Targeting extracellular DNA to deliver IGF-1 to the injured heart.

There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The impact of increased flooding occurrence on the mobility of potentially toxic elements in floodplain soil – a review

The frequency and duration of flooding events are increasing due to land-use changes increasing run-off of precipitation, and climate change causing more intense rainfall events. Floodplain soils situated downstream of urban or industrial catchments, which were traditionally considered a sink of potentially toxic elements (PTEs) arriving from the river reach, may now become a source of legacy pollution to the surrounding environment if PTEs are mobilised by unprecedented flooding events. When a soil floods, the mobility of PTEs can increase or decrease due to the net effect of five key processes; (i) the soil redox potential decreases which can directly alter the speciation, and hence mobility, of redox sensitive PTEs (e.g. Cr, As), (ii) pH increases which usually decreases the mobility of metal cations (e.g. Cd2+, Cu2+, Ni2+, Pb2+, Zn2+), (iii) dissolved organic matter (DOM) increases, which chelates and mobilises PTEs, (iv) Fe and Mn hydroxides undergo reductive dissolution, releasing adsorbed and co-precipitated PTEs, and (v) sulphate is reduced and PTEs are immobilised due to precipitation of metal sulphides. These factors may be independent mechanisms, but they interact with one another to affect the mobility of PTEs, meaning the effect of flooding on PTE mobility is not easy to predict. Many of the processes involved in mobilising PTEs are microbially mediated, temperature dependent and the kinetics are poorly understood. Soil mineralogy and texture are properties that change spatially and will affect how the mobility of PTEs in a specific soil may be impacted by flooding. As a result, knowledge based on one river catchment may not be particularly useful for predicting the impacts of flooding at another site. This review provides a critical discussion of the mechanisms controlling the mobility of PTEs in floodplain soils. It summarises current understanding, identifies limitations to existing knowledge, and highlights requirements for further research

Sex differences in circulating and renal angiotensins of hypertensive mRen(2).Lewis but not normotensive Lewis rats

Sex differences in blood pressure are evident in experimental models and human subjects, yet the mechanisms underlying this disparity remain equivocal. The current study sought to define the extent of male-female differences in the circulating and tissue renin-angiotensin aldosterone systems (RAASs) of congenic mRen(2).Lewis and control Lewis rats. Male congenics exhibited higher systolic blood pressure than females [200 ± 4 vs. 146 ± 7 mmHg, P < 0.01] or Lewis males and females [113 ± 2 vs. 112 ± 2 mmHg, P > 0.05]. Plasma ANG II levels were twofold higher in male congenics [47 ± 3 vs. 19 ± 3 pM, P < 0.01] and fivefold higher than in male or female Lewis rats [6 ± 1 vs. 6 ± 1 pM]. ANG I levels were also highest in the males; however, plasma ANG-(1-7) was higher in female congenics. Male congenics exhibited greater circulating renin and angiotensin-converting enzyme (ACE) activities, as well as angiotensinogen, than female littermates. Renal cortical and medullary ANG II levels were also higher in the male congenics versus all the other groups; ANG I was lower in the males. Cortical ACE2 activity was higher in male congenics, yet neprilysin activity and protein were greater in the females, which may contribute to reduced renal levels of ANG II. These data reveal that sex differences in both the circulating and renal RAAS are apparent primarily in the hypertensive group. The enhanced activity of the RAAS in male congenics may contribute to the higher pressure and tissue injury evident in the strain