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Partial Inhibition (partial + inhibition)
Selected AbstractsSelective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liverHEPATOLOGY, Issue 2 2002Ping Zhao Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N -acetyl- p -benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1). However, CYP2E1 induction appears to be insufficient to explain the claimed magnitude of the interaction. We assessed the role of selective depletion of liver mitochondrial glutathione (GSH) by chronic ethanol. Rats were fed the Lieber-DeCarli diet for 10 days or 6 weeks. APAP toxicity in liver slices (% glutathione- S -transferase , released to the medium, GST release) and NAPQI toxicity in isolated liver mitochondria (succinate dehydrogenase inactivation, SDH) from these rats were compared with pair-fed controls. Ethanol induced CYP2E1 in both the 10-day and 6-week groups by ,2-fold. APAP toxicity in liver slices was higher in the 6-week ethanol group than the 10-day ethanol group. Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only. Ethanol selectively depleted liver mitochondrial GSH only in the 6-week group (by 52%) without altering cytosolic GSH. Significantly greater GSH loss and APAP covalent binding were observed in liver slice mitochondria of the 6-week ethanol group. Isolated mitochondria of the 6-week ethanol group were ,50% more susceptible to NAPQI (25-165 ,mol/L) induced SDH inactivation. This increased susceptibility was reproduced in pair-fed control mitochondria pretreated with diethylmaleate. In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH. [source] Characterization of a human monoclonal antibody obtained after immunization with plasma vaccine and a booster with recombinant-DNA hepatitis B vaccineJOURNAL OF MEDICAL VIROLOGY, Issue 3 2002R.A. Heijtink Abstract A human monoclonal antibody type IgG4, designated 1Ff4, was obtained by Epstein Barr virus transformation of peripheral blood lymphocytes from a hepatitis B vaccinee (HB-VAX: plasma-derived vaccine) after one boost of yeast recombinant DNA derived vaccine (Engerix-B). 1Ff4 binds preferentially to HBsAg/adw2 and HBsAg/ayw1. In binding experiments, it competes with antibodies induced by vaccination with HB-VAX-DNA (yeast recombinant) and HB-VAX (plasma-derived vaccine). 1Ff4 competes in part with a monoclonal antibody for the w/r region. Partial inhibition of binding of HBsAg/adw2 to solid phase anti-HBs was detected, resembling inhibition obtained using other human monoclonal specific for the "a"-loop. 1Ff4 does not bind to linear peptides covering the two "a"-loops or to an adw2/G145R mutant, its binding to wild type HBsAg strongly depends on the presence of disulphide bonds. In a large series of HBsAg-positive samples from an endemic area, 1Ff4 antibodies were successfully used to discriminate between an adw2 and an adrq+ strain. The characterisation of 1Ff4 and other human monoclonal anti-HBs antibodies may help to understand the fine specificity of protective antibodies elicited by immunization. J. Med. Virol. 66:304-311, 2002. © 2002 Wiley-Liss, Inc. [source] Sensitivity of Actinobacillus actinomycetemcomitans and Capnocytophaga spp. to the bactericidal action of LL-37: a cathelicidin found in human leukocytes and epitheliumMOLECULAR ORAL MICROBIOLOGY, Issue 4 2000D. Tanaka The bactericidal activity of synthetic LL-37, a cathelicidin, was assessed against Actinobacillus actinomycetemcomitans (three strains) and Capnocytophaga spp. (three strains). All strains were sensitive to LL-37, and exhibited 99% effective dose of 7.5-to-11.6 ,g/ml. An amidated form of LL-37, pentamide-37, killed with about the same efficacy as LL-37. Partial inhibition of killing was noted at physiologic concentrations of NaCl, and complete inhibition was observed at 400 mM NaCl. At approximately the 99% effective dose , i.e., 10 ,g/ml , LL-37 also lost activity against A. actinomycetemcomitans in the presence of native or heat-inactivated 10,15% normal human AB serum. Pentamide-37 was less sensitive to serum inhibition than LL-37. In conclusion, certain oral, gram-negative bacteria are sensitive to the bactericidal activity of LL-37 at low concentrations of serum and salt, a condition likely to be found within the membrane-delimited phagolysosome. Modified forms of LL-37, such as pentamide-37, may be more suitable for future therapeutic application in the presence of serum. [source] Role of mitogen-activated protein kinase cascades in P2Y receptor-mediated trophic activation of astroglial cells ,DRUG DEVELOPMENT RESEARCH, Issue 2-3 2001Joseph T. Neary Abstract The trophic actions of extracellular nucleotides and nucleosides on astroglial cells in the central nervous system may be important in development as well as injury and repair. Here we summarize recent findings on the signal transduction mechanisms and gene expression that mediate the trophic effects of extracellular ATP on astrocyte cultures, with a particular emphasis on mitogenesis. Activation of ATP/P2Y receptors leads to the stimulation of mitogen-activated protein kinase (MAPK) cascades, which play a crucial role in cellular proliferation, differentiation, and survival. Inhibition of ERK and p38, members of two distinct MAPK cascades, interferes with the ability of extracellular ATP to stimulate astrocyte proliferation, thereby indicating their importance in mitogenic signaling by P2Y receptors. Signaling from P2Y receptors to ERK involves phospholipase D and a calcium-independent protein kinase C isoform, PKC; this pathway is independent of the phosphatidylinositol-phospholipase C / calcium pathway which is also coupled to P2Y receptors. Pharmacological studies suggest that astrocytes may express an as-yet uncloned P2Y receptor that recruits a novel MEK activator in the ERK cascade. Extracellular ATP can also potentiate fibroblast growth factor (FGF)-2-induced proliferation, and studies on interactions between ATP and FGF-2 signaling pathways have revealed that although ATP does not activate cRaf-1, the first protein kinase in the ERK cascade, it can reduce cRaf-1 activation by FGF-2. As intermediate levels of Raf activity stimulate the cell cycle, the partial inhibition of FGF-induced Raf activity by ATP may contribute to the enhancing effect of ATP on FGF-2-induced astrocyte proliferation. Activation of P2Y receptors also leads to nuclear signaling, and the use of DNA arrays has shown that treatment of astrocytes with extracellular ATP results in the up- and downregulation of a number of genes; studies to determine which of these genes are regulated by MAPKs are now in progress. Elucidation of the components of MAPK pathways linked to P2Y receptors and subsequent changes in gene expression may provide targets for a new avenue of drug development aimed at the management of astrogliosis which occurs in many types of neurological disorders and neurodegeneration. Drug Dev. Res. 53:158,165, 2001. Published 2001 Wiley-Liss, Inc. [source] Effects of trimetazidine, a partial inhibitor of fatty acid oxidation, on ventricular function and survival after myocardial infarction and reperfusion in the ratFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010Frederic Mouquet Abstract Trimetazidine (TMZ), a partial inhibitor of fatty acid oxidation, has been effective in treating chronic angina, but its effects on the development of post-myocardial infarction (MI) left ventricular remodeling are not defined. In this study, we tested whether chronic pre-MI administration of TMZ would be beneficial during and after acute MI. Two-hundred male Wistar rats were studied in four groups: sham + TMZ diet (n = 20), sham + control diet (n = 20), MI + TMZ diet (n = 80), and MI + control diet (n = 80) splitted into one short-term and one long-term experiments. Sham surgery consisted of a thoracotomy without coronary ligation. MI was induced by coronary occlusion followed by reperfusion. Left ventricle (LV) function and remodeling were assessed by serial echocardiography throughout a 24-week post-MI period. LV remodeling was also assessed by quantitative histological analysis of post-MI scar formation at 24 weeks post-MI. During the short-term experiment, 10/80 rats died after MI, with no difference between groups (MI + control = 7/40, MI + TMZ = 3/40, P = 0.3). In the long-term experiment, the deaths occurred irregularly over the 24 weeks with no difference between groups (MI + control = 16% mortality, MI + TMZ = 17%, P = 0.8). There was no difference between groups as regard to LV ejection fraction (MI + control = 36 ± 13%, MI + TMZ = 35 ± 13%, P = 0.6). In this experimental model, TMZ had no effects on the post-MI occurrence of LV dysfunction or remodeling. Further investigations are warranted to assess whether the partial inhibition of fatty acid oxidation may limit the ability of the heart to respond to acute severe stress. [source] Gastrointestinal, selective airways and urinary bladder relaxant effects of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Ca2+ channelsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008Anwarul Hassan Gilani Abstract This study describes the spasmolytic, antidiarrhoeal, antisecretory, bronchodilatory and urinary bladder relaxant properties of Hyoscyamus niger to rationalize some of its medicinal uses. The crude extract of H. niger seeds (Hn.Cr) caused a complete concentration-dependent relaxation of spontaneous contractions of rabbit jejunum, similar to that caused by verapamil, whereas atropine produced partial inhibition. Hn.Cr inhibited contractions induced by carbachol (1 ,m) and K+ (80 mm) in a pattern similar to that of dicyclomine, but different from verapamil and atropine. Hn.Cr shifted the Ca2+ concentration,response curves to the right, similar to that caused by verapamil and dicyclomine, suggesting a Ca2+ channel-blocking mechanism in addition to an anticholinergic effect. In the guinea-pig ileum, Hn.Cr produced a rightward parallel shift of the acetylcholine curves, followed by a non-parallel shift with suppression of the maximum response at a higher concentration, similar to that caused by dicyclomine, but different from that of verapamil and atropine. Hn.Cr exhibited antidiarrhoeal and antisecretory effects against castor oil-induced diarrhoea and intestinal fluid accumulation in mice. In guinea-pig trachea and rabbit urinary bladder tissues, Hn.Cr caused relaxation of carbachol (1 ,m) and K+ (80 mm) induced contractions at around 10 and 25 times lower concentrations than in gut, respectively, and shifted carbachol curves to the right. Only the organic fractions of the extract had a Ca2+ antagonist effect, whereas both organic and aqueous fractions had anticholinergic effect. A constituent, ,-sitosterol exhibited Ca2+ channel-blocking action. These results suggest that the antispasmodic effect of H. niger is mediated through a combination of anticholinergic and Ca2+ antagonist mechanisms. The relaxant effects of Hn.Cr occur at much lower concentrations in the trachea and bladder. This study offers explanations for the medicinal use of H. niger in treating gastrointestinal and respiratory disorders and bladder hyperactivity. [source] Integrating laccase,mediator treatment into an industrial-type sequence for totally chlorine-free bleaching of eucalypt kraft pulpJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 7 2006David Ibarra Abstract Enzymatic delignification using the high-redox potential thermostable laccase from the fungus Pycnoporus cinnabarinus and a chemical mediator (1-hydroxybenzotriazole) was investigated to improve totally chlorine-free (TCF) bleaching of Eucalyptus globulus kraft pulps. Different points of incorporation of the enzyme treatment into an industrial-type bleaching sequence (consisting of double oxygen, chelation and peroxide stages) were investigated in pressurized laboratory reactors. The best final pulp properties were obtained using an OOLQPoP sequence, where a laccase,mediator stage (L) was incorporated between double oxygen and chelation. The worse results, when the enzymatic and chelation treatments were combined in a unique stage, seemed related to partial inhibition of laccase-mediator activity by the chelator. The new TCF sequence including the laccase stage permitted to improve eucalypt pulp delignification to values around kappa 5 (hexenuronic acid contribution over 50%) compared to kappa 7 using only TCF chemical reagents. In a similar way, the final brightness obtained, over 91% ISO, was 3,4 points higher than that obtained in the chemical sequences. Although technical and economic issues are to be solved, the results obtained show the feasibility of integrating a laccase,mediator treatment into a TCF sequence for bleaching eucalypt kraft pulp. Copyright © 2006 Society of Chemical Industry [source] Ca2+ -induced permeabilization promotes free radical release from rat brain mitochondria with partially inhibited complex IJOURNAL OF NEUROCHEMISTRY, Issue 3 2005Tatyana V. Votyakova Abstract Mitochondrial complex I dysfunction has been implicated in a number of brain pathologies, putatively owing to an increased rate of reactive oxygen species (ROS) release. However, the mechanisms regulating the ROS burden are poorly understood. In this study we investigated the effect of Ca2+ loads on ROS release from rat brain mitochondria with complex I partially inhibited by rotenone. The addition of 20 nm rotenone to brain mitochondria increased ROS release. Ca2+ (100 µm) alone had no effect on ROS release, but greatly potentiated the effects of rotenone. The effect of Ca2+ was decreased by ruthenium red. Ca2+ -challenged mitochondria lose about 88% of their glutathione and 46% of their cytochrome c under these conditions, although this depends only on Ca2+ loading and not complex I inhibition. ADP in combination with oligomycin decreased the loss of glutathione and cytochrome c and free radical generation. Cyclosporin A alone was ineffective in preventing these effects, but augmented the protection provided by ADP and oligomycin. Non-specific permeabilization of mitochondria with alamethicin also increased the ROS signal, but only when combined with partial inhibition of complex I. These results demonstrate that Ca2+ can greatly increase ROS release by brain mitochondria when complex I is impaired. [source] Fibroblast growth factor-9 inhibits astrocyte differentiation of adult mouse neural progenitor cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 10 2009Maggie Lum Abstract Fibroblast growth factor-9 (FGF9) is expressed in the CNS and is reported to be a mitogen for glial cells, to promote neuronal survival, and to retard oligodendrocyte differentiation. Here we examined the effects of FGF9 on the differentiation, survival, and proliferation of adult neural progenitor cells derived from the adult mouse subventricular zone. FGF9 by itself induced neurosphere proliferation, but its effects were modest compared with those of epidermal growth factor and FGF2. When neurospheres were dissociated and plated for differentiation, FGF9 increased total cell number over time in a dose-dependent manner. Ki67 immunostaining and bromodeoxyuridine incorporation indicated that this was at least partially due to the continued presence of proliferative nestin-positive neural progenitor cells and ,III tubulin-positive neuronal precursors. FGF9 also promoted cell survival as indicated by a decreased number of TUNEL-positive cells over time. Assessment of differentiation showed that FGF9 increased neuron generation that reflected the increase in total cell number; however, the percentage of progenitor cells differentiating into neurons was slightly decreased. FGF9 had a modest effect on oligodendrocyte generation, although it appeared to slow the maturation of oligodenrocytes at higher concentrations. The most marked effect on differentiation was an almost total lack of glial fibrillary acidic protein (GFAP)-positive astrocytes up to 7 days following FGF9 addition, indicating that astrocyte differentiation was strongly inhibited. Total inhibition required prolonged treatment, although a 1-hr pulse was sufficient for partial inhibition, and bone morphogenic protein-4 could partially overcome the FGF9 inhibition of astrocyte differentiation. FGF9 therefore has multiple effects on adult neural precursor cell function, enhancing neuronal precursor proliferation and specifically inhibiting GFAP expression. © 2009 Wiley-Liss, Inc. [source] Differential phosphorylation of myosin light chain (Thr)18 and (Ser)19 and functional implications in plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2010T. M. GETZ Summary. Background:, Myosin IIA is an essential platelet contractile protein that is regulated by phosphorylation of its regulatory light chain (MLC) on residues (Thr)18 and (Ser)19 via the myosin light chain kinase (MLCK). Objective:, The present study was carried out to elucidate the mechanisms regulating MLC (Ser)19 and (Thr)18 phosphorylation and the functional consequence of each phosphorylation event in platelets. Results:, Induction of 2MeSADP-induced shape change occurs within 5 s along with robust phosphorylation of MLC (Ser)19 with minimal phosphorylation of MLC (Thr)18. Selective activation of G12/13 produces both slow shape change and comparably slow MLC (Thr)18 and (Ser)19 phosphorylation. Stimulation with agonists that trigger ATP secretion caused rapid MLC (Ser)19 phosphorylation while MLC (Thr)18 phosphorylation was coincident with secretion. Platelets treated with p160ROCK inhibitor Y-27632 exhibited a partial inhibition in secretion and had a substantial inhibition in MLC (Thr)18 phosphorylation without effecting MLC (Ser)19 phosphorylation. These data suggest that phosphorylation of MLC (Ser)19 is downstream of Gq/Ca2+ -dependent mechanisms and sufficient for shape change, whereas MLC (Thr)18 phosphorylation is substantially downstream of G12/13 -regulated Rho kinase pathways and necessary, probably in concert with MLC (Ser)19 phosphorylation, for full contractile activity leading to dense granule secretion. Overall, we suggest that the amplitude of the platelet contractile response is differentially regulated by a least two different signaling pathways, which lead to different phosphorylation patterns of the myosin light chain, and this mechanism results in a graded response rather than a simple on/off switch. [source] Salivary immunoglobulin A directed to oral microbial GroEL in patients with periodontitis and their potential protective roleMOLECULAR ORAL MICROBIOLOGY, Issue 5 2006M. Fukui The aim of this study was to identify salivary immunoglobulin A (IgA) directed to oral microbial GroEL in patients with periodontitis and to demonstrate their potential protective role through a reduction of inflammatory cytokine production induced by microbial GroEL. Using five different proteins belonging to the heat-shock protein 60 family, Western immunoblot analysis of salivary IgA from 63 subjects revealed immunoreactivities with Campylobacter rectus GroEL and Porphyromonas gingivalis GroEL in subjects with periodontitis (P < 0.05) compared to control subjects. Using the BIACORE 1000 to measure the salivary IgA titers directed towards C. rectus GroEL, high resonance unit (RU) values were observed in the saliva samples from patients with periodontitis (P < 0.01). Furthermore, the number of teeth with deep pocket depth (,5 mm) showed a high correlation coefficient with the RU value (r = 0.50, P < 0.01). C. rectus GroEL possessed the ability to stimulate the production of interleukin-6 by gingival fibroblasts. Interestingly, salivary IgA antibody directed to C. rectus GroEL caused a partial inhibition of interleukin-6 production. This study showed a relationship between high levels of salivary IgA directed to GroEL and periodontal disease severity. Although additional investigations are required, salivary IgA to GroEL may have a protective role by reducing the inflammatory response induced by GroEL derived from periodontopathogenic bacteria. [source] The Bmi1 polycomb gene as a target for therapies against retinal degenerationACTA OPHTHALMOLOGICA, Issue 2009Y ARSENIJEVIC Purpose In several neurodegenerative diseases the reactivation of cell cycle proteins is a key event that precedes neuronal apoptosis. We asked whether a similar phenomenon occurs in Rd1 mice, a model of retinitis pigmentosa widely used to study photoreceptor (PR) loss. Methods We used different knockout mouse models to reveal whether proteins involved in the cell cycle regulation are responsible for photoreceptor loss in the Rd1 mouse. Results At P12, an early stage of the disease, Rd1 mice displayed an increased expression of CDK4 and CDK2 among PR nuclei. PRs also undergo DNA synthesis. At P12, the polycomb protein Bmi1 was expressed in virtually all the nuclei in the inner and outer nuclear layer of both wild-type (WT) and Rd1 mice. Bmi1 promotes cell cycle progression via the repression of tumor suppressor genes. We reasoned that Bmi1 deletion could impede the aberrant CDK reactivation that characterizes neuronal apoptosis and may therefore delay retinal degeneration. We compared the histology of WT, Rd1 and Rd1;Bmi1-/- and observed the presence of 7 rows of PRs in Rd1;Bmi1-/- mice at P33, while Rd1 littermates displayed a single scattered row of PRs. ERG recordings revealed the ability of Rd1:Bmi1-/- retinas to respond to light stimuli. Both DNA synthesis and CDK4 were strongly decreased in Rd1;Bmi1-/- mice, respectively by 70% and 50% as compared to Rd1 littermates. Conclusion In conclusion, our data show for the first time a mechanism of retina degeneration involving a reactivation of the cell cycle that precedes PR death in Rd1 mice and reveal that the partial inhibition of cell cycle re-entry strongly delays PR loss. [source] Anaphylaxis after hamster bites , identification of a novel allergenCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2004D. L. Lim Summary Background Hamsters are popular household pets and anaphylaxis after their bites have described. However, the putative allergen has not been identified. Objective This study was conducted to identify the allergen causing dwarf hamster (Phodopus sungoris) bite-induced anaphylaxis. Methods Two children with hamster bite-induced anaphylaxis were enrolled. They both had negative results to skin testing and specific IgE to hamster epithelium. However, they were both allergic to Dermatophagoides pteronyssinus (Der p). Identification of the putative IgE-binding allergens from the hamster saliva was performed using immunoblot analysis. Results A specific IgE-binding component at 21 kD in the hamster saliva was identified. ELISA inhibition tests showed partial inhibition with Der p. Conclusions The putative allergen from the hamster saliva causing dwarf hamster-induced anaphylaxis was identified. Possible cross-reactivity with Der p was demonstrated. Further studies will be needed to identify the exact nature and function of this allergen. [source] Neural correlates of successful and partial inhibitions in children: An ERP studyDEVELOPMENTAL PSYCHOBIOLOGY, Issue 7 2009Lucy Cragg Abstract This experiment used event-related potentials (ERPs) to investigate the neural processes underlying the development of response inhibition in a modified version of the go/no-go paradigm [Cragg and Nation [2008] Developmental Science 11(6): 819,827]. N2 and P3 ERP components on correct go trials and partial and successful inhibitions were compared in 7- and 9-year-old children. A larger N2 effect on successful inhibitions was found in 9-year-olds compared to 7-year-olds at fronto-central electrodes. N2 amplitude was positively related to behavioral performance in the 7-year-olds suggesting it may reflect inhibitory processes; however, this relationship was not present in the 9-year-olds. Age differences were also apparent in the go P3, perhaps indicating differences in stimulus processing. The no-go P3 component was larger on successful than partial inhibitions. In contrast, there was no difference in N2 amplitude between partial and successful inhibitions. A significant difference was found in N2 latency however. This suggests that inhibitory processes are similar in both cases but initiated earlier on successful inhibitions. N2 latency was also shorter in 9-year-olds than 7-year-olds supporting an increase in the efficiency of response inhibition with age. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 533,543, 2009. [source] | |||||||||||||