Research Theme within School of Biosciences:Molecular and Cell Biology - Toxicology
We are interested in the cellular consequences of pertubation of redox homeostasis both by chemical and biological mechanisms.
OGG1: The DNA repair protein OGG1 is critical in the repair of the oxidatively damaged base 8 oxo dG which if not removed before DNA replication mispairs with adenine and thymine causing point mutations. We are interested in the common ser326cys polymorphism in human OGG1 and are studying its activity and location compared to the “normal” protein. Work in our lab using genetically engineered cell lines has shown that the variant form of the protein is repair deficient particularly under conditions of cellular oxidative stress when it is needed most and we are currently studying the mechanistic basis for this observation.
Cellular oxidative stress: We are using a number of experimental approaches to study the consequences of intracellular oxidative stress: These include treatment with pro-oxidants, tungsten alloys, engineered nanoparticles, depletion of the protective factor glutathione and over-expression of cytochrome P450s for which there is evidence that once “un-coupled” for example by futile substrates like polychlorinated chemicals these enzyme systems can generate substantial level of toxic free radicals in cells. We are particularly interested in oxidative DNA damage through so called “secondary genotoxicity” and the existence of potential thresholds of effect in relation to these mechanisms of toxicity.
Cytoglobin: We are interested in cytoglobin a poorly understood homologue of haemoglobin with no known function but which may be involved in detoxification of reactive oxygen species as well as having signalling and oxygen transporter functions in a wide range of non muscle tissues especially those of a fibroblast lineage. Through collaboration with AstraZeneca were are studying the role of cytoglobin in fibrotic disease and as a potential target for drug toxicity. The cytoglobin gene also maps to a genetic disease called tylosis with oesphageal cancer (TOC) and in collaboration with The University of Liverpool we are working on the genetic regulation of this gene and trying to determine its molecular function.
Iron cylinders: In collaboration with Professors Mike Hannon and Kevin Chipman we are investigating the cellular properties of iron and related cylinders which have potent cytostatic effects in a broad range of cell lines. You can read more about these exciting molecules on the homepage of Professor Mike Hannon http://www.chem.bham.ac.uk/staff/hannon.shtml.
Example recent publications from the Hodges lab:
DNA repair related:
Kaur MP, Guggenheim EJ, Pulisciano C, Akbar S, Kershaw RM and Hodges NJ. 2014. Cellular accumulation of Cys326-OGG1 proteins complexes under conditions of oxidative stress. Biochem Biophy Res Comm. 447, pp 12–18.
Kershaw RM and Hodges NJ. 2012. Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1. Mutagenesis, 27(4) pp 501–10.
Zielinska A, Davies OT, Meldrum RA and Hodges NJ. 2011. Direct visualization of repair of oxidative damage by OGG1 in the nuclei of live cells. Journal of Biochemical and Molecular Toxicology. 25(1), pp 1–7.
Mirbahai L, Kershaw RM, Green RM, Hayden RE, Meldrum RA, Hodges NJ. Use of a molecular beacon to track the activity of base excision repair protein OGG1 in live cells. DNA Repair. 2010;9(2):144-52.
Oxidative stress related:
McRonald FE, Risk JM and Hodges NJ. 2012. Protection from intracellular oxidative stress by cytoglobin in normal and cancerous oesophageal cells. PloS1 7(2) e30587.
Harris RM, Williams TD, Hodges NJ and Waring RM. 2011. Reactive oxygen species and oxidative DNA damage mediate the cytotoxicity of tungsten-nickel-cobalt alloys in vitro. Toxicology and Applied Pharmacology. 250(1), pp 19–28.
Turner JE, Hodges NåJ, Bosch JA and Aldred S. 2011. Prolonged depletion of antioxidant capacity after ultra-endurance exercise. Medicine and Science in Sports and Exercise. 43(9), pp 1770–76.
Hodges NJ, Innocent N, Dhanda S, Graham M. Cellular protection from oxidative DNA damage by over-expression of the novel globin cytoglobin in vitro. Mutagenesis. 2008;23(4):293-8.
Green RM, Hodges NJ, Chipman JK, O'Donovan MR, Graham M. Reactive oxygen species from the uncoupling of human cytochrome P450 1B1 may contribute to the carcinogenicity of dioxin-like polychlorinated biphenyls. Mutagenesis. 2008;23(6):457-63.
Iron cylinder and ferrocene related:
Nguyen HV, Sallustrau A, Balzarini Y, Bedford MR, Eden JC, Georgousi N, Hodges NJ Kedge J, Mehellou Y, Tselepis C and Tucker JHR. 2014. Organometallic Nucleoside Analogues with Ferrocenyl Linker Groups: Synthesis and Cancer Cell Line Studies. J Med Chem. 57: pp 5817-22.
Cardo L, Sadovnikova V, Phongtongpasuk S, Hodges NJ, Hannon MJ. Arginine conjugates of metallo-supramolecular cylinders prescribe helicity and enhance DNA junction binding and cellular activity. Chem Commun (Camb). 2011 Jun 21;47(23):6575-77.
Ducani C, Leczkowska A, Hodges NJ and Hannon MJ. 2010. Noncovalent DNA-binding metallo-supramolecular cylinders prevent DNA transactions in vitro. Angewandte Chemie. 122(47), pp 9126–29.
Hotze AC, Hodges NJ, Hayden RE, Sanchez-Cano C, Paines C, Male N, Tse MK, Bunce CM, Chipman JK, Hannon MJ. Supramolecular iron cylinder with unprecedented DNA binding is a potent cytostatic and apoptotic agent without exhibiting genotoxicity. Chem Biol. 2008;15(12):1258-67.
Kendall M, Hodges NJ, Whitwell H, Tyrrell J and Cangui H. 2014. Nanoparticle growth in conditioned media: Effects of surface chemistry and surface-sequestered peptides. Philosophical Transactions of the Royal Society B:(Biological Sciences). In Press
Rogers NJ, Claire S, Harris RM, Zikeli G, Farabi S, Styles IB, Hodges NJ, Pikramenou Z. 2014. High coatings of Ru(II) complexes on gold nanoparticles for single particle luminescence imaging in cells. Chemical Communications. 50: pp 617-619