Obesity and the Dysregulation of Fatty Acid Metabolism: Implications for Healthy Aging

This is an Accepted Manuscript of an article published by Taylor & Francis in Expert Review of Endocrinology & Metabolism on 17/10/2016, available online: http://dx.doi.org/10.1080/17446651.2016.1245141The population of the world is aging. In 2010, an estimated 524 million people were aged 65 years or older presenting eight percent of the global population. By 2050, this number is expected to nearly triple to approximately 1.5 billion, 16 percent of the world’s population. Although people are living longer, the quality of their lives are often compromised due to ill-health. Areas covered. Of the conditions which compromise health as we age, obesity is at the forefront. Over half of the global older population were overweight or obese in 2010, significantly increasing the risk of a range of metabolic diseases. Although, it is well recognised excessive calorie intake is a fundamental driver of adipose tissue dysfunction, the relationship between obesity; intrinsic aging; and fat metabolism is less understood. In this review we discuss the intersection between obesity, aging and the factors which contribute to the dysregulation of whole-body fat metabolism. Expert Commentary. Being obese disrupts an array of physiological systems and there is significant crosstalk among these. Moreover it is imperative to acknowledge the contribution intrinsic aging makes to the dysregulation of these systems and the onset of disease

Introduction to special issue:New Times Revisited: Britain in the 1980s

The authors in this volume are collectively engaged with a historical puzzle: What happens if we examine the decade once we step out of the shadows cast by Thatcher? That is, does the decade of the 1980s as a significant and meaningful periodisation (equivalent to that of the 1960s) still work if Thatcher becomes but one part of the story rather than the story itself? The essays in this collection suggest that the 1980s only makes sense as a political period. They situate the 1980s within various longer term trajectories that show the events of the decade to be as much the consequence as the cause of bigger, long-term historical processes. This introduction contextualises the collection within the wider literature, before explaining the collective and individual contributions made

A mixed-methods study exploring the characteristics and needs of long-stay patients in high and medium secure settings in England: implications for service organisation

Background: Forensic psychiatric services provide care for those with mental disorders and offending behaviour. Concerns have been expressed that patients may stay for too long in too high levels of security. The economic burden of these services is high, and they are highly restrictive for patients. There is no agreed standard for ‘long stay’; we defined a length of stay exceeding 5 years in medium secure care, 10 years in high secure care or 15 years in a combination of both settings as long stay. Objectives: To (1) estimate the number of long-stay patients in secure settings; (2) describe patients’ characteristics, needs and care pathways and the reasons for their prolonged stay; (3) identify patients’ perceptions of their treatment and quality of life; and (4) explore stakeholders’ views on long stay. Design: A mixed-methods approach, including a cross-sectional survey (on 1 April 2013) of all patients in participating units to identify long-stay patients [work package (WP) 1], file reviews and consultant questionnaires for long-stay patients (WP2), interviews with patients (WP3) and focus groups with other stakeholders (WP4). Setting: All three high secure hospitals and 23 medium secure units (16 NHS and 9 independent providers) in England. Participants: Information was gathered on all patients in participating units (WP1), from which 401 long-stay patients were identified (WP2), 40 patients (WP3), 17 international and 31 UK experts were interviewed and three focus groups were held (WP4). Results: Approximately 23.5% of high secure patients and 18% of medium secure patients were long-stay patients. We estimated that there are currently about 730 forensic long-stay patients in England. The source of a patient’s admission and the current section of the Mental Health Act [Great Britain. Mental Health Act 1983 (as Amended by the Mental Health Act 2007). London: The Stationery Office; 2007] under which they were admitted predicted long-stay status. Long-stay patients had complex pathways, moving ‘around’ between settings rather than moving forward. They were most likely to be detained under a hospital order with restrictions (section 37/41) and to have disturbed backgrounds with previous psychiatric admissions, self-harm and significant offending histories. The most common diagnosis was schizophrenia, but 47% had been diagnosed with personality disorder. Only 50% had current formal psychological therapies. The rates of violent incidents within institutions and seclusion were high, and a large proportion had unsuccessful referrals to less secure settings. Most patients had some contact with their families. We identified five classes of patients within the long-stay sample with different characteristics. Patients differed in their attribution of reasons for long stay (internal/external), outlook (positive/negative), approach (active/passive) and readiness for change. Other countries have successfully developed specific long-stay services; however, UK experts were reluctant to accept the reality of long stay and that the medical model of ‘cure’ does not work with this group. Limitations: We did not conduct file reviews on non-long-stay patients; therefore, we cannot say which factors differentiate between long-stay patients and non-long-stay patients. Conclusions: The number of long-stay patients in England is high, resulting in high resource use. Significant barriers were identified in developing designated long-stay services. Without a national strategy, these issues are likely to remain. Future work: To compare long-stay patients and non-long-stay patients. To evaluate new service models specifically designed for long-stay patients. Study registration: The National Institute for Health Research (NIHR) Clinical Research Network Portfolio 129376. Funding: The NIHR Health Services and Delivery Research programm

Accurate and Reliable Prediction of the Binding Affinities of Macrocycles to Their Protein Targets

Macrocycles have been emerging as a very important drug class in the past few decades largely due to their expanded chemical diversity benefiting from advances in synthetic methods. Macrocyclization has been recognized as an effective way to restrict the conformational space of acyclic small molecule inhibitors with the hope of improving potency, selectivity, and metabolic stability. Because of their relatively larger size as compared to typical small molecule drugs and the complexity of the structures, efficient sampling of the accessible macrocycle conformational space and accurate prediction of their binding affinities to their target protein receptors poses a great challenge of central importance in computational macrocycle drug design. In this article, we present a novel method for relative binding free energy calculations between macrocycles with different ring sizes and between the macrocycles and their corresponding acyclic counterparts. We have applied the method to seven pharmaceutically interesting data sets taken from recent drug discovery projects including 33 macrocyclic ligands covering a diverse chemical space. The predicted binding free energies are in good agreement with experimental data with an overall root-mean-square error (RMSE) of 0.94 kcal/mol. This is to our knowledge the first time where the free energy of the macrocyclization of linear molecules has been directly calculated with rigorous physics-based free energy calculation methods, and we anticipate the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for macrocycle drug discovery

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists. [Display omitted] •Selective Modulation of PPARγ offers therapeutic advantage over full agonism in NS•GQ-16 reduces proteinuria in NS and associated comorbidities with high efficacy•RNA-Seq identified common and distinct glomerular gene expression by GQ-16 and pioglitazone•Pioglitazone induces more markers of adipogenesis, and GQ-16 induces adipokines to a greater degree Nephrology; Molecular physiology; Cell biolog

DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1

Autophagy can protect cancer cells from acute starvation and enhance resistance to chemotherapy. Previously, we reported that autophagy plays a critical role in the survival of dormant, drug resistant ovarian cancer cells using human xenograft models and correlated the up-regulation of autophagy and DIRAS3 expression in clinical samples obtained during “second look„ operations. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kD GTPase with homology to RAS that inhibits cancer cell proliferation and motility. Re-expression of DIRAS3 in ovarian cancer xenografts also induces dormancy and autophagy. DIRAS3 can bind to Beclin1 forming the Autophagy Initiation Complex that triggers autophagosome formation. Both the N-terminus of DIRAS3 (residues 15–33) and the switch II region of DIRAS3 (residues 93–107) interact directly with BECN1. We have identified an autophagy-inhibiting peptide based on the switch II region of DIRAS3 linked to Tat peptide that is taken up by ovarian cancer cells, binds Beclin1 and inhibits starvation-induced DIRAS3-mediated autophagy

Loss of Insulin Signaling in Vascular Endothelial Cells Accelerates Atherosclerosis in Apolipoprotein E Null Mice

To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.Stem Cell and Regenerative Biolog