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The syntheses of non-oxido/non-nitrido bis(thiosemicarbazonato)technetium(V) complexes featuring a series of alkyl and ether substituents is presented. The bis(thiosemicarbazones) were radiolabelled with technetium-99m using an optimised one-pot synthesis from [99mTc][TcO4]-. Mass spectrometry and computational chemistry data suggested a distorted trigonal prismatic coordination environment for the bis(thiosemicarbazonato)technetium(V) complexes by way of a bis(thiosemicarbazone)technetium(V)-oxido intermediate complex. The lipophilicities of the complexes were estimated using distribution ratios and three of the new complexes were investigated in mice using kinetic planar imaging and ex vivo biodistribution experiments and were compared to [99mTc][TcO4]-. Modification of the technetium complexes with various lipophilic functional groups altered the biodistributions of the complexes in mice despite evidence suggesting limited stability of the complexes to biologically relevant conditions. The most hydrophilic complex had higher uptake in the kidneys compared to the most lipophilic, which had higher liver uptake, suggesting modification of the excretion pathways.

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity.

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction.

The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls. Bone marrow chimera experiments revealed that the presence of Mincle in the central nervous system, rather than recruited immune cells, was the critical regulator of a poor outcome following transient middle cerebral artery occlusion. There was no evidence for a direct role for Mincle in microglia or neural activation, but expression in a subset of macrophages resident in the perivascular niche provided new clues on Mincle's role in ischemic stroke.

PCOS, the most common female endocrine disorder of unknown etiology is characterized by reproductive abnormalities and associated metabolic conditions comprising insulin resistance, Type 2 diabetes mellitus and dyslipidemia. We previously reported that transgenic overexpression of NGF, a marker of sympathetic hyperactivity, directed to the ovary by the mouse 17alpha-hydroxylase promoter (17NF mice), results in ovarian abnormalities similar to those seen in PCOS women (1). To investigate whether ovarian overproduction of NGF also induces common metabolic alterations of PCOS we assessed glucose homeostasis by glucose tolerance test, plasma insulin levels and body composition by Dexa scan in young female 17NF mice compared with WT mice. 17NF mice exhibited increased body weight and alterations in body fat distribution with a greater accumulation of visceral fat compared to subcutaneous fat (p<0.01). 17NF mice also displayed glucose intolerance (p<0.01) and hyperinsulinemia (p<0.05), which, similar to PCOS patients, occurred independently of body weight. Since we have previously established that 17NF mice exhibit increased extrinsic sympathetic input to the ovary (1) we went on to determine whether overexpression of ovarian NGF is capable of altering systemic sympathetic outflow by measuring interscapular brown adipose tissue temperature (iBAT-T) and UCP1 expression. We found that 24h iBAT-T was higher in 17NF mice than WT mice and was significantly different when just the dark period (19:00-07:00) was considered (p<0.05). Interestingly, 17NF mice also exhibited cardiac dysfunction similar to what has been reported in chronic hypertensive subjects. Echocardiography revealed left ventricular enlargement (p<0.01),) and left ventricular posterior wall thinning (p<0.01). Moreover, the internal diameter of the right common carotid artery (RCCA) was increased during systole and diastole (p<0.001). Systolic-diastolic changes in the diameter of the RCCA and area of the left ven

Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R-/-) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R-/- (DELTA30+/-4 mm Hg) relative to wild-type (DELTA41+/-5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R-/- mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor-beta expression. BAFF-R-/- mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by =35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies - currently used for autoimmune diseases - may hold promise as future treatments for hypertension.Copyright © 2015 American Heart Association, Inc.