO 2) with a particle size of 1--3 microns. Inhibiting effectiveness increased as the particle sized decreased for all powders. The KHCO3 was approximately twice as effective as the NaHCO3, NaBr and KBr for similar particle sizes. These powders were approximately 10 times more efficient than silica and CF3Br on a mass basis.

Truett, Leonard Franklin, III


Inhibition of soybean urease by triketone oximes.  


Competitive inhibition of soybean urease by 15 triketone oximes has been studied at 36 degrees C in aqueous solution (pH 4.95). The studied oximes are supposed chelators for the nickel atom in the urease metallocenter. The inhibition constants of urea hydrolysis (K(i)) varied in the range 2.7-248 microM depending on the oxime structure. Analysis of this dependency demonstrates that the optimal inhibitor is the one containing carbonyl group in position 1 of the cycle, the ethoxyimino group and alkyl residue in the substituent in position 2, as well as the methoxycarbonyl group in position 4 of the cycle. PMID:15627389

Tarun, E I; Rubinov, D B; Metelitza, D I



PARP inhibitors: polypharmacology versus selective inhibition.  


Inhibition of ADP-ribosyltransferases with diphtheria toxin homology (ARTD), widely known as the poly(ADP-ribose) polymerase (PARP) family, is a strategy under development for treatment of various conditions, including cancers and ischemia. Here, we give a brief summary of ARTD enzyme functions and the implications for their potential as therapeutic targets. We present an overview of the PARP inhibitors that have been used in clinical trials. Finally, we summarize recent insights from structural biology, and discuss the molecular aspects of PARP inhibitors in terms of broad-range versus selective inhibition of ARTD family enzymes. PMID:23601167

Ekblad, Torun; Camaioni, Emidio; Schüler, Herwig; Macchiarulo, Antonio



[Further investigations on correlative bud inhibition].  


By paper chromatographic analysis with isopropanol-water-ammonia two fractions which inhibit growth and germination and two fractions which promote straight growth but have no effect on germination were isolated from ether extracts of green pea shoots. The four fractions have the following properties:Rf 0.35; acid; promotes Avena straight growth; has no effect on germination of Lepidium;Rf 0.6; acid; inhibits straight growth and germination;Rf 0.75; acid; behaves like fraction Rf 0.35 but is less active;Rf 0.85; neutral or alkaline; acts similarly to fraction Rf 0.6.The activity of the two inhibiting fractions Rf 0.6 and 0.85 in inhibiting Avena straight growth and Lepidium germination is not changed when a neutral solvent (isopropanol-water) is used instead of the alkaline solvent isopropanol-water-ammonia.There is no evidence for an alkaline germination-inhibiting substance with a Rf-value of 0.55, the so-called correlation inhibitor reported by LIBBERT and LIEBENOW (1964).The behavior of the four fractions was investigated especially in two different bud growth tests. 1. Lateral buds from decapitated pea seedlings are prevented from outgrowth by application of lanolin pastes containing the two straight growth and germination inhibitors. The fraction Rf 0.6 is more active in this test than the fraction Rf 0.85. The inhibition is partly cancelled by the simultaneous addition of gibberellic acid. The fractions Rf 0.35 and 0.75 are inactive in this test. 2. In a second bud growth test isolated nodes with a single bud were used. These test organs are placed horizontally with the buds upward into aqueous solutions containing the chromatographic fractions. Bud growth is inhibited by fraction Rf 0.35 and (to a lesser extent) by fraction Rf 0.75; the fractions Rf 0.6 and 0.85 are inactive. The different action of these growth regulators in the described bud growth tests and their possible role in correlative bud inhibition in vivo is discussed. PMID:24557985

Dörffling, K



Tehranolide inhibits cell proliferation via calmodulin inhibition, PDE, and PKA activation.  


Tehranolide, natural sesquiterpene lactone with an endoperoxide group, has been shown to inhibit cell growth in cancer cells. Tehranolide was purified from Artemisia diffusa. To detect cell viability and proliferation, MTT assay was performed. In order to determine the role of tehranolide on calmodulin (CaM) structure and activity, its effects were evaluated with fluorescence emission spectra and CaM-mediated activation of phosphodiesterase (PDE1), in comparison with artemisinin. In fact, PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were examined. The inhibitory effect of tehranolide on CaM structure is more than artemisinin. The kinetic analysis of tehranolide-CaM interaction has shown that this agent competitively inhibited the activation of PDE1 without affecting Vmax. Tehranolide increased Km value in higher amounts compared with artemisinin. Moreover, tehranolide had a cytotoxic effect on K562 cell line but not on normal human lymphocytes. Additionally, PDE inhibition and consequent cAMP accumulation and PKA activity were required for inhibiting cancer cell growth by tehranolide. Our results show that tehranolide significantly reduces cell proliferation in a time and dose-dependent manner in K562 cells via CaM inhibition, following PDE inhibition, cAMP accumulation, and consequent PKA activity. PMID:24222327

Noori, Shokoofe; Hassan, Zuhair M



Trifluoperazine inhibits insulin action on glucose metabolism in fat cells without affecting inhibition of lipolysis.  

PubMed Central

One of the specific inhibitors of calmodulin action, trifluoperazine, blocked the stimulating action of insulin on 2-deoxyglucose uptake and glucose metabolism. The inhibitory effect of insulin on lipolysis was not altered by the drug. The active (insulin-stimulated) state and the basal state of lipogenesis were inhibited half-maximally at 80 and 550 microM trifluoperazine, respectively. 2-Deoxyglucose uptake was inhibited half-maximally at a trifluoperazine concentration of 70 microM. Other less potent calmodulin inhibitors also inhibited glucose metabolism in fat cells but in a nonspecific manner. The inhibition was noncompetitive and was not altered in Ca2+- free medium. The stimulating activity of wheat germ agglutinin and of sodium vanadate were also inhibited by trifluoperazine. The dose-dependent inhibitions were indistinguishable whether the active (stimulated) state was produced by insulin, wheat germ agglutinin, or vanadate. The data indicate that a late event in the sequence that ultimately leads to enhanced glucose transport activity in fat cells is specifically inhibited by trifluoperazine. The possible involvement of calmodulin or another related Ca2+-dependent regulatory protein in the exocytic (fusion) reaction that recruits glucose-transport activity from storage sites to the plasma membranes is discussed. PMID:6582491

Shechter, Y



Sparse coding and lateral inhibition arising from balanced and unbalanced dendrodendritic excitation and inhibition.  


The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral-granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

Yu, Yuguo; Migliore, Michele; Hines, Michael L; Shepherd, Gordon M



Effects of acemannan on macrophages  

E-print Network

T cefl proliferation (73), and inhibits mast cell degranulation, neutrophil diapedesis and smooth muscle migration and/or proliferation (67). However, the biological action of nitric oxide is critically dependent on the flux of nitric oxide reaching...

Zhang, Linna



Cell Reports Presenilin Deficiency or Lysosomal Inhibition  

E-print Network

was found in cells deficient in presenilin, a protein associ- ated with Alzheimer's disease. The Wnt by presenilin deficiency. INTRODUCTION Canonical Wnt signaling is essential for embryonic development, stem cell#12;Cell Reports Article Presenilin Deficiency or Lysosomal Inhibition Enhances Wnt Signaling

De Robertis, Eddy M.


Is Inhibition of Return a Reflexive Effect?  

ERIC Educational Resources Information Center

The inhibition of return (IOR) phenomenon is routinely considered an effect of reflexive attention because the paradigm used to generate IOR employs peripheral cues that are uninformative as to where a target will appear. Because the cues are spatially unreliable it is thought that there is no reason for attention to be committed volitionally to…

Tipper, Christine; Kingstone, Alan



Inhibition of photosynthesis by heavy metals  

Microsoft Academic Search

Inhibition of photosynthesis by heavy metals is well documented. In this review the results are compared between in vitro experiments on isolated systems (chloroplasts, enzymes ­.), experiments on excised leaves and intact plants and algae in vivo. In vitro experiments suggest potential sites of heavy metal interaction with photosynthesis at several levels of organisation, which are not necessarily confirmed in

H. Clijsters; F. Assche



Kinetics of ethanol inhibition in alcohol fermentation  

Microsoft Academic Search

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

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



Dexamethasone Inhibits Interleukin-1?-Induced Corneal Neovascularization  

PubMed Central

Dexamethasone, a synthetic corticosteroid, is widely used as a potent anti-inflammatory drug in various diseases including corneal angiogenesis. However, dexamethasone’s impact on interleukin (IL)-1?-dependent inflammatory angiogenesis is unknown. Here, we show that dexamethasone inhibits IL-1?-induced neovascularization and the expression of the angiogenesis-related factors, vascular endothelial growth factor-A, KC, and prostaglandin E2 in the mouse cornea 2 days after IL-1? implantation. IL-1? caused I?B-? phosphorylation in corneal stromal cells but not in infiltrated CD11b+ cells 2 days after IL-1? implantation. In contrast, both cell types were positive for phosphorylated I?B-? 4 days after IL-1? implantation. Dexamethasone significantly inhibited I?B-? phosphorylation 2 and 4 days after IL-1? implantation. Furthermore, dexamethasone inhibited IL-1?-induced expression of vascular endothelial growth factor-A, KC, and prostaglandin E2, and signaling of nuclear factor (NF)-?B in corneal fibroblasts in vitro. A selective NF-?B inhibitor attenuated IL-1?-induced corneal angiogenesis. These findings suggest that NF-?B activation in the corneal stromal cells is an important early event during IL-1?-induced corneal angiogenesis and that dexamethasone inhibits IL-1?-induced angiogenesis partially via blocking NF-?B signaling. PMID:17690185

Nakao, Shintaro; Hata, Yasuaki; Miura, Muneki; Noda, Kousuke; Kimura, Yusuke N.; Kawahara, Shuhei; Kita, Takeshi; Hisatomi, Toshio; Nakazawa, Toru; Jin, Yiping; Dana, M. Reza; Kuwano, Michihiko; Ono, Mayumi; Ishibashi, Tatsuro; Hafezi-Moghadam, Ali



How Does Interferon Inhibit Tumour Growth?: Discussion  

Microsoft Academic Search

Interferon can inhibit tumour growth in experimental animals and in some patients with benign and malignant tumours. There is experimental evidence to suggest that several mechanisms may be involved: a direct effect on the tumour or an indirect effect via the host, or both. Thus, interferon may slow the rate of tumour cell multiplication and this may lead to cell

Michael Stoker



Inhibition of amyloid-? aggregation in Alzheimer's disease.  


The assembly of naturally occurring amyloid peptides into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in over 25 human diseases. Blocking of or interfering with the aggregation of amyloid peptides such as amyloid-? (A?) using small organic molecules, peptides and peptidomimetics, and nanoparticles that selectively bind or inhibit A? aggregates is a promising strategy for the development of novel pharmaceutical approaches and agents to treat Alzheimer's disease (AD). In a broad sense, considering many common features in structure, kinetics, and biological activity of amyloid peptides, potent inhibitors and associated inhibition strategies that are developed for targeting A? aggregation could also be generally applied to other amyloid-forming peptides in "protein-aggregation diseases". Due to the complex nature of A? self-assembly process, increasing knowledge in high-resolution structures of A? oligomers, atomic-level A?-inhibitor binding information, and cost-effective high-throughput screening method will improve our fundamental understanding of amyloid formation and inhibition mechanisms, as well as practical design of pharmaceutical strategies and drugs to treat AD. This review summarizes major findings, recent advances, and future challenges for the development of new A?-aggregation inhibitors, mainly focusing on three major classes of A? inhibitors with associated inhibition mechanisms and practical. examples. PMID:23713775

Wang, Qiuming; Yu, Xiang; Li, Lingyan; Zheng, Jie



Psychiatric drugs and inhibited female orgasm  

Microsoft Academic Search

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.

R. T. Segraves



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...


Behavioral Inhibition in Children with Learning Disabilities  

ERIC Educational Resources Information Center

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…

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



Target Predictability, Sustained Attention, and Response Inhibition  

ERIC Educational Resources Information Center

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…

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



Search Asymmetry, Sustained Attention, and Response Inhibition  

ERIC Educational Resources Information Center

In the present experiment, we used search asymmetry to test whether the sustained attention to response task is a better measure of response inhibition or sustained attention. Participants performed feature present and feature absent target detection tasks using either a sustained attention to response task (SART; high Go low No-Go) or a…

Stevenson, Hugh; Russell, Paul N.; Helton, William S.



Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis  

SciTech Connect

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.

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: [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)



Notch Receptor Activation Inhibits Oligodendrocyte Differentiation  

Microsoft Academic Search

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

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



Plant pathology Growth inhibition of Agaricus bisporus  

E-print Network

Plant pathology Growth inhibition of Agaricus bisporus and associated thermophilic species limited the radial growth of A bisporus mycelium. The IC50 values of benomyl, carbendazim, flusilazol fortement li- mitée que par le tébuconazole. Les valeurs de CI50 du bénomyl, du carbendazime, du flusilazole

Paris-Sud XI, Université de


Neprilysin inhibition in chronic kidney disease.  


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

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



Nitric oxide synthases: structure, function and inhibition  

Microsoft Academic Search

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.

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



Inhibition of denitrification by ultraviolet radiation  

NASA Astrophysics Data System (ADS)

It has been shown that UV-A (? = 320- 400 nm) and UV-B (? = 280 - 320 nm) inhibit photosynthesis, nitrogen fixation and nitrification. The purpose of this study was to determine the effects, if any, on denitrification in a microbial community inhabiting the intertidal. The community studied is the microbial mat consisting primarily of Lyngbya that inhabits the Pacific marine intertidal, Baja California, Mexico. Rates of denitrification were determined using the acetylene blockage technique. Pseudomonas fluorescens (ATCC # 17400) was used as a control organism, and treated similarly to the mat samples. Samples were incubated either beneath a PAR transparent, UV opaque screen (OP3), or a mylar screen to block UV-B, or a UV transparent screen (UVT) for 2 to 3 hours. Sets of samples were also treated with nitrapyrin to inhibit nitrification, or DCMU to inhibit photosynthesis and treated similarly. Denitrification rates were greater in the UV protected samples than in the UV exposed samples the mat samples as well as for the Ps. fluorescens cultures. Killed controls exhibited no activity. In the DCMU and nitrapyrin treated samples denitrification rates were the same as in the untreated samples. These data indicate that denitrification is directly inhibited by UV radiation.

Mancinelli, R. L.; White, M. R.


Nitrite inhibition of denitrification by Pseudomonas fluorescens  

SciTech Connect

Using a pure culture of Pseudomonas fluorescens as a model system nitrite inhibition of denitrification was studied. A mineral media with acetate and nitrate as sole electron donor and acceptor, respectively, was used. Results obtained in continuous stirred-tank reactors (CSTR) operated at pH values between 6.6 and 7.8 showed that growth inhibition depended only on the nitrite undissociated fraction concentration (nitrous acid). A mathematical model to describe this dependence is put forward. The maximum nitrous acid concentration compatible with cell growth and denitrification activity was found to be 66 {mu}g N/L. Denitrification activity was partially associated with growth, as described by the Luedeking-Piret equation. However, when the freshly inoculated reactor was operated discontinuously, nitrite accumulation caused growth uncoupling from denitrification activity. The authors suggest that these results can be interpreted considering that (a) nitrous acid acts as a proton uncoupler; and (b) cultures continuously exposed to nitrous acid prevent the uncoupling effect but not the growth inhibition. Examination of the growth dependence on nitrite concentration at pH 7.0 showed that adapted cultures (growth on CSTR) are less sensitive to nitrous acid inhibition than the ones cultivated in batch.

Almeida, J.S.; Julio, S.M.; Reis, M.A.M. [FCT/UNL, Monte da Caparica (Portugal); Carrondo, M.J.T. [FCT/UNL, Monte da Caparica (Portugal)]|[Inst. de Biologia Experimental e Tecnologica, Oeiras (Portugal)



Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis  

E-print Network

Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis Zsolt Tallo´czy1 Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly specific evidence that Meth at pharmacological concentrations exerts a direct immunosuppressive effect

Sulzer, David


Inhibition of erythrocyte calcium transport by cetiedil.  


The elevated calcium content found in red cells from patients with sickle cell anemia may be of pathophysiologic importance in the hemolysis and vasoocclusion which characterize this disorder. Cetiedil, an antisickling agent, has been reported to inhibit the activity of enzymes that are stimulated by the calcium regulatory protein calmodulin. To investigate the mechanism by which cetiedil modifies calcium-mediated erythrocyte function, the effect of the drug on the active transport of calcium into inside-out erythrocyte vesicles was examined and its influence on the activities of phosphodiesterase and Ca-ATPase studied. Cetiedil, in the presence of calmodulin, significantly inhibited calcium transport into inside-out vesicles that were prepared with erythrocytes from normal controls and from patients with sickle cell anemia. However, in the absence of calmodulin, no inhibition was observed. Likewise, cetiedil inhibited calmodulin-stimulated, but not basal, activities of phosphodiesterase and Ca-ATPase. These data, along with previous reports, suggest that cetiedil does not act by lowering the intracellular calcium content. It is, therefore, likely that the beneficial effect of cetiedil is due to its ability to protect the red cell from the deleterious consequences of an elevated concentration of intracellular calcium. PMID:2829242

Levine, S N; Berkowitz, L R; Orringer, E P




Technology Transfer Automated Retrieval System (TEKTRAN)

The capacity for 1-methylcyclopropene (MCP) to inhibit color change and firmness loss for tomato fruit was evaluated as a function of MCP concentration, multiple and continuous applications, and stage of ripeness. In addition, the relationship between external fruit color and itnernal color, aroma,...


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...


Role of RANKL inhibition in osteoporosis  

Microsoft Academic Search

When the rate of bone resorption exceeds that of bone formation, destruction of bone tissue occurs, resulting in a fragile skeleton. The clinical consequences, namely osteoporosis and fragility fractures, are common and costly problems. Treatments that normalize the balance of bone turnover by inhibiting bone resorption preserve bone mass and reduce fracture risk. The discovery of receptor activator of nuclear

Michael McClung



Motivational Influences on Response Inhibition Measures  

ERIC Educational Resources Information Center

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…

Leotti, Lauren A.; Wager, Tor D.




EPA Science Inventory

Rats with electrodes chronically implanted in the perforant path for electrical stimulation, and dentate gyrus for recording were treated with a single oral administration of either saline, 5 mg/kg trimethyltin (TMT) or 6 mg/kg TMT. Recurrent inhibition was assessed by paired pul...


Optical Interference Coatings for Inhibiting of Counterfeiting  

Microsoft Academic Search

Counterfeiting of valuable papers and identification documents made of paper or plastics, such as banknotes, credit cards, passports, etc., is presently inhibited through the use of inks of many colours, intricate engraved designs on special papers which sometimes contain watermarks or embedded coloured paper platelets or metal threads. These methods have not always offered adequate protection. It is proposed to

J. A. Dobrowolski; K. M. Baird; P. D. Carman; A. Waldorf



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...


Inhibited interferon production after space flight  

NASA Technical Reports Server (NTRS)

Several studies have been performed in our laboratories indicating that interferon production may be impaired in rodents after space flight. Using an antiorthostatic suspension model that simulates some of the effects of microgravity seen during space flight, we have shown that interferon-alpha/beta production was inhibited. The inhibition was not due solely to the stress of suspension. The inhibited interferon production was transient, as suspended animals returned to normal caging recovered the ability to produce interferon. Antiorthostatic suspension of mice also resulted in a loss of resistance to infection with the diabetogenic strain of encephalomyocarditis virus, which correlated with the drop in interferon production. In rats flown in US Space Shuttle mission SL-3, interferon-gamma production was inhibited severely when spleen cells were challenged with concanavalin-A upon return to earth. In contrast, interleukin-3 production by these cells was normal. These results suggest that immune responses may be altered after antiorthostatic modeling or space flight, and the resistance to viral infections may be especially affected.

Sonnenfeld, G.; Gould, C. L.; Williams, J.; Mandel, A. D.



Serum amyloid P inhibits dermal wound healing  

Technology Transfer Automated Retrieval System (TEKTRAN)

The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...


Reduced response readiness delays stop signal inhibition  

E-print Network

on go trials and response inhibition on nogo trials. An occasional cue informed subjects that a nogo and the upcoming nogo trial. This setup was meant to create test episodes of reduced response readi- ness (i.e., trial sequences initiated by the cue and terminated by the nogo signal) and control episodes, in which

Logan, Gordon D.


Temporal Preparation, Response Inhibition and Impulsivity  

ERIC Educational Resources Information Center

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…

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



Inhibition of planarian regeneration by melatonin  

Microsoft Academic Search

Melatonin, which is a substance produced by the pineal body in vertebrates, inhibited regeneration in the planarian Dugesia japonica japonica Ichikawa et Kawakatsu. When decapitated planarians were maintained in a 1 mmol dm-3 solution of melatonin, formation of the head was retarded; formation of the eyes, however, was not disturbed. Similarly in animals from which the tail was cut, regeneration

Yasuhiro Yoshizawa; Katsumi Wakabayashi; Takao Shinozawa



Inhibiting Adaptation 1 Kathleen M. Carley  

E-print Network

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

Sadeh, Norman M.


Inhibited ethylene glycol as the solar nexus  

Microsoft Academic Search

Well-inhibited ethylene glycol base fluids (ethylene glycol with anti-corrosion additives) are considered quite capable of protecting flat plate solar collector systems from corrosion. Current formulations are designed for multimetal systems, but as solar systems become more standardized, it is possible that the mix of inhibitor additives can be optimized for a given combination of metals. Factors accelerating corrosion in a

E. Beynon



The Mechanism Underlying Inhibition of Saccadic Return  

ERIC Educational Resources Information Center

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…

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



MFR PAPER 1339 Phosphonoacetic Acid Inhibition of  

E-print Network

of DNA viruses. Mem- bers of this diverse family of viruses are found throughout the phylogeny phosphonoace- tic acid (PAA), functions specifically by inhibiting the herpesvirus coded DNA dependent DNA by trypan blue dye exclu- sion at the beginning and end (72 hours postinoculation) of each experiment in


Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption.  


The present experiments were carried out to test the hypothesis that artery calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with the bisphosphonates alendronate and ibandronate will inhibit artery calcification. Artery calcification was first induced by treatment of 42-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and has been shown to cause extensive calcification of the artery media within 2 weeks. These experiments revealed that ibandronate (0.05 mg. kg(-1). d(-1)) and alendronate (0.1 mg x kg(-1) x d(-1)) completely inhibited calcification of all arteries and heart valves examined after 2 and 4 weeks of warfarin treatment. A 10-fold lower dose of alendronate reduced artery calcification by 50% (P<0.005). These bisphosphonate doses are comparable to those that inhibit bone resorption in rats of this age. More rapid artery calcification was induced by treatment with warfarin together with high doses of vitamin D, a procedure that causes extensive artery calcification by 84 hours. Alendronate and ibandronate again completely inhibited calcification of all arteries and heart valves examined. The subcutaneous doses of alendronate and ibandronate necessary to inhibit artery calcification are comparable to the daily subcutaneous doses of these drugs that have previously been shown to inhibit bone resorption in rats of the same age, with 50% inhibition of artery calcification at 20 microg alendronate x kg(-1) x d(-1) and at 1 microg ibandronate x kg(-1) x d(-1) x Bisphosphonate treatment did not affect serum calcium and phosphate, and so the inhibition of artery calcification cannot be due to a simple lowering of the serum calcium phosphate ion product. We conclude that bisphosphonates inhibit the calcification of arteries and heart valves at doses comparable to the doses that inhibit bone resorption. These results support the hypothesis that artery calcification is linked to bone resorption. The mechanism of this linkage remains to be established, however, and an alternative explanation for the present results is also considered. PMID:11348880

Price, P A; Faus, S A; Williamson, M K



Collaborative inhibition in spatial memory retrieval.  


Collaborative inhibition refers to the finding that pairs of people working together to retrieve information from memory-a collaborative group-often retrieve fewer unique items than do nominal pairs, who retrieve individually but whose performance is pooled. Two experiments were designed to explore whether collaborative inhibition, which has heretofore been studied using traditional memory stimuli such as word lists, also characterizes spatial memory retrieval. In the present study, participants learned a layout of objects and then reconstructed the layout from memory, either individually or in pairs. The layouts created by collaborative pairs were more accurate than those created by individuals, but less accurate than those of nominal pairs, providing evidence for collaborative inhibition in spatial memory retrieval. Collaborative inhibition occurred when participants were allowed to dictate the order of object placement during reconstruction (Exp. 1), and also when object order was imposed by the experimenter (Exp. 2), which was intended to disrupt the retrieval processes of pairs as well as of individuals. Individual tests of perspective taking indicated that the underlying representations of pair members were no different than those of individuals; in all cases, spatial memories were organized around a reference frame aligned with the studied perspective. These results suggest that inhibition is caused by the product of group recall (i.e., seeing a partner's object placement), not by the process of group recall (i.e., taking turns choosing an object to place). The present study has implications for how group performance on a collaborative spatial memory task may be optimized. PMID:24622929

Sjolund, Lori A; Erdman, Matthew; Kelly, Jonathan W



Reversible inhibition of Chlamydomonas flagellar surface motility  

PubMed Central

Chlamydomonas exhibits force transduction in association with its flagellar surface; this can be visualized by the saltatory movements of attached polystyrene microspheres. This flagellar surface motility has been quantitated by determining the percentage of attached microspheres in motion at the time of observation (60% in the case of control cells at 25 degrees C). A number of experimental treatments reversibly inhibit flagellar surface motility. These include an increase in sodium or potassium chloride concentration, a decrease in temperature, or a decrease in the free calcium concentration in the medium. Many of the conditions that result in inhibition of flagellar surface motility also result in an induction of flagellar resorption. Although both flagellar stability and flagellar surface motility are dependent on the availability of calcium, the two processes are separable; under appropriate conditions, flagellar surface motility can occur at normal levels on flagella that are resorbing. Inhibition of protein synthesis results in a gradual loss of both the binding of microspheres to the flagellum and the flagellar surface motility. After resumption of protein synthesis, both binding and movement return to control levels. The effect of the inhibition of protein synthesis is interpreted in terms of selective turnover of certain components within the intact flagellum, one or more of these components being necessary for the binding of the microspheres and their subsequent movement. If this turnover is inhibited by keeping the cells below 5 degrees C, the absence of protein synthesis no longer has an effect on microsphere attachment and motility, when measured immediately after warming the cells to 25 degrees C. PMID:117013



Gastric and salivary mucins inhibit angiotensin-converting enzyme. Inhibition is partly due to oligosaccharides.  

PubMed Central

Pig gastric mucin, a highly glycosylated glycoprotein, inhibits angiotensin-converting enzyme (ACE) with an IC50 of 2 mM-neutral hexose content. Pig submaxillary mucin at 2.3 mM inhibits by 73%. To determine whether the oligosaccharide moieties of the mucins contribute to this inhibition, oligosaccharides were prepared from each mucin by reductive beta-elimination and their effects on enzyme activity determined. Total oligosaccharides from gastric mucin inhibited enzyme activity with an IC50 of 0.3 mM based on the neutral hexose content of the oligosaccharide solution. Fractions isolated from gastric mucin by chromatography on DEAE-cellulose and Bio-Gel P-2 inhibited ACE with IC50 values ranging from 2 to 16 mM-oligosaccharide. Larger oligosaccharides inhibited with lower IC50 values than did smaller oligosaccharides. Fractions of average molecular mass 1100 and 740 Da prepared from submaxillary mucin inhibited with IC50 values of 40 and 80 mM-oligosaccharide respectively. Monosaccharides commonly present in serum and membrane glycoproteins were also tested for their effect on ACE. Galactose, N-acetylglucosamine, N-acetylgalactosamine and glucosamine were inhibitory. N-Acetylneuraminic acid stimulated the activity of ACE. Fucose, ethylene glycol and sucrose had no effect on the activity of the enzyme. The influences of different buffers, ion concentrations, pH and substrate structure on the effect of carbohydrate on enzyme activity were also evaluated. The extent of inhibition by the monosaccharide galactose was strongly influenced by buffer ion and substrate concentration. The effects of the oligosaccharide moieties and intact mucins were less sensitive to assay conditions. Images Fig. 2. PMID:1530575

Schönherr, E; Jones, G A; Slakey, L L



Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition.  

PubMed Central

1. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2. With a half-maximal inhibitory concentration of 5 microM, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3. Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 microM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4. Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N-acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5. DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6. The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan. PMID:3207996

Lenzen, S.; Brand, F. H.; Panten, U.



Amiloride inhibits the initiation of Coxsackievirus and poliovirus RNA replication by inhibiting VPg uridylylation.  


The mechanism of amiloride inhibition of Coxsackievirus B3 (CVB3) and poliovirus type 1 (PV1) RNA replication was investigated using membrane-associated RNA replication complexes. Amiloride was shown to inhibit viral RNA replication and VPgpUpU synthesis. However, the drug had no effect on polymerase elongation activity during either (-) strand or (+) strand synthesis. These findings indicated that amiloride inhibited the initiation of RNA synthesis by inhibiting VPg uridylylation. In addition, in silico binding studies showed that amiloride docks in the VPg binding site on the back of the viral RNA polymerase, 3D(pol). Since VPg binding at this site on PV1 3D(pol) was previously shown to be required for VPg uridylylation, our results suggest that amiloride inhibits VPg binding to 3D(pol). In summary, our findings are consistent with a model in which amiloride inhibits VPgpUpU synthesis and viral RNA replication by competing with VPg for binding to 3D(pol). PMID:25058507

Ogram, Sushma A; Boone, Christopher D; McKenna, Robert; Flanegan, James B



Inhibition studies of carbamoyl phosphate synthetase from Escherichia coli  

E-print Network

of these compounds. These plots were also utilized in identifying the linear inhibitors, nonlinear inhibitors and partial inhibitors. Inhibition patterns were obtained with these compounds using various assay formats. Partial inhibition displayed by phosphono formate...

Tripathi, Neha



Allosteric inhibition of the neuropeptidase neurolysin.  


Neuropeptidases specialize in the hydrolysis of the small bioactive peptides that play a variety of signaling roles in the nervous and endocrine systems. One neuropeptidase, neurolysin, helps control the levels of the dopaminergic circuit modulator neurotensin and is a member of a fold group that includes the antihypertensive target angiotensin converting enzyme. We report the discovery of a potent inhibitor that, unexpectedly, binds away from the enzyme catalytic site. The location of the bound inhibitor suggests it disrupts activity by preventing a hinge-like motion associated with substrate binding and catalysis. In support of this model, the inhibition kinetics are mixed, with both noncompetitive and competitive components, and fluorescence polarization shows directly that the inhibitor reverses a substrate-associated conformational change. This new type of inhibition may have widespread utility in targeting neuropeptidases. PMID:25378390

Hines, Christina S; Ray, Kallol; Schmidt, Jack J; Xiong, Fei; Feenstra, Rolf W; Pras-Raves, Mia; de Moes, Jan Peter; Lange, Jos H M; Melikishvili, Manana; Fried, Michael G; Mortenson, Paul; Charlton, Michael; Patel, Yogendra; Courtney, Stephen M; Kruse, Chris G; Rodgers, David W



Preventing MIC through microbial adhesion inhibition  

SciTech Connect

The key to the alteration of conditions at a metal surface before the initiation of microbially induced corrosion (MIC) is the formation of a biofilm. Thus, prevention of bacterial adhesion processes on metal surfaces would be one of the potential weapons to avoid MIC. Serum globulin and by-products were used to prevent bacterial adhesion on different corrosion resistant metal surfaces generally used as implantable biomaterials. In this paper an immunoglobulin combination (IgA, IgG and IgM) has been used to prevent the formation of Pseudomonas fluorescens (P.fluorescens) biofilms on carbon steel and two different types of stainless steel (SS). A marked inhibition of bacterial adhesion was found under different experimental conditions. Several microscopic techniques were used for assessing adhesion inhibition while the electrochemical behavior of the steels was evaluated by means of different electrochemical techniques applied in the presence and in the absence of the immunoglobulins.

Videla, H.A. [Univ. of La Plata (Argentina). Dept. of Chemistry; Guiamet, P.S.; Gomez de Saravia, S.G. [INIFTA, La Plata (Argentina). Bioelectrochemistry Section



Behavioral inhibition in children with learning disabilities.  


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 significantly more commission errors on alphanumeric (letter and digit) modalities compared to the non-alphanumeric picture modality. As compared to children without MD, children with MD made as much commission errors on the picture modality as on the letter modality. No significant interaction-effect was found between RD and MD. These results can be considered as evidence for behavioral inhibition deficits related to alphanumeric stimuli in children with RD but not in children with MD. PMID:23584180

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



Dietary linoleic acid, immune inhibition and disease  

PubMed Central

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

Sammon, A.



Emotional inhibition: a discourse analysis of disclosure.  


Evidence generated within the emotional disclosure paradigm (EDP) suggests that talking or writing about emotional experiences produces health benefits, but recent meta-analyses have questioned its efficacy. Studies within the EDP typically rely upon a unidimensional and relatively unsophisticated notion of emotional inhibition, and tend to use quantitative forms of content analysis to identify associations between percentages of word types and positive or negative health outcomes. In this article, we use a case study to show how a qualitative discourse analysis has the potential to identify more of the complexity linking the disclosure practices and styles that may be associated with emotional inhibition. This may illuminate the apparent lack of evidence for efficacy of the EDP by enabling more comprehensive theorisations of the variations within it. PMID:21678182

Ellis, Darren; Cromby, John



Delayed fluorescence in algal growth inhibition tests  

Microsoft Academic Search

A series of 72-hour growth inhibition tests with green alga Desmodesmus (Scenedesmus) subspicatus (ISO 8692) has been performed to test the delayed fluorescence (DF) parameters as possible endpoint measurements. Sensitivity\\u000a to five toxicants with direct and indirect effects on photosynthesis was tested, and the median effective concentration (EC50) values derived from the cell concentration, absorbance and DF were compared. The

Maja Berden-Zrimec; Luka Drinovec; Alexis Zrimec; Tatjana Tišler



Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis  

PubMed Central

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

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



Fermented broth in tyrosinase- and melanogenesis inhibition.  


Fermented broth has a long history of applications in the food, pharmaceutical and cosmetic industries. Recently, the use of fermented broth in skin care products is in ascendance. This review investigates the efficacy of fermented broth in inhibiting tyrosinase and melanogenesis. Possible active ingredients and hypopigmentation mechanisms of fermented broth are discussed, and potential applications of fermented broth in the cosmetic industry are also addressed. PMID:25255749

Chan, Chin-Feng; Huang, Ching-Cheng; Lee, Ming-Yuan; Lin, Yung-Sheng



Inhibition of photosynthetic reactions by light  

Microsoft Academic Search

Illumination of isolated intact chloroplasts of Spinacia oleracea L. for 10 min with 850 W m-2 red light in the absence of substrate levels of bicarbonate caused severe inhibition of subsequently measured photosynthetic activities. The capacity of CO2-dependent O2 evolution and of non-cyclic electron transport were impaired to similar degrees. This photoinactivation was prevented by addition of bicarbonate which allowed

Beate Barényi; G. H. Krause



Caffeine Inhibits Acetylcholinesterase, But Not Butyrylcholinesterase  

PubMed Central

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

Pohanka, Miroslav; Dobes, Petr



When inhibition not excitation synchronizes neural firing  

Microsoft Academic Search

Excitatory and inhibitory synaptic coupling can have counter-intuitive effects on the synchronization of neuronal firing. While it might appear that excitatory coupling would lead to synchronization, we show that frequently inhibition rather than excitation synchronizes firing. We study two identical neurons described by integrate-and-fire models, general phase-coupled models or the Hodgkin-Huxley model with mutual, non-instantaneous excitatory or inhibitory synapses between

CARL VAN VREESWIJK; L. F. Abbott; G. Bard Ermentrout



Wnt modulating agents inhibit human cytomegalovirus replication.  


Infection with human cytomegalovirus (HCMV) continues to be a threat for pregnant women and immunocompromised hosts. Although limited anti-HCMV therapies are available, development of new agents is desired. The Wnt signaling pathway plays a critical role in embryonic and cancer stem cell development and is targeted by gammaherpesviruses, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). HCMV infects stem cells, including neural progenitor cells, during embryogenesis. To investigate the role of Wnt in HCMV replication in vitro, we tested monensin, nigericin, and salinomycin, compounds that inhibit cancer stem cell growth by modulating the Wnt pathway. These compounds inhibited the replication of HCMV Towne and a clinical isolate. Inhibition occurred prior to DNA replication but persisted throughout the full replication cycle. There was a significant decrease in expression of IE2, UL44, and pp65 proteins. HCMV infection resulted in a significant and sustained decrease in expression of phosphorylated and total lipoprotein receptor-related protein 6 (pLRP6 and LRP6, respectively), Wnt 5a/b, and ?-catenin and a modest decrease in Dvl2/3, while levels of the negative regulator axin 1 were increased. Nigericin decreased the expression of pLRP6, LRP6, axin 1, and Wnt 5a/b in noninfected and HCMV-infected cells. For all three compounds, a correlation was found between expression levels of Wnt 5a/b and axin 1 and HCMV inhibition. The decrease in Wnt 5a/b and axin 1 expression was more significant in HCMV-infected cells than noninfected cells. These data illustrate the complex effects of HCMV on the Wnt pathway and the fine balance between Wnt and HCMV, resulting in abrogation of HCMV replication. Additional studies are required to elucidate how HCMV targets Wnt for its benefit. PMID:23571549

Kapoor, Arun; He, Ran; Venkatadri, Rajkumar; Forman, Michael; Arav-Boger, Ravit



Peroxynitrite inhibits glutathione S-conjugate transport.  


Peroxynitrite was demonstrated to inhibit the active efflux of glutathione S-conjugates (2,4-dinitrophenyl-S-glutathione and bimane-S-glutathione) from human erythrocytes and the erythrocyte membrane ATPase activity stimulated by glutathione S-conjugates. As the multidrug resistance-associated protein (MRP) is responsible for the transport of glutathione S-conjugates in mammalian cells, these results point to the possibility of the effect of peroxynitrite on the MRP function. PMID:9106491

Soszy?ski, M; Bartosz, G



Immunoregulatory functions of mTOR inhibition  

Microsoft Academic Search

The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine\\/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and

H?th R. Turnquist; Giorgio Raimondi; Angus W. Thomson



Arthropod venom citrate inhibits phospholipase A 2  

Microsoft Academic Search

Citrate has been identified as a major component of honey bee (Apis mellifera) venom by gas liquid chromatography-mass spectrometry. A citrate concentration of 9% was found for dried bee venom by a coupled enzyme assay, aconitase-isocitric dehydrogenase. A liquid honey bee venom would contain 140 mM citrate concentration (if the solids content were 30%). Bee venom phospholipase was inhibited at

Aron W. Fenton; Paul R. West; George V. Odell; Sueann M. Hudiburg; Charlotte L. Ownby; John N. Mills; Bradley T. Scroggins; Scott B. Shannon



Chondroitin sulphate inhibits connective tissue mast cells  

PubMed Central

Mast cells derive from the bone marrow and are responsible for the development of allergic and possibly inflammatory reactions. Mast cells are stimulated by immunoglobulin E (IgE) and specific antigen, but also by a number of neuropeptides such as neurotensin (NT), somatostatin or substance P (SP), to secrete numerous pro-inflammatory molecules that include histamine, cytokines and proteolytic enzymes.Chondroitin sulphate, a major constituent of connective tissues and of mast cell secretory granules, had a dose-dependent inhibitory effect on rat peritoneal mast cell release of histamine induced by the mast cell secretagogue compound 48/80 (48/80). This inhibition was stronger than that of the clinically available mast cell ‘stabilizer' disodium cromoglycate (cromolyn). Inhibition by chondroitin sulphate increased with the length of preincubation and persisted after the drug was washed off, while the effect of cromolyn was limited by rapid tachyphylaxis.Immunologic stimulation of histamine secretion from rat connective tissue mast cells (CTMC) was also inhibited, but this effect was weaker in umbilical cord-derived human mast cells and was absent in rat basophilic leukemia (RBL) cells which are considered homologous to mucosal mast cells (MMC). Oligo- and monosaccharides were not as effective as the polysaccharides.Inhibition, documented by light and electron microscopy, involved a decrease of intracellular calcium ion levels shown by confocal microscopy and image analysis. Autoradiography at the ultrastructural level showed that chondroitin sulphate was mostly associated with plasma and perigranular membranes.Chondroitin sulphate appears to be a potent mast cell inhibitor of allergic and nonimmune stimulation with potential clinical implications. PMID:11082109

Theoharides, T C; Patra, P; Boucher, W; Letourneau, R; Kempuraj, D; Chiang, G; Jeudy, S; Hesse, Leah; Athanasiou, A



Role of inhibition in respiratory pattern generation.  


Postsynaptic inhibition is a key element of neural circuits underlying behavior, with 20-50% of all mammalian (nongranule) neurons considered inhibitory. For rhythmic movements in mammals, e.g., walking, swimming, suckling, chewing, and breathing, inhibition is often hypothesized to play an essential rhythmogenic role. Here we study the role of fast synaptic inhibitory neurotransmission in the generation of breathing pattern by blocking GABA(A) and glycine receptors in the preBötzinger complex (preBötC), a site essential for generation of normal breathing pattern, and in the neighboring Bötzinger complex (BötC). The breathing rhythm continued following this blockade, but the lung inflation-induced Breuer-Hering inspiratory inhibitory reflex was suppressed. The antagonists were efficacious, as this blockade abolished the profound effects of the exogenously applied GABA(A) receptor agonist muscimol or glycine, either of which under control conditions stopped breathing in vagus-intact or vagotomized, anesthetized, spontaneously breathing adult rats. In vagotomized rats, GABA(A)ergic and glycinergic antagonists had little, if any, effect on rhythm. The effect in vagus-intact rats was to slow the rhythm to a pace equivalent to that seen after suppression of the aforementioned Breuer-Hering inflation reflex. We conclude that postsynaptic inhibition within the preBötC and BötC is not essential for generation of normal respiratory rhythm in intact mammals. We suggest the primary role of inhibition is in shaping the pattern of respiratory motor output, assuring its stability, and in mediating reflex or volitional apnea, but not in the generation of rhythm per se. PMID:23536061

Janczewski, Wiktor A; Tashima, Alexis; Hsu, Paul; Cui, Yan; Feldman, Jack L




PubMed Central

Postsynaptic inhibition is a key element of neural circuits underlying behavior, with 20-50% of all mammalian (non-granule) neurons considered inhibitory. For rhythmic movements in mammals, e.g., walking, swimming, suckling, chewing, breathing, inhibition is often hypothesized to play an essential rhythmogenic role. Here we study the role of fast synaptic inhibitory neurotransmission in the generation of breathing pattern by blocking GABAA and glycine receptors in the preBötzinger Complex (preBötC), a site essential for generation of normal breathing pattern, and in the neighboring Bötzinger Complex (BötC). The breathing rhythm continued following this blockade, but the lung inflation-induced Breuer-Hering inspiratory-inhibitory reflex was suppressed. The antagonists were efficacious, as this blockade abolished the profound effects of the exogenously applied GABAA receptor agonist muscimol or glycine, either of which under control conditions stopped breathing in vagus-intact or vagotomized, anesthetized, spontaneously breathing adult rats. In vagotomized rats, GABAAergic and glycinergic antagonists had little, if any, effect on rhythm. The effect in vagus intact rats was to slow the rhythm to a pace equivalent to that seen after suppression of the aforementioned Breuer-Hering inflation reflex. We conclude that postsynaptic inhibition within the preBötC and BötC is not essential for generation of normal respiratory rhythm in intact mammals. We suggest the primary role of inhibition is in shaping the pattern of respiratory motor output, assuring its stability, and in mediating reflex or volitional apnea, but not in the generation of rhythm per se. PMID:23536061

Janczewski, Wiktor A.; Tashima, Alexis; Hsu, Paul; Cui, Yan; Feldman, Jack L.



Inhibition of glomerular cell apoptosis by heparin  

Microsoft Academic Search

Inhibition of glomerular cell apoptosis by heparin.BackgroundHeparin, the multifunctional glycosaminoglycan, has been considered a therapeutic agent for glomerular diseases. Although a number of biological properties are postulated to explain its therapeutic utility, it is unknown whether heparin affects cell survival in the glomerulus. In this report, we investigated the effect of heparin on apoptosis of glomerular cells.MethodsCultured rat mesangial cells

Yoshihisa Ishikawa; Masanori Kitamura



Henri Laborit and the inhibition of action  

PubMed Central

Henri Laborit was one of the founders of modern neuropsychopharmacology, having discovered, or participated in, the discovery of chlorpromazine, gamma-OH, clomethiazole, and minaprine. He also put forward a theory regarding the necessity of counteracting the negative consequences of defense mechanisms during anesthesia or behavioral inhibition. The scope of his work covers neurophysiology, pharmacology, psychiatry, and psychosomatics. His independence of spirit meant that most of his research was not done within university settings. PMID:24733976

Kunz, Edward



Tetracyclines Inhibit Protein Glycation in Experimental Diabetes  

Microsoft Academic Search

Glycation of proteins, which is accelerated in the diabetic state, has been implicated in many of the long-term complications of diabetes. This process can be inhibited by members of the tetracycline family of compounds. This novel finding is supported by studies conducted on drug (streptozotocin)induced Type I and genetic (ZDF\\/Gmi-fa\\/fa) Type II diabetic rats. These animals were orally gavaged daily

M. E. Ryan; N. S. Ramamurthy; L. M. Golub



Arsenic Inhibits Myogenic Differentiation and Muscle Regeneration  

PubMed Central

Background The incidence of low birth weights is increased in offspring of women who are exposed to high concentrations of arsenic in drinking water compared with other women. We hypothesized that effects of arsenic on birth weight may be related to effects on myogenic differentiation. Objective We investigated the effects of arsenic trioxide (As2O3) on the myogenic differentiation of myoblasts in vitro and muscle regeneration in vivo. Methods C2C12 myoblasts and primary mouse and human myoblasts were cultured in differentiation media with or without As2O3 (0.1–0.5 ?M) for 4 days. Myogenic differentiation was assessed by myogenin and myosin heavy chain expression and multinucleated myotube formation in vitro; skeletal muscle regeneration was tested using an in vivo mouse model with experimental glycerol myopathy. Results A submicromolar concentration of As2O3 dose-dependently inhibited myogenic differentiation without apparent effects on cell viability. As2O3 significantly and dose-dependently decreased phosphorylation of Akt and p70s6k proteins during myogenic differentiation. As2O3-induced inhibition in myotube formation and muscle-specific protein expression was reversed by transfection with the constitutively active form of Akt. Sections of soleus muscles stained with hematoxylin and eosin showed typical changes of injury and regeneration after local glycerol injection in mice. Regeneration of glycerol-injured soleus muscles, myogenin expression, and Akt phosphorylation were suppressed in muscles isolated from As2O3-treated mice compared with untreated mice. Conclusion Our results suggest that As2O3 inhibits myogenic differentiation by inhibiting Akt-regulated signaling. PMID:20299303

Yen, Yuan-Peng; Tsai, Keh-Sung; Chen, Ya-Wen; Huang, Chun-Fa; Yang, Rong-Sen; Liu, Shing-Hwa



Lipoproteins inhibit macrophage activation by lipoteichoic acid  

Microsoft Academic Search

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

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


Stress-induced plasticity of GABAergic inhibition  

PubMed Central

GABAergic neurotransmission is highly plastic, undergoing dynamic alterations in response to changes in the environment, such as following both acute and chronic stress. Stress-induced plasticity of GABAergic inhibition is thought to contribute to changes in neuronal excitability associated with stress, which is particularly relevant for stress-related disorders and seizure susceptibility. Here we review the literature demonstrating several mechanisms altering GABAergic inhibition associated with stress, including brain region-specific alterations in GABAA receptor (GABAAR) subunit expression, changes in chloride homeostasis, and plasticity at GABAergic synapses. Alterations in the expression of specific GABAAR subunits have been documented in multiple brain regions associated with acute or chronic stress. In addition, recent work demonstrates stress-induced alterations in GABAergic inhibition resulting from plasticity in intracellular chloride levels. Acute and chronic stress-induced dephosphorylation and downregulation of the K+/Cl? co-transporter, KCC2, has been implicated in compromising GABAergic control of corticotropin-releasing hormone (CRH) neurons necessary for mounting the physiological response to stress. Acute stress also unmasks the capacity for both long-term potentiation and long-term depression, in distinct temporal windows, at GABAergic synapses on parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus (PVN) of the hypothalamus. This review highlights the complexity in the plasticity of GABAergic neurotransmission associated with stress and the relationship to neuronal excitability, including alterations in GABAAR expression, synaptic plasticity at GABAergic synapses, and changes in chloride homeostasis. PMID:24936173

Maguire, Jamie



Anandamide inhibits breast tumor-induced angiogenesis  

PubMed Central

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

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



[Inhibition of soybean urease by polycarbonyl compounds].  


Competitive inhibition of soybean urease was studied at 36 degrees C in aqueous solution (pH 4.95) in the presence of polycarbonyl compounds (PCCs): oxalyldihydrazide (ODH), its polydisulfide (poly(DSODH)), three cyclic beta-triketones (CTKs), and seven cyclic PCC species of differing structure. The inhibition constants of ureolysis (Ki) varied in the range 8.5-3800 microM depending on the structure of organic chelators for the nickel atom in urease. It was shown that pH variation within the range from 3.85 to 7.40 exerted a strong effect on the values of Ki] of three CTKs and hydroxyurea, which was used as a reference: pH dependences of lgK(i) were linear in all cases and displayed a break at pH 6.0-6.5. The most effective inhibitor of ureolysis was poly(DSODH), which contained approximately 28 carbonyl groups in the polymer molecule. The role of such factors as the number of carbonyl groups per PCC molecule, mutual arrangement, and reaction medium pH in the efficiency of the process of urease inhibition is discussed. PMID:15810727

Tarun, E I; Rubinov, D B; Metelitsa, D I



Trace element inhibition of phytase activity.  


Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p?inhibit exogenous phytase activity. PMID:25416530

Santos, T; Connolly, C; Murphy, R



Hydrogen sulfide inhibits plasma renin activity.  


The development of renovascular hypertension depends on the release of renin from the juxtaglomerular (JG) cells, a process regulated by intracellular cAMP. Hydrogen sulfide (H2S) downregulates cAMP production in some cell types by inhibiting adenylyl cyclase, suggesting the possibility that it may modulate renin release. Here, we investigated the effect of H2S on plasma renin activity and BP in rat models of renovascular hypertension. In the two-kidney-one-clip (2K1C) model of renovascular hypertension, the H2S donor NaHS prevented and treated hypertension. Compared with vehicle, NaHS significantly attenuated the elevation in plasma renin activity and angiotensin II levels but did not affect plasma angiotensin-converting enzyme activity. Furthermore, NaHS inhibited the upregulation of renin mRNA and protein levels in the clipped kidneys of 2K1C rats. In primary cultures of renin-rich kidney cells, NaHS markedly suppressed forskolin-stimulated renin activity in the medium and the intracellular increase in cAMP. In contrast, NaHS did not affect BP or plasma renin activity in normal or one-kidney-one-clip (1K1C) rats, both of which had normal plasma renin activity. In conclusion, these results demonstrate that H2S may inhibit renin activity by decreasing the synthesis and release of renin, suggesting its potential therapeutic value for renovascular hypertension. PMID:20360313

Lu, Ming; Liu, Yi-Hong; Goh, Hong Swen; Wang, Josh Jia Xing; Yong, Qian-Chen; Wang, Rui; Bian, Jin-Song



Pharmacological Inhibition of Feline Immunodeficiency Virus (FIV)  

PubMed Central

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

Mohammadi, Hakimeh; Bienzle, Dorothee



Phytic Acid Inhibits Lipid Peroxidation In Vitro  

PubMed Central

Phytic acid (PA) has been recognized as a potent antioxidant and inhibitor of iron-catalyzed hydroxyl radical formation under in vitro and in vivo conditions. Therefore, the aim of the present study was to investigate, with the use of HPLC/MS/MS, whether PA is capable of inhibiting linoleic acid autoxidation and Fe(II)/ascorbate-induced peroxidation, as well as Fe(II)/ascorbate-induced lipid peroxidation in human colonic epithelial cells. PA at 100??M and 500??M effectively inhibited the decay of linoleic acid, both in the absence and presence of Fe(II)/ascorbate. The observed inhibitory effect of PA on Fe(II)/ascorbate-induced lipid peroxidation was lower (10–20%) compared to that of autoxidation. PA did not change linoleic acid hydroperoxides concentration levels after 24 hours of Fe(II)/ascorbate-induced peroxidation. In the absence of Fe(II)/ascorbate, PA at 100??M and 500??M significantly suppressed decomposition of linoleic acid hydroperoxides. Moreover, PA at the tested nontoxic concentrations (100??M and 500??M) significantly decreased 4-hydroxyalkenal levels in Caco-2 cells which structurally and functionally resemble the small intestinal epithelium. It is concluded that PA inhibits linoleic acid oxidation and reduces the formation of 4-hydroxyalkenals. Acting as an antioxidant it may help to prevent intestinal diseases induced by oxygen radicals and lipid peroxidation products. PMID:24260736

W?glarz, Ludmi?a; Dzier?ewicz, Zofia



Overcoming potassium-mediated triplex inhibition.  

PubMed Central

Sequence-specific duplex DNA recognition by oligonucleotide-directed triple helix formation is a possible approach to in vivo gene inhibition. However, triple helix formation involving guanine-rich oligonucleotides is inhibited by physiological ions, particularly K+, most likely due to oligonucleotide aggregation via guanine quartets. Three oligodeoxynucleotide (ODN) derivatives were tested for their ability to resist guanine quartet-mediated aggregation, yet form stable triplexes. Electrophoretic mobility shift and dimethyl sulfate footprinting assays were used to analyze the formation of triplexes involving these oligonucleotide derivatives. In the absence of K+, all ODNs had similar binding affinities for the duplex target. Triplexes involving a 14mer ODN derivative containing 7-deazaxanthine substituted for three thymine bases or an 18mer ODN containing two additional thymines on both the 5' and 3' termini were abolished by 50 mM K+. Remarkably, triplexes involving an ODN derivative containing four 6-thioguanine bases substituted for guanine resisted K+ inhibition up to 200 mM. We hypothesize that the increased radius and decreased electronegativity of sulfur in the 6-position of guanine destabilize potential guanine quartets. These results improve the prospects for creating ODNS that might serve as specific and efficient gene repressors in vivo. Images PMID:7596821

Olivas, W M; Maher, L J



Ormeloxifene efficiently inhibits ovarian cancer growth.  


Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer. PMID:25306892

Maher, Diane M; Khan, Sheema; Nordquist, Jordan L; Ebeling, Mara C; Bauer, Nichole A; Kopel, Lucas; Singh, Man Mohan; Halaweish, Fathi; Bell, Maria C; Jaggi, Meena; Chauhan, Subhash C



Stress-induced plasticity of GABAergic inhibition.  


GABAergic neurotransmission is highly plastic, undergoing dynamic alterations in response to changes in the environment, such as following both acute and chronic stress. Stress-induced plasticity of GABAergic inhibition is thought to contribute to changes in neuronal excitability associated with stress, which is particularly relevant for stress-related disorders and seizure susceptibility. Here we review the literature demonstrating several mechanisms altering GABAergic inhibition associated with stress, including brain region-specific alterations in GABAA receptor (GABAAR) subunit expression, changes in chloride homeostasis, and plasticity at GABAergic synapses. Alterations in the expression of specific GABAAR subunits have been documented in multiple brain regions associated with acute or chronic stress. In addition, recent work demonstrates stress-induced alterations in GABAergic inhibition resulting from plasticity in intracellular chloride levels. Acute and chronic stress-induced dephosphorylation and downregulation of the K(+)/Cl(-) co-transporter, KCC2, has been implicated in compromising GABAergic control of corticotropin-releasing hormone (CRH) neurons necessary for mounting the physiological response to stress. Acute stress also unmasks the capacity for both long-term potentiation and long-term depression, in distinct temporal windows, at GABAergic synapses on parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus (PVN) of the hypothalamus. This review highlights the complexity in the plasticity of GABAergic neurotransmission associated with stress and the relationship to neuronal excitability, including alterations in GABAAR expression, synaptic plasticity at GABAergic synapses, and changes in chloride homeostasis. PMID:24936173

Maguire, Jamie



‘FAS’t inhibition of malaria  

PubMed Central

Malaria, a tropical disease caused by Plasmodium sp., has been haunting mankind for ages. Unsuccessful attempts to develop a vaccine, the emergence of resistance against the existing drugs and the increasing mortality rate all call for immediate strategies to treat it. Intense attempts are underway to develop potent analogues of the current antimalarials, as well as a search for novel drug targets in the parasite. The indispensability of apicoplast (plastid) to the survival of the parasite has attracted a lot of attention in the recent past. The present review describes the origin and the essentiality of this relict organelle to the parasite. We also show that among the apicoplast specific pathways, the fatty acid biosynthesis system is an attractive target, because its inhibition decimates the parasite swiftly unlike the ‘delayed death’ phenotype exhibited by the inhibition of the other apicoplast processes. As the enzymes of the fatty acid biosynthesis system are present as discrete entities, unlike those of the host, they are amenable to inhibition without impairing the operation of the host-specific pathway. The present review describes the role of these enzymes, the status of their molecular characterization and the current advancements in the area of developing inhibitors against each of the enzymes of the pathway. PMID:15315475



Clathrin-mediated endocytosis is inhibited during mitosis  

E-print Network

. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, we show that the inhibition of transferrin up- take in mitosis occurs despite abundant transferrin


The Inhibition Capacities of Children with Mathematical Disabilities  

Microsoft Academic Search

Several authors have argued that mathematical disabilities might result from difficulties in inhibiting irrelevant information. The present study addresses this issue by assessing three inhibition functions in 40 ten-year-old children: suppression of irrelevant information from working memory, inhibition of prepotent responses, and interference control. We found no significant differences between children with math disabilities and typically achieving controls, or between

Sandrine Censabella; Marie-Pascale Noël



Possible mechanisms for the inhibition of photosynthesis by ozone  

Microsoft Academic Search

Tropospheric ozone produced by industrial civilization is widespread. Although the levels are not clearly life threatening, they do have the potential to inhibit normal plant productivity, thought to be by an inhibition of photosynthesis. While the mechanism for this inhibition is not yet clear, there are several hypotheses for its cause. It is unlikely that ozone can penetrate the cell

Robert L. Heath



Mechanism of nitrite inhibition of cellular respiration in Pseudomonas aeruginosa  

Microsoft Academic Search

One of the principal mechanisms of nitrite inhibition of cellular respiration has been considered to be the interference with the action of iron-containing enzymes. In procaryotic systems, the effect of nitrite on cellular metabolism remains unclear. This study provides evidence which shows a direct inhibition by a low concentration of nitrite on a highly purified oxidase inPseudomonas aeruginosa. The inhibition

Tsanyen Yang



Thiomers: Inhibition of cytochrome P450 activity.  


The aim of the present study was to investigate the potential of different thiolated polymers (thiomers) on the catalytic activity of CYP450s on one hand and to explore new inhibitors for CYP activity on the other hand. Several thiolated polymers including poly(acrylic acid)-cysteine (PAA-cysteine), chitosan-thioglycolic acid (chitosan-TGA), and thiolated PEG-g-PEI copolymer along with brij 35, myrj 52 and the well-established CYPP450 inhibitor verapamil were screened for their CYP3A4 and CYP2A6 inhibitory activity, and their IC(50) values were determined. Both enzyme inhibition assays were performed in 96-well microtiter plates. 7-Benzyloxy-4-(trifluoromethyl)-coumarin (BFC) and 7-hydroxycoumarin (7-HC) were used as fluorescent substrates in order to determine CYP3A4 and CYP2A6 catalytic activity, respectively. All investigated compounds inhibited CYP3A4 as well as CYP2A6 activity. All tested (thiolated) polymers were found to be more potent inhibitors of CYP3A4 than of CYP2A6 catalytic activity. Apart from verapamil that is a known CYP3A4 inhibitor, brij 35 and myrj 52 were explored as potent inhibitors of CYP3A4 and CYP2A6 catalytic activity. Among the tested polymers, the rank order for CYP3A4 inhibition was PAA-cysteine (100 kDa)>brij 35>thiolated PEG-g-PEI copolymer (16 kDa)>myrj 52>PAA (100 kDa)>PAA-cysteine (450 kDa)>verapamil>PAA (450 kDa)>chitosan-TGA (150 kDa)>chitosan (150 kDa). On the other hand, the rank order of CYP2A6 inhibition was brij 35>PAA-cysteine (100kDa)>chitosan-TGA (150 kDa)>PAA (100 kDa)>thiolated PEG-g-PEI copolymer (16 kDa)>PAA-cysteine (450 kDa)>chitosan (150 kDa)>verapamil>PAA (450 kDa)>myrj 52. Thus, this study suggests that (thiolated) polymers display a promising potential to inhibit cytochrome P450s activity and might turn out to be potentially valuable tools for improving the oral bioavailability of actively secreted compounds by avoiding intestinal metabolism. PMID:21362475

Iqbal, Javed; Sakloetsakun, Duangkamon; Bernkop-Schnürch, Andreas



Multiple components of ipsilaterally evoked inhibition in the inferior colliculus.  


The central nucleus of the inferior colliculus (ICc) receives a large number of convergent inputs that are both excitatory and inhibitory. Although excitatory inputs typically are evoked by stimulation of the contralateral ear, inhibitory inputs can be recruited by either ear. Here we evaluate ipsilaterally evoked inhibition in single ICc cells in awake Mexican free-tailed bats. The principal question we addressed concerns the degree to which ipsilateral inhibition at the ICc suppresses contralaterally evoked discharges and thus creates the excitatory-inhibitory (EI) properties of ICc neurons. To study ipsilaterally evoked inhibition, we iontophoretically applied excitatory neurotransmitters and visualized the ipsilateral inhibition as a gap in the carpet of background activity evoked by the transmitters. Ipsilateral inhibition was seen in 86% of ICc cells. The inhibition in most cells had both glycinergic and GABAergic components that could be blocked by the iontophoretic application of bicuculline and strychnine. In 80% of the cells that were inhibited, the ipsilateral inhibition and contralateral excitation were temporally coincident. In many of these cells, the ipsilateral inhibition suppressed contralateral discharges and thus generated the cell's EI property in the ICc. In other cells, the ipsilateral inhibition was coincident with the initial portion of the excitation, but the inhibition was only 2-4 ms in duration and suppressed only the first few contralaterally evoked discharges. The suppression was so slight that it often could not be detected as a decrease in the spike count generated by increasing ipsilateral intensities. Twenty percent of the cells that expressed inhibition, however, had inhibitory latencies that were longer than the excitatory latencies. In these neurons, the inhibition arrived too late to suppress most or any of the discharges. Finally, in the majority of cells, the ipsilateral inhibition persisted for tens of milliseconds beyond the duration of the signal that evoked it. Thus ipsilateral inhibition has multiple components and one or more of these components are typically evoked in ICc neurons by sound received at the ipsilateral ear. PMID:10444659

Klug, A; Bauer, E E; Pollak, G D



Reaction time inhibition from subliminal cues: is it related to inhibition of return?  


Task-irrelevant visual cues with near zero visibility proved apt to retard reaction time for the detection of supraliminal visual targets presented at the cued location. The time course of the effect was similar to that of the so-called inhibition-of return (IOR), which is assumed to be due to the withdrawal of attention from the inhibited location. However the present subliminal cues consistently failed to induce an RT facilitation prior to the RT inhibition, contrary to what would be expected if the cue were able to attract attention to the cued location. Since the RT inhibition from subliminal cues could not be attributed to the withdrawal of attention from the cued location, it can be argued that such cues acted both outside of consciousness and without the influence of attention. Therefore, the RT inhibitory effect seems best accounted for by an automatic, unconscious and attention-independent self-inhibition of response tendencies instructed by irrelevant information, akin to that postulated by (Eimer, M., & Schlaghecken, F. (1998). Effects of masked stimuli on motor activation: behavioural and electrophysiological evidence. Journal of Experimental Psychology Human Perception and Performance, 24, 1737-1747.) to explain the negative compatibility effect. PMID:18206184

Mele, Sonia; Savazzi, Silvia; Marzi, Carlo A; Berlucchi, Giovanni



A Comparator View of Pavlovian and Differential Inhibition  

PubMed Central

In 3 experiments using rats as subjects, the authors varied trial spacing to investigate the conditions under which Pavlovian and differential inhibition are observed. Experiment 1 compared Pavlovian and differential inhibition with spaced training trials. Spaced trials resulted in only the Pavlovian inhibitor passing both summation and retardation tests. Conversely, Experiment 2 compared these 2 types of inhibition with massed training trials. This training resulted in only the differential inhibitor passing both tests for conditioned inhibition. Finally, in Experiment 3 all subjects experienced Pavlovian inhibition training with massed trials. Although this training by itself did not result in behavior indicative of inhibition, subjects that also experienced posttraining extinction of the training context did pass both tests for inhibition. Overall, these results are anticipated by the extended comparator hypothesis (Denniston, Savastano, & Miller, 2001) but are problematic for most contemporary associative learning theories. PMID:16834494

Urcelay, Gonzalo P.; Miller, Ralph R.




PubMed Central

We studied the functional properties and underlying neural mechanisms associated with inhibitory combination-sensitive neurons in the mustached bat’s inferior colliculus (IC). In these neurons, the excitatory response to best frequency tones was suppressed by lower frequency signals (usually in the range 12-30 kHz) in a time-dependant manner. Of 143 inhibitory units, the majority (71%) were type I, in which low frequency sounds evoked inhibition only. In the remainder, however, the low frequency inhibitory signal also evoked excitation. Of these, excitation preceded the inhibition in type E/I units (16%), while in type I/E units (13%) excitation followed the inhibition. Type E/I and I/E units were distinct in the tuning and threshold sensitivity of low frequency responses, while type I units overlapped the other types in these features. In 71 neurons, antagonists to receptors for glycine (strychnine, STRY) or ?-aminobutyric acid (GABA) (bicuculline, BIC) were applied micro-iontophoretically. These antagonists failed to eliminate combination-sensitive inhibition in 92% (STRY), 93% (BIC), and 87% (BIC+STRY) of the type I units tested. However, inhibition was reduced in many neurons. Results were similar for type E/I and I/E inhibitory neurons. The results indicate that there are distinct populations of combination-sensitive inhibited neurons in the IC, and that these populations are at least partly independent of glycine or GABAA receptors in the IC. We propose that these populations originate in different brainstem auditory nuclei, that they may be modified by interactions within the IC, and that they may perform different spectrotemporal analyses of vocal signals. PMID:16371455

Nataraj, Kiran; Wenstrup, Jeffrey J.



Metabotropic glutamate receptors inhibit microglial glutamate release  

PubMed Central

Pro-inflammatory stimuli evoke an export of glutamate from microglia that is sufficient to contribute to excitotoxicity in neighbouring neurons. Since microglia also express various glutamate receptors themselves, we were interested in the potential feedback of glutamate on this system. Several agonists of mGluRs (metabotropic glutamate receptors) were applied to primary rat microglia, and the export of glutamate into their culture medium was evoked by LPS (lipopolysaccharide). Agonists of group-II and -III mGluR ACPD [(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid] and L-AP4 [L-(+)-2-amino-4-phosphonobutyric acid] were both capable of completely blocking the glutamate export without interfering with the production of NO (nitric oxide); the group-I agonist tADA (trans-azetidine-2,4-dicarboxylic acid) was ineffective. Consistent with the possibility of feedback, inhibition of mGluR by MSPG [(R,S)-?-2-methyl-4sulfonophenylglycine] potentiated glutamate export. As the group-II and -III mGluR are coupled to G?i-containing G-proteins and the inhibition of adenylate cyclase, we explored the role of cAMP in this effect. Inhibition of cAMP-dependent protein kinase [also known as protein kinase A (PKA)] by H89 mimicked the effect of ACPD, and the mGluR agonist had its actions reversed by artificially sustaining cAMP through the PDE (phosphodiesterase) inhibitor IBMX (isobutylmethylxanthine) or the cAMP mimetic dbcAMP (dibutyryl cAMP). These data indicate that mGluR activation attenuates a potentially neurotoxic export of glutamate from activated microglia and implicate cAMP as a contributor to this aspect of microglial action. PMID:22770428

McMullan, Stephen M; Phanavanh, Bounleut; Guo Li, Gary; Barger, Steven W



Inhibition, Executive Function, and Freezing of Gait  

PubMed Central

Background Studies suggest that freezing of gait (FoG) in people with Parkinson’s disease (PD) is associated with declines in executive function (EF). However, EF is multi-faceted, including three dissociable components: inhibiting prepotent responses, switching between task sets, and updating working memory. Objective This study investigated which aspect of EF is most strongly associated with FoG in PD. Method Three groups were studied: adults with PD (with and without FoG) and age-matched, healthy adults. All participants completed a battery of cognitive tasks previously shown to discriminate among the three EF components. Participants also completed a turning-in-place task that was scored for FoG by neurologists blind to subjects’ self-reported FoG. Results Compared to both other groups, participants with FoG showed significant performance deficits in tasks associated with inhibitory control, even after accounting for differences in disease severity, but no significant deficits in task-switching or updating working memory. Surprisingly, the strongest effect was an intermittent tendency of participants with FoG to hesitate, and thus miss the response window, on go trials in the Go-Nogo task. The FoG group also made slower responses in the conflict condition of the Stroop task. Physician-rated FoG scores were correlated both with failures to respond on go trials and with failures to inhibit responses on nogo trials in the Go-Nogo task. Conclusion These results suggest that FoG is associated with a specific inability to appropriately engage and release inhibition, rather than with a general executive deficit. PMID:24496099

Cohen, Rajal G.; Klein, Krystal A.; Nomura, Mariko; Fleming, Michael; Mancini, Martina; Giladi, Nir; Nutt, John G.; Horak, Fay B.



Ozone inhibition of photosynthesis in Chlorella sorokiniana  

SciTech Connect

Exposure of Chlorella sorokiniana (07-11-05) to ozone inhibits photosynthesis. In this study, the effects of ozone on O/sub 2/ evolution and fluorescence yields are used to characterize this inhibition. At an ozone dose of about 3 micromoles delivered to 2 x 10/sup 9/ cells, the photosynthetic rate of the cells is inhibited 50%, as indicated by a decrease in bicarbonate-stimulated O/sub 2/ evolution (control rate, 1.4 +- 0.3 x 10/sup -15/ moles per cell per minute). Normal patterns of chlorophyll fluorescence are also altered. Upon continuous exposure to ozone (3.5 x 10/sup -7/ moles O/sub 3/ per minute), three stages of change in relative fluorescence yields are observed: (a) a rise in variable yield with no corresponding change in nonvariable yield (after 1-2 minutes), which was interpreted to be a shift in the energy flow pathway; (b) a decline in variable yield with a slight rise in nonvariable yield (requiring 3-5 minutes), interpreted to be a blockage in the CO/sub 2/ fixation pathways; and (c) complete blockage of variable yield with a concurrent decline in nonvariable yield (8-10 minutes), interpreted to be a destruction of the pigment system. The timing of each stage depended upon the ozone concentration and its delivery rate to the cell suspension. These results are compared with ozone-induced decline in photosynthesis and leaf water potential changes reported for other plant systems. Evidence is also presented to suggest that ozone effects on the photosynthetic processes are attributable to ionic imbalances brought about by ozone interaction with the plasmalemma rather than a direct effect on the chloroplast. 25 references, 6 figures, 2 tables.

Heath, R.L.; Frederick, P.E.; Chimiklis, P.E.



Saw palmetto ethanol extract inhibits adipocyte differentiation.  


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

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



Inhibition of ?-galactosidases with mono- and disaccharides  

NASA Astrophysics Data System (ADS)

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).

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



Triaryl Pyrazoline Compound Inhibits Flavivirus RNA Replication  

Microsoft Academic Search

Triaryl pyrazoline {(5-(4-chloro-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl)-phenyl-methanone} in- hibits flavivirus infection in cell culture. The inhibitor was identified through high-throughput screening of a compound library using a luciferase-expressing West Nile (WN) virus infection assay. The compound inhibited an epidemic strain of WN virus without detectable cytotoxicity (a 50% effective concentration of 28 M and a compound concentration of >300 M required to reduce 50%

Francesc Puig-Basagoiti; Mark Tilgner; Brett M. Forshey; Sean M. Philpott; Noel G. Espina; David E. Wentworth; Scott J. Goebel; Paul S. Masters; Barry Falgout; Ping Ren; David M. Ferguson; Pei-Yong Shi



IGF-1 receptor antagonism inhibits autophagy  

E-print Network

License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Human Molecular Genetics, 2013 1–17 doi:10.1093/hmg/ddt300 HMG Advance... pharmacological point of view, such modules could result more challenging to be targeted than the receptor itself. Indeed, it is tempting to speculate that one may be able to achieve synergistic benefits by inhibiting the key effectors of the IGF-1R pathway...

Renna, Maurizio; Bento, Carla F.; Fleming, Angeleen; Menzies, Fiona M.; Siddiqi, Farah H.; Ravikumar, Brinda; Puri, Claudia; Garcia-Arencibia, Moises; Sadiq, Oana; Corrochano, Silvia; Carter, Sarah; Brown, Steve D. M.; Acevedo-Arozena, Abraham; Rubinsztein, David C.



Hsp90 Inhibitor Can Inhibit UV Carcinogenesis.  


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

Katiyar, Santosh K



Inhibition of AGEs formation by natural products.  


Since advanced glycation end-products (AGEs) inhibitors such as benfotiamine, pyridoxamine and aminoguanidine significantly inhibit the development of retinopathy and neuropathy in streptozotocin-induced diabetic rats, treatment with AGEs inhibitors is believed to be a potential strategy for preventing lifestyle-related diseases such as diabetic complications and atherosclerosis. Furthermore, preventive medicine is the most important approach to preventing lifestyle-related diseases, and improving daily nutritional intake is thought to prevent the pathogenesis of such diseases. Therefore, AGEs inhibitors that can be obtained from daily meals are preferred to prescribed drugs. In this article, we describe a strategy for developing new AGEs inhibitors from natural products. PMID:23504149

Nagai, Ryoji; Shirakawa, Jun-Ichi; Ohno, Rei-Ichi; Moroishi, Narumi; Nagai, Mime



Inhibition of synaptosomal neurotransmitter uptake by hallucinogens.  


The effect of 13 hallucinogens on the uptake of serotonin and norepinephrine into hippocampal synaptosomes and of serotonin and dopamine into caudate synaptosomes was found to be inhibitory, except for lysergic acid diethylamide and 2-bromolysergic acid diethylamide, which were inactive. The indolealkylamines were generally more potent than the phenylethylamines. The reported inhibition of uptake of serotonin by 5-methoxy-N,N-dimethyltryptamine and lysergic acid diethylamide into whole brain synaptosomes was not reproducible at concentrations 10(2) to 10(4) times higher than those stated in the literature. PMID:6131933

Whipple, M R; Reinecke, M G; Gage, F H



Formation and inhibition of photochemical smog  

SciTech Connect

Photochemical smog is caused by a free-radical chain mechanism which converts NO to NO/sub 2/. The NO/sub 2/ further reacts to produce ozone, nitric acid, and peracylnitrates. This chain mechanism can be inhibited by suitable free-radical scavengers. The chemistry and toxicology of one such free-radical scavenger, diethylhydroxylamine, has been studied in depth. It has been shown to be effective, safe, and practical for use in urban atmospheres to prevent photochemical smog formation. 42 references.

Heicklen, J.



Calcimimetics inhibit renal pathology in rodent nephronophthisis.  


The development and progression of renal cysts appears to be driven by reduced cellular calcium and increased cyclic adenosine monophosphate (cAMP) from G-protein-coupled receptors. To test whether treatment with a calcimimetic that stimulates the G-protein-coupled calcium-sensing receptor might normalize cystic epithelial cell intracellular calcium and cAMP, thereby inhibiting cyst progression, we used pcy mice. These animals develop cysts principally in the collecting duct, as do humans with nephronophthisis (NPHP). We administered the calcimimetic R-568 mixed in their food at early or late stages in the pathogenesis of cyst formation. The treatment reduced cyst enlargement, and the early treatment inhibited development of renal fibrosis. Although the effect of later treatment was more modest, both stages of the disease responded positively to treatment. Additionally, R-568 decreased total kidney cAMP in the pcy mice and, in vitro, decreased cAMP levels and cell proliferation, while increasing intracellular calcium in immortalized human autosomal recessive polycystic kidney disease renal epithelial cells. The latter two effects were unique to R-568 and not replicated by raising extracellular calcium. Thus, treating pcy mice with R-568 was effective in reducing cyst progression in this rodent model of NPHP. Direct studies will be needed to determine whether these results can be applied to the human disease. PMID:21633408

Chen, Neal X; Moe, Sharon M; Eggleston-Gulyas, Tracy; Chen, Xianming; Hoffmeyer, William D; Bacallao, Robert L; Herbert, Brittney S; Gattone, Vincent H



Inhibition of Aflatoxin Production by Surfactants  

PubMed Central

The effect of 12 surfactants on aflatoxin production, growth, and conidial germination by the fungus Aspergillus flavus is reported. Five nonionic surfactants, Triton X-100, Tergitol NP-7, Tergitol NP-10, polyoxyethylene (POE) 10 lauryl ether, and Latron AG-98, reduced aflatoxin production by 96 to 99% at 1% (wt/vol). Colony growth was restricted by the five nonionic surfactants at this concentration. Aflatoxin production was inhibited 31 to 53% by lower concentrations of Triton X-100 (0.001 to 0.0001%) at which colony growth was not affected. Triton X-301, a POE-derived anionic surfactant, had an effect on colony growth and aflatoxin production similar to that of the five POE-derived nonionic surfactants. Sodium dodecyl sulfate (SDS), an anionic surfactant, and dodecyltrimethylammonium bromide, a cationic surfactant, suppressed conidial germination at 1% (wt/vol). SDS had no effect on aflatoxin production or colony growth at 0.001%. The degree of aflatoxin inhibition by a surfactant appears to be a function of the length of the hydrophobic and hydrophilic chains of POE-derived surfactants. Images PMID:16349144

Rodriguez, Susan B.; Mahoney, Noreen E.



Inhibition Of Washed Sludge With Sodium Nitrite  

SciTech Connect

This report describes the results of electrochemical tests used to determine the relationship between the concentration of the aggressive anions in washed sludge and the minimum effective inhibitor concentration. Sodium nitrate was added as the inhibitor because of its compatibility with the DWPF process. A minimum of 0.05M nitrite is required to inhibit the washed sludge simulant solution used in this study. When the worst case compositions and safety margins are considered, it is expected that a minimum operating limit of nearly 0.1M nitrite will be specified. The validity of this limit is dependent on the accuracy of the concentrations and solubility splits previously reported. Sodium nitrite additions to obtain 0.1M nitrite concentrations in washed sludge will necessitate the additional washing of washed precipitate in order to decrease its sodium nitrite inhibitor requirements sufficiently to remain below the sodium limits in the feed to the DWPF. Nitrite will be the controlling anion in "fresh" washed sludge unless the soluble chloride concentration is about ten times higher than predicted by the solubility splits. Inhibition of "aged" washed sludge will not be a problem unless significant chloride dissolution occurs during storage. It will be very important tomonitor the composition of washed sludge during processing and storage.

Congdon, J. W.; Lozier, J. S.



Fluoride Does Not Inhibit Enamel Protease Activity  

PubMed Central

Fluorosed enamel can be porous, mottled, discolored, hypomineralized, and protein-rich if the enamel matrix is not completely removed. Proteolytic processing by matrix metalloproteinase-20 (MMP20) and kallikrein-4 (KLK4) is critical for enamel formation, and homozygous mutation of either protease results in hypomineralized, protein-rich enamel. Herein, we demonstrate that the lysosomal proteinase cathepsin K is expressed in the enamel organ in a developmentally defined manner that suggests a role for cathepsin K in degrading re-absorbed enamel matrix proteins. We therefore asked if fluoride directly inhibits the activity of MMP20, KLK4, dipeptidyl peptidase I (DPPI) (an in vitro activator of KLK4), or cathepsin K. Enzyme kinetics were studied with quenched fluorescent peptides with purified enzyme in the presence of 0–10 mM NaF, and data were fit to Michaelis-Menten curves. Increasing concentrations of known inhibitors showed decreases in enzyme activity. However, concentrations of up to 10 mM NaF had no effect on KLK4, MMP20, DPPI, or cathepsin K activity. Our results show that fluoride does not directly inhibit enamel proteolytic activity. PMID:21118795

Tye, C.E.; Antone, J.V.; Bartlett, J.D.



Diindolilmethane (DIM) selectively inhibits cancer stem cells.  


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

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



Glycerol inhibition of ruminal lipolysis in vitro.  


Supplemental glycerol inhibits rumen lipolysis, a prerequisite for rumen biohydrogenation, which is responsible for the saturation of dietary fatty acids consumed by ruminant animals. Feeding excess glycerol, however, adversely affects dry matter digestibility. To more clearly define the effect of supplemental glycerol on rumen lipolysis, mixed populations of ruminal bacteria were incubated with 6 or 20% glycerol (vol/vol). After 48-h anaerobic incubation of mixed culture rumen fluid, rates of free fatty acid production (nmol/mL per h) for the 6 and 20% glycerol-supplemented samples were decreased by 80 and 86%, respectively, compared with rates from nonsupplemented control cultures (12.4±1.0; mean ± SE). Conversely, assay of the prominent ruminal lipase-producing bacteria Anaerovibrio lipolyticus 5S, Butyrivibrio fibrisolvens 49, and Propionibacterium species avidum and acnes revealed no effect of 2 or 10% (vol/vol) added glycerol on lipolytic activity by these organisms. Supplementing glycerol at 6% on a vol/vol basis, equivalent to supplementing glycerol at approximately 8 to 15% of diet dry matter, effectively reduced lipolysis. However, the mechanism of glycerol inhibition of ruminal lipolysis remains to be demonstrated. PMID:22916923

Edwards, H D; Anderson, R C; Miller, R K; Taylor, T M; Hardin, M D; Smith, S B; Krueger, N A; Nisbet, D J




PubMed Central

H3-colchicine of high specific activity (2.5 curies per mM) was prepared in order to study the mechanism of colchicine inhibition of mitosis in cultures of human cells, strain K.B. No direct effects on the duration of the cell cycle or macromolecular synthesis were demonstrable at a concentration of colchicine which completely inhibited mitosis. The radioactive compound was bound to the cells at a rate proportional to colchicine concentration. The binding appeared to be reversible since the radioactivity of the cells reached a maximum value for a given concentration and was slowly lost after resuspension of the cells in fresh medium. A suitable exposure to colchicine produced accumulation of metaphase-blocked mitoses after the colchicine was removed from the medium. An exposure of 6 to 8 hours at 10-7 M was sufficient to block essentially all the cells in metaphase, thus indicating that colchicine is bound to the majority of interphase cells. The data are in quantitative agreement with a mechanism involving reversible binding of colchicine to a set of cellular sites. Based on the correlation between the time of first appearance of blocked mitoses and the radioactivity per cell, it is suggested that if a critical fraction (3 to 5 per cent) of the sites are complexed, the cell is unable to form a functional mitotic spindle. PMID:14342828

Taylor, Edwin W.



Experimental muscle pain impairs descending inhibition  

PubMed Central

In chronic musculoskeletal pain conditions, the balance between supraspinal facilitation and inhibition of pain shifts towards an overall decrease in inhibition. Application of a tonic painful stimulus results in activation of diffuse noxious inhibitory controls (DNIC). The aims of the present experimental human study were (1) to compare DNIC, evoked separately, by hypertonic saline (6%)-induced muscle pain (tibialis anterior) or cold pressor pain; (2) to investigate DNIC evoked by concomitant experimental muscle pain and cold pressor pain, and (3) to analyze for gender differences. Ten males and 10 age matched females participated in two sessions. In the first session unilateral muscle pain or unilateral cold pressor pain were induced separately; in the second session unilateral muscle pain and unilateral cold pressor pain were induced concomitantly. Pressure pain thresholds (PPT) were measured around the knee joint before, during, and after DNIC induction. Cold pressor pain increased PPT in both males and females with greater increases in males. Hypertonic saline-evoked muscle pain significantly increased PPT in males but not in females. When cold pressor and muscle pain were applied concomitantly the PPT increases were smaller when compared to the individual sessions. This study showed for the first time that two concurrent conditioning tonic pain stimuli (muscle pain and cold pressor pain) cause less DNIC compared with either of the conditioning stimuli given alone; and males showed greater DNIC than females. This may explain why patients with chronic musculoskeletal pain have impaired DNIC. PMID:18977598

Arendt-Nielsen, Lars; Sluka, Kathleen A.; Nie, Hong Ling



Tigecycline inhibits proliferation of Acanthamoeba castellanii.  


Acanthamoeba is an opportunistic protozoan parasite responsible for different diseases in humans, such as granulomatous amoebic encephalitis and amoebic keratitis. Tigecycline, a third-generation tetracycline antibiotic, has potential activity to treat most of the antibiotic resistant bacterial infections. The effects of tigecycline in eukaryotic cells as well as parasites are less well studied. In the present study, we tested the effects of tigecycline on trophozoites of Acanthamoeba castellanii. The inhibitory effect of tigecycline on Acanthamoeba was determined by resazurin reduction and trypan blue exclusion assays. We found that tigecycline significantly inhibited the growth of Acanthamoeba (46.4 % inhibition at the concentration of 100 ?M) without affecting cell viability and induction of encystation, whereas other tetracycline groups of antibiotics such as tetracycline and doxycycline showed no inhibitory effects. Furthermore, tigecycline decreased cellular adenosine triphosphate (ATP) level by 26 % than the control and increased mitochondrial mass, suggesting mitochondrial dysfunction in tigecycline-treated cells. These findings suggest that mitochondrial dysfunction with decreased ATP production might play an important mechanism of tigecycline in suppression of Acanthamoeba proliferation. PMID:25563616

Jha, Bijay Kumar; Seo, Incheol; Kong, Hyun-Hee; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki



A Wee1 checkpoint inhibits anaphase onset  

PubMed Central

Cdk1 drives both mitotic entry and the metaphase-to-anaphase transition. Past work has shown that Wee1 inhibition of Cdk1 blocks mitotic entry. Here we show that the budding yeast Wee1 kinase, Swe1, also restrains the metaphase-to-anaphase transition by preventing Cdk1 phosphorylation and activation of the mitotic form of the anaphase-promoting complex/cyclosome (APCCdc20). Deletion of SWE1 or its opposing phosphatase MIH1 (the budding yeast cdc25+) altered the timing of anaphase onset, and activation of the Swe1-dependent morphogenesis checkpoint or overexpression of Swe1 blocked cells in metaphase with reduced APC activity in vivo and in vitro. The morphogenesis checkpoint also depended on Cdc55, a regulatory subunit of protein phosphatase 2A (PP2A). cdc55? checkpoint defects were rescued by mutating 12 Cdk1 phosphorylation sites on the APC, demonstrating that the APC is a target of this checkpoint. These data suggest a model in which stepwise activation of Cdk1 and inhibition of PP2ACdc55 triggers anaphase onset. PMID:23751495

Lianga, Noel; Williams, Elizabeth C.; Kennedy, Erin K.; Doré, Carole; Pilon, Sophie; Girard, Stéphanie L.; Deneault, Jean-Sebastien



Spongian diterpenoids inhibit androgen receptor activity  

PubMed Central

Androgen receptor (AR) is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiological ligands for AR ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit AR transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semi-synthetic analogues (T2 and T3) revealed that these diterpenoids have antiandrogen properties that include inhibition of both androgen-dependent proliferation and AR transcriptional activity by a mechanism that involved competing with androgen for AR LBD and blocking essential N/C interactions required for androgen-induced AR transcriptional activity. Structure activity relationship analyses revealed some chemical features of T1 that are associated with activity and yielded T3 as the most potent analogue. In vivo, T3 significantly reduced the weight of seminal vesicles, which are an androgen-dependent tissue, thereby confirming T3’s on-target activity. The ability to create analogues of diterpenoids that have varying antiandrogen activity represents a novel class of chemical compounds for the analysis of AR ligand-binding properties and therapeutic development. PMID:23443807

Yang, Yu Chi; Meimetis, Labros G; Tien, Amy H; Mawji, Nasrin R; Carr, Gavin; Wang, Jun; Andersen, Raymond J; Sadar, Marianne D



Direct renin inhibition: extricating facts from façades.  


The renin-angiotensin system (RAS) affects vascular tone, cardiac output and kidney function. By these means the RAS plays a key role in the pathogenesis of arterial hypertension. As a result, RAS inhibition is highly effective not only in lowering blood pressure but also in reducing kidney disease progression (particularly when associated with proteinuria) and cardiovascular events. Among RAS blocking agents, direct renin inhibitors have shown not only excellent efficacy in hypertension control but also pharmacologic tolerance that is comparable with other renin-angiotensin suppressors. Indeed, aliskiren, the only direct renin inhibitor available is effective in controlling blood pressure as monotherapy or in combination with other antihypertensive drugs, irrespective of patient's age, ethnicity or sex. It is also effective in patients with metabolic syndrome, obesity and diabetes. Long-term studies comparing 'hard endpoints' of aliskiren therapy versus treatment with other RAS inhibitors, including cardiac and kidney protection, are currently ongoing. Combined with other antihypertensive agents, aliskiren not only improves their hypotensive response but may also lessen the adverse effects of other drugs. In high-risk patients, however, precautions should be taken when combining two or more renin-angiotensin inhibiting agents, as tissue perfusion may be highly renin-dependent in these patients and serious adverse side effects could take place. PMID:23487045

Juncos, Luis



Aurin tricarboxylic acid inhibits experimental venous thrombosis.  


In vitro, aurin tricarboxylic acid (ATA) inhibited ristocetin-induced human platelet agglutination in a dose-dependent manner. The IC50 value (dose which inhibits 50% of platelet agglutination) was 60 +/- 8.7 micrograms/ml. In vivo, the i.v. administration of ATA to rats reduced the thrombus formation in an arteriovenous shunt with an ED50 value of 9.0 +/- 1.6 mg/kg. In a venous thrombosis model, using a combination of a thrombogenic challenge and stasis, ATA displayed a significant, dose-dependent antithrombotic effect, the ED50 value being of 18.3 +/- 2.0 mg/kg. In an experimental model of disseminated intravascular coagulation, ATA protected mice from the lethal effect of thromboplastin-induced thromboembolism with a ED50 value of 1.1 +/- 0.15 mg/kg, being in that respect 12 times less potent than standard heparin (ED50 = 90 +/- 15 micrograms/kg). These observations therefore show that ATA is active in both arterial- or venous-type thrombosis models and suggest that von Willebrand Factor might be important not only in arterial but also in venous thrombosis. PMID:8091404

Bernat, A; Lale, A; Herbert, J M



GABAergic Inhibition in Visual Cortical Plasticity  

PubMed Central

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition. PMID:20407586

Sale, Alessandro; Berardi, Nicoletta; Spolidoro, Maria; Baroncelli, Laura; Maffei, Lamberto



Understanding biocatalyst inhibition by carboxylic acids.  


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

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



Oxidation Inhibits Iron-Induced Blood Coagulation  

PubMed Central

Blood coagulation under physiological conditions is activated by thrombin, which converts soluble plasma fibrinogen (FBG) into an insoluble clot. The structure of the enzymatically-generated clot is very characteristic being composed of thick fibrin fibers susceptible to the fibrinolytic degradation. However, in chronic degenerative diseases, such as atherosclerosis, diabetes mellitus, cancer, and neurological disorders, fibrin clots are very different forming dense matted deposits (DMD) that are not effectively removed and thus create a condition known as thrombosis. We have recently shown that trivalent iron (ferric ions) generates hydroxyl radicals, which subsequently convert FBG into abnormal fibrin clots in the form of DMDs. A characteristic feature of DMDs is their remarkable and permanent resistance to the enzymatic degradation. Therefore, in order to prevent thrombotic incidences in the degenerative diseases it is essential to inhibit the iron-induced generation of hydroxyl radicals. This can be achieved by the pretreatment with a direct free radical scavenger (e.g. salicylate), and as shown in this paper by the treatment with oxidizing agents such as hydrogen peroxide, methylene blue, and sodium selenite. Although the actual mechanism of this phenomenon is not yet known, it is possible that hydroxyl radicals are neutralized by their conversion to the molecular oxygen and water, thus inhibiting the formation of dense matted fibrin deposits in human blood. PMID:23170793

Pretorius, Etheresia; Bester, Janette; Vermeulen, Natasha; Lipinski, Boguslaw



Expressive Inhibition Following Interpersonal Trauma: An Analysis of Reported Function  

PubMed Central

Existing research indicates veterans with PTSD may deliberately inhibit the expression of emotion. However, the degree to which inhibition generalizes to other trauma populations and the specific reasons survivors with PTSD inhibit expression remains unclear. The present study looked to evaluate expressive inhibition among survivors of intimate partner violence (N = 74), to determine reasons for inhibition in this population, and to examine whether any justifications for inhibition are unique to individuals with PTSD. The frequency and intensity of inhibition scores were similar to those noted in previous research although no differences were observed across women with and without PTSD. Self-reported justifications for inhibition indicated five general themes: Concern for others, Mistrust/fear of exploitation, Perception of others as indifferent/uncaring, Control/Experiential avoidance, and Situation-specific inhibition. Only mistrust/exploitation motives were uniquely associated with PTSD. Whereas expressive inhibition may be elevated within help-seeking samples, individuals who develop PTSD appear to hold unique reasons for restricting emotional expression. PMID:24507632

Clapp, Joshua D.; Jones, Judiann M.; Jaconis, Maryanne; Olsen, Shira A.; Woodward, Matthew J.; Beck, J. Gayle



Features of contralaterally evoked inhibition in the inferior colliculus.  


Cells in the central nucleus of the inferior colliculus (ICc) receive a large number of convergent inputs that are not only excitatory but inhibitory as well. While the excitatory responses of ICc cells have been studied extensively, less attention has been paid to the effects that inhibitory inputs have on auditory processing in the ICc. The purpose of this study was to examine the role of contralaterally evoked inhibition in single ICc cells in awake Mexican free-tailed bats. To study the contralaterally evoked inhibition, we created background activity by the iontophoretic application of the excitatory neurotransmitters glutamate and aspartate and visualized the inhibition as a gap in the carpet of background activity. We found that 85% of ICc cells exhibit a contralaterally evoked excitation followed by a period of inhibition. The inhibition acts primarily through GABA(A)20 ms) tones in generating persistent inhibition. While the early inhibition has clear roles in the shaping of excitatory response properties to a stimulus, the later persistent component of the inhibition is more enigmatic. The fact that the persistent inhibition lasts well beyond the duration of excitatory inputs to the ICc cell implies that the persistent inhibition may be important for the temporal segregation of the responses to multiple sound sources. PMID:10713497

Bauer, E E; Klug, A; Pollak, G D



Ketoconazole Inhibits the Cellular Uptake of Anandamide via Inhibition of FAAH at Pharmacologically Relevant Concentrations  

PubMed Central

Background The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 µM. Conclusions/Significance The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer. PMID:24466356

Björklund, Emmelie; Larsson, Therése N. L.; Jacobsson, Stig O. P.; Fowler, Christopher J.



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

PubMed Central

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




Inhibition in Neuroscience The term inhibition has been used in neuroscience since  

E-print Network

nucleus, which then sends a GABAergic projection onto a cell in the thalamus--thus modulating incoming," and "recurrent inhibition," all of which the reader can explore in a standard neuroscience text (e.g., Kandel neurophysiologically or clearly operationalized in terms of behavior. Unfortunately, this is not the case in psychology

Aron, Adam


Distinct Neural Correlates for Two Types of Inhibition in Bilinguals: Response Inhibition versus Interference Suppression  

ERIC Educational Resources Information Center

To examine the effects of bilingualism on cognitive control, we studied monolingual and bilingual young adults performing a flanker task with functional MRI. The trial types of primary interest for this report were incongruent and no-go trials, representing interference suppression and response inhibition, respectively. Response times were similar…

Luk, Gigi; Anderson, John A. E.; Craik, Fergus I. M.; Grady, Cheryl; Bialystok, Ellen



Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis.  


Mammalian stanniocalcin-2 (STC2) is a secreted polypeptide widely expressed in developing and adult tissues. However, although transgenic expression in mice is known to cause severe dwarfism, and targeted deletion of STC2 causes increased postnatal growth, its precise biological role is still unknown. We found that STC2 potently inhibits the proteolytic activity of the growth-promoting metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). Proteolytic inhibition requires covalent binding of STC2 to PAPP-A and is mediated by a disulfide bond, which involves Cys-120 of STC2. Binding of STC2 prevents PAPP-A cleavage of insulin-like growth factor-binding protein (IGFBP)-4 and hence release within tissues of bioactive IGF, required for normal growth. Concordantly, we show that STC2 efficiently inhibits PAPP-A-mediated IGF receptor signaling in vitro and that transgenic mice expressing a mutated variant of STC2, STC2(C120A), which is unable to inhibit PAPP-A, grow like wild-type mice. Our work identifies STC2 as a novel proteinase inhibitor and a previously unrecognized extracellular component of the IGF system. PMID:25533459

Jepsen, Malene R; Kløverpris, Søren; Mikkelsen, Jakob H; Pedersen, Josefine H; Füchtbauer, Ernst-Martin; Laursen, Lisbeth S; Oxvig, Claus



Thymol inhibits Staphylococcus aureus internalization into bovine mammary epithelial cells by inhibiting NF-?B activation.  


Bovine mastitis is one of the most costly and prevalent diseases in the dairy industry and is characterised by inflammatory and infectious processes. Staphylococcus aureus (S. aureus), a Gram-positive organism, is a frequent cause of subclinical, chronic mastitis. Thymol, a monocyclic monoterpene compound isolated from Thymus vulgaris, has been reported to have antibacterial properties. However, the effect of thymol on S. aureus internalization into bovine mammary epithelial cells (bMEC) has not been investigated. In this study, we evaluated the effect of thymol on S. aureus internalization into bMEC, the expression of tracheal antimicrobial peptide (TAP) and ?-defensin (BNBD5), and the inhibition of NF-?B activation in bMEC infected with S. aureus. Our results showed that thymol (16-64 ?g/ml) could reduce the internalization of S. aureus into bMEC and down-regulate the mRNA expression of TAP and BNBD5 in bMEC infected with S. aureus. In addition, thymol was found to inhibit S. aureus-induced nitric oxide (NO) production in bMEC and suppress S. aureus-induced NF-?B activation in a dose-dependent manner. In conclusion, these results indicated that thymol inhibits S. aureus internalization into bMEC by inhibiting NF-?B activation. PMID:24583152

Wei, Zhengkai; Zhou, Ershun; Guo, Changming; Fu, Yunhe; Yu, Yuqiang; Li, Yimeng; Yao, Minjun; Zhang, Naisheng; Yang, Zhengtao



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


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

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



Molecular mechanisms of DNA repair inhibition by caffeine  

SciTech Connect

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.

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



Molecular mechanisms of DNA repair inhibition by caffeine.  

PubMed Central

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. Images PMID:2185474

Selby, C P; Sancar, A



Colchicine inhibition of plasma protein release from rat hepatocytes  

PubMed Central

Colchicine, both in vitro and in vivo, inhibits secretion of albumin and other plasma proteins. In vitro, secretion by rat liver slices is inhibited at 10-minus 6 M with maximal effect at 10-minus 5 M. Inhibition of secretion is accompanied by a concomitant retention of nonsecreted proteins within the slices. Colchicine does not inhibit protein synthesis at these concentrations. Vinblastine also inhibits plasma protein secretion but lumicolchicine, griseofulvin, and cytochalasin B do not. Colchicine also acts in vivo at 10-25 mumol/100 g body weight. Inhibition of secretion is not due to changes in the intracellular nucleotide phosphate levels. Colchicine, administered intravenously, acts within 2 min and its inhibitory effect lasts for at least 3 h. Colchicine has no effect on transport of secretory proteins in the rough or smooth endoplasmic reticulum but it causes these proteins to accumulate in Golgi-derived secretory vesicles. PMID:1141379



Enhancing Allosteric Inhibition in Thermus thermophilus Phosphofructokinase.  


The coupling between the binding of the substrate Fru-6-P and the inhibitor phospho(enol)pyruvate (PEP) in phosphofructokinase (PFK) from the extreme thermophile Thermus thermophilus is much weaker than that seen in a PFK from Bacillus stearothermophilus. From the crystal structures of Bacillus stearothermophilus PFK (BsPFK) the residues at positions 59, 158, and 215 in BsPFK are located on the path leading from the allosteric site to the nearest active site and are part of the intricate hydrogen-bonding network connecting the two sites. Substituting the corresponding residues in Thermus thermophilus PFK (TtPFK) with the amino acids found at these positions in BsPFK allowed us to enhance the allosteric inhibition by PEP by nearly 3 kcal mol(-1) (50-fold) to a value greater than or equal to the coupling observed in BsPFK. Interestingly, each single variant N59D, A158T, and S215H produced a roughly 1 kcal mol(-1) increase in coupling free energy of inhibition. The effects of these variants were essentially additive in the three combinations of double variants N59D/A158T, N59D/S215H, and A158T/S215H as well as in the triple variant N59D/A158T/S215H. Consequently, while the hydrogen-bonding network identified is likely involved in the inhibitory allosteric communication, a model requiring a linked chain of interactions connecting the sites is not supported by these data. Despite the fact that the allosteric activator of the bacterial PFK, MgADP, binds at the same allosteric site, the substitutions at positions 59, 158, and 215 do not have an equally dramatic effect on the binding affinity and the allosteric activation by MgADP. The effect of the S215H and N59D/A158T/S215H substitutions on the activation by MgADP could not be determined because of a dramatic drop in MgADP binding affinity that resulted from the S215H substitution. The single variants N59D and A158T supported binding but showed little change in the free energy of activation by MgADP compared to the wild type TtPFK. These results support previous suggestions that heterotropic inhibition and activation occur by different pathways prokaryotic PFK. PMID:25531642

McGresham, Maria S; Reinhart, Gregory D



Inhibition of granulocyte migration by tiotropium bromide  

PubMed Central

Study objectives Neutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS). Method AM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 ?g/ml). AM supernatant was tested for TNF?, IL8, IL6, LTB4, GM-CSF, MIP?/? and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 ?g/ml). Potential contribution of M1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors. Results Supernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNF? release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIP?/? release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition. Conclusion Our data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNF? mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation. PMID:21352583



Inhibition of Protein Synthesis by Cycloheximide (Actidione) in Chlorella  

Microsoft Academic Search

Cycloheximide is an antibiotic produced by Streptomyces griseus. It inhibits the growth of fungi1,2, algae3, protozoa4 and higher plants5, but has no effect on bacterial growth1. In yeast cells6,7 and mammalian cells8 cycloheximide inhibits both protein and DNA synthesis simultaneously, whereas the inhibition of RNA synthesis is delayed. With intact cells, it was not possible to resolve the controversy over

I. Morris



Method for inhibiting oxidation of metal sulfide-containing material  


The present invention provides means for inhibiting the oxidation of a metal sulfide-containing material, such as ore mine waste rock or metal sulfide taiulings, by coating the metal sulfide-containing material with an oxidation-inhibiting two-tail lipid coating (12) thereon, thereby inhibiting oxidation of the metal sulfide-containing material in acid mine drainage conditions. The lipids may be selected from phospholipids, sphingolipids, glycolipids and combinations thereof.

Elsetinow, Alicia; Borda, Michael J.; Schoonen, Martin A.; Strongin, Daniel R.



Synthesis and glycosidase inhibition of australine and its fluorinated derivatives.  


Australine (1), 7-epi-australine (2), and their C-7-fluorinated derivatives 4 and 5 have been synthesized efficiently from d-arabinose-derived cyclic nitrone 11. Fluorination at the C-7 position enhanced the inhibition against A. niger ?-glucosidase, and this constitutes the first example of fluorination substitution for a hydroxyl increasing the inhibition of any glycosidases. The enantiomers synthesized from nitrone ent-11 showed no inhibition of the corresponding enzymes. PMID:25621897

Li, Yi-Xian; Shimada, Yousuke; Sato, Kasumi; Kato, Atsushi; Zhang, Wei; Jia, Yue-Mei; Fleet, George W J; Xiao, Min; Yu, Chu-Yi



High molecular weight polysaccharide that binds and inhibits virus  


This invention provides a high molecular weight polysaccharide capable of binding to and inhibiting virus and related pharmaceutical formulations and methods on inhibiting viral infectivity and/or pathogenicity, as well as immunogenic compositions. The invention further methods of inhibiting the growth of cancer cells and of ameliorating a symptom of aging. Additionally, the invention provides methods of detecting and/or quantifying and/or isolating viruses.

Konowalchuk, Thomas W



Inhibition of the ablation rate of graphite by gaseous chlorine.  

NASA Technical Reports Server (NTRS)

Investigation of the inhibiting effect of gaseous chlorine on the ablation rate of graphite. It is shown that small amounts of chlorine gas, when present in a supersonic high-temperature air environment, can inhibit the ablation rate of graphite and depress its surface temperature below that measured in pure air. The ablation inhibition performance of chlorine is presented in graphs in terms of mass loss rate and surface temperature depression as a function of chlorine concentration.

Maahs, H. G.



The IFITM proteins inhibit HIV-1 infection.  


Type I interferon protects cells from virus infection through the induction of a group of genes collectively named interferon-stimulated genes (ISGs). In this study, we utilized short hairpin RNA (shRNA) to deplete ISGs in SupT1 cells in order to identify ISGs that suppress the production of human immunodeficiency virus type 1 (HIV-1). Among the ISG candidates thus identified were interferon-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, that potently inhibit HIV-1 replication at least partially through interfering with virus entry. Further mutagenesis analysis shows that the intracellular region, rather than the N- and C-terminal extracellular domains, is essential for the antiviral activity of IFITM1. Altogether, these data suggest that the IFITM proteins serve as important components of the innate immune system to restrict HIV-1 infection. PMID:21177806

Lu, Jennifer; Pan, Qinghua; Rong, Liwei; He, Wei; Liu, Shan-Lu; Liang, Chen



Behavioral inhibition and PTSD symptoms in veterans  

PubMed Central

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

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



Selective Raf Inhibition in Cancer Therapy  

PubMed Central

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

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



Behavioral inhibition and attentional network functioning.  


The goal of the present study was to examine the interrelations between the sensitivity of the Behavioral Inhibition System (BIS) and attentional network functioning (i.e., the orienting, alerting, and executive attentional networks), with the aim of identifying a potentially relevant mechanism for understanding the relation between BIS sensitivity and the pathogenesis of anxiety and its disorders. To this end, 99 participants were recruited from the community and administered a questionnaire assessing BIS sensitivity, as well as the Attentional Network Test. Results demonstrated a significant association between BIS sensitivity and enhanced orienting attention. Further, BIS sensitivity predicted orienting attention above and beyond relevant covariates, including state negative affect. Results are discussed in terms of their implications for understanding the role of BIS sensitivity in the pathogenesis of pathological anxiety. PMID:22017656

Tull, Matthew T; Maack, Danielle J; Viana, Andres G; Gratz, Kim L



Hydrogen sulfide inhibits human platelet aggregation.  


Gaseous mediators such as nitric oxide (NO) play a major regulatory role in the cardiovascular system homeostasis, including platelet aggregation. Here, we investigated whether hydrogen sulfide (H(2)S), a newly recognized endogenous mediator, can affects aggregation of human platelets, using sodium hydrogen sulfide (NaHS) as H(2)S-donor. NaHS inhibited platelet aggregation induced by ADP, collagen, epinephrine, arachidonic acid, thromboxane mimetic, U46619, and thrombin. H(2)S effect was not dependent by cAMP/cGMP generation, NO production or potassium-channels opening. NaHS concentrations (up to 10 mM) did not exert toxic effects on platelet viability. The possible protective role of endogenous H(2)S in cardiovascular system is discussed. PMID:17291489

Zagli, Giovanni; Patacchini, Riccardo; Trevisani, Marcello; Abbate, Rosanna; Cinotti, Sandro; Gensini, Gian Franco; Masotti, Giulio; Geppetti, Pierangelo



Learning and latent inhibition in old mice.  


The inhibitory component of selective attention has been compared in young (7-8 weeks) and older (9-10 months) female mice using the latent inhibition (LI) paradigm. LI consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In the present work, active avoidance of an electric footshock signaled with a sound was used. Avoidances of the electric footshocks were significantly reduced in old relative to young mice which did not differ regarding pain threshold. This likely results from a slower learning in old mice. LI was significantly present and of the same importance in both young (46%) and old (49%) mice. These results suggest that in 8-9 months-old mice, the learning ability is reduced but the inhibitory component of selective attention is not altered. PMID:11716988

Francès, H; Tebbakha, M R; Bourre, J M



Paliperidon mediated modification of cortical inhibition.  


Transcranial magnetic stimulation is a neurophysiological method which enables direct quantitative in vivo assessment of cortical excitability and inhibition. The aim of the study was to assess the impact of paliperidone on the motor threshold and cortical silent period, in a drug-naive patient, with first episode schizophrenia using this technique. Paliperidone monotherapy caused a significant reduction of severity of schizophrenic symptomatology in the patient. At the same time, a significant prolongation of the cortical silent period, from 118.68 ms before to 185.13 ms after therapy, occurred. Because the cortical silent period is a function of GABA(B) receptors, we can assume that paliperidone may have the ability to enhance GABA(B) receptor-mediated neurotransmission. PMID:19855366

Prikryl, Radovan; Ustohal, Libor; Kucerova, Hana Prikrylova; Ceskova, Eva



Selenium nanoparticles inhibit Staphylococcus aureus growth  

PubMed Central

Staphylococcus aureus is a key bacterium commonly found in numerous infections. S. aureus infections are difficult to treat due to their biofilm formation and documented antibiotic resistance. While selenium has been used for a wide range of applications including anticancer applications, the effects of selenium nanoparticles on microorganisms remain largely unknown to date. The objective of this in vitro study was thus to examine the growth of S. aureus in the presence of selenium nanoparticles. Results of this study provided the first evidence of strongly inhibited growth of S. aureus in the presence of selenium nanoparticles after 3, 4, and 5 hours at 7.8, 15.5, and 31 ?g/mL. The percentage of live bacteria also decreased in the presence of selenium nanoparticles. Therefore, this study suggests that selenium nanoparticles may be used to effectively prevent and treat S. aureus infections and thus should be further studied for such applications. PMID:21845045

Tran, Phong A; Webster, Thomas J



Inhibition of strigolactones promotes adventitious root formation  

PubMed Central

Roots that form from non-root tissues (adventitious roots) are crucial for cutting propagation in the forestry and horticulture industries. Strigolactone has been demonstrated to be an important regulator of these roots in both Arabidopsis and pea using strigolactone deficient mutants and exogenous hormone applications. Strigolactones are produced from a carotenoid precursor which can be blocked using the widely available but broad terpenoid biosynthesis blocker, fluridone. We demonstrate here that fluridone can be used to promote adventitious rooting in the model species Pisum sativum (pea). In addition, in the garden species Plumbago auriculata and Jasminium polyanthum fluridone was equally as successful at promoting roots as a commercial rooting compound containing NAA and IBA. Our findings demonstrate that inhibition of strigolactone signaling has the potential to be used to improve adventitious rooting in commercially relevant species. PMID:22580687

Beveridge, Christine A.; Geelen, Danny



Inhibition of Action, Thought, and Emotion: A Selective Neurobiological Review  

PubMed Central

The neural bases of inhibitory function are reviewed, covering data from paradigms assessing inhibition of motor responses (antisaccade, go/nogo, stop-signal), cognitive sets (e.g., Wisconsin Card Sort Test), and emotion (fear extinction). The frontal cortex supports performance on these paradigms, but the specific neural circuitry varies: response inhibition depends upon fronto-basal ganglia networks, inhibition of cognitive sets is supported by orbitofrontal cortex, and retention of fear extinction reflects ventromedial prefrontal cortexamygdala interactions. Inhibition is thus neurobiologically heterogeneous, although right ventrolateral prefrontal cortex may support a general inhibitory process. Dysfunctions in these circuits may contribute to psychopathological conditions marked by inhibitory deficits. PMID:19050749

Dillon, Daniel G.; Pizzagalli, Diego A.



Selective and nonselective inhibition of competitors in picture naming.  


The present study examined the relation between nonselective inhibition and selective inhibition in picture naming performance. Nonselective inhibition refers to the ability to suppress any unwanted response, whereas selective inhibition refers to the ability to suppress specific competing responses. The degree of competition in picture naming was manipulated by presenting targets along with distractor words that could be semantically related (e.g., a picture of a dog combined with the word cat) or unrelated (tree) to the picture name. The mean naming response time (RT) was longer in the related than in the unrelated condition, reflecting semantic interference. Delta plot analyses showed that participants with small mean semantic interference effects employed selective inhibition more effectively than did participants with larger semantic interference effects. The participants were also tested on the stop-signal task, which taps nonselective inhibition. Their performance on this task was correlated with their mean naming RT but, importantly, not with the selective inhibition indexed by the delta plot analyses and the magnitude of the semantic interference effect. These results indicate that nonselective inhibition ability and selective inhibition of competitors in picture naming are separable to some extent. PMID:23716003

Shao, Zeshu; Meyer, Antje S; Roelofs, Ardi



In Vitro Measurement of Pollen Tube Growth Inhibition  

PubMed Central

A method for estimating inhibition of pollen tube growth was developed. Pollen is placed in straight lines on an agar surface where it responds uniformly and predictably to aqueous solutions of germination-inhibiting substances located in wells at the ends of the lines. A scale of ratings, roughly corresponding to serial, doubled concentrations of inhibiting substances, was devised. Water-soluble organic solvents are relatively noninhibitory, salts are variable, and metabolic inhibitors have strong inhibitory effects. Pollens differ in their susceptibility to inhibition and in their response to particular substances. PMID:16658085

Martin, Franklin W.



Direct Inhibition of Plant Mitochondrial Respiration by Elevated CO2.  

PubMed Central

Doubling the concentration of atmospheric CO2 often inhibits plant respiration, but the mechanistic basis of this effect is unknown. We investigated the direct effects of increasing the concentration of CO2 by 360 [mu]L L-1 above ambient on O2 uptake in isolated mitochondria from soybean (Glycine max L. cv Ransom) cotyledons. Increasing the CO2 concentration inhibited the oxidation of succinate, external NADH, and succinate and external NADH combined. The inhibition was greater when mitochondria were preincubated for 10 min in the presence of the elevated CO2 concentration prior to the measurement of O2 uptake. Elevated CO2 concentration inhibited the salicylhydroxamic acid-resistant cytochrome pathway, but had no direct effect on the cyanide-resistant alternative pathway. We also investigated the direct effects of elevated CO2 concentration on the activities of cytochrome c oxidase and succinate dehydrogenase (SDH) and found that the activity of both enzymes was inhibited. The kinetics of inhibition of cytochrome c oxidase were time-dependent. The level of SDH inhibition depended on the concentration of succinate in the reaction mixture. Direct inhibition of respiration by elevated CO2 in plants and intact tissues may be due at least in part to the inhibition of cytochrome c oxidase and SDH. PMID:12226450

Gonzalez-Meler, M. A.; Ribas-Carbo, M.; Siedow, J. N.; Drake, B. G.



Inhibition of gastrin gene expression by somatostatin.  

PubMed Central

Previous studies performed in this laboratory have demonstrated somatostatin-containing cells in close proximity to gastrin cells in antral mucosa and have shown that somatostatin exerts a local regulatory effect on gastrin release. The present studies were directed to determine whether the effects of somatostatin on the antral gastrin cell involve pretranslational events. The effects of somatostatin on gastrin mRNA were determined by dot blot hybridization using a gastrin antisense RNA probe derived from human gastrin cDNA. Inclusion of somatostatin in the incubation medium caused a dose-dependent inhibition of steady-state gastrin mRNA. Conversely, when antral somatostatin was neutralized by the addition of specific somatostatin antibodies to the incubation medium, gastrin mRNA levels increased by 116 +/- 31% over control values (P less than 0.01). Northern blot hybridization of total antral RNA demonstrated a single major band with a molecular size of approximately 620 nucleotides, closely matching the predicted size of gastrin mRNA. The effect of somatostatin on the rate of gastrin gene transcription was examined using nuclear run-off transcription assays. Inclusion of antibodies to somatostatin in the incubation medium resulted in a 33.8 +/- 3.3% increase in gastrin gene transcriptional activity (P less than 0.01). These studies indicate that, in addition to its established effect on peptide release, somatostatin exerts inhibitory effects on antral gastrin cells at the pretranslational level. Although this inhibition appears to occur in part at the gene transcriptional level, the results also indicate that somatostatin may affect posttranscriptional processing of gastrin mRNA. Images PMID:2563264

Karnik, P S; Monahan, S J; Wolfe, M M



Structural basis of kynurenine 3-monooxygenase inhibition  

PubMed Central

Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (i.e. kynurenine pathway), leads to amelioration of Huntington’s disease-relevant phenotypes in yeast, fruit fly, and mouse models1–5, as well as a mouse model of Alzheimer’s disease3. KMO is a FAD-dependent monooxygenase, and is located in the outer mitochondrial membrane where it converts L-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders6, as well as cancer7,8, and several peripheral inflammatory conditions9. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained hitherto unknown. Here we report the first crystal structure of KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active site structure, preventing productive binding of the substrate kynurenine. Functional assays and targeted mutagenesis revealed that the active site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO:UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s diseases. PMID:23575632

Amaral, Marta; Levy, Colin; Heyes, Derren J.; Lafite, Pierre; Outeiro, Tiago F.; Giorgini, Flaviano; Leys, David; Scrutton, Nigel S.



Inhibition studies on Vibrio cholerae neuraminidase.  


A series of viral neuraminidase inhibitors showing no structural analogy to neuraminic acids have been tested to find whether they are effective inhibitors of V. cholerae neuraminidase, too. Here we report the results obtained with the N-phenyloxamic acid derivatives 2 to 6 (R-NH-CO-COOR'; R = -C6H5NO2, -C6H5OH, -C6H5NH2; R' = -H, -C2H5; see Table 1) and with simple aromatic compounds structurally related to R, i.e. 4-nitroaniline (7), N-acetyl-4-nitroaniline (8), 4-nitrophenol (9), 2,4-dinitrophenol (10), and 4-aminophenol (11) (see Table 2). The inhibitory effects of 2 to 11 were studied according to the method of Dixon[19] in 0.1m sodium acetate buffer, pH 5.5, 2mM CaCl2, at 37 degrees C using the benzyl-alpha-ketoside of N-acetyl-D-neuraminic acid (1) as a substrate. The compounds 2 to 11 are shown to be competitive inhibitors of the enzymatic hydrolysis of the alpha-ketoside 1. The competitive inhibition kinetics are supported by the method of Lineweaver and Burk[20]. The inhibition constants (Ki) are found to be in the range of 0.03 to 5.7 mM. The simple aromatic compounds 7 to 11 show higher inhibitory activities than the phenyloxamic acid derivatives 2 to 6. In addition, significant differences in the Ki values were observed within the two series of inhibitors, whereby those containing a nitro group were most effective. PMID:856712

Brossmer, R; Keilich, G; Ziegler, D



Nitric oxide synthases: structure, function and inhibition.  

PubMed Central

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

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



Aldose reductase inhibition suppresses airway inflammation.  


Airway inflammation induced by reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors is the hallmark of asthma, a prevalent chronic respiratory disease. In various cellular and animal models, we have recently demonstrated that, in response to multiple stimuli, aldose reductase (AKR1B1) regulates the inflammatory signals via NF-kappa B activation. Since NF-?B activation is implicated in asthma pathogenesis, we investigated whether AKR1B1 inhibition could prevent ovalbumin (Ova)- and ragweed pollen extract (RWE)-induced airway inflammation and hyper-responsiveness in mice models and tumor necrosis factor-alpha (TNF-?)-, lipopolysachharide (LPS)- and RWE-induced cytotoxic and inflammatory signals in primary human small airway epithelial cells (SAEC). Sensitization and challenge with Ova or RWE caused airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid, airway hyperresponsiveness, elevated IgE levels and release of Th2 cytokines in the airway and treatment with AKR1B1 inhibitors markedly reduced these pathological changes in mice. In SAEC, treatment with TNF-?, LPS or RWE induced apoptosis, reactive oxygen species generation, synthesis of inflammatory markers IL-6, IL-8, and PGE2 and activation of NF-?B and AP-1. Pharmacological inhibition prevented these changes suggesting that AKR1B1 mediates ROS induced inflammation in small airway epithelial cells. Our results indicate that AKR1B1 inhibitors may offer a novel therapeutic approach to treat inflammatory airway diseases such as asthma. PMID:21334316

Yadav, Umesh C S; Ramana, Kota V; Srivastava, Satish K



Milk Inhibits the Biological Activity of Ricin  

PubMed Central

Ricin is a highly toxic protein produced by the castor plant Ricinus communis. The toxin is relatively easy to isolate and can be used as a biological weapon. There is great interest in identifying effective inhibitors for ricin. In this study, we demonstrated by three independent assays that a component of reconstituted powdered milk has a high binding affinity to ricin. We discovered that milk can competitively bind to and reduce the amount of toxin available to asialofetuin type II, which is used as a model to study the binding of ricin to galactose cell-surface receptors. Milk also removes ricin bound to the microtiter plate. In parallel experiments, we demonstrated by activity assay and by immuno-PCR that milk can bind competitively to 1 ng/ml ricin, reducing the amount of toxin uptake by the cells, and thus inhibit the biological activity of ricin. The inhibitory effect of milk on ricin activity in Vero cells was at the same level as by anti-ricin antibodies. We also found that (a) milk did not inhibit ricin at concentrations of 10 or 100 ng/ml; (b) autoclaving 10 and 100 ng/ml ricin in DMEM at 121 °C for 30 min completely abolished activity; and (c) milk did not affect the activity of another ribosome inactivating protein, Shiga toxin type 2 (Stx2), produced by pathogenic Escherichia coli O157:H7. Unlike ricin, which is internalized into the cells via a galactose-binding site, Stx2 is internalized through the cell surface receptor glycolipid globotriasylceramides Gb3 and Gb4. These observations suggest that ricin toxicity may possibly be reduced at room temperature by a widely consumed natural liquid food. PMID:22733821

Rasooly, Reuven; He, Xiaohua; Friedman, Mendel



Emodin enhances osteogenesis and inhibits adipogenesis  

PubMed Central

Background It has been suggested that the formation of osteoblasts in bone marrow is closely associated with adipogenesis, and the balance between osteogenesis and adipogenesis differentiation of MSCs (mesenchymal stem cells) is disrupted in osteoporosis. In order to improve the treatment of osteoporosis, available agents with roles of regulating the balance is highly desirable. Emodin is a natural anthraquinone derivative extracted from Chinese herbs, which have been used to treat bone diseases for thousands of years. However, the underlying molecular mechanisms of emodin in modulating osteogenesis and adipogenesis remain poorly understood. Methods The molecular mechanisms of emodin on the processes of osteogenesis and adipogenesis in ovariectomized mouse and BMSCs (bone marrow mesenchymal stem cells) have been studied. We have analyzed the effects of emodin in vivo and in vitro. Female ICR mice were assigned to three groups: sham group, ovariectomy group, emodin group. Efficacy was evaluated by H&E, immunohistochemical assay and Micro-CT. In vitro, we analyze the effect of emodin—at concentrations between 0.1 ?M and 10 ?M-on the processes of inducing osteogenesis and inhibiting adipogenesis in BMSCs by ALP, Oil red O staining, real time RT-PCR and western blot. Results As our experiment shows that emodin could increase the number of osteoblast, BMD (bone mineral density), BV/TV (trabecular bone volume fraction), Tb.N (trabecular number) and Conn.D (connectivity density) of OVX (ovariectomized) mice and decrease the bone marrow fat tissue and adipocytes. The genes and proteins expression of osteogenesis markers, such as Runx2, osterix, collagen type I, osteocalcin, or ALP were up-regulated. While, the genes and proteins involved in adipogenesis, PPAR?, C/EBP? and ap2 were down-regulated. Conclusion It proves that emodin inhibits adipocyte differentiation and enhances osteoblast differentiation from BMSCs. PMID:24565373



Cartilage proteoglycans inhibit fibronectin-mediated adhesion  

NASA Astrophysics Data System (ADS)

Normal tissues and organs show, on histological examination, a pattern of cellular and acellular zones that is characteristic and unique for each organ or tissue. This pattern is maintained in health but is sometimes destroyed by disease. For example, in mobile joints, the articular surfaces consist of relatively acellular hyaline cartilage, and the joint space is enclosed by a capsule of loose connective tissue with a lining of fibroblasts and macrophages. In the normal joint these cells are confined to the synovial lining and the articular surface remains acellular. In in vitro culture, macrophages and their precursor monocytes are very adhesive, and fibroblasts can migrate and overgrow surfaces such as collagen or plastic used for tissue culture. The fibroblasts adhere to collagen by means of fibronectin, which they synthesize and secrete1. Because the collagen of cartilage is capable of binding serum fibronectin2 and fibronectin is present in cartilage during its development3, these cells should, in theory, slowly migrate from the synovial lining to the articular surface. It is their absence from the articular cartilage in normal circumstances, and then presence in such pathological states as rheumatoid arthritis, that is striking. We therefore set out to determine whether a component of cartilage could prevent fibroblast adherence in a defined adhesion assay. As normal cartilage is composed of 50% proteoglycans and 50% collagen by dry weight4, we tested the possibility that the proteoglycans in cartilage inhibit fibroblast adhesion to collagen. We present here evidence that fibroblast spreading and adhesion to collagenous substrates is inhibited by cartilage proteoglycans.

Rich, A. M.; Pearlstein, E.; Weissmann, G.; Hoffstein, S. T.



Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase.  


Clopidogrel, like the homologous thienopyridine derivative ticlopidine, selectively inhibits platelet aggregation induced by ADP. We have previously described two nucleotide-binding sites on platelets related to ADP-mediated platelet responses. The first is a high-affinity binding site for 2-methylthio-ADP (2-MeSADP) that is linked to the inhibition of stimulated adenylate cyclase. The second is the 100-kd exofacial membrane protein aggregin, which is labeled by the reactive ADP analogue 5'-p-fluorosulfonylbenzoyl adenosine (FSBA) that is related to shape change and aggregation. We set out to determine if either of these sites is blocked in vivo by clopidogrel or its active metabolite. Six subjects were given clopidogrel (75 mg/day for 10 days) in a double-blind crossover experiment. All of the subjects developed prolonged bleeding times while taking the drug. The rate of onset of the effect on bleeding time varied among subjects. Platelet aggregation induced by ADP or thrombin was significantly impaired by the drug treatment, but no effect was detected on shape change. The incorporation of [3H]FSBA into aggregin was also unaffected. Inhibition of adenylate cyclase by ADP or by 2-MeSADP was greatly reduced in all subjects, and in the case of 2-MeSADP, there was evidence for a noncompetitive effect. Inhibition of adenylate cyclase by epinephrine was unaffected. In the three subjects for whom binding measurements were made, the number of binding sites for [32P]2-MeSADP was reduced from 534 +/- 44 molecules per platelet during control and placebo periods (11 determinations) to 199 +/- 78 molecules per platelet during drug treatment (three determinations). There was no consistent change in the binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1558834

Mills, D C; Puri, R; Hu, C J; Minniti, C; Grana, G; Freedman, M D; Colman, R F; Colman, R W



Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression  

PubMed Central

Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF–HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF. PMID:22271573

Schulz, Ramona; Marchenko, Natalia D.; Holembowski, Lena; Fingerle-Rowson, Günter; Pesic, Marina; Zender, Lars; Dobbelstein, Matthias



Novel PKC?-mediated phosphorylation site(s) on cofilin and their potential role in terminating histamine release  

PubMed Central

Using specific inhibitors, kinase-negative mutants, and small interfering RNA against protein kinase C? (PKC?) or PKC?I, we find that PKC?I positively regulates degranulation in rat basophilic leukemia–2H3 cells, whereas PKC? negatively regulates degranulation. Mass spectrometric and mutagenic analyses reveal that PKC? phosphorylates cofilin at Ser-23 and/or Ser-24 during degranulation. Overexpression of a nonphosphorylatable form (S23,24A), but not that of a mutant-mimicking phosphorylated form (S23,24E), increases degranulation. Furthermore, the S23,24A mutant binds to F-actin and retains its depolymerizing and/or cleavage activity; conversely, the S23,24E mutant is unable to sever actin filaments, resulting in F-actin polymerization. In addition, the S23,24E mutant preferentially binds to the 14-3-3? protein. Fluorescence-activated cell sorting analysis with fluorescein isothiocyanate–phalloidin and simultaneous observation of degranulation, PKC translocation, and actin polymerization reveals that during degranulation, actin polymerization is dependent on PKC? activity. These results indicate that a novel PKC?-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize F-actin and bind to 14-3-3?, thereby promoting F-actin polymerization, which is necessary for cessation of degranulation. PMID:22855535

Sakuma, Megumi; Shirai, Yasuhito; Yoshino, Ken-ichi; Kuramasu, Maho; Nakamura, Tomofumi; Yanagita, Toshihiko; Mizuno, Kensaku; Hide, Izumi; Nakata, Yoshihiro; Saito, Naoaki



Cycloheximide: Aspects of Inhibition of Protein Synthesis in Mammalian Cells  

Microsoft Academic Search

Cycloheximide and acetoxy-cycloheximide specifically inhibit protein synthesis in L-cells growing in suspension culture. In extracts of rat liver, the drugs inhibit transfer of amino acid from soluble RNA to polypeptide. Unlike puromycin, these drugs do not accelerate release of nascent polypeptide chains. The drugs have no effect on protein synthesis in extracts of Escherichia coli.

H. L. Ennis; M. Lubin



Fermentation of lignocellulosic hydrolysates. I: inhibition and detoxification  

Microsoft Academic Search

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

Eva Palmqvist; Bärbel Hahn-Hägerdal



Frontostriatal Dysfunction During Response Inhibition in Williams Syndrome  

E-print Network

Frontostriatal Dysfunction During Response Inhibition in Williams Syndrome Dean Mobbs, Mark A: Williams syndrome (WS) has provided researchers with an exciting opportunity to understand the complex Words: fMRI, Go/NoGo, prefrontal cortex, response inhibition, striatum, Williams syndrome W illiams

Bellugi, Ursula

First Page Previous Page 1 2 3 4 5 6 7 8 9 10 11