Endocrine Abstracts

Commercialisation and the development of new technologies may be thought of as the natural conclusion of academic research. Typically this has been the preserve of industry, however, more recently translation has become a key aspect of any scientific research programme. The processes involved in the translation of basic and clinical research will be discussed in the context of an in-house drug discovery programme, highlighting the differences between hypothesis and goal-driven...

Autotaxin (ATX) is a secreted enzyme that generates the lipid signalling molecule LPAs from LPCs. The ATX/lPA axis is strongly linked to fibrotic diseases and therapeutic inhibitors are in development. Assessing the balance of LPC/lPA in diseased target tissues is critical to inform pharmacokinetics/pharmacodynamics (PK-PD) and predict efficacy of ATX inhibitors in vivo. Mass spectrometry imaging (MSI) allows concomitant measurement of multiple molecules with histopat...

The global prevalence of obesity continues to rise, creating a growing need for new effective medicines. Selective targeting of visceral obesity (fat around the internal organs) would be particularly advantageous because it carries a greater risk for cardiometabolic diseases. The ectonucleotide pyrophosphatase (ENPP) enzyme family participates in several pathological conditions including diabetes (ENPP1, and ENPP2, also known as autotaxin) and vascular dysfunction (ENPP3-4). O...

Excess action of glucocorticoid hormones is implicated in metabolic disease and cognitive decline, 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) catalysing generation of active glucocorticoid hormones in tissues. The penetration rates and tissue-specific contribution of 11βHSD1 to glucocorticoid turnover were assessed using tracer kinetics. 9,11,12,12-d4-Cortisol (d4F) was infused (1.75 mg/day, 7 days) into C57Bl6/J male mice and mice lacking 11βHSD1 (n<...

7-Oxysterols modulate lipid transport and promote oxidative stress and apoptosis in the vascular wall. 7-Ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC) are inter-converted by 11β-hydroxysteroid dehydrogenase-1 (11βHSD1), better known for metabolising glucocorticoids. Pharmacological inhibition of 11βHSD1 protects against atherosclerosis and these beneficial effects may be mediated through changes in glucocorticoids or oxysterols. To establish ...

Background: Liver fibrosis in cirrhosis is characterized by accumulation of extracellular matrix from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) limit HSC activation in vitro. Local GC levels are regulated by 11β-hydroxysteroid dehydrogenase-1 (11βHSD1) which converts inactive GCs (11-dehydrocorticosterone) into active GCs (corticosterone). In this study we hypothesized that 11βHSD1 could potentially inhibit liver fibrosis.<p cla...

Glucocorticoids (GCs) protect cardiomyocytes immediately after myocardial infarction (MI), but GCs subsequently regenerated within the heart by 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) are detrimental during infarct repair, with functional outcomes post-MI improved in mice lacking 11βHSD1. Pharmacological 11βHSD1 inhibition (AZD8329 50mg/kg, 11βHSD1i) was compared to standard clinical therapy (SCT) in a translational pig model (female, 11βHSD1...