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Effective Inhibition (effective + inhibition)
Selected AbstractsEffective inhibition of melanosome transfer to keratinocytes by lectins and niacinamide is reversibleEXPERIMENTAL DERMATOLOGY, Issue 7 2005Amanda Greatens Abstract:, Skin pigmentation results in part from the transfer of melanized melanosomes synthesized by melanocytes to neighboring keratinocytes. Plasma membrane lectins and their glycoconjugates expressed by these epidermal cells are critical molecules involved in this transfer process. In addition, the derivative of vitamin B3, niacinamide, can inhibit melanosome transfer and induce skin lightening. We investigated the effects of these molecules on the viability of melanocytes and keratinocytes and on the reversibility of melanosome-transfer inhibition induced by these agents using an in vitro melanocyte,keratinocyte coculture model system. While lectins and neoglycoproteins could induce apoptosis in a dose-dependent manner to melanocytes or keratinocytes in monoculture, similar dosages of the lectins, as opposed to neoglycoproteins, did not induce apoptosis to either cell type when treated in coculture. The dosages of lectins and niacinamide not affecting cell viability produced an inhibitory effect on melanosome transfer, when used either alone or together in cocultures of melanocytes,keratinocytes. Cocultures treated with lectins or niacinamide resumed normal melanosome transfer in 3 days after removal of the inhibitor, while cocultures treated with a combination of lectins and niacinamide demonstrated a lag in this recovery. Subsequently, we assessed the effect of niacinamide on facial hyperpigmented spots using a vehicle-controlled, split-faced design human clinical trial. Topical application of niacinamide resulted in a dose-dependent and reversible reduction in hyperpigmented lesions. These results suggest that lectins and niacinamide at concentrations that do not affect cell viability are reversible inhibitors of melanosome transfer. [source] Comprehensive proteomic and transcriptomic analysis reveals early induction of a protective anti-oxidative stress response by low-dose proteasome inhibitionPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 12 2009Sven Bieler Abstract Effective inhibition of the proteasome by high doses of proteasome inhibitors induces apoptotic cell death. In contrast, partial proteasome inhibition by low inhibitor doses mediates a protective cellular stress response. The early targets and mediators of these dose-dependent effects of proteasome inhibitors are unknown. Primary human umbilical cord vein endothelial cells were treated with low and high doses of the proteasome inhibitor MG132 for 2,h. In a combined 2-DE and MS approach, we identified more than 20 new targets of proteasome inhibition. These proteins are involved in cell cycle regulation, signaling, cytoskeletal rearrangement, and cellular stress response. Accompanying Affymetrix analysis revealed that these proteins are not regulated on the transcriptional level but are mainly stabilized by proteasome inhibition. The proteasome-dependent accumulation of the anti-oxidative sensor proteins DJ-1, peroxiredoxin-1 and -6 was accompanied by dose-dependent induction of oxidative stress after 2,h of proteasome inhibition and contributed to the differential transcriptional stress response to low- and high-dose proteasome inhibition: Whereas low-dose proteasome inhibition induces a transcriptional profile reminiscent of a physiological stress response that preconditions and protects endothelial cells from oxidative stress, high inhibitor doses induce massive transcriptional dysregulation and pronounced oxidative stress triggering apoptosis. [source] The effects of 1-methylcyclopropene on peach fruit (Prunus persica L. cv. Jiubao) ripening and disease resistanceINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 1 2005Hongxia Liu Summary In order to learn how 1-methylcyclopropene (1-MCP) affects ripening and disease-resistance of peach fruit (Prunus persica L. cv. Jiubao) after harvest, they were treated with 1-MCP and some were inoculated with Penicillium expansum. Treating peach fruit with 0.2 ,L L,1 of 1-MCP at 22 °C for 24 h effectively slowed the decline in fruit firmness. The minimal concentration of 1-MCP able to inhibit fruit softening was 0.6 ,L L,1. Changes in other parameters related to peach ripening, such as content of soluble solids, total soluble sugar, titratable acidity, soluble pectin and ethylene production were also significantly reduced or delayed by 1-MCP. Repeated treatment of peach with 1-MCP resulted in more effective inhibition of ripening. Post-harvest decay of peach fruit was reduced by treatment with 1-MCP and disease progress in fruit inoculated with P. expansum was reduced. The activities of phenylalanine ammonialyase, polyphenoloxidase and peroxidase in the inoculated fruit were also enhanced by 1-MCP. [source] Efficacy of natamycin for control of growth and ochratoxin A production by Aspergillus carbonarius strains under different environmental conditionsJOURNAL OF APPLIED MICROBIOLOGY, Issue 6 2007Á. Medina Abstract Aims:, To examine the efficacy of natamycin produced by Streptomyces natalensis against strains of Aspergillus carbonarius growth and ochratoxin A (OTA) production under different environmental factors on a grape juice-based medium. Methods and Results:, Detailed studies in the range 0,20 ng ml,1 for control of growth and ochratoxin production by strains of A. carbonarius at 0·98, 0·96 and 0·94 water availabilities (aw) and 15,25°C on a fresh red grape extract medium were examined. Inhibition of growth was depending on temperature and aw level. At 15°C, 5,10 ng ml,1 natamycin was effective in reducing growth almost completely. However, at 20,25°C and all the three aw levels, growth was only slightly inhibited by 5,10 ng ml,1 natamycin. There were strain differences with regard to inhibition of OTA production. At 15°C and 0·98 aw, 10 ng ml,1 was required to inhibit production by >90%. However, at 0·96 and 0·94 aw, almost complete inhibition occurred. At 20°C, OTA production was only significantly inhibited by 10 ng ml,1 natamycin at 0·94 aw. At 0·96 and 0·98 aw, some inhibition occurred with 5,10 ng ml,1, but greater concentrations would be required for effective inhibition. At 25°C, 5 ng ml,1 was effective at all aw levels. However, at 15°C and 25°C and a wide range of aw levels, natamycin effectively controlled OTA production. Conclusions:, Natamycin appears to be a very effective for controlling growth and OTA production by strains of A. carbonarius over a range of aw and temperature conditions on grape-based media. Significance and Impact of the Study:, This is the first detailed study to demonstrate the impact of natamycin against A. carbonarius. This study suggests that use of natamycin at 50,100 ng ml,1 can give complete inhibition of growth of A. carbonarius and OTA production over a range of environmental conditions. Natamycin could be an important component of a system to prevent OTA contamination of wine as well during the drying and production of vine fruits. [source] Discovery and design of novel inhibitors of botulinus neurotoxin A: targeted ,hinge' peptide librariesJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2003J. Hayden Abstract Intoxication by the zinc protease botulinus neurotoxin A (BoNT-A) results from cleavage of a single Q,R bond in the neuronal protein SNAP-25, which disables the docking mechanism required for neurotransmitter release. In the present study, potential inhibitors of BoNT-A were assessed from their effects on the BoNT-A cleavage of a synthetic 17-mer peptide (SNAP-25, residues 187,203) spanning the Q,R cleavage site. Compounds that inhibited BoNT-A included thiols (zinc chelators) such as dithiothreitol, dimercaptopropanesulfonic acid, mercaptosuccinic acid and captopril. In addition, compounds containing multiple acidic functions, such as the SNARE motif V2 (ELDDRADALQ), the tripeptide Glu-Glu-Glu and the steroid glycoside glycyrrhizic acid, were effective inhibitors. ,Hinge' peptide mini-libraries (PMLs) having the structure acetyl-X1 -X2 -linker-X3 -X4 -NH2 or X1 -X2 -linker-X3, where X1,X4 were mixtures of selected amino acids and the flexible linker was 4-aminobutyric acid, also provided effective inhibition. Targeted PMLs containing the acidic amino acids Asp and Glu, the scissile-bond amino acids Gln and Arg and the zinc chelators His and Cys produced pronounced inhibition of BoNT-A. Deconvolution of these libraries will provide novel ligands with improved inhibitory potency as leads in the design of peptide mimetics to treat BoNT poisoning. Copyright ? 2003 Crown in the right of Canada. Published by John Wiley and Sons, Ltd. [source] GLYCOSIDASE INHIBITORY ACTIVITY AND ANTIOXIDANT PROPERTIES OF A POLYSACCHARIDE FROM THE MUSHROOM INONOTUS OBLIQUUSJOURNAL OF FOOD BIOCHEMISTRY, Issue 2010HAIXIA CHEN ABSTRACT A water-soluble polysaccharide from Inonotus obliquus (IOPS) was isolated from the mushroom Inonotus obliquus (Fr.) Pilat. The chemical compositions, molecular weight and inhibitory activities on glycosidase and antioxidant properties of IOPS were investigated. The results indicated that IOPS was an acid protein-bound polysaccharide, with a molecular weight of 1.7 × 104 Da and the contents of neutral sugar, protein and uronic acids being 42.5, 18.5 and 6.1%, respectively. IOPS exhibited an inhibitory activity against ,-glucosidase with the IC50 value of 93.3 µg/mL, whereas it had no effective inhibition on ,-amylase. Results of antioxidant activity assays revealed that IOPS had inhibitory activity on the concentration-dependent quenching of 1,1-Diphenyl-2-picrylhydrazyl and hydroxyl radicals. Furthermore, IOPS inhibited the formation of thiobarbituric acid-reactive substances in Fe2+/ascorbate-induced lipid peroxidation in rat liver tissue. These results clearly demonstrated that IOPS was one of the main bioactive components of I. obliquus that contributed to hypoglycemic activity and antioxidant activity. PRACTICAL APPLICATIONS Diabetes mellitus is one of the primary threats to human health because of its increasing prevalence, chronic course and disabling complications. Postprandial hyperglycemia plays an important role in the development of type 2 diabetes mellitus and complications associated with the disease. One therapeutic approach to decrease postprandial hyperglycemia is to retard the absorption of glucose through inhibition of carbohydrate-hydrolyzing enzymes in the digestive organs. In this study, a polysaccharide isolated from the mushroom Inonotus obliquus (IOPS) was shown to have notable glycosidase inhibitory effects and antioxidant activities. This research will benefit for the investigation of effective and safe ,-glucosidase inhibitors from natural materials. IOPS could be a good candidate for application in food and medicinal fields. It might be developed for functional food or lead compounds for use in antidiabetes. [source] Effects of antibodies against a fusion protein consisting of parts of cell surface protein antigen and glucosyltransferase of Streptococcus sobrinus on cell adhesion of mutans streptococciMOLECULAR ORAL MICROBIOLOGY, Issue 1 2008T. Kawato Background/aims:, The cell surface protein antigen (PAg) and glucosyltransferases (GTFs) produced by Streptococcus sobrinus are considered to be major colonization factors of the organism. Methods:, We constructed a fusion gene encoding a protein composed of the alanine-rich region of PAg (PAgA) and the glucan-binding domain (GB) of GTF-I, which catalyzes the synthesis of water-insoluble glucan in S. sobrinus. The fusion protein PAgA-GB was purified from cell extracts of Escherichia coli harboring the fusion gene, and antibodies against the fusion protein were prepared in rabbits. Results:, In the presence of sucrose, the antibody against PAgA-GB significantly inhibited the adhesion of both S. sobrinus MT8145 and Streptococcus mutans Xc to saliva-coated hydroxyapatite beads, and the inhibitory effect on S. sobrinus was stronger than that on S. mutans. In the absence of sucrose, the antibody against PAgA-GB significantly inhibited the adhesion of both S. sobrinus and S. mutans, however the inhibitory effect on S. sobrinus was unexpectedly weaker than that on S. mutans. A similar result was observed with the antibody against the intact recombinant PAg protein (rPAg), while the same antibody reacted more strongly against S. sobrinus than against S. mutans cells. Conclusion:, Taken together, these results show that the antibody against S. sobrinus GTF-I may be useful for effective inhibition of the sucrose-dependent adhesion of S. sobrinus. However, PAg of S. sobrinus may not function primarily as a receptor for acquired pellicles, and other cell surface proteins may be involved in the sucrose-independent adhesion of S. sobrinus. [source] Alterations and reversibility in the chromatin, cytoskeleton and development of pig oocytes treated with roscovitineMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2003Jyh-Cherng Ju Abstract Germinal vesicle (GV) breakdown in mammalian oocytes is regulated by the activation of maturation promoting factor (MPF). We investigated a specific cdc2 kinase inhibitor, roscovitine, to maintain pig oocytes in the GV stage. Cumulus-oocyte complexes (COCs) were aspirated from slaughterhouse ovaries and cultured for 44 hr in NCSU#23 medium containing different levels of roscovitine (0, 10, 20, 30, 40, 50 ,M in Experiment 1 and 0, 40, 60, 80, 100, 120 ,M in Experiment 2). The COCs were cultured for another 44 hr after removal of the chemical. Twenty oocytes in each group were fixed at 44 hr for immunocytochemical labeling of the cytoskeleton and the rest (,20/group) were fixed at the end of 88 hr after culture. Results showed that the inhibition of the oocyte in the GV stage was not effective when 10,50 ,M (Experiment 1) of roscovitine were used (19,34%). When oocytes were released from the inhibitor, similar proportions (70,83%) of oocytes were observed in the MII or advanced stages among treatments. However, when higher concentrations of roscovitine were used (Experiment 2), significantly greater inhibitory effect was observed at the levels of 80,120 ,M with 83,91% oocytes being blocked in the GV stage when compared to the control (9%) and the 40,60 ,M (27,43%) groups (P,<,0.05). Although 15,21% of the oocytes showed abnormal MII morphology with aberrant meiotic spindles and/or formation of cytoplasmic microtubules, a substantial number of oocytes resumed meiosis and reached MII stage at 44 hr after removal of this chemical. In Experiment 3, different concentrations of roscovitine (0, 20, 40, and 80 ,M) were tested to examine the length of intervals (0, 11, 22, 33, and 44 hr) for an effective inhibition. Results showed that the inhibitory effect was significantly more prominent at 22 hr than that at 33 and 44 hr after roscovitine treatment in all treatment groups (P,<,0.05). This study demonstrated that roscovitine-treated oocytes resumed meiosis after removal of the inhibitor. This could provide flexibility for studying porcine oocyte development and embryo cloning and may have application in other species. Mol. Reprod. Dev. 64: 482,491, 2003. © 2003 Wiley-Liss, Inc. [source] Metabolism of a Highly Selective Gelatinase Inhibitor Generates Active MetaboliteCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2007Mijoon Lee (4-Phenoxyphenylsulfonyl)methylthiirane (inhibitor 1) is a highly selective inhibitor of gelatinases (matrix metalloproteinases 2 and 9), which is showing considerable promise in animal models for cancer and stroke. Despite demonstrated potent, selective, and effective inhibition of gelatinases both in vitro and in vivo, the compound is rapidly metabolized, implying that the likely activity in vivo is due to a metabolite rather than the compound itself. To this end, metabolism of inhibitor 1 was investigated in in vitro systems. Four metabolites were identified by LC/MS-MS and the structures of three of them were further validated by comparison with authentic synthetic samples. One metabolite, 4-(4-thiiranylmethanesulfonylphenoxy)phenol (compound 21), was generated by hydroxylation of the terminal phenyl group of 1. This compound was investigated in kinetics of inhibition of several matrix metalloproteinases. This metabolite was a more potent slow-binding inhibitor of gelatinases (matrix metalloproteinase-2 and matrix metalloproteinase-9) than the parent compound 1, but it also served as a slow-binding inhibitor of matrix metalloproteinase-14, the upstream activator of matrix metalloproteinase-2. [source] | ||||||||||||||||