Search

Your search keyword '"Kitteringham, N.R."' showing total 26 results
Start Over Author "Kitteringham, N.R."
26 results on '"Kitteringham, N.R."'

2. Human Pluripotent Stem Cells for Modeling Toxicity

Author

Sison-Young, R.L.C., primary, Kia, R., additional, Heslop, J., additional, Kelly, L., additional, Rowe, C., additional, Cross, M.J., additional, Kitteringham, N.R., additional, Hanley, N., additional, Park, B.K., additional, and Goldring, C.E.P., additional

Published
2012
Full Text
View/download PDF

4. Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney

Author

Shelton, L.M., Lister, A., Walsh, J., Jenkins, R.E., Wong, M.H., Rowe, C., Ricci, E., Ressel, L., Fang, Y., Demougin, P., Vukojevic, V., O'Neill, P.M., Goldring, C.E., Kitteringham, N.R., Park, B.K., Odermatt, A., and Copple, I.M.

Subjects
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], respiratory system, digestive system, environment and public health
Abstract

Item does not contain fulltext The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target. 01 december 2015

Published
2015

5. Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management.

Author

Sutton, P.A., Jithesh, P.V., Jones, R.P., Evans, J.P., Vimalachandran, D., Malik, H.Z., Park, B.K., Goldring, C.E., Palmer, D.H., and Kitteringham, N.R.

Subjects
COLON cancer treatment, LIVER metastasis, CANCER chemotherapy, TUMOR genetics, NEEDLE biopsy, THERAPEUTICS
Abstract

Background Next generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour. Methods We performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis. Results Exome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours. Conclusion Only 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

14. Optimal dose identification: predicting a safe dose in man from animal studies

Author

Park, B.K., Kitteringham, N.R., Maggs, J.L., Boocock, D., White, I., Elsby, R., and Pirmohamed, M.

Abstract

Adverse drug reactions remain a major clinical problem and impairment to safe drug development. The CPMP provides guidelines for preclinical studies. Safety margins for target-organ toxicity must be calculated. It is necessary to be aware of species differences in pharmacodynamic effects and in routes and rates of metabolism. The relevance of the test system to the intended human use must be defined. It is important to learn lessons from past experience with drugs that have caused serious toxicity in man. Idiosyncratic toxicity is only detected late in drug development. The pathophysiology of such reactions is complex and poorly understood. In man, genetics and disease may be predisposing factors. Therefore, it is not surprising that conventional animal models fail to identify drugs which cause idiosyncratic toxicity. At present, we have to depend on the identification of structural alerts in drugs and metabolites to screen out the potential for toxicity. Recent advances in molecular toxicology allow the investigator to explore biochemical stress, in both in vitro and in vivo models, at doses of drugs and chemicals that do not cause overt toxicity. It is, thus, possible to address physiological, pharmacological and toxicological aspects of adverse reactions. Ultimately, it may be possible to relate cellular changes in these test systems to serious toxicities seen in man (anaphylaxis, hepatotoxicity, blood dyscrasias and severe skin reactions) and, thus, provide more physiologically relevant assays for the prediction of human drug toxicity.

Published
2001
Full Text
View/download PDF

25. Protection against paracetamol hepatotoxicity in glutathione S-transferase Pi knockout mice does not involve altered covalent binding.

Author

Kitteringham, N.R., Powell, H., Henderson, C.J., and Wolf, C.R.

Subjects
*ACETAMINOPHEN, *HEPATOTOXICOLOGY, *GLUTATHIONE transferase
Abstract

Examines the protection of glutathione S-transferase Pi knockout mice from paracetamol hepatotoxicity. Mediators of hepatotoxicity; Drug dosage and administration; Role of an altered metabolism in the protection against hepatotoxicity.

Published
1999

Catalog

Books, media, physical & digital resources
See catalog results