Tyrosinase activated melanoma prodrugs

Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.

Scope and Limitations of The Co-Drug Approach to Topical Drug Delivery

Many currently available drugs show unfavourable physicochemical properties for delivery into or across the skin and temporary chemical modulation of the penetrant is one option to achieve improved delivery properties. Pro-drugs are chemical derivatives of an active drug which is covalently bonded to an inactive pro-moiety in order to overcome pharmaceutical and pharmacokinetic barriers. A pro-drug relies upon conversion within the body to release the parent active drug (and pro-moiety) to elicit its pharmacological effect. The main drawback of this approach is that the pro-moiety is essentially an unwanted ballast which, when released, can lead to adverse effects. The term ‘co-drug’ refers to two or more therapeutic compounds active against the same disease bonded via a covalent chemical linkage and it is this approach which is reviewed for the first time in the current article. For topically applied co-drugs, each moiety is liberated in situ, either chemically or enzymatically, once the stratum corneum barrier has been overcome by the co-drug. Advantages include synergistic modulation of the disease process, enhancement of drug delivery and pharmacokinetic properties and the potential to enhance stability by masking of labile functional groups. The amount of published work on co-drugs is limited but the available data suggest the co-drug concept could provide a significant therapeutic improvement in dermatological diseases. However, the applicability of the co-drug approach is subject to strict limitations pertaining mainly to the availability of compatible moieties and physicochemical properties of the overall molecule.

An integrated assessment of carbon dioxide capture and storage in the UK

Geological carbon dioxide storage (CCS) has the potential to make a significant contribution to the decarbonisation of the UK. Amid concerns over maintaining security, and hence diversity, of supply, CCS could allow the continued use of coal, oil and gas whilst avoiding the CO2 emissions currently associated with fossil fuel use. This project has explored some of the geological, environmental, technical, economic and social implications of this technology. The UK is well placed to exploit CCS with a large offshore storage capacity, both in disused oil and gas fields and saline aquifers. This capacity should be sufficient to store CO2 from the power sector (at current levels) for a least one century, using well understood and therefore likely to be lower-risk, depleted hydrocarbon fields and contained parts of aquifers. It is very difficult to produce reliable estimates of the (potentially much larger) storage capacity of the less well understood geological reservoirs such as non-confined parts of aquifers. With the majority of its large coal fired power stations due to be retired during the next 15 to 20 years, the UK is at a natural decision point with respect to the future of power generation from coal; the existence of both national reserves and the infrastructure for receiving imported coal makes clean coal technology a realistic option. The notion of CCS as a ‘bridging’ or ‘stop-gap’ technology (i.e. whilst we develop ‘genuinely’ sustainable renewable energy technologies) needs to be examined somewhat critically, especially given the scale of global coal reserves. If CCS plant is built, then it is likely that technological innovation will bring down the costs of CO2 capture, such that it could become increasingly attractive. As with any capitalintensive option, there is a danger of becoming ‘locked-in’ to a CCS system. The costs of CCS in our model for UK power stations in the East Midlands and Yorkshire to reservoirs in the North Sea are between £25 and £60 per tonne of CO2 captured, transported and stored. This is between about 2 and 4 times the current traded price of a tonne of CO2 in the EU Emissions Trading Scheme. In addition to the technical and economic requirements of the CCS technology, it should also be socially and environmentally acceptable. Our research has shown that, given an acceptance of the severity and urgency of addressing climate change, CCS is viewed favourably by members of the public, provided it is adopted within a portfolio of other measures. The most commonly voiced concern from the public is that of leakage and this remains perhaps the greatest uncertainty with CCS. It is not possible to make general statements concerning storage security; assessments must be site specific. The impacts of any potential leakage are also somewhat uncertain but should be balanced against the deleterious effects of increased acidification in the oceans due to uptake of elevated atmospheric CO2 that have already been observed. Provided adequate long term monitoring can be ensured, any leakage of CO2 from a storage site is likely to have minimal localised impacts as long as leaks are rapidly repaired. A regulatory framework for CCS will need to include risk assessment of potential environmental and health and safety impacts, accounting and monitoring and liability for the long term. In summary, although there remain uncertainties to be resolved through research and demonstration projects, our assessment demonstrates that CCS holds great potential for significant cuts in CO2 emissions as we develop long term alternatives to fossil fuel use. CCS can contribute to reducing emissions of CO2 into the atmosphere in the near term (i.e. peak-shaving the future atmospheric concentration of CO2), with the potential to continue to deliver significant CO2 reductions over the long term.

Neuroinflammation and its modulation by flavonoids

There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO•) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation.

Modulation of the human gut microflora towards improved health using prebiotics: assessment of efficacy

There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An 'optimal' gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.

The gut microbiota and lipid metabolism: implications for human health and coronary heart disease

Coronary heart disease (CHD) is the leading cause of mortality in Western societies, affecting about one third of the population before their seventieth year. Over the past decades modifiable risk factors of CHD have been identified, including smoking and diet. These factors when altered can have a significant impact on an individuals' risk of developing CHD, their overall health and quality of life. There is strong evidence suggesting that dietary intake of plant foods rich in fibre and polyphenolic compounds, effectively lowers the risk of developing CHD. However, the efficacy of these foods often appears to be greater than the sum of their recognised biologically active parts. Here we discuss the hypothesis that beneficial metabolic and vascular effects of dietary fibre and plant polyphenols are due to an up regulation of the colon-systemic metabolic axis by these compounds. Fibres and many polyphenols are converted into biologically active compounds by the colonic microbiota. This microbiota imparts great metabolic versatility and dynamism, with many of their reductive or hydrolytic activities appearing complementary to oxidative or conjugative human metabolism. Understanding these microbial activities is central to determining the role of different dietary components in preventing or beneficially impacting on the impaired lipid metabolism and vascular dysfunction that typifies CHD and type 11 diabetes. This approach lays the foundation for rational selection of health promoting foods, rational target driven design of functional foods, and provides an essential thus-far, overlooked, dynamic to our understanding of how foods recognised as "healthy" impact on the human metabonome.

Informing people about the risks and benefits of medicines: implications for the safe and effective use of medicinal products

Providing effective information about drug risks and benefits has become a major challenge for health professionals, as many people are ill equipped to understand, retain and use the information effectively. This paper reviews the growing evidence that people’s understanding (and health behaviour) is not only affected by the content of medicines information, but also by the particular way in which it is presented. Such presentational factors include whether information is presented verbally or numerically, framed positively or negatively, whether risk reductions are described in relative or absolute terms (and baseline information included), and whether information is personalized or tailored in any way. It also looks at how understanding is affected by the order in which information is presented, and the way in which it is processed. The paper concludes by making a number of recommendations for providers of medicines information, about both the content and presentation of such information, that should enhance safe and effective medicines usage.

Animal health challenges and veterinary aspects of organic livestock farming identified through a 3 year EU network project

From 2003-2006, an EU network project ‘Sustaining Animal Health and Food Safety in Organic Farming' (SAFO), was carried out with 26 partners from 20 EU-countries and 4 related partners from 4 candidate or new member states. The focus was the integration of animal health and welfare issues in organic farming with food safety aspects. Four very consistent conclusions became apparent: 1) The climatic, physical and socio-economic conditions vary considerably throughout Europe, leading to different livestock farming systems. This limits the possibility for technology transfer between regions, and creates several challenges for a harmonised regulation, 2) Implementing organic standards at farm level does not always ensure that animal health and welfare reach the high ideals of the organic principles, 3) To overcome these deficiencies, organic farmers and farmer organisations need to take ownership of organic values and, 4) In all participating countries, a strong need for training of farmers and in particular veterinarians in animal health promotion and organic principles was identified. The article presents a summary of papers presented at the five SAFO workshops.

The impact of urban wind environments on natural ventilation

The aim of this paper is to illustrate the impact of urban wind environments when assessing the availability of natural ventilation. A numerical study of urban airflow for a complex of five building blocks located at the University of Reading, UK is presented. The computational fluid dynamics software package ANSYS was used to simulate six typical cases of urban wind environments and the potential for natural ventilation assessed. The study highlights the impact of three typical architectural forms (street canyons, semi-enclosures and courtyards) on the local wind environment. Simulation results have also been compared with experimental data collected from six locations on the building complex. The study demonstrates that ventilation strategies formed using regional weather data, may have a propensity to over-estimate the potential for natural ventilation and cooling, due to the impact of urban form which creates a unique microclimate. Characteristics of urban wind flow patterns are presented as a guideline and can be used to assess the design and performance of natural or hybrid ventilation and the opportunity for passive cooling.

Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

Formation of vesicles through solvent assisted self-assembly of hydrophobic pentapeptides: encapsulation and pH responsive release of dyes by the vesicles

In the biomimetic design two hydrophobic pentapetides Boc-Ile-Aib-Leu-Phe-Ala-OMe ( I) and Boc-Gly-Ile-Aib-Leu-Phe-OMe (II) (Aib: alpha-aminoisobutyric acid) containing one Aib each are found to undergo solvent assisted self-assembly in methanol/water to form vesicular structures, which can be disrupted by simple addition of acid. The nanovesicles are found to encapsulate dye molecules that can be released by the addition of acid as confirmed by fluorescence microscopy and UV studies. The influence of solvent polarity on the morphology of the materials generated from the peptides has been examined systematically, and shows that fibrillar structures are formed in less polar chloroform/petroleum ether mixture and vesicular structures are formed in more polar methanol/water. Single crystal X-ray diffraction studies reveal that while beta-sheet mediated self-assembly leads to the formation of fibrillar structures, the solvated beta-sheet structure leads to the formation of vesicular structures. The results demonstrate that even hydrophobic peptides can generate vesicular structures from polar solvent which may be employed in model studies of complex biological phenomena.

Glycemic Index, glycemic control and beyond

It is currently estimated that over 370 million individuals have diabetes, making diabetes a major public health issue contributing significantly to global morbidity and mortality. The steep rise in diabetes prevalence over the past decades is attributable, in a large part, to lifestyle changes, with dietary habits and behaviour significant contributors. Despite the relatively wide availability of anti-diabetic medicine, it is lifestyle approaches that still remain the cornerstone of diabetes prevention and treatment. Glycemic index (GI) is a nutritional tool, which represents the glycemic response to carbohydrate ingestion. In light of the major impact of nutrition on diabetes pathophysiology, with the rising need to combat the escalating diabetes epidemic, this review will focus on the role of GI in glycemic control, the primary target of diabetic treatment and beyond. The review will present the evidence relating GI and diabetes treatment and prevention, as well as weight loss, weight maintenance and CVD risk factors.