Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which ...catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.
Since the discovery of glucocorticoids in the 1940s and the recognition of their anti-inflammatory effects, they have been amongst the most widely used and effective treatments to control ...inflammatory and autoimmune diseases. However, their clinical efficacy is compromised by the metabolic effects of long-term treatment, which include osteoporosis, hypertension, dyslipidaemia and insulin resistance/type 2 diabetes mellitus. In recent years, a great deal of effort has been invested in identifying compounds that separate the beneficial anti-inflammatory effects from the adverse metabolic effects of glucocorticoids, with limited effect. It is clear that for these efforts to be effective, a greater understanding is required of the mechanisms by which glucocorticoids exert their anti-inflammatory and immunosuppressive actions. Recent research is shedding new light on some of these mechanisms and has produced some surprising new findings. Some of these recent developments are reviewed here.
The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) and to the widely consumed ...plant phytocannabinoid Δ
-tetrahydrocannabinol (THC). The cannabinoid receptors have been the targets of intensive drug discovery efforts, because modulation of these receptors has therapeutic potential to control pain, epilepsy, obesity, and other disorders. Although much progress in understanding the biophysical properties of GPCRs has recently been made, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. Here we report the use of GPCR engineering and lipidic cubic phase crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6-Å resolution. We found that the extracellular surface of CB1, including the highly conserved membrane-proximal N-terminal region, is distinct from those of other lipid-activated GPCRs, forming a critical part of the ligand-binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function and will aid the design and optimization of therapeutic modulators of the endocannabinoid system.
Coronavirus disease (COVID-19) is caused by a new strain of coronavirus, the severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2. At the time of writing, SARS-CoV-2 has infected over 5 ...million people worldwide. A key step in understanding the pathobiology of the SARS-CoV-2 was the identification of -converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 to gain entry into host cells. ACE2 is an established component of the ‘protective arm’ of the renin-angiotensin-aldosterone-system (RAAS) that opposes ACE/angiotensin II (ANG II) pressor and tissue remodelling actions. Identification of ACE2 as the entry point for SARS-CoV-2 into cells quickly focused attention on the use of ACE inhibitors (ACEi), angiotensin receptor blockers (ARB) and mineralocorticoid receptor antagonists (MRA) in patients with hypertension and cardiovascular disease given that these pharmacological agents upregulate ACE2 expression in target cells. ACE2 is cleaved from the cells by metalloproteases ADAM10 and ADAM17. Steroid hormone receptors regulate multiple components of the RAAS and may contribute to the observed variation in the incidence of severe COVID-19 between men and women, and in patients with pre-existing endocrine-related disease. Moreover, glucocorticoids play a critical role in the acute and chronic management of inflammatory disease, independent of any effect on RAAS activity. Dexamethasone, a synthetic glucocorticoid, has emerged as a life-saving treatment in severe COVID-19. This review will examine the endocrine mechanisms that control ACE2 and discusses the impact of therapies targeting the RAAS, glucocorticoid and other endocrine systems for their relevance to the impact of SARS-CoV-2 infection and the treatment and recovery from COVID-19-related critical illness.
This article focuses on therapeutic filmmaking and how it is used by analyzing selected works of Agnès Varda and Sophie Calle. I assert that these artists used this approach to assist them with ...processing grief after the deaths of their loved one by analyzing selected works from the genres of documentary, journal intime, and visual art. An overview of palliative care and palliative arts, and their relationship with therapeutic filmmaking is also included in this article.
Organisms with targeted genomic modifications are efficiently produced by gene editing in embryos using CRISPR/Cas9 RNA-guided DNA endonuclease. Here, to facilitate germline editing in rats, we used ...CRISPR/Cas9 to catalyze targeted genomic mutations in rat spermatogonial stem cell cultures. CRISPR/Cas9-modified spermatogonia regenerated spermatogenesis and displayed long-term sperm-forming potential following transplantation into rat testes. Targeted germline mutations in Epsti1 and Erbb3 were vertically transmitted from recipients to exclusively generate “pure,” non-mosaic mutant progeny. Epsti1 mutant rats were produced with or without genetic selection of donor spermatogonia. Monoclonal enrichment of Erbb3 null germlines unmasked recessive spermatogenesis defects in culture that were buffered in recipients, yielding mutant progeny isogenic at targeted alleles. Thus, spermatogonial gene editing with CRISPR/Cas9 provided a platform for generating targeted germline mutations in rats and for studying spermatogenesis.
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•CRISPR/Cas9 targets heritable germline modifications in donor spermatogonia•Direct germline editing eliminates CRISPR/Cas9-catalyzed animal mosaicism•In vitro and in vivo recessive genetic screens for spermatogenesis
Chapman et al. now use CRISPR/Cas9 to target heritable mutations within spermatogonia, fully functional rat germline stem cells. Clonally enriched target alleles were vertically transmitted from donor spermatogonia to rat progeny. Direct germline editing in spermatogonia prevented CRISPR/Cas9-catalyzed animal mosaicism by avoiding totipotent and pluripotent states of embryogenesis.
Glucocorticoids are essential in mammals to mature fetal organs and tissues in order to survive after birth. Hence, antenatal glucocorticoid treatment (termed antenatal corticosteroid therapy) can be ...life-saving in preterm babies and is commonly used in women at risk of preterm birth. While the effects of glucocorticoids on lung maturation have been well described, the effects on the fetal heart remain less clear. Experiments in mice have shown that endogenous glucocorticoid action is required to mature the fetal heart. However, whether the potent synthetic glucocorticoids used in antenatal corticosteroid therapy have similar maturational effects on the fetal heart is less clear. Moreover, antenatal corticosteroid therapy may increase the risk of cardiovascular disease in adulthood. Here, we present a narrative review of the evidence relating to the effects of antenatal glucocorticoid action on the fetal heart and discuss the implications for antenatal corticosteroid therapy.
► Glucocorticoids (GCs) are anti-inflammatory, but result in adverse side effects. ► Anti-inflammatory actions thought to be independent of GC receptor dimerisation. ► However, receptor dimerisation ...crucial to some anti-inflammatory actions. ► Here we explore the role of GC receptor dimerisation and its consequences.
For a number of years, there has been a widespread view that the adverse side-effects of prolonged glucocorticoid (GC) treatment are a result of glucocorticoid receptor (GR)-mediated gene activation, whilst the beneficial anti-inflammatory effects result from GR-mediated ‘transrepression’. Since the introduction of the dimerisation-deficient GR mutant, GRdim, was apparently unable to activate gene transcription, yet still able to repress pro-inflammatory gene transcription, the search for novel GR modulators has centred on the separation of gene activation from repression by prevention of GR dimerisation. However, recent work has questioned the conclusions drawn from these early GRdim studies, with evidence that GRdim mutants not only activate gene transcription, but that, in direct contradiction to the initial GRdim work, are also capable of forming dimers. This review of the current literature highlights the versatility of the GR in forming homodimer interactions, as well as the ability to bind to alternate nuclear receptors, and investigates the potential implications such varying GR dimer conformations may have for the design of GR ligands with a safer side effect profile.
ABSTRACT
BACKGROUND
Improving children's fruit and vegetable (FV) preferences may be important as preferences can predict FV consumption. The purpose of this study was to evaluate FV preferences over ...time, with repeated experience, as part of the Fresh Fruit and Vegetable Program (FFVP).
METHODS
Fruits (F; N = 28) and vegetables (V; N = 29) were distributed twice a week, over 35 weeks, at a participating FFVP school (N = 236 students, 12 teachers, K‐2nd grade). Preference ratings using 3‐point Likert scale were analyzed over 35 weeks.
RESULTS
For 57 FVs rated for preference, ratings revealed that F had higher frequency of children choosing “I like it” than for V (78% F; 38.2% V; p < .05) and liking distribution was different between F and V (p < .001). Significant relations were found between liking and: (1) grade (r = −0.02, p = .02), and (2) time (r = −0.09, p < .001). Models indicated that V served (β = −0.40), timepoint (β = −0.07), and grade level (β = −0.02) accounted for significant variance for preference ratings (R2 = 0.17, p < .001), indicating that preference ratings declined over time.
CONCLUSIONS
Fruits were preferred over vegetables. Overall preference ratings were negatively impacted by time, grade level, and vegetables served. Being exposed one time to a variety of FVs did not improve ratings for vegetables.
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