ORCID Profile
0000-0002-5888-1424
Current Organisation
University of Reading
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Publisher: Portland Press Ltd.
Date: 24-08-2004
DOI: 10.1042/BJ20031481
Abstract: Repair of the mature mammalian myocardium following injury is impaired by the inability of the majority of cardiomyocytes to undergo cell ision. We show that overexpression of the cyclin B1–CDC2 (cell ision cycle 2 kinase) complex re-initiates cell ision in adult cardiomyocytes. Thus strategies targeting the cyclin B1–CDC2 complex might re-initiate cell ision in mature cardiomyocytes in vivo and facilitate myocardial regeneration following injury.
Publisher: Oxford University Press (OUP)
Date: 2006
Abstract: The E2F transcription factors are instrumental in regulating cell cycle progression and growth, including that in cardiomyocytes, which exit the cell cycle shortly after birth. E2F-6 has been demonstrated to act as a transcriptional repressor however, its potential role in normal cardiomyocyte proliferation and hypertrophy has not previously been investigated. Here we report the isolation and characterisation of E2F-6 and E2F-6b in rat cardiomyocytes and consider its potential as a target for myocardial regeneration following injury. At the mRNA level, both rat E2F-6 and the alternatively spliced variant, E2F-6b, were expressed in E18 myocytes and levels were maintained throughout development into adulthood. Interestingly, E2F-6 protein expression was down-regulated during myocyte development suggesting that it is regulated post-transcriptionally in these cells. During myocyte hypertrophy, the mRNA expressions of E2F-6 and E2F-6b were not regulated whereas E2F-6 protein was up-regulated significantly. Indeed, E2F-6 protein expression levels closely parallel the developmental withdrawal of myocytes from the cell cycle and the subsequent reactivation of their cell cycle machinery during hypertrophic growth. Furthermore, depletion of E2F-6, using anti-sense technology, results in death of cultured neonatal myocytes. Taken together, abrogation of E2F-6 expression in neonatal cardiomyocytes leads to a significant decrease in their viability, consistent with the notion that E2F-6 might be required for maintaining normal myocyte growth.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.YJMCC.2007.01.006
Abstract: Cardiac repair following myocardial injury is restricted due to the limited proliferative potential of adult cardiomyocytes. The ability of mammalian cardiomyocytes to proliferate is lost shortly after birth as cardiomyocytes withdraw from the cell cycle and differentiate. We do not fully understand the molecular and cellular mechanisms that regulate this cell cycle withdrawal, although if we could it might lead to the discovery of novel therapeutic targets for improving cardiac repair following myocardial injury. For the last decade, researchers have investigated cardiomyocyte cell cycle control, commonly using transgenic mouse models or recombinant adenoviruses to manipulate cell cycle regulators in vivo or in vitro. This review discusses cardiomyocyte cell cycle regulation and summarises recent data from studies manipulating the expressions and activities of cell cycle regulators in cardiomyocytes. The validity of therapeutic strategies that aim to reinstate the proliferative potential of cardiomyocytes to improve myocardial repair following injury will be discussed.
Publisher: Elsevier BV
Date: 06-2003
Publisher: Oxford University Press (OUP)
Date: 05-2007
Abstract: The completion of the Human Genome Project has revealed a multitude of potential avenues for the identification of therapeutic targets. Extensive sequence information enables the identification of novel genes but does not facilitate a thorough understanding of how changes in gene expression control the molecular mechanisms underlying the development and regulation of a cell or the progression of disease. Proteomics encompasses the study of proteins expressed by a population of cells, and evaluates changes in protein expression, post-translational modifications, protein interactions, protein structure and splice variants, all of which are imperative for a complete understanding of protein function within the cell. From the outset, proteomics has been used to compare the protein profiles of cells in healthy and diseased states and as such can be used to identify proteins associated with disease development and progression. These candidate proteins might provide novel targets for new therapeutic agents or aid the development of assays for disease biomarkers. This review provides an overview of the current proteomic techniques available and focuses on their application in the search for novel therapeutic targets for the treatment of disease.
Publisher: Microbiology Society
Date: 11-1994
DOI: 10.1099/0022-1317-75-11-3211
Abstract: The polyhedrin gene (polh) of Helicoverpa zea single nucleocapsid nuclear polyhedrosis virus (HzSNPV) was identified and shown by sequence analysis of the EcoRI I genomic fragment to encode a 246 amino acid polypeptide that has greater than 80% sequence identity to known polyhedrins. It is preceded by an AT-rich region containing the conserved late promoter motif TAAG, which was identified as a transcription start point. Downstream of polh there were several similarities in genome arrangement to other nuclear polyhedrosis viruses (NPVs). These include open reading frame (ORF) 8, immediately downstream of polh, encoding a 412 amino acid protein with multiple tandem proline residues, which is homologous to ORF8 (ORF1629) of Autographa californica multiple nucleocapsid NPV. Phylogenetic analysis of the polh gene region shows that HzSNPV is a member of the previously described lepidopteran NPV group II and that it is most closely related to polh of the NPVs of Malacosoma nuestria, Spodoptera littoralis, Orgyia pseudotsugata (single nucleocapsid-type virus) and Buzura supressaria.
Publisher: Oxford University Press (OUP)
Date: 05-2007
DOI: 10.1016/J.CARDIORES.2007.02.023
Abstract: Myostatin, a member of the transforming growth factor-beta (TGF-beta) family, plays a key role in skeletal muscle myogenesis by limiting hyperplastic and hypertrophic muscle growth. In cardiac muscle, myostatin has been shown to limit agonist-induced cardiac hypertrophic growth. However, its role in cardiac hyperplastic growth remains undetermined. The aim of this study was to characterise the expression of myostatin in developing myocardium, determine its effect on cardiomyocyte proliferation, and explore the signalling mechanisms affected by myostatin in iding cardiomyocytes. We used quantitative PCR and Western blotting to study the expression of myostatin in cardiomyocytes isolated from rat myocardium at different developmental ages. We determined the effect of recombinant myostatin on proliferation and cell viability in iding cardiomyocytes in culture. We analysed myostatin's effect on cardiomyocyte cell cycle progression by flow cytometry and used Western blotting to explore the signalling mechanisms involved. Myostatin is expressed differentially in cardiomyocytes during cardiac development such that increasing expression correlated with a low cardiomyocyte proliferation index. Proliferating foetal cardiomyocytes, from embryos at 18 days of gestation, expressed low levels of myostatin mRNA and protein, whereas isolated cardiomyocytes from postnatal day 10 hearts, wherein the majority of cardiomyocytes have lost their ability to proliferate, displayed a 6-fold increase in myostatin expression. Our in vitro studies demonstrated that myostatin inhibited proliferation of iding foetal and neonatal cardiomyocytes. Flow cytometric analysis showed that this inhibition occurs mainly via a block in the G1-S phase transition of the cardiomyocyte cell cycle. Western blot analysis showed that part of the mechanism underpinning the inhibition of cardiomyocyte proliferation by myostatin involves phosphorylation of SMAD2 and altered expressions of the cell cycle proteins p21 and CDK2. We conclude that myostatin is an inhibitor of cardiomyocyte proliferation with the potential to limit cardiomyocyte hyperplastic growth by altering cardiac cell cycle progression.
Publisher: Public Library of Science (PLoS)
Date: 25-08-2009
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BBRC.2005.05.022
Abstract: Nucleolin is a multi-functional protein that is located to the nucleolus. In tissue culture cells, the stability of nucleolin is related to the proliferation status of the cell. During development, rat cardiomyocytes proliferate actively with increases in the mass of the heart being due to both hyperplasia and hypertrophy. The timing of this shift in the phenotype of the myocyte from one capable of undergoing hyperplasia to one that can grow only by hypertrophy occurs within 4 days of post-natal development. Thus, cardiomyocytes are an ideal model system in which to study the regulation of nucleolin during growth in vivo. Using Western blot and quantitative RT-PCR (TaqMan) we found that the amount of nucleolin is regulated both at the level of transcription and translation during the development of the cardiomyocyte. However, in cells which had exited the cell cycle and were subsequently given a hypertrophic stimulus, nucleolin was regulated post-transcriptionally.
Publisher: Elsevier BV
Date: 08-2000
Publisher: Oxford University Press (OUP)
Date: 05-2003
DOI: 10.1211/002235703765344487
Abstract: Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell ision and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.
Publisher: Wiley
Date: 10-06-2013
Abstract: Branched polyethylenimine (25 kDa) is thiolated and compared with redox-sensitive crosslinked derivatives. Both polymers thiol contents are assessed the thiolated polymers have 390-2300 mmol SH groups/mol, whereas the crosslinked polymers have lower thiol contents. Cytotoxicity assays show that both modified polymers give lower hemolysis than unmodified PEI. Increased thiol content increases gene transfer efficiency but also elevates cytotoxicity. Crosslinking improves plasmid DNA condensation and enhances transfection efficiency, but extensive crosslinking overstabilizes the polyplexes and decreases transfection, emphasizing the need to balance polyplex stabilization and unpacking. Thus, at low levels of crosslinking, 25 kDa PEI can be an efficient redox-sensitive carrier system.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.IJPHARM.2009.05.052
Abstract: Polyethylenimine (PEI) is an efficient nonviral gene delivery vector because of its high buffering capacity and DNA condensation ability. In our study, the amino groups on the polymeric backbone were acylated using acetic or propionic anhydride to alter the protonation behaviour and the hydrophilic/hydrophobic balance of the polymer. The concentration of acylated primary amines was determined using trinitrobenzene sulphonic acid assay. Results showed that our modified polymers had lower buffering capacities in solutions compared to PEI. The polymers were complexed with plasmid encoding enhanced green fluorescent protein at three different ratios (1:1, 1:2 and 1:10 w/w DNA to polymer) to form polyplexes and their toxicities and transfection efficiencies were evaluated in HEK 293 cells. Acylation reduced the number of primary amines on the polymer and the surface charge, improving haemocompatibility and reducing cytotoxicity. The reduction in the concentration of amino groups helped to optimise DNA compaction and facilitated polyplex dissociation in the cell, which increased transfection efficiency of the modified polymers compared to the parent polymer. Polymers with buffering capacities greater than 50% and less than 80% relative to PEI, showed higher transfection efficiencies than PEI. The propionic anhydride modified polymers had appropriate interactions with DNA which provided both DNA compaction and polyplex dissociation. These systems interacted better with the cell membrane because of their slightly higher lipophilicity and formed polyplexes which were less cytotoxic than polyplexes of acetic anhydride modified polymers. Among the vectors tested, 1:0.3 mol/mol PEI:propionic anhydride in a 1:2 w/w DNA:polymer composition provided the best transfection system with improved transfection efficiency and reduced cytotoxicity.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.COPH.2007.12.015
Abstract: Coronary artery disease is one of the most common heart pathologies. Restriction of blood flow to the heart by atherosclerotic lesions, leading to angina pectoris and myocardial infarction, damages the heart, resulting in impaired cardiac function. Damaged myocardium is replaced by scar tissue since surviving cardiomyocytes are unable to proliferate to replace lost heart tissue. Although narrowing of the coronary arteries can be treated successfully using coronary revascularisation procedures, re-occlusion of the treated vessels remains a significant clinical problem. Cell cycle control mechanisms are key in both the impaired cardiac repair by surviving cardiomyocytes and re-narrowing of treated vessels by maladaptive proliferation of vascular smooth muscle cells. Strategies targeting the cell cycle machinery in the heart and vasculature offer promise both for the improvement of cardiac repair following MI and the prevention of restenosis and bypass graft failure following revascularisation procedures.
Publisher: American Chemical Society (ACS)
Date: 30-10-2015
DOI: 10.1021/ACS.JNATPROD.5B00075
Abstract: Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features that relate to their activity, as well as reliably predicted the activity of compounds with unknown activity. Contour maps emphasized the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C-ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimization of novel bone anabolics.
Publisher: Wiley
Date: 2007
DOI: 10.1002/PTR.2030
Abstract: Bone metabolism involves a complex balance between the deposition of matrix and mineralization and resorption. There is now good evidence that dietary components and herbal products can influence these processes, particularly by inhibiting bone resorption, thus having beneficial effects on the skeleton. For ex le, it has been reported that a number of common vegetables, including onion, garlic and parsley, can inhibit bone resorption in ovariectomized rats. Essential oils derived from sage, rosemary, thyme and other herbs inhibit osteoclast activity in vitro and in vitro and leading to an increase in bone mineral density. Soya, a rich source of isoflavones, has shown promising results and epidemiological evidence to support a use in maintaining bone health, and various traditional herbal formulae in Chinese and Ayurvedic medicine also have demonstrable effects in pharmacological models of osteoporosis. Recently, cannabinoids have been described as having positive effects on osteoblast differentiation, and the presence of cannabinoid receptors in bone tissue indicates a more complex role in bone metabolism than previously thought. The first part of this review briefly discusses normal bone metabolism and disorders caused by its disruption, with particular reference to osteoporosis and current pharmacological treatments. The effects of natural products on bone and connective tissue are then discussed, to include items of diet, herbal extracts and food supplements, with evidence for their efficacy outlined.
Publisher: American Society for Microbiology
Date: 15-04-2006
DOI: 10.1128/JVI.80.8.4147-4156.2006
Abstract: In eukaryotic cells, cell growth and ision occur in a stepwise, orderly fashion described by a process known as the cell cycle. The relationship between positive-strand RNA viruses and the cell cycle and the concomitant effects on virus replication are not clearly understood. We have shown that infection of asynchronously replicating and synchronized replicating cells with the avian coronavirus infectious bronchitis virus (IBV), a positive-strand RNA virus, resulted in the accumulation of infected cells in the G 2 /M phase of the cell cycle. Analysis of various cell cycle-regulatory proteins and cellular morphology indicated that there was a down-regulation of cyclins D1 and D2 (G 1 regulatory cyclins) and that a proportion of virus-infected cells underwent aberrant cytokinesis, in which the cells underwent nuclear, but not cytoplasmic, ision. We assessed the impact of the perturbations on the cell cycle for virus-infected cells and found that IBV-infected G 2 /M-phase-synchronized cells exhibited increased viral protein production when released from the block when compared to cells synchronized in the G 0 phase or asynchronously replicating cells. Our data suggested that IBV induces a G 2 /M phase arrest in infected cells to promote favorable conditions for viral replication.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.MCE.2008.09.032
Abstract: Gamma-melanocyte stimulating hormone (gamma-MSH) is a peptide derived from the ACTH precursor, pro-opiomelanocortin (POMC), and belongs to a family of peptides called the melanocortins that also comprises alpha- and beta-MSH. Although conserved in tetrapods, the biological role of gamma-MSH remains largely undefined. It has been demonstrated previously that gamma-MSH is involved in the regulating the activity of hormone sensitive lipase (HSL) activity in the adrenal and more recently, in the adipocyte. It has been shown also to have effects on the cardiovascular and renal systems. This short review will provide a brief overview of the role of gamma-MSH in the adrenal and the more recent report that it can also regulate HSL function in the adipocyte. We also present some preliminary data purporting a direct role for Lys-gamma(3)-MSH in the regulation of HSL phosphorylation in the heart. Taken together these data suggest that gamma-MSH peptides might play a more widespread role in lipid and cholesterol utilization.
Publisher: Oxford University Press (OUP)
Date: 20-01-2014
DOI: 10.1111/JPHP.12203
Abstract: The search for agents that are capable of preventing restenosis and reduce the risk of late thrombosis is of utmost importance. In this study we aim to evaluate the in vitro effects of ibuprofen on proliferation and migration of human coronary artery smooth muscle cells and on endothelial cells. Cell proliferation was evaluated by trypan blue exclusion. Cell migration was assessed by wound-healing ‘scratch’ assay and time-lapse video microscopy. Protein expression was assessed by immunoblotting, and morphology by immunocytochemistry. The involvement of the PPARγ pathway was studied with the agonist troglitazone, and the use of selective antagonists such as PGF2α and GW9662. We demonstrate that ibuprofen inhibits proliferation and migration of HCASMCs and induces a switch in HCASMCs towards a differentiated and contractile phenotype, and that these effects are mediated through the PPARγ pathway. Importantly we also show that the effects of ibuprofen are cell type-specific as it does not affect migration and proliferation of endothelial cells. Taken together, our results suggest that ibuprofen could be an effective drug for the development of novel drug-eluting stents that could lead to reduced rates of restenosis and potentially other complications of DES implantation.
Publisher: Elsevier BV
Date: 05-1997
DOI: 10.1016/S0168-1702(97)01454-8
Abstract: Nucleotide sequence analysis of the Helicoverpa zea S-type nucleopolyhedrovirus (HzSNPV) genomic interval between the polh and iel genes has revealed an open reading frame (HOAR ORF) that contains a complex A 1-T rich triplet repeat region (RAT-repeats). HOAR ORF is predicted to encode an acidic, arginine residue rich. 712 aa protein, with a C3HC4 (RING-finger) zinc binding motif. RAT-repeats, distributed over 450 bp. consist of GAT. AAT, and GTT codons, correspond to Asp, Asn and Val residues which display an extreme codon bias not seen with nine other genes of this virus. A survey of four other (field) isolates of Helicoverpa sp. NPVs confirms a high incidence of mutation in the RAT-repeat region. A 158-bp conserved block, homologous to the pe38-ien promoter of AcMNPV, was identified upstream of HOAR ORF. The sub-region of the genome in which HOAR ORF is located is susceptible to rearrangement.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
No related grants have been discovered for Katrina Bicknell.