A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids

Kilner, Josephine; Corfe, Bernard M.; McAuley, Mark T.; Wilkinson, Stephen J.

doi:10.1039/c5mb00211g

Cited by 26 publications

(10 citation statements)

References 58 publications

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“…The essence of this approach is to utilise novel approaches to study molecules, cells or entire organisms. Nutrition research is no different and is beginning to benefit from this new paradigm (74)(75)(76)(77)(78)(79)(80) . It can be argued that electrochemical techniques come under this umbrella of systems techniques.…”

Section: Detecting Dna Methylationmentioning

confidence: 99%

The role of DNA methylation in ageing and cancer

2018

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The aim of the present review paper is to survey the literature related to DNA methylation, and its association with cancer and ageing. The review will outline the key factors, including diet, which modulate DNA methylation. Our rationale for conducting this review is that ageing and diseases, including cancer, are often accompanied by aberrant DNA methylation, a key epigenetic process, which is crucial to the regulation of gene expression. Significantly, it has been observed that with age and certain disease states, DNA methylation status can become disrupted. For instance, a broad array of cancers are associated with promoter-specific hypermethylation and concomitant gene silencing. This review highlights that hypermethylation, and gene silencing, of the EN1 gene promoter, a crucial homeobox gene, has been detected in various forms of cancer. This has led to this region being proposed as a potential biomarker for diseases such as cancer. We conclude the review by describing a recently developed novel electrochemical method that can be used to quantify the level of methylation within the EN1 promoter and emphasise the growing trend in the use of electrochemical techniques for the detection of aberrant DNA methylation.

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Section: Detecting Dna Methylationmentioning

confidence: 99%

The role of DNA methylation in ageing and cancer

2018

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“…The systems biology paradigm contrasts with the more traditional reductionist approach, commonly used in nutrition research, and offers a more integrated way to study this multifaceted system (14,113,114) . A fundamental element of this paradigm shift is the close coupling of computational modelling with experimental work (115)(116)(117)(118) . Our group has used computational systems biology to investigate cholesterol metabolism and ageing (119) .…”

Section: Applying Systems Biology To Our Understanding Of Cholesterolmentioning

confidence: 99%

Investigating cholesterol metabolism and ageing using a systems biology approach

et al. 2016

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CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.

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“…However, a significant obstacle to this is that the human liver is subject to a multitude of dynamic processes. Recently, ageing research and lipid metabolism have benefited from adopting the systems biology paradigm (45)(46)(47)(48). This framework provides a means of handling the complexities of hepatic cholesterol metabolism and ageing.…”

Section: Investigating the Hypothesismentioning

confidence: 99%

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge

Auley

Mooney

2017

Medical Hypotheses

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The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people.

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A deterministic oscillatory model of microtubule growth and shrinkage for differential actions of short chain fatty acids

Cited by 26 publications

References 58 publications

The role of DNA methylation in ageing and cancer

The role of DNA methylation in ageing and cancer

Investigating cholesterol metabolism and ageing using a systems biology approach

LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge

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