Home About us Contact
|
Home About us Contact | ||
|
|
||
Significant Activity (significant + activity)
Selected AbstractsSignificant activity of a modified ribozyme with N7-deazaguanine at G10.1: the double-metal-ion mechanism of catalysis in reactions catalysed by hammerhead ribozymesGENES TO CELLS, Issue 8 2000Yuka Nakamatsu Background Several reports have appeared recently of experimental evidence for a double-metal-ion mechanism of catalysis in reactions catalysed by hammerhead ribozymes. In one case, hammerhead ribozyme-mediated cleavage was analysed as a function of the concentration of La3+ ions in the presence of a fixed concentration of Mg2+ ions so that the role of metal ions that are directly involved in the cleavage reaction could be monitored. The resultant bell-shaped curve for activation of cleavage was used to support the proposed double-metal-ion mechanism of catalysis. However, other studies have demonstrated that the binding of a metal ion (the most conserved P9 metal ion) to the pro-Rp oxygen (P9 oxygen) of the phosphate moiety of nucleotide A9 and to the N7 of nucleotide G10.1 is critical for efficient catalysis, despite the large distance (,20 Å) between the P9 metal ion and the labile phosphodiester group in the ground state. In fact, it was demonstrated that an added Cd2+ ion binds first to the pro-Rp phosphoryl P9 oxygen but not with the pro-Rp phosphoryl oxygen at the cleavage site. Results In earlier discussions, it was difficult to completely exclude the possibility that La3+ ions might have replaced the P9 metal ion and, as a result, created conditions represented by the bell-shaped curve. In order to clarify this situation, we examined a chemically synthesized hammerhead ribozyme (7-deaza-R34) that included a minimal modification, namely, an N7-deazaguanine residue in place of G10.1. We compared the kinetic properties of this ribozyme with those of the parental ribozyme (R34). Kinetic analysis revealed that, unlike the cases of added Cd2+ ions, the added La3+ ions did not replace the pre-existing P9 metal ion, and that the replacement of N7 by C7 at G10.1 reduced the catalytic activity to a limited extent. This result indicates that the binding of a Mg2+ ion to N7 at G10.1 is catalytically important but not indispensable. Most importantly, 7-deaza-R34 also yielded a bell-shaped curve upon addition of La3+ ions to the reaction mixture. Conclusions Since the data based on our experiments with 7-deaza-R34 are completely free from potential artefacts, due to the binding of a La3+ ion to N7 at G10.1, our results, that 7-deaza-R34 yielded a bell-shaped curve following the addition of La3+ ions to the Mg2+ -background reaction mixture, strongly supports the proposal that a double-metal-ion mechanism is operative in the cleavage reaction which is catalysed by hammerhead ribozymes. [source] Analysis of Escherichia coli anaplerotic metabolism and its regulation mechanisms from the metabolic responses to altered dilution rates and phosphoenolpyruvate carboxykinase knockoutBIOTECHNOLOGY & BIOENGINEERING, Issue 2 2003Chen Yang Abstract The gluconeogenic phosphoenolpyruvate (PEP) carboxykinase is active in Escherichia coli during its growth on glucose. The present study investigated the influence of growth rates and PEP carboxykinase knockout on the anaplerotic fluxes in E. coli. The intracellular fluxes were determined using the complementary methods of flux ratio analysis and metabolic flux analysis based on [U- 13C6]glucose labeling experiments and 2D nuclear magnetic resonance (NMR) spectroscopy of cellular amino acids and glycerol. Significant activity of PEP carboxykinase was identified in wild-type E. coli, and the ATP dissipation for the futile cycling via this reaction accounted for up to 8.2% of the total energy flux. Flux analysis of pck deletion mutant revealed that abolishment of PEP carboxykinase activity resulted in a remarkably reduced flux through the anaplerotic PEP carboxylase and the activation of the glyoxylate shunt, with 23% of isocitrate found being channeled in the glyoxylate shunt. The changes in intracellular metabolite concentrations and specific enzyme activities associated with different growth rates and pck deletion, were also determined. Combining the measurement data of in vivo fluxes, metabolite concentrations and enzyme activities, the in vivo regulations of PEP carboxykinase flux, PEP carboxylation, and glyoxylate shunt in E. coli are discussed. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 84: 129,144, 2003. [source] Characterization of tanshinones with quinone reductase induction activity from Radix Salvia miltiorrhiza by liquid chromatography/tandem mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 18 2009Zhongjun Ma Quinone reductase (QR) induction is a reliable biomarker of phase II enzyme induction. In this study, glutathione (GSH) was employed and a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was introduced to reveal the chemical constituents with QR activity from the ethyl acetate extract of roots Salvia miltiorrhiza (,Danshen') and nine tanshinones (9, 13, 17-19, 21, 24,26), which could conjugate with GSH, were characterized by LC/MS/MS and considered to have QR activities. Then, thirteen tanshinones, including six compounds (17, 18, 21, 24,26) of the above nine tanshinones, were isolated to conduct QR induction evaluation, and it was found that miltirone and its derivatives (18, 20, 24, 26) exhibited significant activities. The GSH conjugate abilities of the isolated tanshinones were also examined; this showed that compounds 18, 20, 24 and 26 had good conjugating abilities with GSH. Compared with the in vitro bioactivity screening results, this proved that conjugate ability is related with QR activity, so an LC/MS/MS method can be applied to find more active compounds. Copyright © 2009 John Wiley & Sons, Ltd. [source] Regulation of the Neurofibromatosis 2 gene promoter expression during embryonic developmentDEVELOPMENTAL DYNAMICS, Issue 10 2006Elena M. Akhmametyeva Abstract Mutations in the Neurofibromatosis 2 (NF2) gene are associated with predisposition to vestibular schwannomas, spinal schwannomas, meningiomas, and ependymomas. Presently, how NF2 is expressed during embryonic development and in the tissues affected by neurofibromatosis type 2 (NF2) has not been well defined. To examine NF2 expression in vivo, we generated transgenic mice carrying a 2.4-kb NF2 promoter driving ,-galactosidase (,-gal) with a nuclear localization signal. Whole-mount embryo staining revealed that the NF2 promoter directed ,-gal expression as early as embryonic day E5.5. Strong expression was detected at E6.5 in the embryonic ectoderm containing many mitotic cells. ,-gal staining was also found in parts of embryonic endoderm and mesoderm. The ,-gal staining pattern in the embryonic tissues was corroborated by in situ hybridization analysis of endogenous Nf2 RNA expression. Importantly, we observed strong NF2 promoter activity in the developing brain and in sites containing migrating cells including the neural tube closure, branchial arches, dorsal aorta, and paraaortic splanchnopleura. Furthermore, we noted a transient change of NF2 promoter activity during neural crest cell migration. While little ,-gal activity was detected in premigratory neural crest cells at the dorsal ridge region of the neural fold, significant activity was seen in the neural crest cells already migrating away from the dorsal neural tube. In addition, we detected considerable NF2 promoter activity in various NF2-affected tissues such as acoustic ganglion, trigeminal ganglion, spinal ganglia, optic chiasma, the ependymal cell-containing tela choroidea, and the pigmented epithelium of the retina. The NF2 promoter expression pattern during embryogenesis suggests a specific regulation of the NF2 gene during neural crest cell migration and further supports the role of merlin in cell adhesion, motility, and proliferation during development. Developmental Dynamics 235:2771,2785, 2006. © 2006 Wiley-Liss, Inc. [source] Bimatoprost, a novel efficacious ocular hypotensive drug now recognized as a member of a new class of agents called prostamidesDRUG DEVELOPMENT RESEARCH, Issue 4 2007Robert M. Burk Pursuit of a new FP-agonist prodrug led to the identification of an interesting series of neutral C1-substituted prostaglandin F2, analogues. Although these initial analogues were devoid of any inherent pharmacological activity at the FP-receptor, two compounds AGN-190910 and AGN-191129, were found to have pronounced effects in lowering intraocular pressure (IOP) in normotensive dogs and monkeys. The cat iris sphincter assay was quickly developed as a primary screen for these analogues, leading to rapid identification of AGN-192024 (17-phenyl PGF2, ethyl amide, bimatoprost). While bimatoprost is structurally similar to naturally occurring mammalian hormones of the prostanoid family, surprisingly it demonstrates no significant activity at any of the known prostanoid receptors. Furthermore, results of considerable additional pharmacological studies provide evidence that it may indeed act through a unique receptor yet to be identified. The effect of Bimatoprost on lowering IOP has also been found to be unique in comparison to prostanoids. Bimatoprost reduces human IOP by increasing aqueous humor outflow through a dual mechanism of action where it improves both pressure-dependent and pressure-independent outflow pathways. First introduced to the market in 2002, bimatoprost is currently the most potent single therapy available for control of ocular hypertension. Drug Dev Res 68:147,155, 2007. ©2007 Wiley-Liss, Inc. [source] Microbiological investigation of methane- and hydrocarbon-discharging mud volcanoes in the Carpathian Mountains, RomaniaENVIRONMENTAL MICROBIOLOGY, Issue 4 2006Karine Alain Summary Paclele Mici is a terrestrial mud volcano field located in the Carpathian Mountains (Romania), where thermal alteration of sedimentary organic compounds leads to methane, higher hydrocarbons and other petroleum compounds that are continuously released into the environment. The hydrocarbons represent potential substrates for microorganisms. We studied lipid biomarkers, stable isotope ratios, the effect of substrate (methane, other organic compounds) addition and 16S rRNA genes to gain insights into the hitherto unknown microbial community at this site. Quantitative real-time polymerase chain reaction analysis demonstrated that bacteria were much more abundant than archaea. Phylogenetic analyses of 16S rDNA clone sequences indicated the presence of bacterial and archaeal lineages generally associated with the methane cycle (methanogens, aerobic and anaerobic methanotrophs), the sulfur cycle (sulfate reducers), and groups linked to the anaerobic degradation of alkanes or aromatic hydrocarbons. The presence of sulfate reducers, methanogens and methanotrophs in this habitat was also confirmed by concurrent surveys of lipid biomarkers and their isotopic signatures. Incubation experiments with several common and complex substrates revealed the potential of the indigenous microbial community for sulfate reduction, methanogenesis and aerobic methanotrophy. Additionally, consistently to the detection of methane-oxidizing archaea (ANME) and 13C-depleted archaeal lipids, a weak but significant activity of anaerobic methane oxidation was measured by radiotracer techniques and in vitro. This survey is the first to report the presence and activity of ANME in a terrestrial environment. [source] Single-neuron evidence for a contribution of the dorsal pontine nuclei to both types of target-directed eye movements, saccades and smooth-pursuitEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2004Peter W. Dicke Abstract The primate dorsolateral pontine nucleus (DLPN) is a key link in a cerebro-cerebellar pathway for smooth pursuit eye movements, a pathway assumed to be anatomically segregated from tegmental circuits subserving saccades. However, the existence of afferents from several cerebrocortical and subcortical centres for saccades suggests that the DLPN and neighbouring parts of the dorsal pontine nuclei (DPN) might contribute to saccades as well. In order to test this hypothesis, we recorded from the DPN of two monkeys trained to perform smooth pursuit eye movements as well as visually and memory-guided saccades. Out of 281 neurons isolated from the DPN, 138 were responsive in oculomotor tasks. Forty-five were exclusively activated in saccade paradigms, 68 exclusively by smooth pursuit and 25 neurons showed responses in both. Pursuit-related responses reflected sensitivity to eye position, velocity or combinations of velocity and position with minor contributions of acceleration in many cases. When tested in the memory-guided saccades paradigm, 65 out of 70 neurons activated in saccade paradigms showed significant saccade-related bursts and 20 significant activity in the memory period. Our finding of saccade-related activity in the DPN in conjunction with the existence of strong anatomical input from saccade-related cerebrocortical areas suggests that the DPN serves as a precerebellar relay for both pursuit and saccade-related information originating from cerebral cortex, in addition to the classical tecto-tegmental circuitry for saccades. [source] Radon (222Rn) in Ground Water of Fractured Rocks: A Diffusion/Ion Exchange ModelGROUND WATER, Issue 4 2004Warren W. Wood Ground waters from fractured igneous and high-grade sialic metamorphic rocks frequently have elevated activity of dissolved radon (222Rn). A chemically based model is proposed whereby radium (226Ra) from the decay of uranium (238U) diffuses through the primary porosity of the rock to the water-transmitting fracture where it is sorbed on weathering products. Sorption of 226Ra on the fracture surface maintains an activity gradient in the rock matrix, ensuring a continuous supply of 226Ra to fracture surfaces. As a result of the relatively long half-life of 226Ra (1601 years), significant activity can accumulate on fracture surfaces. The proximity of this sorbed 226Ra to the active ground water flow system allows its decay progeny 222Rn to enter directly into the water. Laboratory analyses of primary porosity and diffusion coefficients of the rock matrix, radon emanation, and ion exchange at fracture surfaces are consistent with the requirements of a diffusion/ion-exchange model. A dipole-brine injection/withdrawal experiment conducted between bedrock boreholes in the high-grade metamorphic and granite rocks at the Hubbard Brook Experimental Forest, Grafton County, New Hampshire, United States (42°56,N, 71°43,W) shows a large activity of 226Ra exchanged from fracture surfaces by a magnesium brine. The 226Ra activity removed by the exchange process is 34 times greater than that of 238U activity. These observations are consistent with the diffusion/ion-exchange model. Elutriate isotopic ratios of 223Ra/226Ra and 238U/226Ra are also consistent with the proposed chemically based diffusion/ion-exchange model. [source] Human resource development in remote island communities: an evaluation of tour-guide training in VanuatuINTERNATIONAL JOURNAL OF TOURISM RESEARCH, Issue 2 2002Rosemary Black Abstract About 30% of visitors to Vanuatu visit the outer islands, where ecotourism has recently emerged as a small-scale but significant activity. In the face of increasing competition from comparable Asia,Pacific destinations, there has been pressure on tourism operators and the Vanuatu Government to improve product quality through mechanisms such as the development of high-quality tours. One way to enhance product quality is through the provision of appropriate professional training for tourism sector employees, including local tour guides. The paper outlines a tour-guide training programme delivered on the outer islands, which received financial assistance from several foreign aid agencies. The programme is an instructive example of an attempt to implement a human resource strategy in a developing country arising from the recommendations of a national tourism masterplan that sought the active involvement of international funding agencies in the implementation phase. The paper evaluates the effectiveness of the training programme and outlines the challenges of programme delivery. Copyright © 2002 John Wiley & Sons, Ltd. [source] Isolation of a low-temperature adapted lipolytic enzyme from uncultivated micro-organismJOURNAL OF APPLIED MICROBIOLOGY, Issue 1 2008C. Roh Abstract Aims:, The aim of the study was to isolate a novel lipolytic enzyme from the activated sludge of uncultured micro-organisms. Methods and Results:, The metagenomic DNA was directly extracted from the activated sludge, and a metagenomic library was constructed by using the pUC vector. The library was screened for lipolytic enzyme activity on 1% tributyrin agar plate. A clone among c. 100 000 recombinant libraries showed the lipolytic activity. The putative lipolytic gene encoding lipo1 from the metagenomic library was subcloned and expressed in Escherichia coli BL21 using the pET expression system. The expressed recombinant enzyme was purified by Ni-nitrilotriacetic acid affinity chromatography and characterized using general substrates of lipolytic property. The gene consisted of 972 bp encoding a polypeptide of 324 amino acids with a molecular mass of 35·6 kDa. Typical residues essential for lipolytic activity such as penta-peptide (GXSXG) and catalytic triad sequences (Ser166, Asp221 and His258) were detected. The deduced amino acid sequence of lipo1 showed low identity with amino acid sequences of esterase/lipase (32%, ZP_01528487) from Pseudomonas mendocina ymp and esterase (31%, AAY45707) from uncultured bacterium. This lipolytic enzyme exhibited the highest activity at pH 7·5 and 10°C. At thermal stability analysis, lipo1 was more unstable at 40°C than 10°C. Conclusions:, An activity based strategy has been an effective method for fishing out a low-temperature adapted lipolytic enzyme from the metagenomic library. This lipo1 enzyme can be considered to belong to the hormone-sensitive lipase family due to the enzyme's oxyanion hole by the sequence HGGG. Significance and Impact of the Study:, Lipo1 is a novel psychrophilic esterase obtained directly from the metagenomic library. Owing its support of significant activity at low temperature, this enzyme is expected to be useful for potential application as a biocatalyst in organic chemistry. [source] Synthesis and bio-activity of alkyl/aryl [2-(1,2,4,5-tetrahydro-3-sulfanylene/selenylene naphtha[1,8][1,5,3]diazaphosphocin- 3-yl)methyl amino acid esters]JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2010S. Subba Reddy Synthesis of alkyl/aryl [2-(1,2,4,5-tetrahydro-3-sulfanylene/selenylene naphtha[1,8- f,g][1,5,3]diazaphosphocin-3-yl) methyl amino acid esters] (6,15) was accomplished in three steps. 1, 8-diamino naphthalene (2) was reacted with tris (bromomethyl) phosphine (1) in the presence of triethylamine in dry tetrahydrofuran (THF) under N2 atmosphere to form a PIII intermediate (3). It was converted to the corresponding sulfide (4) and selenide (5) by reacting with sulfur and selenium, respectively. The intermediates 4 and 5 were further reacted with amino acid esters to obtain the title compounds (6,15). The structures of the title compounds were established by elemental analysis and spectral data (IR, 1H, 13C, 31P NMR, and FAB mass). The antimicrobial activity of these compounds was evaluated and they exhibited significant activity. J. Heterocyclic Chem., (2010). [source] Synthesis and antimicrobial activity of novel 2-alkyl/arylcarbamato-6-(1,1-dimethylethyl)-3-cyclohexyl-3,4-dihydro-2H -1,3,2-benzoxazaphosphorine-2-oxidesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2002Y. Hari Babu Novel 2-alkyl/arylcarbamato-6-(1,1-dimethylethyl)-3-cyclohexyl-3,4-dihydro-2H -1,3,2-benzoxaza-phosphorine-2-oxides (IV) have been synthesized from reactions of 2-cyclohexylaminomethyl-4- t -butylphenol I [8c] with various dichlorophosphinyl carbamates (III) [8a-b] in dry toluene in the presence of triethylamine at 40-50 °C. All the title compounds (IVa-j) at reflux temperature are degraded to 2-amino-6-(1,1-dimethylethyl)-3-cyclohexyl-3,4-dihydro-2H -1,3,2-benzoxazaphosphorine-2-oxide (IVk) exclusively. The structures are determined by ir, nmr and mass spectral studies. They were screened for antifungal activity against Penicillium notatum, Aspergillus niger and Helminthosporium sps, and antibacterial activity on Escherchia coli, Staphylococcus aureus and Pseudomonas aeruginosa. A few of them possess significant activity. [source] Synthesis of indazol-4,7-dione derivatives as potential trypanocidal agentsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2002Ricardo A. Tapia The synthesis of new indazol-4,7-dione derivatives via 1,3-dipolar cycloaddition of diazomethane with 2,3-dimethyl-1,4-benzoquinone (2) and 1,4-naphthoquinone (7) followed by N -alkylation of the pyrazol nitrogen atom of the corresponding quinones (3) and (8) with methyl chloroacetate is described. A series of amides from esters (5) and (10) were also obtained. These compounds were tested in vitro as potential anti-trypanosomal agents. Compounds (4) and (8) were found to have significant activity. [source] Chemical composition and antimicrobial activity of Anzer tea essential oilJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 7 2007ekero Abstract Anzer tea (Thymus praecox, subsp. caucasicus var. caucasicus) naturally grows in the eastern Black Sea region of Turkey. Anzer tea, a creeping plant with crimson-pink flowers, is important for honey production in the region. In the present study, content, composition and antimicrobial properties of Anzer tea's essential oil were investigated. Essential oil content of dried aerial plant parts varied between 1.53% and 2.05%. Essential oil composition was studied by means of gas chromatography,mass spectrometry, and 26 components were identified. The major components were thymol (47.45%), ,-terpinene (8.73%), p -cymene (8.30%), terpinyl acetate (4.88%) and carvacrol (4.66%). Essential oil was also screened for its antibacterial activity. In a screen for antibacterial activity, Anzer tea essential oil had significant activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Candida albicans. Copyright © 2007 Society of Chemical Industry [source] Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström MacroglobulinemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Irene M. Ghobrial This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70,98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] The pediatric preclinical testing program: Description of models and early testing results,PEDIATRIC BLOOD & CANCER, Issue 7 2007Peter J. Houghton PhD Abstract Background The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. Procedures Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. Results Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. Conclusions We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity. Pediatr Blood Cancer 2007;49:928,940. Published 2006 Wiley-Liss, Inc. [source] In vitro cytotoxic, antiprotozoal and antimicrobial activities of medicinal plants from VanuatuPHYTOTHERAPY RESEARCH, Issue 6 2010Gesine Bradacs Abstract Sixty-three extracts obtained from 18 plants traditionally used in the South Pacific archipelago Vanuatu for the treatment of infectious diseases were screened for antimicrobial and antiprotozoal activities. In addition, the extracts were subjected to a detailed analysis on cytotoxic effects toward a panel of human cancer cell lines, designed as a smaller version of the NCI60 screen. Intriguingly, 15 plant extracts exhibited strong cytotoxic effects specific for only one cancer cell line. Extracts of the leaves of Acalypha grandis Benth. significantly affected Plasmodium falciparum without showing obvious effects against the other protozoa tested. The leaves of Gyrocarpus americanus Jacq. displayed significant activity against Trypanosoma b. brucei and the leaves of Tabernaemontana pandacaqui Lam. I as well as the stems of Macropiper latifolium (L.f.) against Trypanosoma cruzi. In contrast none of the extracts showed relevant antibacterial or antifungal activity. Copyright © 2009 John Wiley & Sons, Ltd. [source] Astragalus membranaceus prevents daunorubicin-induced apoptosis of cultured neonatal cardiomyocytes: role of free radical effect of Astragalus membranaceus on daunorubicin cardiotoxicityPHYTOTHERAPY RESEARCH, Issue 6 2009ZhongGuang Luo Abstract Anthracyclines are antitumor antibiotics with significant activity against solid and hematologic malignancies. One problem preventing more widespread use has been the development of cardiotoxicity. To determine whether antioxidant agents can reduce the cardiotoxicity of anthracyclines, a herb Astragalus membranaceus was introduced, which has been widely used for the treatment of cardiovascular diseases in China and was confirmed to be an effective antioxidant agent recently. Pre-treatment with Astragalus membranaceus significantly attenuated the daunorubicin-induced increases of reactive oxygen species (p < 0.001), apoptosis (p < 0.05) and the secretions of LDH (p < 0.01) in cultured neonatal cardiomyocytes. Astragalus membranaceus also raised the EC50 of daunorubicin 1.24-fold. Compared with Astragalus membranaceus, N -acetyl- l -cysteine had similar effects on daunorubicin-induced cell injury, however, superoxide dismutase reduced reactive oxygen species without attenuating apoptosis. The subcellular distribution of DNR was similar to the distribution of MitoTracker Red 580 in mitochondria, which was mainly in the cytoplasm around the nuclear membrane in cultured neonatal cardiomyocytes. In conclusion, the results suggested that Astragalus membranaceus is potentially protective against daunorubicin cardiotoxicity by decreasing free radical release and apoptosis in cultured neonatal cardiomyocytes. The main subcellular distribution of daunorubicin may be in the mitochondria. Copyright © 2009 John Wiley & Sons, Ltd. [source] Inhibition of early and late phase allergic reactions by Euphorbia hirta L.PHYTOTHERAPY RESEARCH, Issue 4 2006G. D. Singh Abstract 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- , (IFN- ,) 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. Copyright © 2006 John Wiley & Sons, Ltd. [source] Evaluation of antiprotozoal and plasmodial enoyl-ACP reductase inhibition potential of turkish medicinal plantsPHYTOTHERAPY RESEARCH, Issue 2 2005D. Tasdemir Abstract A total of 58 extracts of different polarity were prepared from various organs of 16 species of Turkish plants and screened for their antitrypanosomal, antileishmanial and antiplasmodial activities. No significant activity was observed against Trypanosoma cruzi, whereas many extracts showed appreciable trypanocidal potential against T. brucei rhodesiense, with the CHCl3 -soluble portion of Phlomis kurdica being the most active (IC50 2.7 µg[sol ]mL). Almost all extracts, particularly the CHCl3 phases, exhibited growth inhibition activity against Leishmania donovani amastigotes. The CHCl3 -solubles of Putoria calabrica roots (IC50 1.9 µg[sol ]mL), Wendlandia ligustroides leaves (IC50 2.1 µg[sol ]mL) and Rhododendronluteum leaves (IC50 2.3 µg[sol ]mL) displayed the highest leishmanicidal potential. The majority of the extracts also possessed antiplasmodial activity against the multi-drug resistant K1 Plasmodium falciparum strain. The most potent antiplasmodial activity was observed with the CHCl3 extracts of Phlomis kurdica (IC50 1.5 µg[sol ]mL), P. leucophracta (IC50 1.6 µg[sol ]mL), Scrophularia cryptophila (IC50 1.8 µg[sol ]mL), Morina persica (IC50 1.9 µg[sol ]mL) and the aqueous root extract of Asperula nitida subsp. subcapitellata (IC50 1.6 µg[sol ]mL). Twenty-one extracts with significant antimalarial activity (IC50 < 5 µg[sol ]mL) were also tested for their ability to inhibit the purified enoyl-ACP reductase (FabI), a crucial enzyme in the fatty acid biosynthesis of P. falciparum. The CHCl3 extract of Rhododendronungernii leaves (IC50 10 µg[sol ]mL) and the H2O-soluble portion of Rhododendronsmirnovii leaves (IC50 0.4 µg[sol ]mL) strongly inhibited the FabI enzyme. The preliminary data indicate that some (poly)phenolic compounds are responsible for the FabI inhibition potential of these extracts. The presented work reports for the first time the antiprotozoal activity of nine different genera as well as a target specific antimalarial screening for the identification of P. falciparum FabI inhibitors from medicinal plant extracts. Copyright © 2005 John Wiley & Sons, Ltd. [source] Probation and the Tragedy of PunishmentTHE HOWARD JOURNAL OF CRIMINAL JUSTICE, Issue 3 2007ROB CANTON Values should be expressed in action; reciprocally, experiences of trying to realise aims and values should contribute to their progressive refinement. These considerations and awareness of diversity imply wide discretion and other characteristics that sit uncomfortably with contemporary managerialism. Probation is a morally significant activity and not reducible to techniques of effectiveness. [source] Comparative activity and stability under salinity conditions of different antimicrobial peptides isolated from aquatic animalsAQUACULTURE RESEARCH, Issue 16 2009Sara Emelie Löfgren Abstract This study reports the in vitro activity of six antimicrobial peptides (AMPs) produced by aquatic animals (most marine invertebrates): tachyplesin (Tach), magainin (Mag), clavanin (Clav), penaeidin (Pen), mytilin (Myt) and antilipopolysaccharide factor (ALF) against marine vibrios, filamentous fungi and yeast. Their stability under salinity conditions and seawater was also examined. The results showed that Mag, Myt and especially Tach and ALF (minimum inhibitory concentration<1.5 ,M) had a potent activity against all tested vibrio species, whereas Clav and Pen were ineffective (up to 50 ,M). With respect to the antifungal activity, each AMP had a different potency according to the fungal species. In general terms, Tach was the most potent peptide, followed by Mag. Interestingly, Tach, Myt and ALF had a significant effect on the filamentous fungus Fusarium solani that could be pathogenic to marine organisms. All AMPs had a tendency to decrease or lose their activity at high salinity (>225 mM NaCl). Tach and Myt were the most stable peptides, maintaining significant activity under seawater salinity (450 mM). Curiously, all peptides lost their effect under seawater conditions. The results suggest that Tach, ALF and Myt are the most promising candidates for potential therapeutic use in farmed-marine species, because all have a significant and broad antimicrobial activity maintained at high salinity. [source] Platinum and Palladium-triazole Complexes as Highly Potential Antitumor AgentsARCHIV DER PHARMAZIE, Issue 4 2010Najim A. Al-Masoudi Abstract The palladium complexes [(dppe)Pd(L)2PdCl2], [(dppe)Pd(L)2PtCl2], [(dppp)Pd(L)2PdCl2], [(dppm) Pd(L)2NiCl2], and [(dppm)Pd(L)2SnCl4] 15,19 were prepared. The antiproliferative activity of the newly synthesized complexes as well as their previously prepared analogues 3,14 and 20,26 were screened against a large panel of human cancer cell lines derived from haematological CD4+ human T-cells containing an integrated HTLV-1 genome (MT-4). The complex 12a, b exhibited remarkable antiproliferative activity against MT-4, CD4+ human acute T-lymphoblastic leukemia (CCRF-CEM), human splenic B-lymphoblastoid cells (WIL-2NS), human acute B-lymphoblastic leukemia (CCRF-SB), skin melanoma (SK-MEL-28), and prostate carcinoma (DU145) cell lines (CC50 = 0.5 ,M, 0.4 ± 0.05 ,M, 0.6 ± 0.05 ,M, 0.4 ± 0.1 ,M, and 0.8 ± 0.2 ,M, respectively), meanwhile, 9a, b, 14a, b, and 23 showed significant activity against the CCRF-SB cell lines (CC50 = 0.6 ± 0.06 ,M, 0.7 ± 0.05 ,M, 0.6 ± 0.05 ,M, and 0.8 ± 0.15 ,M, respectively). Further, 19 exhibited activity against the CCRF-CEM cell line (CC50 = 0.4 ± 0.05 ,M). [source] Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenonARTHRITIS & RHEUMATISM, Issue 9 2002Peter A. Merkel Objective To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. Methods Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. Results Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18,82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 ± 2.33 (mean ± SD) daily RP attacks (range 0.8,14.6), with a duration of 82.1 ± 91.6 minutes/attack. RCS for RP activity (possible range 0,10) was 4.30 ± 1.92. HAQ scores (0,3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33,0.76). Conclusion Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2). [source] Myrica nagi Attenuates Cumene Hydroperoxide-Induced Cutaneous Oxidative Stress and Toxicity in Swiss Albino MiceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2000Aftab Alam In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron-ascorbate-induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S-transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (P<0.05). In addition the depleted level of glutathione, the inhibited activities of antioxidants, and phase II metabolizing enzymes were recovered to a significant level (P<0.05). The protective effect of Myrica nagi was dose-dependent. In summary our data suggest that Myrica nagi is an effective chemopreventive agent in skin and capable of ameliorating cumene hydroperoxide-induced cutaneous oxidative stress and toxicity. [source] Study of stationary phase metabolism via isotopomer analysis of amino acids from an isolated proteinBIOTECHNOLOGY PROGRESS, Issue 1 2010Afshan S. Shaikh Abstract Microbial production of many commercially important secondary metabolites occurs during stationary phase, and methods to measure metabolic flux during this growth phase would be valuable. Metabolic flux analysis is often based on isotopomer information from proteinogenic amino acids. As such, flux analysis primarily reflects the metabolism pertinent to the growth phase during which most proteins are synthesized. To investigate central metabolism and amino acids synthesis activity during stationary phase, addition of fully 13C-labeled glucose followed by induction of green fluorescent protein (GFP) expression during stationary phase was used. Our results indicate that Escherichia coli was able to produce new proteins (i.e., GFP) in the stationary phase, and the amino acids in GFP were mostly from degraded proteins synthesized during the exponential growth phase. Among amino acid biosynthetic pathways, only those for serine, alanine, glutamate/glutamine, and aspartate/asparagine had significant activity during the stationary phase. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] Efficacy of low-dose dexamethasone in castration-refractory prostate cancerBJU INTERNATIONAL, Issue 4 2008Ramachandran Venkitaraman OBJECTIVE To evaluate the prostate-specific antigen (PSA) response rate and duration of PSA response to dexamethasone in patients with castration-refractory prostate cancer (CRPC), as corticosteroids are frequently used as second-line hormonal treatment of CRPC and there is little published evidence concerning the efficacy of low-dose dexamethasone in this setting. PATIENTS AND METHODS In all, 102 patients with progressive CRPC received oral dexamethasone (0.5 mg daily) between January 2003 and October 2006. The median pretreatment PSA level was 83 ng/mL. The main endpoint was the PSA response rate according to the PSA Working Group criteria. RESULTS In all, 50 patients (49%) had a confirmed PSA response. The median (range) time to PSA progression for the entire cohort was 7.4 (1,28) months. In responders, the median duration of the PSA response was 11.6 (1,24) months. CONCLUSION Low-dose dexamethasone has significant activity in CRPC. Subject to validation with more clinically meaningful endpoints, dexamethasone could become the corticosteroid of choice in the management of CRPC, and its potential for use in combination with novel agents should be explored. [source] PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2005Heather E. Oakervee Summary Bortezomib (formerly PS-341) has significant activity in patients with relapsed multiple myeloma (MM), its efficacy is increased with the addition of dexamethasone and it demonstrates synergy with doxorubicin, thus providing the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD). Patients with untreated MM received four 21-d cycles of PAD, comprising bortezomib 1·3 mg/m2 on days 1, 4, 8 and 11, along with dexamethasone 40 mg on days 1,4, 8,11 and 15,18 during cycle 1 and days 1,4 during cycles 2,4. During days 1,4, patients also received 0, 4·5 or 9 mg/m2 of doxorubicin at dose levels 1, 2, and 3 respectively. Following peripheral blood stem cell (PBSC) collection, patients received high-dose melphalan (MEL200) with PBSC transplantation (PBSCT). After PAD induction alone, 20 of 21 patients (95%) achieved at least a partial response (PR), including complete response (CR) in five patients (24%). Twenty of 21 had PBSC mobilized, and 18 of 20 received MEL200/PBSCT. In an intention-to-treat analysis, response rates were: CR 43%, near CR 14%, very good PR 24%, PR 14% and stable disease 5%. PAD was effective, did not prejudice subsequent PBSC collection, and should be further evaluated in prospective randomized trials. [source] A multiinstitutional, concurrent chemoradiation trial of strontium-89, estramustine, and vinblastine for hormone refractory prostate carcinoma involving boneCANCER, Issue 6 2002Wallace Akerley M.D. Abstract BACKGROUND Estramustine phosphate (EMP) and vinblastine have radiosensitizing properties and significant activity against hormone refractory prostate carcinoma. Strontium-89 is a palliative agent that acts as a selective radiation source for bone metastasis. The combination of EMP, vinblastine, and strontium-89 was developed to exploit the potential for radiosynergy. PATIENTS AND METHODS Forty-four patients at the Brown Oncology Group affiliated hospitals were treated with oral EMP 600 mg/m2 daily on Weeks 1,4 and 7,10, vinblastine 4 mg/m2 intravenously once each week on Weeks 1,4 and 7,10, and strontium-89 2.2 MBq/kg on Day 1. Courses were repeated every 12 weeks. Response assessment was based on a change in the serum prostate specific antigen (PSA) levels, correlated with change in measurable disease and bone scan appearance. RESULTS A greater than or equal to 50% decline in PSA for at least 6 weeks was observed in 21 patients (48%, 95% confidence interval, 33,62%). Median duration of response was 23 weeks (range, 6,70.8 weeks). The median survival was 13 months with 1- and 2-year survival rates of 55% and 25%, respectively. After completion of protocol therapy, a retrospective review showed that only nine patients received subsequent palliative external beam radiation after progression. CONCLUSIONS The addition of strontium-89 to the regimen of EMP and vinblastine can be delivered safely and in repeated doses, provides effective palliation, and may decrease the need for future radiation therapy. A randomized trial is necessary to quantify these effects. Cancer 2002;94:1654,60. © 2002 American Cancer Society. DOI 10.1002/cncr.10437 [source] Living Radical Polymerization of Acrylates Mediated by 1,3-Bis(2-pyridylimino)isoindolatocobalt(II) Complexes: Monitoring the Chain Growth at the MetalCHEMISTRY - A EUROPEAN JOURNAL, Issue 33 2008Björn Abstract A new type of mediator for cobalt(II)-mediated radical polymerization is reported which is based on 1,3-bis(2-pyridylimino)isoindolate (bpi) as ancillary ligand. The modular synthesis of the bis(pyridylimino)isoindoles (bpiH) employed in this work is based on the condensation of 2-aminopyridines with phthalodinitriles. Reaction of the bpiH protio-ligands with a twofold excess of cobalt(II) acetate or cobalt(II) acetylacetonate in methanol gave [Co(bpi)(OAc)], which crystallize as coordination polymers, and a series of [Co(acac)(bpi)(MeOH)], which are mononuclear octahedral complexes. Upon heating the [Co(acac)(bpi)(MeOH)] compounds to 100,°C under high vacuum, the coordinated methanol was removed to give the five-coordinate complexes [Co(acac)(bpi)]. The polymerization of methyl acrylate at 60,°C was investigated by using one molar equivalent of the relatively short-lived radical source 2,2,-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) as initiator (monomer/catalyst/V-70: 600:1:1). The low solubility of the acetato complexes inhibits their significant activity as mediators in this reaction, whereas the acetylacetonate complexes control the radical polymerization of methyl acrylate more effectively. The radical polymerizations of the hexacoordinate complexes did not show a linear increase in number-average molecular weight (Mn) with conversion; however, the polydispersities were relatively low (PDI=1.12,1.40). By using the pentacoordinate complexes [Co(acac)(bpi)] as mediators, a linear increase in Mn values with conversion, which were very close to the theoretical values for living systems, and very low polydispersities (PDI<1.13) were obtained. This was also achieved in the block copolymerization of methyl acrylate and n -butyl acrylate. The intermediates with the growing acrylate polymer radical (.PA) were identified by liquid injection field desorption/ionization mass spectrometry as following the general formula [Co(acac)(4-methoxy-bpi)-(MA)n -R] (MA: methyl acrylate; R: C(CH3)(CH2C(CH3)2OCH3)CN), a notion also confirmed by NMR end-group analysis. [source] | |||||||||||||||||||||||||||||||