Biomedical subjects

Jason J Ashworth

Publications and source records attributed to Jason J Ashworth.

6 recordsLinked to original sources

PubMed2007

Closed-loop, multiobjective optimization of two-dimensional gas chromatography/mass spectrometry for serum metabolomics.

Metabolomics seeks to measure potentially all the metabolites in a biological sample, and consequently, we need to develop and optimize methods to increase significantly the number of metabolites we can detect. We extended the closed-loop (iterative, automated) optimization system that we had previously developed for one-dimensional GC-TOF-MS (O'Hagan, S.; Dunn, W. B.; Brown, M.; Knowles, J. D.; Kell, D. B. Anal. Chem. 2005, 77, 290-303) to comprehensive two-dimensional (GCxGC) chromatography. The heuristic approach used was a multiobjective version of the efficient global optimization algorithm. In just 300 automated runs, we improved the number of metabolites observable relative to those in 1D GC by some 3-fold. The optimized conditions allowed for the detection of over 4000 raw peaks, of which some 1800 were considered to be real metabolite peaks and not impurities or peaks with a signal/noise ratio of less than 5. A variety of computational methods served to explain the basis for the improvement. This closed-loop optimization strategy is a generic and powerful approach for the optimization of any analytical instrumentation.

Biomarkers↗

PubMed2006

Androgens modulate the inflammatory response during acute wound healing.

Impaired wound healing states in the elderly lead to substantial morbidity and mortality, and a cost to the health services of over 9 billion dollars per annum. In addition to intrinsic ageing processes that per se cause delayed healing, studies have suggested marked differences in wound repair between the sexes. We have previously reported that, castration of male mice results in a striking acceleration of local cutaneous wound healing and dampens the associated inflammatory response. In this study, we report that systemic 5alpha-reductase inhibition, which blocks the conversion of testosterone to its more active metabolite 5alpha-dihydrotestosterone, mimics the effects of castration in a rat model of cutaneous wound healing. The mechanisms underlying the observed effects involve a direct, cell-specific upregulation of pro-inflammatory cytokine expression by macrophages, but not fibroblasts, in response to androgens. Androgens require the transforming growth factor beta signalling intermediate Smad3 to be present in order to influence repair and local pro-inflammatory cytokine levels. That reducing 5alpha-dihydrotestosterone levels through 5alpha-reductase antagonism markedly accelerates healing suggests a specific target for future therapeutic intervention in impaired wound healing states in elderly males.

Aged↗

PubMed2005

The dinucleotide (CA) repeat polymorphism of estrogen receptor beta but not the dinucleotide (TA) repeat polymorphism of estrogen receptor alpha is associated with venous ulceration.

Venous ulcers are the predominant form of chronic wound in the elderly, accounting for around 70% of all cases. The steroid sex hormone estrogen plays a crucial role in normal human skin maintenance and during cutaneous wound repair following injury. Estrogen can reverse age-related impaired wound healing by dampening the inflammatory response and increasing matrix deposition at the wound site. The molecular actions of estrogen are mediated through two nuclear sex steroid hormone receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta). We have conducted a case-control study to investigate whether dinucleotide repeat polymorphisms in the estrogen receptor genes are associated with venous ulceration in the UK Caucasian population. Genomic fragments containing the ERalpha dinucleotide (TA)(n) repeat polymorphism or the ERbeta dinucleotide (CA)(n) repeat polymorphism were amplified by polymerase chain reaction in subject DNA samples and genotyped according to fragment length by capillary electrophoresis. There was no evidence to suggest that the TA repeat polymorphism of ERalpha was associated with venous ulceration. However, the CA*18 allele of the ERbeta CA repeat polymorphism was significantly associated with venous ulceration (n = 120, OR = 1.8, 95% CI = 1.1-2.8, P = 0.02). When the CA repeats alleles were grouped together into either low (L < or = 18) or high (H > 18) numbers of CA repeats, the low (L) repeat allele was significantly associated with venous ulceration (OR = 1.5, 95% CI = 1.0-2.2, P = 0.03). Our results show that a specific ERbeta variant is associated with impaired healing in the elderly, predisposing individuals to venous ulceration.

Aged↗

PubMed2005

The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptors.

Age-related impaired wound healing states lead to substantial morbidity and cost, with treatment in the USA resulting in an expenditure of over $9 billion per annum. Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with immunomodulatory properties whose levels decline significantly with advanced age in humans. Conversion of DHEA locally to downstream steroid hormones leads to estrogenic and/or androgenic effects which may be important in age-related skin homeostasis, and which would avoid systemic adverse effects related to estrogen. We report that systemic DHEA levels are strongly associated with protection against chronic venous ulceration in humans. DHEA accelerated impaired healing in an impaired healing model (mice rendered hypogonadal) associated with increased matrix deposition and dampens the exaggerated inflammatory response. Such effects were mediated by local conversion of DHEA to estrogen, acting through the estrogen receptor, and vitro studies suggest a direct effect on specific pro-inflammatory cytokine production by macrophages via mitogen activated kinase (MAP) and phosphatidylinositol 3 (PI3) kinase pathways. In addition, we show that local injection of DHEA accelerates impaired healing in an ageing mouse colony. We suggest that exogenous application of DHEA accelerates impaired wound repair, results which may be applicable to the prophylaxis and treatment of human impaired wound healing states.

Aging↗

PubMed2003

Potential role of estrogens in wound healing.

Estrogens play a vital role in the development of sexually dimorphic characteristics essential for reproduction. In recent years, insight has been gained into the role of estrogens in non-reproductive pathophysiological processes, including neoplasia, vascular disease and osteoporosis. Intriguingly, the skin appears to act as an end-organ target for estrogenic action; marked structural and functional skin changes occurring after the menopause can be related to altered hormonal profiles. One of the most important consequences of such hormonal changes is the age-related delay in cutaneous wound healing, leading to substantial morbidity and mortality, and increased costs to health services. Reduced estrogen levels have major downstream effects on cellular and tissue responses to injury; such downstream effects include impaired cytokine signal transduction, unchecked inflammation, and altered protein balance, and have a major impact on the rate of wound healing. Further understanding of the complex interaction between aging cells and the hormonal micro-environment is essential to develop focused therapeutic strategies to improve cutaneous wound healing in hypogonadal individuals, including the elderly.

Aging↗

PubMed2002

Ageing and wound healing.

Cutaneous wound healing is a complex process encompassing a number of overlapping events including leukocyte recruitment, matrix deposition, epithelialization, and ultimately resolution of inflammation with the formation of a mature scar. Morbidity associated with age-related delayed wound healing imposes an enormous social and financial burden; unless improved wound care strategies are developed the projected relative and absolute increase in the elderly population will further exacerbate this problem. In recent years insight has been gained into the impact of ageing on cellular and tissue responses, resulting from impaired cytokine signal transduction, unchecked inflammation, an altered balance of protein synthesis and degradation, and subsequent downstream effects on the rate and quality of the wound healing response. Further understanding of the complex interaction between the ageing cell and its microenvironment is essential in order to develop focussed therapeutic strategies to improve healing in the elderly.

Aging↗