Pharmacist-initiated naloxone discharge prescribing for high-risk hospitalized internal medicine patients.

Pharmacists nationwide may play a critical role in expanding naloxone access after several states enacted legislation to allow pharmacist prescribing of opioid antagonists. This created a unique opportunity for inpatient pharmacists to participate in combating the opioid epidemic by prescribing naloxone at hospital discharge. A multifaceted intervention was developed to identify and educate hospitalized patients eligible for naloxone prescribing.

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.

GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1-indole as a high affinity and highly selective competitive antagonist of human GPR84.

AMP-activated protein kinase complexes containing the β2 regulatory subunit are up-regulated during and contribute to adipogenesis.

AMP-activated protein kinase (AMPK) is a heterotrimer of α-catalytic and β- and γ-regulatory subunits that acts to regulate cellular and whole-body nutrient metabolism. The key role of AMPK in sensing energy status has led to significant interest in AMPK as a therapeutic target for dysfunctional metabolism in type 2 diabetes, insulin resistance and obesity. Despite the actions of AMPK in the liver and skeletal muscle being extensively studied, the role of AMPK in adipose tissue and adipocytes remains less well characterised.

On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.

Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists.

A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase.

Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies have largely used indirect activators of AMPK. The effects of the allosteric AMPK activator A769662 on insulin signalling and endothelial function was therefore examined in cultured human macrovascular ECs.

Triage and Treatment of Mass Casualty Decompression Sickness After Depressurization at 6400 m.

Decompression sickness is a condition that results from an abrupt change from a higher to a lower pressure. It is described most commonly in divers; however, it can occur in aviation incidents, which this case report will discuss. Following an acute cabin depressurization incident, 36 patients presented to a small outpatient clinic with multiple symptoms, including fatigue, headache, nausea, vomiting, and dizziness.

Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms.

Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect cardiovascular tissues, however, remains unclear. We have previously reported that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase (AMPK) in immortalised cell lines and murine hepatocytes.

Investigating the Role of AMPK in Inflammation.

In addition to the well-characterized role of AMPK in the regulation of nutrient metabolism, it is increasingly clear that AMPK activation has multiple actions on inflammatory signalling. Here we describe methods to identify effects of AMPK activity on pro-inflammatory signalling, specifically (1) the nuclear localization of the key inflammatory mediators nuclear factor-κB (NFκB) and phosphorylated c-Jun N-terminal kinase (JNK), (2) preparation of conditioned medium to analyze the secretion of cytokines/chemokines, and (3) the pro-inflammatory adhesion of leukocytes to cultured cells.

Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling.

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in various cells.

Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation.

Inflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the mechanisms underlying this remain poorly characterised. The effect of AMPK activation on cytokine-stimulated proinflammatory signalling was therefore assessed in cultured adipocytes.

Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487.

The key metabolic regulator, AMP-activated protein kinase (AMPK), is reported to be down-regulated in metabolic disorders, but the mechanisms are poorly characterised. Recent studies have identified phosphorylation of the AMPKα1/α2 catalytic subunit isoforms at Ser487/491, respectively, as an inhibitory regulation mechanism. Vascular endothelial growth factor (VEGF) stimulates AMPK and protein kinase B (Akt) in cultured human endothelial cells.

The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels.

Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin.

Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation.

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance.