Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.

The identification of clinical candidate LY3522348 (compound ) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient ()-2-(2-methylazetidin-1-yl)-6-(1-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile ().

Effect of captopril on post-infarction remodelling visualized by light sheet microscopy and echocardiography.

Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI). The mechanisms of captopril action remain inadequately understood due to its diverse effects on multiple signalling pathways at different time periods following MI. Here we aimed to establish the role of captopril in late-stage post-MI remodelling.

Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants.

Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination.

Vitamin D receptor activation reduces VCaP xenograft tumor growth and counteracts ERG activity despite induction of TMPRSS2:ERG.

Whether vitamin D is chemopreventive and/or has potential therapeutically in prostate cancer is unresolved. One confounding factor is that many prostate cancers express a TMPRSS2:ERG fusion gene whose expression is increased both by androgens and by vitamin D receptor (VDR) activation. Two challenges that limit VDR agonist use clinically are hypercalcemia and the cooperation of VDR with ERG to hyper-induce the 1α,25-dihydroxyvitamin D3 metabolizing enzyme, CYP24A1, thus reducing VDR activity.

Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration.

The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.

Fiber type-specific differences in glucose uptake by single fibers from skeletal muscles of 9- and 25-month-old rats.

The primary purpose of this study was to assess the feasibility of applying a novel approach to measure myosin heavy chain (MHC) isoform expression, glucose uptake, fiber volume, and protein abundance in single muscle fibers of adult (9 months) and old (25 months) rats. Epitrochlearis muscle fibers were successfully isolated and analyzed for MHC isoform expression, glucose uptake, fiber volume, and protein (COXIV, APPL1, IκB-β) abundance. Insulin-stimulated glucose uptake by single fibers did not differ between age groups, but there was a significant difference between fiber types (IIA > IIX > IIB/X ≈ IIB).

A novel method to measure glucose uptake and myosin heavy chain isoform expression of single fibers from rat skeletal muscle.

Skeletal muscle includes many individual fibers with diverse phenotypes. A barrier to understanding muscle glucose uptake at the cellular level has been the absence of a method to measure glucose uptake by single fibers from mammalian skeletal muscle. This study's primary objective was to develop a procedure to measure glucose uptake by single fibers from rat skeletal muscle.

Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not.

Skeletal muscle is a heterogeneous tissue. To further elucidate this heterogeneity, we probed relationships between myosin heavy chain (MHC) isoform composition and abundance of GLUT4 and four other proteins that are established or putative GLUT4 regulators [Akt substrate of 160 kDa (AS160), Tre-2/Bub2/Cdc 16-domain member 1 (TBC1D1), Tethering protein containing an UBX-domain for GLUT4 (TUG), and RuvB-like protein two (RUVBL2)] in 12 skeletal muscles or muscle regions from Wistar rats [adductor longus, extensor digitorum longus, epitrochlearis, gastrocnemius (mixed, red, and white), plantaris, soleus, tibialis anterior (red and white), tensor fasciae latae, and white vastus lateralis]. Key results were 1) significant differences found among the muscles (range of muscle expression values) for GLUT4 (2.

Insulin resistance for glucose uptake and Akt2 phosphorylation in the soleus, but not epitrochlearis, muscles of old vs. adult rats.

The slow-twitch soleus, but not fast-twitch muscle, of old vs. adult rats has previously been demonstrated to become insulin resistant for in vivo glucose uptake. We probed cellular mechanisms for the age effect by assessing whether insulin resistance for glucose uptake was an intrinsic characteristic of the muscle ex vivo and by analyzing key insulin signaling steps.

Response of bone subjected to optimized high dose irradiation.

Allograft tissues are used in over one million musculoskeletal procedures per year. Consequently, it is crucial tissue banks use procedures to militate against allograft associated bacterial and viral infections. Recent studies have identified an important pathogen inactivation technology for musculoskeletal allografts that utilizes high-dose gamma irradiation (50 kGy) under controlled conditions.