20 research outputs found
Transgenic Animal Models in Toxicology: Historical Perspectives and Future Outlook
No full textTransgenic animal models are powerful tools for developing a more detailed understanding on the roles of specific genes in biological pathways and systems. Applications of these models have been made within the field of toxicology, most notably for the screening of mutagenic and carcinogenic potential and for the characterization of toxic mechanisms of action. It has long been a goal of research toxicologists to use the data from these models to refine hazard identification and characterization to better inform human health risk assessments. This review provides an overview on the applications of transgenic animal models in the assessment of mutagenicity and carcinogenicity, their use as reporter systems, and as tools for understanding the roles of xenobiotic-metabolizing enzymes and biological receptors in the etiology of chemical toxicity. Perspectives are also shared on the future outlook for these models in toxicology and risk assessment and how transgenic technologies are likely to be an integral tool for toxicity testing in the 21st century.</p
The effect of implantation of osmotic pumps on rat thyroid hormone and testosterone levels in the plasma, an implication for tissue ‘Srs phase studies
No full textA novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response
No full textThe pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans.</p
Microsomes and Drug Oxidations Edited by A.R. Boobis, J. Caldwell, F. De Matteis and C.R. Elcombe Taylor and Francis; London, 1985 xv + 413 pages. £40.00
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Deuterium NMR and x-ray crystallographic studies of guest and host motions in the thiourea/1, 4-di-tert-butylbenzene inclusion compound
No full textDeuterium nuclear magnetic resonance (NMR) spectra and spin-lattice relaxation times are used to investigate the guest and host molecular dynamics of solid 1,4-di-tert-butylbenzene-d4 (DTBB-d4), 1,4-di-tert-butylbenzene-d18 (DTBB-d18), the thiourea/ 1,4-di-tert-butylbenzene-d4 inclusion compound (TU/DTBB-d4), the thiourea/ 1,4-di-tert-butylbenzene-d22 inclusion compound (TU/DTBB-d22), the thiourea-d4/1,4-di-tert-butylbenzene inclusion compound (TU-d4/DTBB), and thiourea-d4 (TU-d4). X-ray crystallographic studies of TU/DTBB-d4 have been carried out at 291 K. In solid DTBB the phenyl ring is essentially static whereas the tert-butyl groups are undergoing rapid reorientation of both methyl and tert-butyl groups. Attempts to analyze the H-2 spectra and T1 data for DTBB-d18 suggest that the dynamics of the methyl and tert-butyl groups are nearly equivalent, and as a result, a satisfactory analysis, yielding methyl and tert-butyl rotational activation energies, was not possible. X-ray diffraction results for TU/DTBB-d4 suggest that, at 291 K, the phenyl ring is occupying three nearly equivalent sites. The H-2 NMR line shapes between 186 and 392 K were interpreted using a model in which the phenyl ring is rapidly flipping between three positions, with one position less favored, At 296 and 186 K the populations are 0.81:1.00:1.00 and 0.20:1.00.1.00, respectively. Relaxation times obtained between 111 and 322 K show no minimum, supporting the assumption of very rapid phenyl ring reorientation. For TU/DTBB-d22 a high-temperature T1 minimum is well-defined, and a second minimum, corresponding to tert-butyl group rotation, is reached at the lowest attainable temperatures. Line-shape simulations of the spectrum at 77 K yield methyl and tert-butyl group rotational rates of 1.0 x 10(3) and 2.0 x 10(6) s-1, respectively. Analysis of the higher temperature spectra (109-172 K) and T1 data (167-300 K) yield methyl rotation activation energies of 12.7 and 12.3 kJ/mol, respectively. Deuterium line-shape studies of the thiourea dynamics in TU-d4 and TU-d4/DTBB yield activation energies for 180-degrees flips about the C=S bond of 47 and 46 kJ/mol, respectively.PT: J; CR: 1974, INT TABLES XRAY CRYS, V4 ARONSON M, 1981, CHEM PHYS, V63, P349 ATWOOD JL, 1984, INCLUSION COMPOUNDS, V1 BECKMANN P, 1979, J MAGN RESON, V36, P199 BECKMANN P, 1981, CHEM PHYS, V63, P359 BECKMANN PA, 1984, J MAGN RESON, V59, P63 BLOEMBERGEN N, 1948, PHYS REV, V73, P679 CANNAROZZI GM, 1991, J PHYS CHEM-US, V95, P1525 CLEMENT R, 1974, J CHEM SOC CHEM COMM, P654 CLEMENT R, 1977, J CHEM PHYS, V67, P5381 COLLINS MJ, 1989, J PHYS CHEM-US, V93, P7495 DAVIS JH, 1976, CHEM PHYS LETT, V42, P390 DAVIS JH, 1991, ISOTOPES PHYSICAL BI, V2, CH2 DRAVERS MA, 1980, CRYST STRUCT COMMUN, V9, P951 ELCOMBE MM, 1968, ACTA CRYSTALLOGR A, V24, P410 FLOVENICIO F, 1976, ACTA CRYSTALLOGR B, V32, P2480 GABE EJ, 1981, ACTA CRYSTALLOGR B, V37, P197 GABE EJ, 1989, J APPL CRYSTALLOGR, V22, P384 GELERINTER E, 1990, J PHYS CHEM-US, V94, P5391 GELERINTER E, 1990, J PHYS CHEM-US, V94, P8845 GOPAL R, 1989, ACTA CRYSTALLOGR C, V45, P257 GREENFIELD MS, 1987, J MAGN RESON, V72, P89 GRIFFIN RG, 1981, METHOD ENZYMOL, V72, P108 GRIFFITH EAH, 1972, CAN J CHEM, V50, P2972 GRUWEL MLH, 1990, Z NATURFORSCH A, V45, P55 HEATON NJ, 1989, J AM CHEM SOC, V111, P3211 HEYES SJ, 1990, MAGN RESON CHEM S, V37 HEYES SJ, 1991, J PHYS CHEM-US, V95, P1547 HOUGH E, 1978, J CHEM SOC DA, P15 HUFFMAN JC, 1990, INORG CHEM, V19, P2749 IKEDA R, 1989, J PHYS CHEM-US, V93, P7315 IWASAKI F, 1979, ACTA CRYSTALLOGR B, V35, P2099 IWASAKI F, 1980, ACTA CRYSTALLOGR B, V36, P1700 JUNGK AE, 1971, CHEM BER, V104, P3289 KENNEDY MA, 1991, J MAGN RESON, V91, P301 KOERFER M, 1989, Z NATURFORSCH A, V44, P1177 KRAVERS MA, 1979, CRYST STRUCT COMMUN, V8, P427 KRAVERS MA, 1980, CRYST STRUCT COMMUN, V9, P955 LIFSHITZ E, 1986, J PHYS CHEM SOLIDS, V47, P1045 LOWERY MD, 1990, J AM CHEM SOC, V112, P4212 MACK JW, 1991, J PHYS CHEM-US, V95, P4207 MAGDOFF BS, 1951, ACTA CRYSTALLOGR, V4, P176 MCDANIEL PL, 1988, J PHYS CHEM-US, V92, P626 MEIROVITCH E, 1987, J PHYS CHEM-US, V91, P5014 NISHIKIORI S, 1990, J PHYS CHEM-US, V94, P8098 OK JH, 1989, J PHYS CHEM-US, V93, P7618 OREILLY DE, 1971, J CHEM PHYS, V54, P1304 POLSON JM, 1991, J CHEM PHYS, V94, P3381 POUPKO R, 1989, J AM CHEM SOC, V111, P6094 POUPKO R, 1991, J PHYS CHEM-US, V95, P407 RATCLIFFE CI, 1990, J PHYS CHEM-US, V94, P152 ROESSLER G, 1989, BER BUNSEN GEN PHYS, V93, P1241 ROY AK, 1990, PROGR NMR SPECTROSCO, V22 SPIESS HW, 1980, J CHEM PHYS, V72, P6755 SPIESS HW, 1985, ADV POLYM SCI, V66, P23 TAKEMOTO K, 1984, INCLUSION COMPOUNDS, V2, CH2 TORCHIA DA, 1981, J MAGN RESON, V42, P381 WASYLISHEN RE, COMMUNICATION WENDOLOSKI JJ, 1990, SCIENCE, V247, P431 WITTEBORT RJ, 1987, J CHEM PHYS, V86, P5411 ZAMIR S, 1991, J CHEM PHYS, V94, P5939; NR: 61; TC: 14; J9: J PHYS CHEM; PG: 9; GA: HY322Source type: Electronic(1
Clinical and cognitive correlates of structural hippocampal change in "at-risk" older adults
No full textWith estimates of dementia expected to rise over the coming decades, there is interest in understanding the factors associated with promoting neuroprotection and limiting neurodegeneration. In this study, we examined the change in the volume of the hippocampus over a 2-month period in 34 older people "at risk" of cognitive decline (mean age = 66.8 years, 38% male). Factors that were examined included cognitive reserve, neuropsychological functioning, depression as well as a lifestyle (cognitive training) intervention. The results showed that over a 2-month period, increases in hippocampal size were associated with having higher premorbid intellect, greater occupational attainment, superior memory, and higher levels of functioning. Conversely, depression and disability were associated with decreases in hippocampal volume. Cognitive training was not associated with changes in hippocampal volume. These findings suggest that factors associated with cognitive reserve, cognition and depression may play an integral pathophysiological role in determining hippocampal volumes in "at-risk" older adults. © The Author(s) 2013
1H-NMR spectroscopy of biofluids and the investigation of xenobiotic-induced changes in liver biochemistry
No full textAuthor Correction: Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice (Nature Genetics, (2021), 53, 4, (500-510), 10.1038/s41588-021-00803-4)
No full text\ua9 The Author(s), under exclusive licence to Springer Nature America, Inc. 2022. n the version of this article initially published, there was a numbering error in the affiliation for Christoph Klein. The author’s proper affiliation is 30, Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany, and not Newcastle University, UK. The change has been made to the online version of the article
Anti-tumor activity of CXR1002, a novel anti-cancer clinical phase compound that induces ER stress and inhibits PIM kinases:Human tumor xenograft efficacy and in vitro mode of action
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