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Synthesis Inhibitor (synthesis + inhibitor)
Kinds of Synthesis Inhibitor Terms modified by Synthesis Inhibitor Selected AbstractsFR171456, a Novel Cholesterol Synthesis Inhibitor Produced by Sporormiella minima No. 15604.CHEMINFORM, Issue 38 2004Part 1. Abstract For Abstract see ChemInform Abstract in Full Text. [source] The Development of New Bicyclic Pyrazole-Based Cytokine Synthesis Inhibitors.CHEMINFORM, Issue 3 2005Jennifer A. Townes Abstract For Abstract see ChemInform Abstract in Full Text. [source] Protein synthesis inhibition before or after stress exposure results in divergent endocrine and BDNF responses disassociated from behavioral responsesDEPRESSION AND ANXIETY, Issue 5 2008Nitsan Kozlovsky Ph.D. Abstract This study aimed to assess the effects of anisomycin, a protein synthesis inhibitor, on behavioral responses, brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels, and circulating corticosterone in rats,when administered before or after initial exposure to a predator scent stress stimulus. Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and exaggerated startle reaction as well as corticosterone levels and mRNA BDNF and TrkB were compared in rats exposed to predator stress, microinjected with anisomycin before or after stress exposure. Administration of anisomycin before or after stress exposure reduced anxiety-like behavior in the elevated plus-maze and reduced the mean startle amplitude 7 days postexposure. Although the behavioral responses were similar when anisomycin was microinjected before or after stress exposure, the levels of mRNAs for BDNF and TrkB, which play a role in modulation of synaptic plasticity and the consolidation process, showed varying responses. Depression and Anxiety 0:1,11, 2007. © 2007 Wiley-Liss, Inc. [source] Oral toxicity of the cyanobacterial toxin cylindrospermopsin in male Swiss albino mice: Determination of no observed adverse effect level for deriving a drinking water guideline valueENVIRONMENTAL TOXICOLOGY, Issue 2 2003A. R. Humpage Abstract The cyanobacterial toxin cylindrospermopsin (CYN) is a frequent contaminant of freshwaters throughout the world, including those that are sources of drinking water. The first cases of human poisoning attributed to this toxin occurred from a treated drinking water supply in Queensland, Australia, in 1979. The toxin causes extensive damage to the liver, kidneys, spleen, heart, and other organs. It is known to be a potent protein synthesis inhibitor, but there is mounting evidence for genotoxicity and that it metabolizes to even more toxic forms. As part of a risk assessment process leading to a guideline for a safe drinking water level for this toxin, we performed a series of experiments to determine a no-observed-adverse-effect level (NOAEL) for this toxin. In the first trial male mice were exposed to CYN-containing cyanobacterial extract in their drinking water (0,657 ,g CYN kg,1 day,1) for 10 weeks. In the second trial mice received purified CYN by daily gavage (0,240 ,g CYN kg,1 day,1) for 11 weeks. Body and organ weights were recorded; urine, serum, and hematology analyses were performed; and histopathological examination of tissues was carried out. Body weights were significantly increased at low doses (30 and 60 ,g kg,1 day,1) and decreased at high doses (432 and 657 ,g kg,1 day,1). Liver and kidney weights were significantly increased at doses of 240 ,g kg,1 day,1 and 60 ,g kg,1 day,1, respectively. Serum bilirubin levels were significantly increased and bile acids significantly decreased at doses of 216 ,g kg day,1 and greater. Urine total protein was significantly decreased at doses above 60 ,g kg,1 day,1. The kidney appeared to be the more sensitive organ to this toxin. If it is assumed that increased organ weights and changes in functional capacity are responses to an underlying toxic effect, then the NOAEL based on this data is 30 ,g kg,1 day,1, which, with standard calculations and uncertainty factors, provides a proposed guideline safety value of 1 ,g/L in drinking water. © 2003 Wiley Periodicals, Inc. Environ Toxicol 18: 94,103, 2003. [source] Synergistic interaction of endocrine-disrupting chemicals: Model development using an ecdysone receptor antagonist and a hormone synthesis inhibitorENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2004Xueyan Mu Abstract Endocrine toxicants can interfere with hormone signaling through various mechanisms. Some of these mechanisms are interrelated in a manner that might result in synergistic interactions. Here we tested the hypothesis that combined exposure to chemicals that inhibit hormone synthesis and that function as hormone receptor antagonists would result in greater-than-additive toxicity. This hypothesis was tested by assessing the effects of the ecdysteroid-synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone on ecdysteroid-regulated development in the crustacean Daphnia magna. Both compounds were individually characterized for effects on the development of isolated embryos. Fenarimol caused late developmental abnormalities, consistent with its effect on offspring-derived ecdysone in the maturing embryo. Testosterone interfered with both early and late development of embryos, consistent with its ability to inhibit ecdysone provided by maternal transfer (responsible for early developmental events) or de novo ecdysone synthesis (responsible for late developmental events). We predicted that, by decreasing endogenous levels of hormone, fenarimol would enhance the likelihood of testosterone binding to and inhibiting the ecdysone receptor. Indeed, fenarimol enhanced the toxicity of testosterone, while testosterone had no effect on the toxicity of fenarimol. Algorithms were developed to predict the toxicity of combinations of these two compounds based on independent joint action (IJA) alone as well as IJA with fenarimol-on-testosterone synergy (IJA+SYN). The IJA+SYN model was highly predictive of the experimentally determined combined effects of the two compounds. These results demonstrate that some endocrine toxicants can synergize, and this synergy can be accurately predicted. [source] Neutrophil recruitment in immunized mice depends on MIP-2 inducing the sequential release of MIP-1,, TNF-, and LTB4EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2006Cleber Abstract Neutrophils are thought to play an important role in the tissue damage observed in various autoimmune diseases. Chemokines, cytokines and leukotrienes have recognized roles in the orchestration of neutrophil migration. We have recently shown that antigen-induced neutrophil migration into the peritoneum of immunized mice is mediated by macrophage-inflammatory protein (MIP)-1, which interacts with CCR1 and induces the sequential release of TNF-, and leukotriene,B4 (LTB4). The present study investigates the role of MIP-2 and CXCR2 in the cascade of events leading to mediator generation and neutrophil influx. Antigen challenge of immunized mice induced the expression of CXCR2 and the production of KC and MIP-2 proteins. Antigen-induced neutrophil migration was inhibited by a CXCR2 receptor antagonist (repertaxin) or an anti-MIP-2 antibody, but not by an anti-KC antibody. Administration of MIP-2 promoted a dose-dependent neutrophil migration in naive mice which was inhibited by repertaxin, anti-TNF-,, anti-MIP-1, antibodies or by MK886 (leukotriene synthesis inhibitor). MIP-2 administration induced the release of MIP-1,, TNF-, and LTB4, and the release of the latter two was inhibited by anti-MIP-1, antibody treatment. Our studies highlight the intricate balance between mediator production and action during an immune-mediated inflammatory response and suggest a mediator cascade leading to neutrophil influx following antigen challenge of immunized mice: MIP-2 , MIP-1, , TNF-, , LTB4. [source] Minimizing the release of proinflammatory and toxic bacterial products within the host: A promising approach to improve outcome in life-threatening infectionsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2005Roland Nau Abstract Various bacterial components (e.g., endotoxin, teichoic and lipoteichoic acids, peptidoglycans, DNA) induce or enhance inflammation by stimulating the innate immune system and/or are directly toxic in eukariotic cells (e.g., hemolysins). When antibiotics which inhibit bacterial protein synthesis kill bacteria, smaller quantities of proinflammatory or toxic compounds are released in vitro and in vivo than during killing of bacteria by ,-lactams and other cell-wall active drugs. In general, high antibiotic concentrations liberate lower quantities of bacterial proinflammatory or toxic compounds than concentrations close to the minimum inhibitory concentration. In animal models of Escherichia coli Pseudomonas aeruginosa and Staphylococcus aureus peritonitis/sepsis and of Streptococcus pneumoniae meningitis, a lower release of proinflammatory bacterial compounds was associated with a reduced mortality or neuronal injury. Pre-treatment with a bacterial protein synthesis inhibitor reduced the strong release of bacterial products usually observed during treatment with a ,-lactam antibiotic. Data available strongly encourage clinical trials comparing antibiotic regimens with different release of proinflammatory/toxic bacterial products. The benefit of the approach to reduce the liberation of bacterial products should be greatest in patients with a high bacterial load. [source] From learning to forgetting: Behavioral, circuitry, and molecular properties define the different functional states of the recognition memory traceHIPPOCAMPUS, Issue 5 2010Rocío Romero-Granados Abstract Neuropsychological analyses of amnesic patients, as well as lesion experiments, indicate that the temporal lobe is essential for the encoding, storage, and expression of object recognition memory (ORM). However, temporal lobe structures directly involved in the consolidation and reconsolidation of these memories are not yet well-defined. We report here that systemic administration of a protein synthesis inhibitor before or up to 4 h after training or reactivation sessions impairs consolidation and reconsolidation of ORM, without affecting short-term memory. We have also observed that ORM reconsolidation is sensitive to protein synthesis inhibition, independently of the ORM trace age. Using bdnf and egr-1 gene expression analysis, we defined temporal lobe areas related to consolidation and reconsolidation of ORM. Training and reactivation 21 days after ORM acquisition sessions provoked changes in bdnf mRNA in somatosensory, perirhinal, and hippocampal cortices. Reactivation 2 days after the training session elicited changes in bdnf and egr-1 mRNA in entorhinal and prefrontal cortices, while reactivation 9 days post-training provoked an increase in egr-1 transcription in somatosensory and entorhinal cortices. The differences in activated circuits and in the capacity to recall the memory trace after 9 or 21 days post-training suggest that memory trace suffers functional changes in this period of time. All these results indicate that the functional state of the recognition memory trace, from acquisition to forgetting, can be specifically defined by behavioral, circuitry, and molecular properties. © 2009 Wiley-Liss, Inc. [source] Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1, (HIF-1,) through inhibiting protein synthesisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2008Dae-Hee Lee Abstract Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1, (HIF-1,) in normoxia. In this study, under hypoxic conditions (1% O2), we examined the effect of quercetin on the intracellular level of HIF-1, and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1, accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1, accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O2) in the presence of 100 µM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1, accumulation were observed under hypoxic conditions. Treatment with 100 µM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1, accumulation during hypoxia. These results suggest that suppression of HIF-1, accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis. J. Cell. Biochem. 105: 546,553, 2008. © 2008 Wiley-Liss, Inc. [source] Modulation of O-GlcNAc glycosylation during Xenopus oocyte maturation,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2004Tony Lefebvre Abstract O-linked N -acetylglucosamine (O-GlcNAc) glycosylation is a post-translational modification, which is believed antagonises phosphorylation. We have studied the O-GlcNAc level during Xenopus oocyte meiotic resumption, taking advantage of the high synchrony of this model which is dependent upon a burst of phosphorylation. Stimulation of immature stage VI oocytes using progesterone was followed by a 4.51,±,0.32 fold increase in the GlcNAc content, concomitantly to an increase in phosphorylation, notably on two cytoplasmic proteins of 66 and 97 kDa. The increase of O-GlcNAc for the 97 kDa protein, which we identified as ,-catenin was partly related to its accumulation during maturation, as was demonstrated by the use of the protein synthesis inhibitor,cycloheximide. Microinjection of free GlcNAc, which inhibits O-glycosylated proteins,lectins interactions, delayed the progesterone-induced maturation without affecting the O-GlcNAc content. Our results suggest that O-GlcNAc glycosylation could regulate protein,protein interactions required for the cell cycle kinetic. © 2004 Wiley-Liss, Inc. [source] Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: Therapeutic implications for Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2002Kwok-Keung Tai Abstract It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO4 or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease. © 2002 Wiley-Liss, Inc. [source] Ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist: anti-inflammatory profile in inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2000Carty Background: Thromboxanes, prostaglandins, reactive oxygen metabolites and pro-inflammatory cytokines are produced in excess in inflammatory bowel disease. Preliminary reports suggest that ridogrel, a thromboxane synthesis inhibitor and receptor blocker, may have therapeutic benefits in ulcerative colitis. Aims: To investigate the anti-inflammatory profile of ridogrel. Methods: The effects of ridogrel on the production of eicosanoids, reactive oxygen metabolites and cytokines by cultured inflamed colorectal mucosal biopsies were made using ELISA and chemiluminescence, reactive oxygen metabolite generation in a cell-free system, and platelet activation using flow cytometry. The effects of oral ridogrel on mucosal release of eicosanoids in two patients with active ulcerative colitis were assessed using rectal dialysis. Results: Ridogrel significantly reduced the release of thromboxane B2, but not prostaglandin E2 or tumour necrosis factor-,, from biopsies (P < 0.01 for 10 ,M ridogrel). Ridogrel showed no direct antioxidant activity but significantly reduced reactive oxygen metabolite production from cultured biopsies (P < 0.01 for 10 ,M ridogrel). Platelet activation in vitro was inhibited by ridogrel (P , 0.05 for , 10 ,M ridogrel). Mean rectal mucosal thromboxane B2 release was reduced to 86% of pre-treatment levels in two patients treated with oral ridogrel. Conclusions: Its inhibition of mucosal production of thromboxane B2, reactive oxygen metabolites, and of platelet activation, suggests that ridogrel could have a therapeutic role in inflammatory bowel disease. [source] Proteomic Analysis of Shear Stress-Mediated Protection from TNF-, in Endothelial CellsMICROCIRCULATION, Issue 4 2010Julie K. Freed Microcirculation (2010) 17, 259,270. doi: 10.1111/j.1549-8719.2010.00031.x Abstract Previous studies have shown that physiological levels of shear stress can protect endothelial cells (ECs) from apoptotic stimuli. Here, we differentiate between acute and chronic protection and demonstrate the use of proteomic technologies to uncover mechanisms associated with chronic protection of ECs. We hypothesized that changes in abundance of proteins associated with the TNF-, signaling cascade orchestrate shear stress-mediated protection from TNF-, when cells are preconditioned with shear prior to the exposure of apoptotic stimuli. Detection of cleaved caspase 3 through Western blot analysis confirmed chronic shear stress-mediated protection from TNF-,. In the presence of the nitric oxide synthase inhibitor, LNMA (N, -monomethyl- l -arginine), chronic protection remained. Treatment with a de novo protein synthesis inhibitor, cycloheximide, eliminated this protective effect. Isotopic-labeling experiments, coupled with LC,MS/MS (liquid chromatography,tandem mass spectrometry) of isolated components of the TNF-, pathway revealed that CARD9, a known activator of the NF-,B pathway, was increased (60%) in sheared cells versus nonsheared cells. This result was confirmed through Western blot analysis. Our data suggest that de novo formation of proteins is required for protection from TNF-, in ECs chronically exposed to shear stress, and that CARD9 is a candidate protein in this response. [source] Protective effect of sulforaphane on indomethacin-induced cytotoxicity via heme oxygenase-1 expression in human intestinal Int 407 cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 9 2009Chi-Tai Yeh Abstract Sulforaphane is known to be an indirect antioxidant that acts by inducing NF-E2-related factor 2 (Nrf2)-dependent phase II enzymes. In the present study, we investigated the effect of sulforaphane on the expression of heme oxygenase-1 (HO-1) in human intestinal Int 407 cells. RT-PCR and Western blot data revealed that sulforaphane induced an increase in HO-1 expression at the mRNA and protein levels, respectively. This induction was also marked by an increase in HO-1 activity. Actinomycin D (an RNA synthesis inhibitor) and cycloheximide (a protein synthesis inhibitor) inhibited sulforaphane-responsive HO-1 mRNA expression, indicating that sulforaphane is a requirement for transcription and de novo protein synthesis. Moreover, sulforaphane increased the nuclear levels of Nrf2 and increased the binding activity of nuclear proteins to the antioxidant responsive element consensus sequence. We also found that U0126, an ERK kinase inhibitor, suppressed the sulforaphane-induced HO-1 expression and nuclear translocation of Nrf2. Moreover, the cytoprotective effect of sulforaphane on indomethancin-induced cytotoxicity was partially blocked by ERK and HO-1 inhibitors, further demonstrating that sulforaphane attenuated oxidative stress through a pathway that involved ERK and HO-1. Taken together, this study gives additional support to the possible use of sulforaphane as a dietary preventive agent against oxidative stress-induced intestinal injury. [source] The role of cyclic-AMP on arginase activity by a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitansMOLECULAR ORAL MICROBIOLOGY, Issue 6 2006W. Sosroseno Aims:, The aim of the present study was to determine the role of cyclic adenosine monophosphate (cAMP) on arginase activity in a murine macrophage cell line (RAW264.7 cells) stimulated with lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans. Materials and methods:, The cells were treated with A. actinomycetemcomitans LPS for 24 h. The effects of SQ22536 (an adenylyl cyclase inhibitor), ODQ (a guanylyl cyclase inhibitor), dibutyryl cAMP (a cAMP analog), 8-bromo cyclic guanosine monophosphate (a cGMP analog), forskolin (an adenylyl cylase activator), and cycloheximide (a protein synthesis inhibitor) on arginase activity in A. actinomycetemcomitans LPS-stimulated RAW264.7 cells were also determined. Arginase activity was assessed in LPS-stimulated cells in the presence of 3-isobutyl-1-methylxanthine (IBMX), siguazodan and rolipram [phosphodiesterase (PDE) inhibitors] as well as KT5720 [a protein kinase A (PKA) inhibitor]. Results:, Arginase activity in A. actinomycetemcomitans LPS-stimulated RAW264.7 cells was suppressed by SQ22536 but not ODQ. Enhancement of arginase activity was observed in the presence of cAMP analog or forskolin but not cGMP analog. Cycloheximide blocked arginase activity in the cells in the presence of cAMP analog or forskolin with or without A. actinomycetemcomitans LPS. IBMX augmented arginase activity in A. actinomycetemcomitans LPS-stimulated cells. Rolipram (a PDE4 inhibitor) increased the levels of arginase activity higher than siguazodan (a PDE3 inhibitor) in the antigen-stimulated cells. The effect of cAMP analog or forskolin on arginase activity in the presence or absence of A. actinomycetemcomitans LPS was blocked by the PKA inhibitor (KT5720). Conclusion:, The results of the present study suggest that A. actinomycetemcomitans LPS may stimulate arginase activity in murine macrophages (RAW264.7 cells) in a cAMP-PKA-dependent pathway. [source] Dynamics of lamin A/C in porcine embryos produced by nuclear transferMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 9 2007Kiho Lee Abstract This study was conducted to investigate the presence of lamin A/C in porcine nuclear transfer embryos and to determine whether lamin A/C can serve as a potential marker for nuclear reprogramming. First, lamin A/C was studied in oocytes and embryos produced by fertilization or parthenogenetic oocyte activation. We found that lamin A/C was present in the nuclear lamina of oocytes at the germinal vesicle stage while it was absent in mature oocytes. Lamin A/C was detected throughout preimplantation development in both in vivo-derived and parthenogenetic embryos. Incubation of the activated oocytes in the presence of ,-amanitin (an inhibitor of RNA polymerase II), or cycloheximide (a protein synthesis inhibitor) did not perturb lamin A/C assembly, indicating that the assembly resulted from solubilized lamins dispersed in the cytoplasm. In nuclear transfer embryos, the lamin A/C signal that had previously been identified in fibroblast nuclei disappeared soon after fusion. It became detectable again after the formation of the pronucleus-like structure, and all nuclear transfer embryos displayed lamin A/C staining during early development. Olfactory bulb progenitor cells lacked lamin A/C; however, when such cells were fused with enucleated oocytes, the newly formed nuclear envelopes stained positive for lamin A/C. These findings suggest that recipient oocytes remodel the donor nuclei using type A lamins dispersed in the ooplasm. The results also indicate that lamin A/C is present in the nuclear envelope of pig oocytes and early embryos and unlike in some other species, its presence after nuclear transfer is not an indicator of erroneous reprogramming. Mol. Reprod. Dev. 74: 1221,1227, 2007. © 2007 Wiley-Liss, Inc. [source] Local early induced resistance of plants as the first line of defence against bacteria,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 4 2003Zoltán Klement Abstract This paper is an overview of a non-specific local early induced resistance (EIR) mechanism, distinct from the incompatible-specific hypersensitive reaction (HR). We have shown that the local induced resistance (LIR) described earlier is not a single and uniform response to pathogen infection, because an early (EIR) and a late form can be distinguished. EIR operates from 3,6,h post-inoculation (hpi) until about 20,hpi, and is inhibited by a short heat-shock or the eukaryotic protein synthesis inhibitor, cycloheximide. In contrast, LIR, which corresponds to the induced resistance forms discovered earlier, requires more time (about 24,h) and intensive illumination to develop, and is effective for a longer period. EIR develops parallel with HR and is sometimes able to prevent it when the induction time of HR is longer than the time required for the development of EIR. It seems that EIR inhibits the metabolism of bacteria and the activity of hrp genes which otherwise are required for the induction of HR. In a compatible host,pathogen relationship the effect of EIR fails to take place. The rapid development of EIR is greatly influenced by temperature and the physiological state of the plant. EIR activates the accumulation of hydrogen peroxide at the bacterial attachment, expressing new peroxidase isoenzymes in the initiated plant tissue. It seems that this is a native general local defence mechanism which can localise foreign organisms even at the penetration site. © 2003 Society of Chemical Industry [source] 4-Methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factorsBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2010M. Edward Summary Background, There is a close correlation between tumour progression and hyaluronan production, either by tumour cells or by stromal cells that are stimulated by tumour-derived factors. Inhibition of tumour stimulation of fibroblast hyaluronan may suppress tumour growth and invasion. Objectives, To examine the effect of the hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) on the growth of and hyaluronan synthesis by fibroblasts and C8161 and MV3 melanoma cell lines, invasion, and inhibition of tumour cell-derived factor activation of fibroblasts. Methods, Effects of 4-MU on growth and hyaluronan synthesis by fibroblasts and melanoma cells were examined in monolayer culture and fibroblast-contracted collagen lattices, and their effects on the growth and invasion of tumour cells into collagen lattices were also studied. Results, 4-MU caused a dose-dependent growth inhibition of fibroblast and melanoma cells with maximum inhibition at 0·5 mmol L,1 4-MU. At this dose, 4-MU inhibited 3H-glucosamine incorporation into fibroblast glycosaminoglycans by 52%, and hyaluronan synthesis by 64%. The relative inhibition was more pronounced when fibroblasts were stimulated with C8161 melanoma cell-conditioned medium. 4-MU reduced the level of hyaluronan in fibroblast-contracted collagen lattices, and inhibited both the growth on and invasion into the lattices by melanoma cells. This growth inhibition appears to be predominantly independent of inhibition of hyaluronan synthesis. The effect on growth inhibition was reversible, and 4-MU had no effect on apoptosis. Conclusions, 4-MU is a potent inhibitor of hyaluronan synthesis, induction of stromal hyaluronan accumulation by tumour cells, and fibroblast and melanoma cell proliferation, and results suggest that 4-MU may have potential as a tumour cell anti-invasive and antiproliferative agent. [source] Insecticides with novel modes of action: Mechanism, selectivity and cross-resistanceENTOMOLOGICAL RESEARCH, Issue 3 2007Isaac ISHAAYA Abstract Efforts have been made during the past two decades to develop insecticides with selective properties that act specifically on biochemical sites present in particular insect groups, but whose properties differ from other insecticides. This approach has led to the discovery of compounds that affect the hormonal regulation of molting and developmental processes in insects; for example, ecdysone agonists, juvenile hormone mimics and chitin synthesis inhibitors. In addition, compounds that selectively interact with the insect nicotinic acetylcholine receptor, such as imidacloprid, acetamiprid and thiamethoxam, have been introduced for the control of aphids, whiteflies and other insect species. Natural products acting selectively on insect pests, such as avermectins, spinosad and azadirachtin, have been introduced for controlling selected groups of insect pests. Compounds acting on the nervous site that controls the sucking pump of aphids and whiteflies, such as pymetrozine, or respiration, such as diafenthiuron, have been introduced for controlling sucking pests. All the above compounds are important components in pest and resistance management programs. [source] Resistance of the codling moth Cydia pomonella (L.) (Lep., Tortricidae) to pesticides in IsraelJOURNAL OF APPLIED ENTOMOLOGY, Issue 9-10 2004H. Reuveny Abstract:, Resistance of the codling moth Cydia pomonella (L.) (Lep., Tortricidae) to the organophosphorus compound (OP) azinphosmethyl was observed in apple orchards in Israel. The level of resistance varied with the pest control strategy. Compared with a sensitive laboratory population, the resistance level was highest in insects from the preventative pest control strategy, intermediate in integrated pest management (IPM) orchards, and relatively low in the organic orchards. The level of azinphosmethyl resistance in larvae (but not in adults) exposed for 17 generations in the laboratory to a pesticide-free diet was reduced by 50%. Codling moth larvae resistant to azinphosmethyl were also resistant to various insect growth regulators (IGRs). The IGRs include three chitin synthesis inhibitors (diflubenzuron, novaluron and teflubenzuron), two juvenile hormone mimics (pyriproxyfen and fenoxycarb) and one ecdysone agonist (methoxyfenozide). Codling moth resistant to azinphosmethyl was tolerant to methoxyfenozide and novaluron without previous history of application in apple orchards, indicating the possibility of cross-resistance. According to this study, managing resistance programs in apple orchards should be based on IPM principles with minimum use of conventional neuroactive pesticides. [source] Possible mechanisms for the relative efficacies of ortho -phthalaldehyde and glutaraldehyde against glutaraldehyde-resistant Mycobacterium chelonaeJOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2001S.E. Walsh Aims: This investigation compared glutaraldehyde (GTA)-sensitive and -resistant strains of Mycobacterium chelonae and examined the effects of pretreatment of GTA-sensitive and -resistant strains of Myco. chelonae with chemical agents that interfere with cell wall synthesis. Methods and Results: When exposed to 2% (v/v) GTA at 25°C, GTA-resistant strains of Myco. chelonae dried on to glass carriers were not inactivated to any significant extent. By contrast, GTA-sensitive strains of Myco. chelonae and a strain of Myco. terrae suffered a > 6 log reduction in viability in 5 min. However, ortho -phthalaldehyde (OPA; 0·5% w/v) achieved a corresponding inactivation against two GTA-resistant strains within 5,10 and 10,20 min, respectively. Electron microscopy, using a non-aldehyde fixation process and also negative staining, failed to detect any extensive changes in GTA-sensitive and -resistant cultures exposed to GTA or OPA. Thin-layer chromatography was unsuccessful in detecting differences between GTA-resistant and -sensitive strains of Myco. chelonae. However, pretreatment of GTA-resistant cells with mycobacterial cell wall synthesis inhibitors increased their subsequent susceptibility further to OPA but not to GTA. Conclusions:Ortho -phthalaldehyde is an effective new biocidal agent that, at its in-use concentration, is rapidly bactericidal to non-sporulating bacteria, including GTA-sensitive and -resistant mycobacteria. Significance and Impact of the Study: Pretreatment of GTA-resistant cells with mycobacterial cell wall synthesis inhibitors increased their subsequent susceptibility to OPA but not to GTA. [source] Regulatory volume decrease is actively modulated during the cell cycleJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2002Liwei Wang Nasopharyngeal carcinoma cells, CNE-2Z, when swollen by 47% hypotonic solution, exhibited a regulatory volume decrease (RVD). The RVD was inhibited by extracellular applications of the chloride channel blockers tamoxifen (30 ,M; 61% inhibition), 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 100 ,M; 60% inhibition), and ATP (10 mM; 91% inhibition). The level and time constant of RVD varied greatly between cells. Most cells conducted an incomplete RVD, but a few had the ability to recover their volume completely. There was no obvious correlation between cell volume and RVD capacity. Flow cytometric analysis showed that highly synchronous cells were obtained by the mitotic shake-off technique and that the cells progressed through the cell cycle synchronously when incubated in culture medium. Combined application of DNA synthesis inhibitors, thymidine and hydroxyurea arrested cells at the G1/S boundary and 87% of the cells reached S phase 4 h after being released. RVD capacity changed significantly during the cell cycle progression in cells synchronized by shake-off technique. RVD capacity being at its highest in G1 phase and lowest in S phase. The RVD capacity in G1 (shake-off cells sampled after 4 h of incubation), S (obtained by chemical arrest), and M cells (selected under microscope) was 73, 33, and 58%, respectively, and the time constants were 435, 769, and 2,000 sec, respectively. We conclude that RVD capacity is actively modulated in the cell cycle and RVD may play an important role in cell cycle progress. J. Cell. Physiol. 193: 110,119, 2002. © 2002 Wiley-Liss, Inc. [source] Leukotriene pathway genetics and pharmacogenetics in allergyALLERGY, Issue 6 2009N. P. Duroudier Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC4, LTD4 and, LTE4) and the dihydroxy leukotriene LTB4 are generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity; however, their role remains unclear. Preliminary data also suggest that 5-LO pathway/receptor gene polymorphism can predict patient responses to LTSI and LTRA; however, the exact mechanisms require elucidation. The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes. [source] The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin functionMOLECULAR MICROBIOLOGY, Issue 5 2003Peter R. Kraus Summary Cell wall integrity is crucial for fungal growth, development and stress survival. In the model yeast Saccharomyces cerevisiae, the cell integrity Mpk1/Slt2 MAP kinase and calcineurin pathways monitor cell wall integrity and promote cell wall remodelling under stress conditions. We have identified the Cryptococcus neoformans homologue of the S. cerevisiae Mpk1/Slt2 MAP kinase and have characterized its role in the maintenance of cell integrity in response to elevated growth temperature and in the presence of cell wall synthesis inhibitors. C. neoformans Mpk1 is required for growth at 37°C in vitro, and this growth defect is suppressed by osmotic stabilization. C. neoformans mutants lacking Mpk1 are attenuated for virulence in the mouse model of cryptococcosis. Phosphorylation of Mpk1 is induced in response to perturbations of cell wall biosynthesis by the antifungal drugs nikkomycin Z (a chitin synthase inhibitor), caspofungin (a ,-1,3-glucan synthase inhibitor), or FK506 (a calcineurin inhibitor), and mutants lacking Mpk1 display enhanced sensitivity to nikkomycin Z and caspofungin. Lastly, we show that calcineurin and Mpk1 play complementing roles in regulating cell integrity in C. neoformans. Our studies demonstrate that pharmacological inhibition of the cell integrity pathway would enhance the activity of antifungal drugs that target the cell wall. [source] Chemical induction of rapid and reversible plastid filamentation in Arabidopsis thaliana rootsPHYSIOLOGIA PLANTARUM, Issue 2 2010Ryuuichi D. Itoh Plastids assume various morphologies depending on their developmental status, but the basis for developmentally regulated plastid morphogenesis is poorly understood. Chemical induction of alterations in plastid morphology would be a useful tool for studying this; however, no such chemicals have been identified. Here, we show that antimycin A, an effective respiratory inhibitor, can change plastid morphology rapidly and reversibly in Arabidopsis thaliana. In the root cortex, hypocotyls, cotyledon epidermis and true leaf epidermis, significant differences in mitochondrial morphology were not observed between antimycin-treated and untreated tissues. In contrast, antimycin caused extreme filamentation of plastids in the mature cortices of main roots. This phenomenon was specifically observed in the mature root cortex. Other mitochondrial respiratory inhibitors (rotenone and carbonyl cyanide m -chlorophenylhydrazone), hydrogen peroxide, S -nitroso- N -acetylpenicillamine [a nitric oxide (NO) donor] and 3-(3,4-dichlorophenyl)-1,1-dimethylurea did not mimic the phenomenon under the present study conditions. Antimycin-induced plastid filamentation was initiated within 5 min after the onset of chemical treatment and appeared to complete within 1 h. Plastid morphology was restored within 7 h after the washout of antimycin, suggesting that the filamentation was reversible. Co-applications of antimycin and cytoskeletal inhibitors (demecolcine or latrunculin B) or protein synthesis inhibitors (cycloheximide or chloramphenicol) still caused plastid filamentation. Antimycin A was also effective for plastid filamentation in the chloroplast division mutants atftsZ1-1 and atminE1. Salicylhydroxamic acid, an alternative oxidase inhibitor, was solely found to suppress the filamentation, implying the possibility that this phenomenon was partly mediated by an antimycin-activated alternative oxidase in the mitochondria. [source] Activation of a diverse set of genes during the tobacco resistance response to TMV is independent of salicylic acid; induction of a subset is also ethylene independentTHE PLANT JOURNAL, Issue 5 2000Ailan Guo Summary Through differential screening of a cDNA library, we cloned six groups of genes that are expressed relatively early in the inoculated leaves of tobacco resisting infection by tobacco mosaic virus (TMV). Induction of all these genes was subsequently detected in the uninoculated leaves; thus, their expression is associated with the development of both local and systemic acquired resistance. Exogenously applied salicylic acid (SA) was observed to induce these genes transiently. However, analyses with transgenic NahG plants, which are unable to accumulate SA, demonstrated that expression of these genes in TMV-inoculated leaves is mediated via an SA-independent pathway. Because the expression kinetics of these genes differ from those associated with the well-characterized pathogenesis-related protein (PR-1) and phenylalanine ammonia-lyase (PAL) genes, we propose that they belong to a group which we designate SIS, for SA-independent, systemically induced genes. Interestingly, the expression of several SIS genes in the uninoculated leaves of TMV-infected NahG plants was delayed and/or reduced, raising the possibility that SA is involved in activating some of these genes in systemic tissue. Most of the SIS genes were induced by exogenous ethylene. However, analyses of infected NahG plants treated with ethylene action and/or synthesis inhibitors indicated that the TMV-induced expression of several SIS genes is independent of ethylene as well as SA. [source] The Enteric Nervous System II: Gastrointestinal FunctionsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2003Mark Berner Hansen This Minireview is part two of three and describes the role of the enteric nervous system in gastrointestinal functions (motility, exocrine and endocrine secretions, blood flow, and immune processes) in health and some disease states. In this context, the functional importance of the enteric nervous system for food intake, the gall bladder, and pancreas will be addressed. In specific, dysmotility, diarrhoea, constipation, non-occlusive intestinal ischaemia (intestinal angina), inflammation, cholelithiasis, cholecystitis, postcholecystectomy syndrome, and pancreatitis can be treated with neuroactive pharmacological agents. For example, serotonin receptor type four agonists can be used for the treatment of constipation, while nitric oxide synthesis inhibitors can be employed for the treatment of intestinal angina. [source] Cysteinyl leukotrienes as common mediators of asthma and allergic diseaseCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 2 2003S-E. Dahlén Summary The cysteinyl leukotrienes (CysLTs) induce a number of pro-inflammatory effects including smooth muscle contraction, an increase in blood flow, plasma exudation, mucous secretion, and activation of inflammatory cells. They play a key role in asthma and allergy, and can be recovered from different body fluids (e.g. bronchoaleveolar or nasal lavage and urine) during allergen-induced hypersensitivity reactions. The advent of antileukotriene agents (i.e. leukotriene receptor antagonists or leukotriene synthesis inhibitors) has helped clarify how the different mechanisms contribute to inflammation, as well as offer new treatment options for both asthma and allergy. It is now clear that the release of leukotrienes is the final common path for the many different factors causing airway obstruction and inflammation. In asthma, clinical studies have shown that treatment with antileukotrienes can improve pulmonary function, alleviate symptoms, reduce asthma exacerbations, and decrease the need for bronchodilator therapy. Similarly, in patients with allergic rhinitis, improvements have been seen in nasal symptoms, eye symptoms and quality of life. Antileukotrienes provide a new opportunity for simultaneous management of allergic diseases of the upper and lower respiratory tract, and are a rational treatment approach to the concept of ,one airway' disease. In future, their utility may also extend to inflammatory disorders of other organ systems (e.g. skin). [source] Is there a role for antileukotrienes in urticaria?CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2006G. Di Lorenzo Summary In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma. We searched the MedLine database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin or food additive hypersensitivity or with autoreactivity to intradermal serum injection when taken with an antihistamine but not in moderate chronic idiopathic urticaria. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angio-oedema, and exercise-induced anaphylaxis. [source] Perinatal management of a preterm neonate affected by hyperprostaglandin E2 syndrome (HPS)ACTA PAEDIATRICA, Issue 11 2005MARTIN KÖMHOFF Abstract Background: Neonates affected by hyperprostaglandin E2 syndrome (HPS) present with severe polyuria. Both urinary losses as well as prostaglandin synthesis inhibitors may precipitate acute renal failure (ARF). Aim: Our goal was to maintain euvolaemia by replacement of urinary losses. Patient: Our patient was born prematurely with a family history typical of HPS. Urinary salt and water losses and PGE2 excretion were determined in 2- to 4-h intervals. Salt and water were replaced accordingly. Results: Within the first 48 h, urinary losses and PGE2 increased continuously to 50 ml/kg/h and 374 ng/h/1.73 m2, respectively. Following exposure to 0.05,0.5 mg/kg/d indomethacin, urinary output decreased steadily to 10,15/ ml/kg/h. Conclusion: In euvolaemic preterm neonates with HPS and the need for excessive replacement of salt and water, inhibition of renal PGE2 excretion with indomethacin effectively reduces polyuria and natriuresis without acutely compromising renal function. [source] | |||||||||||||||||||||||||||||||