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151.
152.
Suresh B. Lakshminarayana Helena I. M. Boshoff Joseph Cherian Sindhu Ravindran Anne Goh Jan Jiricek Mahesh Nanjundappa Amit Nayyar Meera Gurumurthy Ramandeep Singh Thomas Dick Francesca Blasco Clifton E. Barry III Paul C. Ho Ujjini H. Manjunatha 《PloS one》2014,9(8)
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in
vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in
vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in
vivo efficacy. Our findings show that the in
vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in
vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs. 相似文献
153.
154.
Salt tolerance was studied in the callus cultures of Suaeda nudiflora Moq. a dicotyledonous succulent halophyte. Growth was significantly inhibited at 50, 100, 150 and 200 mM NaCl. Inorganic
ions and proline accumulated in response to salinity. Ion accumulation pattern reflected the utilization of Na+ as an osmoticum. Na+/K+ ratio rose steadily as a function of external NaCl concentration. Salt stress enhanced the activity of peroxidase, whereas
it decreased activities of superoxide dismutase and catalase.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
155.
A nonhistone protein component (NHPIns) firmly bound to DNA of rat kidney nuclei has been isolated and partially characterized. In vivo studies show that this protein specifically incorporates 35 to 45 times more 203Hg than any other nuclear protein fractions. No difference in the ratio of NHPIns to DNA between normal and mercury-poisoned rat kidney nuclei was observed. NHPIns protein gives a single major band by sodium dodecyl sulfate gel electrophoresis. Electrophoretic pattern as well as amino acid composition of this protein isolated from both normal and mercurypoisoned rats are also found to be similar. Cysteine content is 1.3 to 1.4 mole per cent. 相似文献
156.
Philip T. Cherian Leonid N. Koikov Matthew D. Wortman James J. Knittel 《Bioorganic & medicinal chemistry letters》2009,19(8):2215-2219
A homology model of the p110α catalytic subunit of PI3Kα was generated from the p110γ crystal structure. Using this model, an isonicotinic scaffold was designed for chemically exploring the PI3Kα and γ binding sites. A focused library of derivatives was synthesized and tested. The morpholine acids 5a and 5b proved to be the most potent analogs. 相似文献
157.
158.
Dossey AT Reale V Chatwin H Zachariah C deBono M Evans PD Edison AS 《Biochemistry》2006,45(24):7586-7597
Phe-Met-Arg-Phe-NH2 (FMRFamide)-like peptides (FLPs) are the largest neuropeptide family in animals, particularly invertebrates. FLPs are characterized by a C-N-terminal gradient of decreasing amino acid conservation. Neuropeptide receptor 1 (NPR-1) is a G-protein coupled receptor (GPCR), which has been shown to be a strong regulator of foraging behavior and aggregation responses in Caenorhabditis elegans. Recently, ligands for NPR-1 were identified as neuropeptides coded by the precursor genes flp-18 and flp-21 in C. elegans. The flp-18 gene encodes eight FLPs including DFDGAMPGVLRF-NH2 and EMPGVLRF-NH2. These peptides exhibit considerably different activities on NPR-1, with the longer one showing a lower potency. We have used nuclear magnetic resonance and biological activity to investigate structural features that may explain these activity differences. Our data demonstrate that long-range electrostatic interactions exist between N-terminal aspartates and the C-terminal penultimate arginine as well as N-terminal hydrogen-bonding interactions that form transient loops within DFDGAMPGVLRF-NH2. We hypothesize that these loops, along with peptide charge, diminish the activity of this peptide on NPR-1 relative to that of EMPGVLRF-NH2. These results provide some insight into the large amino acid diversity in FLPs. 相似文献
159.
Kretzer NM Cherian MT Mao C Aninye IO Reynolds PD Schiff R Hergenrother PJ Nordeen SK Wilson EM Shapiro DJ 《The Journal of biological chemistry》2010,285(53):41863-41873
160.
Interaction of metallothionein with tumor suppressor p53 protein 总被引:3,自引:0,他引:3
Previous reports have shown that metallothionein (MT) may modulate p53 activity through zinc exchange. However, little is known on a direct interaction between MT and p53 in cells. The results demonstrate an interaction between MT and p53 can occur in vitro. The complex between MT and p53 was observed in breast cancer epithelial cells with both wild and inactive type of p53. Furthermore, it was shown that wt-p53 was preferentially associated with Apo-MT. Our data suggest that co-expression of MT and p53 and their complex formation in tumor cells may be involved in regulation of apoptosis in these cells. 相似文献