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951.
Kumar A Shah BA Singh S Hamid A Singh SK Sethi VK Saxena AK Singh J Taneja SC 《Bioorganic & medicinal chemistry letters》2012,22(1):431-435
Boswellic acid acylates including their epimers were synthesized and screened against a panel of human cancer cell lines. They exhibited a range of cytotoxicity against various human cancer cell lines thereby leading to the development of a possible SAR. One of the identified lead compounds was found to be an inhibitor of the NF-κB and STAT proteins, warranting further investigations to be developed into a potential anticancer lead. 相似文献
952.
The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer. 相似文献
953.
Maria T. Kuipers Hamid Aslami Alexander P. J. Vlaar Nicole P. Juffermans Anita M. Tuip-de Boer Maria A. Hegeman Geartsje Jongsma Joris J. T. H. Roelofs Tom van der Poll Marcus J. Schultz Catharina W. Wieland 《PloS one》2012,7(11)
Introduction
Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and increased uric acid levels in lung lavage fluid are reported. We studied levels in human lung injury and the contribution of uric acid in experimental VILI.Methods
Uric acid levels in lung lavage fluid of patients with acute lung injury (ALI) were determined. In a different cohort of cardiac surgery patients, uric acid levels were correlated with pulmonary leakage index. In a mouse model of VILI the effect of allopurinol (inhibits uric acid synthesis) and uricase (degrades uric acid) pre-treatment on neutrophil influx, up-regulation of adhesion molecules, pulmonary and systemic cytokine levels, lung pathology, and regulation of receptors involved in the recognition of uric acid was studied. In addition, total protein and immunoglobulin M in lung lavage fluid and pulmonary wet/dry ratios were measured as markers of alveolar barrier dysfunction.Results
Uric acid levels increased in ALI patients. In cardiac surgery patients, elevated levels correlated significantly with the pulmonary leakage index. Allopurinol or uricase treatment did not reduce ventilator-induced inflammation, IκB-α degradation, or up-regulation of NLRP3, Toll-like receptor 2, and Toll-like receptor 4 gene expression in mice. Alveolar barrier dysfunction was attenuated which was most pronounced in mice pre-treated with allopurinol: both treatment strategies reduced wet/dry ratio, allopurinol also lowered total protein and immunoglobulin M levels.Conclusions
Local uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction. 相似文献954.
Gilles Crevel Nicole Vo Isabelle Crevel Sana Hamid Lily Hoa Seiji Miyata Sue Cotterill 《PloS one》2012,7(11)
The RecQ4 protein shows homology to both the S.cerevisiae DNA replication protein Sld2 and the DNA repair related RecQ helicases. Experimental data also suggest replication and repair functions for RecQ4, but the precise details of its involvement remain to be clarified.Here we show that depletion of DmRecQ4 by dsRNA interference in S2 cells causes defects consistent with a replication function for the protein. The cells show reduced proliferation associated with an S phase block, reduced BrdU incorporation, and an increase in cells with a subG1 DNA content. At the molecular level we observe reduced chromatin association of DNA polymerase-alpha and PCNA. We also observe increased chromatin association of phosphorylated H2AvD - consistent with the presence of DNA damage and increased apoptosis.Analysis of DmRecQ4 repair function suggests a direct role in NER, as the protein shows rapid but transient nuclear localisation after UV treatment. Re-localisation is not observed after etoposide or H2O2 treatment, indicating that the involvement of DmRecQ4 in repair is likely to be pathway specific.Deletion analysis of DmRecQ4 suggests that the SLD2 domain was essential, but not sufficient, for replication function. In addition a DmRecQ4 N-terminal deletion could efficiently re-localise on UV treatment, suggesting that the determinants for this response are contained in the C terminus of the protein. Finally several deletions show differential rescue of dsRNA generated replication and proliferation phenotypes. These will be useful for a molecular analysis of the specific role of DmRecQ4 in different cellular pathways. 相似文献
955.
A Heyrani M Maleki A Barati Marnani H Ravaghi M Sedaghat M Jabbari D Farsi A Khajavi Z Abdi 《Implementation science : IS》2012,7(1):84
ABSTRACT: BACKGROUND: Clinical governance (CG) is among the different frameworks proposed to improve the quality of healthcare. Iran, like many other countries, has put healthcare quality improvement in its top health policy priorities. In November 2009, implementation of CG became a task for all hospitals across the country. However, it has been a challenge to clarify the notion of CG and the way to implement it in Iran. The purpose of this action research study is to understand how CG can be defined and implemented in a selected teaching emergency department (ED).Methods/designWe will use Soft Systems Methodology for both designing the study and inquiring into its content. As we considered a complex problem situation regarding the quality of care in the selected ED, we initially conceptualized CG as a cyclic set of purposeful activities designed to explore the situation and find relevant changes to improve the quality of care. Then, implementation of CG will conceptually be to carry out that set of purposeful activities. The activities will be about: understanding the situation and finding out relevant issues concerning the quality of care; exploring different stakeholders' views and ideas about the situation and how it can be improved; and defining actions to improve the quality of care through structured debates and development of accommodations among stakeholders. We will flexibly use qualitative methods of data collection and analysis in the course of the study. To ensure the study rigor, we will use different strategies. DISCUSSION: Successful implementation of CG, like other quality improvement frameworks, requires special consideration of underlying complexities. We believe that addressing the complex situation and reflections on involvement in this action research will make it possible to understand the concept of CG and its implementation in the selected setting. By describing the context and executed flexible methods of implementation, the results of this study would contribute to the development of implementation science and be employed by boards and executives governing other clinical settings to facilitate CG implementation. 相似文献
956.
Particle-size distributions and seasonal diversity of allergenic and pathogenic fungi in outdoor air
Naomichi Yamamoto Kyle Bibby Jing Qian Denina Hospodsky Hamid Rismani-Yazdi William W Nazaroff Jordan Peccia 《The ISME journal》2012,6(10):1801-1811
Fungi are ubiquitous in outdoor air, and their concentration, aerodynamic diameters and taxonomic composition have potentially important implications for human health. Although exposure to fungal allergens is considered a strong risk factor for asthma prevalence and severity, limitations in tracking fungal diversity in air have thus far prevented a clear understanding of their human pathogenic properties. This study used a cascade impactor for sampling, and quantitative real-time PCR plus 454 pyrosequencing for analysis to investigate seasonal, size-resolved fungal communities in outdoor air in an urban setting in the northeastern United States. From the 20 libraries produced with an average of ∼800 internal transcribed spacer (ITS) sequences (total 15 326 reads), 12 864 and 11 280 sequences were determined to the genus and species levels, respectively, and 558 different genera and 1172 different species were identified, including allergens and infectious pathogens. These analyses revealed strong relationships between fungal aerodynamic diameters and features of taxonomic compositions. The relative abundance of airborne allergenic fungi ranged from 2.8% to 10.7% of total airborne fungal taxa, peaked in the fall, and increased with increasing aerodynamic diameter. Fungi that can cause invasive fungal infections peaked in the spring, comprised 0.1–1.6% of fungal taxa and typically increased in relative abundance with decreasing aerodynamic diameter. Atmospheric fungal ecology is a strong function of aerodynamic diameter, whereby through physical processes, the size influences the diversity of airborne fungi that deposit in human airways and the efficiencies with which specific groups of fungi partition from outdoor air to indoor environments. 相似文献
957.
958.
We have previously described an attenuated line of Leishmania infantum (H-line), selected by culturing promastigotes in vitro in the presence of gentamicin. To elucidate the molecular basis for this attenuation, we undertook a comparative proteomic analysis using multiplex 2-dimensional (2D) difference gel electrophoresis. Eighteen proteins that showed significant and reproducible changes in expression were identified. Many of these were components of the thiol-redox control system in Leishmania and this observation, validated by Western blot, prompted us to investigate the sensitivity of the attenuated line to oxidative stress. The attenuated line was found to be significantly more susceptible to hydrogen peroxide, a change which may explain the loss of virulence. In a direct assay of trypanothione-dependent peroxidase activity, hydrogen peroxide metabolism in the H-line was significantly lower than in wild type. Furthermore, trypanothione reductase activity was significantly lower in the H-line, suggesting that gentamicin selection may result in pleiotropic affects on thiol metabolism in Leishmania. A putative RNA-binding protein was very strongly up-regulated in the attenuated line, suggesting a possible target for gentamicin in Leishmania. 相似文献
959.
Masoumeh Alipour Mehdi Khoobi Alireza Foroumadi Hamid Nadri Alireza Moradi Amirhossein Sakhteman Mehdi Ghandi Abbas Shafiee 《Bioorganic & medicinal chemistry》2012,20(24):7214-7222
A novel series of coumarin derivatives linked to benzyl pyridinium group were synthesized and biologically evaluated as inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The enzyme inhibitory activity of synthesized compounds was measured using colorimetric Ellman’s method. It was revealed that compounds 3e, 3h, 3l, 3r and 3s have shown higher activity compared with donepezil hydrochloride as standard drug. Most of the compounds in these series had nanomolar range IC50 in which compound 3r (IC50 = 0.11 nM) was the most active compound against acetylcholinesterase enzyme. 相似文献
960.
We investigated the solution structure and dynamics of the human anti-coagulation protein Z (PZ) in the complex with protein Zdependent protease inhibitor (ZPI) to order to understand key structural changes in the presence and absence of Ca(2+). Structural features of the complete complex of PZ-ZPI are poorly understood due to lack of complete atomic model of the PZ-ZPI complex. We have constructed a model of the complete PZ-ZPI complex and molecular dynamics (MD) simulation of the solvated PZ-ZPI complex with and without Ca(2+) was achieved for 100ns. It is consider that the Ω-loop of GLA domains interacts with negatively charged biological membranes in the presence of Ca(2+) ions. The PZ exerts its role as cofactor in a similar way. However, we used solvent-equilibrated dynamics to show structural features of the PZ-ZPI complex in the presence and the absence of Ca(2+)ions. We observed that the distance between the interacting sites of the ZPI with the PZ and the GLA domain decreases in the presence of Ca(2+) ions. Further, we postulated that the calculated distance between the dominant plane of the Ca(2+) ions and Ser196 of the pseudo-catalytic triad of the PZ is similar to the equivalent distance of FXa. This suggests that the central role of the PZ in the blood coagulation may be to align the inhibitory site of the ZPI with the active site of the FXa, which is depends on the interaction of the calcium bound GLA domain of the PZ with the active membrane. 相似文献