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排序方式: 共有81条查询结果,搜索用时 125 毫秒
1.
Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea 总被引:5,自引:0,他引:5
2.
Chandrakala Aluganti Narasimhulu Krithika SelvarajanMatthew Brown Sampath Parthasarathy 《Atherosclerosis》2014
Objective
Apolipoprotein A1 (ApoA1) and apolipoprotein E (ApoE) mimetic peptides have attracted attention due to their ability to reduce atherosclerosis and exhibit antioxidant, anti-inflammatory, and hypolipidemic properties. In this study, we tested whether three distinct and unrelated cationic peptides would inhibit the oxidation of lipoproteins and whether they would counteract and neutralize the negatively charged modified lipoproteins, inhibit their uptake and inflammation by macrophages.Methods and results
5F-mimetic peptide of ApoA1, LL27 derived from the anti-microbial peptide hCAP, and a human glycodelin derived peptide were commercially synthesized. We noted that these three distinct cationic lysine-rich peptides, two of which were unrelated to any known apolipoproteins, inhibited copper-mediated oxidation of lipoproteins and reduced lipid peroxides in a lysine dependent manner. The peptides also retarded the electrophoretic mobility of previously oxidized LDL and acetylated LDL by virtue of their net positive charge. Pre-incubation of peptides with modified lipoproteins reduced the uptake of the latter by macrophages, thus preventing the formation of foam cells. The cationic peptides inhibited oxidized LDL (Ox-LDL)-induced inflammatory response both in vitro and in vivo.Conclusion
Based on these results, we suggest that in addition to the well known mimetic peptides, other suitable cationic peptides may be of use for controlling Ox-LDL mediated inflammation and atherosclerotic progression. 相似文献3.
4.
An integrated approach to measuring tumor oxygen status using human melanoma xenografts as a model 总被引:3,自引:0,他引:3
Menon C Polin GM Prabakaran I Hsi A Cheung C Culver JP Pingpank JF Sehgal CS Yodh AG Buerk DG Fraker DL 《Cancer research》2003,63(21):7232-7240
Tumor oxygen status is a reliable prognostic marker that impacts malignant progression and outcome of tumor therapy. However, tumor oxygenation is heterogeneous and cannot be sufficiently described by a single parameter. It is influenced by several factors including microvessel density (MVD), blood flow (BF), blood volume (BV), blood oxygen saturation, tissue pO(2), oxygen consumption rate, and hypoxic fraction. The goal of this investigation was to integrate these measurements to obtain a comprehensive profile of tumor oxygenation. Platelet/endothelial cell adhesion molecule immunohistochemistry, the recessed oxygen microelectrode, color and power Doppler ultrasound (DUS), and diffuse light spectroscopy (DLS) were used to measure tumor oxygen status using vascular endothelial growth factor (VEGF)-transfected hypervascular human melanoma xenografts and their nontransfected counterparts as a model. NIH1286 human melanoma cells were transfected with a retroviral vector +/- a 720-bp fragment of human VEGF(121). High VEGF-producing clones were selected by ELISA. Oxygen consumption rate was measured in NIH1286/VEGF+ [VEGF-transfected cells (VEGF+ cells)] and NIH1286/Vec cells [cells transfected with vector alone (Vec cells)] using a standard Clark oxygen electrode. Athymic nude 6-8-week-old mice received s.c. injection in the right flank with 5 x 10(6) VEGF+ or Vec cells. When tumors were 10-14 mm in maximum dimension, serum was analyzed for VEGF by ELISA. Cryopreserved tumor tissue sections were immunostained for platelet/endothelial cell adhesion molecule, and MVD measurements were made. Tumor-bearing mice were anesthetized, and pO(2) measurements were made using Eppendorf pO(2) histograph or the recessed oxygen microelectrode. Tumor BF and BV were measured by quantitative analysis of DUS images. DLS was used to measure tumor BF and blood oxygen saturation variation. VEGF+ cell supernatants had 15,500 pg/ml VEGF, and Vec cells had 10 pg/ml. VEGF+ and Vec cells had equivalent oxygen consumption rates. VEGF+ tumors had a faster growth rate than Vec tumors. Serum from VEGF+ tumor-bearing mice showed 4,211 pg/ml VEGF, whereas VEGF was undetectable in the serum of control mice. MVD values were 74 +/- 11 in VEGF+ tumors and 39 +/- 4 in control tumors at x200 magnification/0.95-mm(2) area. The median pO(2) values were 3.5-fold higher in VEGF+ tumors than in Vec tumors by the recessed oxygen microelectrode and 18-fold higher by Eppendorf pO(2) histograph. DUS showed a 3.3-fold higher mean BF and a 5.5-fold higher BV in VEGF+ tumors than in Vec tumors. DLS showed a 3.2-fold higher mean BF and 1.7-fold higher oxygen saturation in the hypervascular tumors as compared with the control tumor type, consistent with increased BF and BV data by DUS. An integrated approach that yields a comprehensive and consistent profile of oxygen status in tumors could potentially provide critical information for prognosis and treatment. 相似文献
5.
Kulkarni B Shatrugna V Nagalla B Ajeya Kumar P Usha Rani K Chandrakala Omkar A 《The British journal of nutrition》2009,101(10):1527-1533
Lactation is known to be associated with a transient loss of bone mineral density (BMD) during 3-6 months post-partum. Bone changes during lactation in women consuming low dietary calcium are not sufficiently studied. The present longitudinal study examined the BMD changes during lactation in undernourished women and the relationship of bone changes to the nutritional status. Whole-body bone mineral content and BMD at hip, lumbar spine and forearm were assessed using dual-energy X-ray absorptiometry in thirty-six lactating women from the low socio-economic group at four time points -- within 1 month after delivery (baseline), and at 6, 12 and 18 months after delivery. Maternal body composition and biochemical parameters of bone metabolism were estimated at the same time. It was observed that femoral neck BMD reduced by 4.6 % at 6 months, but recovery to the baseline was incomplete at 18 months with a deficit of 2 %. Hip BMD reduction at 6 months was transient. Lumbar spine BMD did not show significant loss at 6 months and BMD increased by 3.6 and 6.3 % at 12 and 18 months, respectively. Regression analyses indicated that baseline lean mass was the most important determinant of bone preservation at femoral neck, hip as well as whole body, whereas baseline body weight was the most important determinant of per cent gain in lumbar spine. Maternal nutritional status as indicated by body weight and lean mass appears to influence the lactation-related BMD changes in undernourished women from the low socio-economic group in India. 相似文献
6.
BACKGROUND: Isolated limb perfusion using high-dose human tumor necrosis factor-alpha with melphalan is effective therapy for bulky extremity in-transit melanoma and sarcoma. OBJECTIVE: While it is widely accepted that melphalan is a DNA alkylating agent, the mechanism of selective antitumor effect of tumor necrosis factor-alpha is unclear. METHODS AND RESULTS: Electron microscopic analyses of human melanoma biopsies, pre- and post-melphalan perfusion, showed that the addition of tumor necrosis factor-alpha caused gapping between endothelial cells by 3 to 6 hours post-treatment followed by vascular erythrostasis in treated tumors. In human melanoma xenografts raised in mice, tumor necrosis factor-alpha selectively increased tumor vascular permeability by 3 hours and decreased tumor blood flow by 6 hours post-treatment relative to treated normal tissue. In an in vitro tumor endothelial cell model, tumor necrosis factor-alpha caused vascular endothelial adherens junction protein, VE-cadherin, to relocalize within the cell membrane away from cell-cell junctions leading to gapping between endothelial cells by 3 to 6 hours post-treatment. Phosphotyrosinylation was a prerequisite for movement of VE-cadherin away from endothelial cell junctions and for gapping between endothelial cells. Clinical isolated limb perfusion tumor specimens, at 3 hours postperfusion, showed a discontinuous and irregular pattern of VE-cadherin expression at endothelial cell junctions when compared with normal (skin) or pretreatment tumor tissue. CONCLUSIONS: Together, the data suggest that tumor necrosis factor-alpha selectively damages the integrity of tumor vasculature by disrupting VE-cadherin complexes at vascular endothelial cell junctions leading to gapping between endothelial cells, causing increased vascular leak and erythrostasis in tumors. VE-cadherin appears to be a potentially good target for selective antitumor therapy. 相似文献
7.
8.
Stachulski AV Pidathala C Row EC Sharma R Berry NG Lawrenson AS Moores SL Iqbal M Bentley J Allman SA Edwards G Helm A Hellier J Korba BE Semple JE Rossignol JF 《Journal of medicinal chemistry》2011,54(24):8670-8680
We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development. 相似文献
9.
Sharma R Lawrenson AS Fisher NE Warman AJ Shone AE Hill A Mbekeani A Pidathala C Amewu RK Leung S Gibbons P Hong DW Stocks P Nixon GL Chadwick J Shearer J Gowers I Cronk D Parel SP O'Neill PM Ward SA Biagini GA Berry NG 《Journal of medicinal chemistry》2012,55(7):3144-3154
Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria. 相似文献
10.
Leung SC Gibbons P Amewu R Nixon GL Pidathala C Hong WD Pacorel B Berry NG Sharma R Stocks PA Srivastava A Shone AE Charoensutthivarakul S Taylor L Berger O Mbekeani A Hill A Fisher NE Warman AJ Biagini GA Ward SA O'Neill PM 《Journal of medicinal chemistry》2012,55(5):1844-1857
Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies. 相似文献