排序方式: 共有27条查询结果,搜索用时 15 毫秒
1.
Rama Jain Michelle Mathur Jiong Lan Abran Costales Gordana Atallah Savithri Ramurthy Sharadha Subramanian Lina Setti Paul Feucht Bob Warne Laura Doyle Stephen Basham Anne B. Jefferson Brent A. Appleton Mika Lindvall Cynthia M. Shafer 《Bioorganic & medicinal chemistry letters》2018,28(19):3197-3201
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation. 相似文献
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Klein RR Bourdon DM Costales CL Wagner CD White WL Williams JD Hicks SN Sondek J Thakker DR 《The Journal of biological chemistry》2011,286(14):12407-12416
Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCβ3 (hPLCβ3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCβ3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6±5 μm. Activation of hPLCβ3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 μm) also activated hPLCγ1 (>10-fold) and hPLCβ2 (~2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes. 相似文献
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Tapan Bhattacharyya Andrew K. Falconar Alejandro O. Luquetti Jaime A. Costales Mario J. Grijalva Michael D. Lewis Louisa A. Messenger Trang T. Tran Juan-David Ramirez Felipe Guhl Hernan J. Carrasco Patricio Diosque Lineth Garcia Sergey V. Litvinov Michael A. Miles 《PLoS neglected tropical diseases》2014,8(5)
Background
Chagas disease, caused by infection with the protozoan Trypanosoma cruzi, remains a serious public health issue in Latin America. Genetically diverse, the species is sub-divided into six lineages, known as TcI–TcVI, which have disparate geographical and ecological distributions. TcII, TcV, and TcVI are associated with severe human disease in the Southern Cone countries, whereas TcI is associated with cardiomyopathy north of the Amazon. T. cruzi persists as a chronic infection, with cardiac and/or gastrointestinal symptoms developing years or decades after initial infection. Identifying an individual''s history of T. cruzi lineage infection directly by genotyping of the parasite is complicated by the low parasitaemia and sequestration in the host tissues.Methodology/Principal Findings
We have applied here serology against lineage-specific epitopes of the T. cruzi surface antigen TSSA, as an indirect approach to allow identification of infecting lineage. Chagasic sera from chronic patients from a range of endemic countries were tested by ELISA against synthetic peptides representing lineage-specific TSSA epitopes bound to avidin-coated ELISA plates via a biotin labelled polyethylene glycol-glycine spacer to increase rotation and ensure each amino acid side chain could freely interact with their antibodies. 79/113 (70%) of samples from Brazil, Bolivia, and Argentina recognised the TSSA epitope common to lineages TcII/TcV/TcVI. Comparison with clinical information showed that a higher proportion of Brazilian TSSApep-II/V/VI responders had ECG abnormalities than non-responders (38% vs 17%; p<0.0001). Among northern chagasic sera 4/20 (20%) from Ecuador reacted with this peptide; 1/12 Venezuelan and 1/34 Colombian samples reacted with TSSApep-IV. In addition, a proposed TcI-specific epitope, described elsewhere, was demonstrated here to be highly conserved across lineages and therefore not applicable to lineage-specific serology.Conclusions/Significance
These results demonstrate the considerable potential for synthetic peptide serology to investigate the infection history of individuals, geographical and clinical associations of T. cruzi lineages. 相似文献5.
Ramurthy S Costales A Jansen JM Levine B Renhowe PA Shafer CM Subramanian S 《Bioorganic & medicinal chemistry letters》2012,22(4):1678-1681
Compounds belonging to several scaffolds-quinazolines, quinolines and quinoxalines-were designed and synthesized as Raf kinase inhibitors. Scaffolds were assessed for in vitro Braf(V600E) inhibition, and overall kinase selectivity. Pharmacokinetic parameters for one of the scaffolds were also determined. 相似文献
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Previous studies at our laboratory have shown that an antibody (antiegressin) present in the serum of chronically infected mice is capable of inhibiting the egress of Trypanosoma cruzi from infected BALB/c fibroblasts. We have used this in vitro system to evaluate whether human chagasic serum is also capable of inhibiting T. cruzi egress. BALB/c fibroblasts were infected with tissue culture-derived parasites. Five-percent solutions of the individual human serum samples in culture medium were added to the wells, and the number of parasites released was determined at day 5 after infection. The cells cultured with serum from infected individuals released between 37% and 72% fewer parasites than those cultured with control serum. A similar reduction in parasite egress resulted from incubation with the protein-A purified IgG fraction from 3 of these human samples. Immunocytochemical staining employing antineuraminidase antibodies supported the notion that the reduction in parasite levels is due to inhibition at the point of parasite egress. These results indicate that human serum of individuals infected with T. cruzi is capable of inhibiting release of the parasite from infected tissue culture cells and that the phenomenon of egress-inhibition may be relevant during infection of human subjects. 相似文献
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Alejandro B. Falcón Juan Carlos Cabrera Daimy Costales Miguel Angel Ramírez Gustavo Cabrera Verónica Toledo Miguel Angel Martínez-Téllez 《World journal of microbiology & biotechnology》2008,24(1):103-112
Enzymatic degradation of chitosan polymer with Pectinex Ultra SPL was used to obtain derivatives with biological potential
as protective agents against Phytophthora parasitica nicotianae (Ppn) in tobacco plants. The 24 h hydrolysate showed the highest Ppn antipathogenic activity and the chitosan native polymer the lowest. The in vitro growth inhibition of several Phytophthora parasitica strains by two chitosans of different DA was compared. While less acetylated chitosan (DA 1%) fully inhibited three P. parasitica strains at the doses 500 and 1000 mg/l the second polymer (DA 36.5%) never completely inhibited such strains. When comparing
two polymers of similar molecular weight and different DA, again the highest antipathogenic activity was for the less acetylated
polymer. However, degraded chitosan always showed the highest pathogen growth inhibition. Additionally, a bioassay in tobacco
seedlings to test plant protection against Ppn by foliar application demonstrated that partially acetylated chitosan and its hydrolysate induced systemic resistance and
higher levels of glucanase activity than less acetylated chitosan. Similarly, when treatments were applied as seeds coating
before planting, about 46% of plant protection was obtained using chitosan hydrolysate. It was concluded that, while less
acetylated and degraded chitosan are better for direct inhibition of pathogen growth, partially acetylated and degraded chitosan
are suitable to protect tobacco against P. parasitica by systemic induction of plant resistance. 相似文献
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Luis E. Hernandez-Castro Anita G. Villacís Arne Jacobs Bachar Cheaib Casey C. Day Sofía Ocaa-Mayorga Cesar A. Yumiseva Antonella Bacigalupo Bjrn Andersson Louise Matthews Erin L. Landguth Jaime A. Costales Martin S. Llewellyn Mario J. Grijalva 《PLoS genetics》2022,18(2)
Accurate prediction of vectors dispersal, as well as identification of adaptations that allow blood-feeding vectors to thrive in built environments, are a basis for effective disease control. Here we adopted a landscape genomics approach to assay gene flow, possible local adaptation, and drivers of population structure in Rhodnius ecuadoriensis, an important vector of Chagas disease. We used a reduced-representation sequencing technique (2b-RADseq) to obtain 2,552 SNP markers across 272 R. ecuadoriensis samples from 25 collection sites in southern Ecuador. Evidence of high and directional gene flow between seven wild and domestic population pairs across our study site indicates insecticide-based control will be hindered by repeated re-infestation of houses from the forest. Preliminary genome scans across multiple population pairs revealed shared outlier loci potentially consistent with local adaptation to the domestic setting, which we mapped to genes involved with embryogenesis and saliva production. Landscape genomic models showed elevation is a key barrier to R. ecuadoriensis dispersal. Together our results shed early light on the genomic adaptation in triatomine vectors and facilitate vector control by predicting that spatially-targeted, proactive interventions would be more efficacious than current, reactive approaches. 相似文献
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Gabriele Volpato Daimy Godínez Angela Beyra 《Human ecology: an interdisciplinary journal》2009,37(1):43-53
Ethnobotanical knowledge and practices are dynamic and they change as they are transferred and appropriated by people who
are adapting to new surroundings and changing environments. Using tifey, a multispecies drink, as a case study, we discuss
the changes that emigration brought about related to tifey, and the processes that determined these changes. Tifey is a Haitian
drink prepared by soaking Artemisia absinthium and other plants in rum or aguardiente. It probably had its origin in the adoption of the absinthe-based liquor used by French
settlers and troops during the colonial period. Haitians progressively added culturally relevant flavorings and medicinal
plants to this drink, and differentiated its production and use for medicinal, medicinal food, ritual (religious and social),
and economic purposes. When Haitians migrated to Cuba, they brought tifey with them, but over the course of the twentieth
century its use declined and its composition changed due to sociocultural factors such as the dissolution of Haitian settlements,
and to ecological factors such as difficulty in cultivation and/or procurement of A. absinthium in the new environment. 相似文献