Non-adenine based purines accelerate wound healing

Wound healing is a complex sequence of cellular and molecular processes that involves multiple cell types and biochemical mediators. Several growth factors have been identified that regulate tissue repair, including the neurotrophin nerve growth factor (NGF). As non-adenine based purines (NABPs) are known to promote cell proliferation and the release of growth factors, we investigated whether NABPs had an effect on wound healing. Full-thickness, excisional wound healing in healthy BALB/c mice was significantly accelerated by daily topical application of NABPs such as guanosine (50% closure by days 2.5′.8). Co-treatment of wounds with guanosine plus anti-NGF reversed the guanosine-promoted acceleration of wound healing, indicating that this effect of guanosine is mediated, at least in part, by NGF. Selective inhibitors of the NGF-inducible serine/threonine protein kinase (protein kinase N), such as 6-methylmercaptopurine riboside abolished the acceleration of wound healing caused by guanosine, confirming that activation of this enzyme is required for this effect of guanosine. Treatment of genetically diabetic BKS.Cg-m+/+lepr db mice, which display impaired wound healing, with guanosine led to accelerated healing of skin wounds (25% closure by days 2.8′.0). These results provide further confirmation that the NABP-mediated acceleration of cutaneous wound healing is mediated via an NGF-dependent mechanism. Thus, NABPs may offer an alternative and viable approach for the treatment of wounds in a clinical setting

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

What is the state of the art in energy and transport poverty metrics? A critical and comprehensive review

This review investigates the state of the art in metrics used in energy (or fuel) and transport poverty with a view to assessing how these overlapping concepts may be unified in their measurement. Our review contributes to ongoing debates over decarbonisation, a politically sensitive and crucial aspect of the energy transition, and one that could exacerbate patterns of inequality or vulnerability. Up to 125 million people across the European Union experience the effects of energy poverty in their daily lives. A more comprehensive understanding of the breadth and depth of these conditions is therefore paramount. This review assessed 1,134 articles and critically analysed a deeper sample of 93. In terms of the use of metrics, we find that multiple indicators are better than any single metric or composite. We find work remains to be conducted in the transport poverty sphere before energy poverty metrics can be fully unified with those of transport poverty, namely the stipulation of travel standards. Without such standards, our ability to unify the metrics of both fields and potentially alleviate both conditions simultaneously is limited. The difficulties in defining necessary travel necessitate the further use of vulnerability lenses and holistic assessments focused on energy and transport services

Energy poverty: Understanding and addressing systemic inequalities

In this chapter I document the emergence of a socially systemic approach to understanding and addressing energy poverty. This approach, which has grown out of studies of the lived experience of energy poverty, understands energy poverty as a fundamentally social phenomenon, which has emerged from a range of policy agendas (energy, welfare, health, housing), and conceives of this systemically, emphasizing the multiple causal interconnections between a wide variety of drivers and outcomes of energy poverty. Here I characterize this socially systemic understanding, drawing on work on the lived experience of energy poverty in the UK, and the politics of energy poverty policy in a range of European nations. A socially systemic understanding of energy poverty has three key facets: (1) energy poverty has to be understood in the context of social, physical and technological conditions; (2) people's experiences are affected by intersecting challenges according to these conditions; and (3) the nature and the progression of these challenges is variable over time. This suggests a need for a politics of energy poverty that embraces the multi-dimensional experience of the energy poor, and that reaches beyond a narrowly focused energy poverty policy