The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (β 2-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the β 2-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I125-cyanopindolol, a β 2-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a β 2-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the β 2-AR. Oral administration of glucose with a non-bioavailable β 2-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical β 2-ARs in stimulating gut glucose uptake, and suggesting enterocyte β 2-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether β 2-ARs mediate glucose sensing also in other tissues.

In cardiac muscle the action of adrenaline on β1 receptors of heart muscle cells is essential to adjust cardiac output to the body's needs. Adrenergic activation leads to enhanced contractility (inotropy), faster heart rate (chronotropy) and faster relaxation (lusitropy), mainly through activation of protein kinase A (PKA). Efficient enhancement of heart output under stress requires all of these responses to work together. Lusitropy is essential for shortening the heartbeat when heart rate increases. It therefore follows that, if the lusitropic response is not present, heart function under stress will be compromised. Current literature suggests that lusitropy is primarily achieved due to PKA phosphorylation of troponin I (TnI) and phospholamban (PLB). It has been well documented that PKA-induced phosphorylation of TnI releases Ca2+ from troponin C faster and increases the rate of cardiac muscle relaxation, while phosphorylation of PLB increases SERCA activity, speeding up Ca2+ removal from the cytoplasm. In this review we consider the current scientific evidences for the connection between suppression of lusitropy and cardiac dysfunction in the context of mutations in phospholamban and thin filament proteins that are associated with cardiomyopathies. We will discuss what advances have been made into understanding the physiological mechanism of lusitropy due to TnI and PLB phosphorylation and its suppression by mutations and we will evaluate the evidence whether lack of lusitropy is sufficient to cause cardiomyopathy, and under what circumstances, and consider the range of pathologies associated with loss of lusitropy. Finally, we will discuss whether suppressed lusitropy due to mutations in thin filament proteins can be therapeutically restored.

Actinobacteria are a rich source of bioactive molecules, and genome sequencing has shown that the vast majority of their biosynthetic potential has yet to be explored. However, many of their biosynthetic gene clusters (BGCs) are poorly expressed in the laboratory, which prevents discovery of their cognate natural products. To exploit their full biosynthetic potential, better understanding of the signals that promote the expression of BGCs is needed. Here, we show that the human stress hormone epinephrine (adrenaline) elicits siderophore production by Actinobacteria. Catechol was established as the likely eliciting moiety, since similar responses were seen for catechol and for the catechol-containing molecules dopamine and catechin but not for related molecules. Exploration of the catechol-responsive strain Streptomyces sp. MBT84 using mass spectral networking revealed elicitation of a BGC that produces the angucycline glycosides aquayamycin, urdamycinone B and galtamycin C. Heterologous expression of the catechol-cleaving enzymes catechol 1,2-dioxygenase or catechol 2,3-dioxygenase counteracted the eliciting effect of catechol. Thus, our work identifies the ubiquitous catechol moiety as a novel elicitor of the expression of BGCs for specialized metabolites.

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.

Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical imaging technique for measuring relative changes in skeletal muscle microvascular perfusion (i.e., fold-change above baseline) during reactive hyperemia testing and exercise and is reported as a blood flow index (BFI). Although it is generally accepted that changes in BFI are primarily driven by changes in muscle perfusion, it is well-known that large, hyperthermia-induced changes in cutaneous blood flow can uncouple this relationship. What remains unknown, is how much of an impact that changes in cutaneous perfusion have on NIR-DCS BFI and estimates of skeletal muscle perfusion under thermoneutral conditions, where changes in cutaneous blood flow are assumed to be relatively low. We therefore used epinephrine-iontophoresis to pharmacologically block changes in cutaneous perfusion throughout a battery of experimental procedures. The data show that: (1) epinephrine-iontophoresis attenuates changes in cutaneous perfusion for up to 4-hours post-treatment, even in the face of significant neural- and local-stimuli, (2) under thermoneutral conditions, cutaneous perfusion does not significantly impact NIR-DCS BFI during reactive hyperemia testing or moderate-intensity exercise, and (3) during passive whole-body heat stress, when cutaneous vasodilation is pronounced, epinephrine-iontophoresis preserves NIR-DCS measures of skeletal muscle BFI during moderate-intensity exercise. Collectively, these data suggest that cutaneous perfusion is unlikely to have a major impact on NIR-DCS estimates of skeletal muscle BFI under thermoneutral conditions, but that epinephrine-iontophoresis can be used to abolish cutaneous contamination of the NIR-DCS BFI signal during studies where skin blood flow may be elevated but skeletal muscle perfusion is of specific interest.

Nanozymes can imitate the catalytic properties of natural enzymes while overcoming the limitations of natural enzymes such as high cost, poor robustness, and difficulty in recycling. However, rational design and facile preparation of nanozymes are still in demand. Inspired by the chemical structure of laccase, we report an amorphous metal-organic coordination nanocomposite named CuNAD, which is composed of copper ions and nicotinamide adenine dinucleotide (NAD+) via a simple coordinating coassembly process. As a single-site nanozyme, CuNAD exhibits excellent robustness under extreme conditions, significantly stronger catalytic activity for phenolic compounds, and 4.02-fold higher sensitivity for epinephrine detection than laccase. Furthermore, by breaking through the functional constraints of laccase, CuNAD is also able to activate H2O2 at neutral pH, benefiting a one-step chromogenic detection platform for cholesterol. This facile approach demonstrates the potential to develop single-site nanozymes by biomimicking natural enzymes and may boost more insights into the structure-function relationship of nanozymes.

Fatal anaphylaxis to food is thankfully rare, but every death is a potentially avoidable tragedy. Usually, there will be a coronial inquest to establish the 'how and why' for each death. Reviewing these food allergy-related deaths identifies a number of common themes and risk factors. While some are non-modifiable (such as age, gender and ethnicity), others are and include delayed epinephrine administration and communication difficulties in allergen avoidance. This review highlights the key messages in food allergy-related fatality prevention for healthcare professionals and patients alike, and where available, we explain the evidence behind such recommendations. We describe the data behind the good practice points to facilitate their adoption in routine practice without generating additional anxiety for what is a comparatively rare event. We also propose an information leaflet for patients and carers, developed with patients and endorsed by two major allergy charities, to facilitate dissemination of the recommendations in this review.

Catecholamines such as norepinephrine or epinephrine have been reported to participate in the development of acute respiratory distress syndrome (ARDS) by activating adrenergic receptors (ARs). But the role of α1-AR in this process has yet to be elucidated.

Hypoglycemia-associated autonomic failure (HAAF) is a serious, life-threatening complication of intensive insulin therapy, particularly in people with type 1 diabetes. The ketogenic diet is reported to beneficially affect glycemic control in people with type 1 diabetes, however its effects on the neurohormonal counterregulatory response to recurrent hypoglycemia and HAAF development are understudied. In this study we used Sprague Dawley rats to establish a HAAF model under non-diabetic and streptozotocin (STZ)-induced diabetic conditions and determined how nutritional ketosis affected the neurohormonal counterregulation and the activity of energy-sensing orexin (OX) neurons. We found that antecedent hypoglycemia diminished the sympathoexcitatory epinephrine response to subsequent hypoglycemia in chow-fed non-diabetic rats, but this did not occur in STZ-diabetic animals. In all cases a ketogenic diet preserved the epinephrine response. Contrary to expectations, STZ-diabetic keto-fed rats showed reduced OX activity in the recurrent hypoglycemia group, which did not occur in any other group. It is possible that the reduced activation of OX neurons is an adaptation aimed at energy conservation accompanied by diminished arousal and exploratory behaviour. Our data suggests that while a ketogenic diet has beneficial effects on glycemia, and epinephrine response, the reduced activation of OX neurons could be detrimental and warrants further investigation.

Background: The association between adrenal insufficiency (AI) and the treatment outcomes of cardiothoracic surgery patients has been little reported. The aims of this study were to investigate the incidence of AI and to compare the post-surgical outcomes of patients with perioperatively treated AI and patients with a normal adrenal response. Methods: A 1.5-year prospective study was conducted in 98 patients scheduled for cardiothoracic surgery. Patients were categorized as either AI or normal-adrenal-response patients. Those with AI were treated with stress doses of glucocorticoid perioperatively. The post-surgical outcomes of patients with AI and of those with a normal adrenaline response were analyzed using multivariable analysis. Results: The overall incidence of AI was 34.7%. There were no statistically significant differences in post-surgical outcomes, including prolonged hospital stay, postoperative infection, prolonged inotropic drug use and relative AI, between the two groups. Only the rate of hyperglycemia requiring insulin infusion was significantly higher in the AI group than in the non-AI group (OR = 14.15, 95% CI = 1.44-138.60, p = 0.02). Conclusions: The proper diagnosis and management of AI can result in surgical outcomes in AI patients comparable to those of normal-adrenal-response patients. Non-life-threatening hyperglycemia requiring insulin infusion was found only in the AI group.

Current guidelines for treating cardiac arrest recommend administering 1 mg of epinephrine every 3-5 min. However, this interval is based solely on expert opinion. We aimed to investigate the impact of the epinephrine administration interval (EAI) on resuscitation outcomes in adults with cardiac arrest. We systematically reviewed the PubMed, EMBASE, and Scopus databases. We included studies comparing different EAIs in adult cardiac arrest patients with reported neurological outcomes. Pooled estimates were calculated using the IVhet meta-analysis, and the heterogeneities were assessed using Q and I2 statistics. We evaluated the study risk of bias and overall quality using validated bias assessment tools. Three studies were included. All were classified as "good quality" studies. Only two reported the primary outcome. Compared with a recommended EAI of 3-5 min, a favorable neurological outcome was not significantly different in patients with the other frequencies: for <3 min, odds ratio (OR) 1.93 (95% CI: 0.82-4.54); for >5 min, OR 1.01 (95% CI: 0.55-1.87). For survival to hospital discharge, administering epinephrine for less than 3 min was not associated with a good outcome (OR 1.66, 95% CI: 0.89-3.10). Moreover, EAI of >5 min did not pose a benefit (OR 0.87, 95% CI: 0.68-1.11). Our review showed that EAI during CPR was not associated with better hospital outcomes. Further clinical trials are necessary to determine the optimal dosing interval for epinephrine in adults with cardiac arrest.

The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH4) biosynthetic pathway. Physiologically, BH4 plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH4 physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH4 production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH4 biosynthetic pathway using established therapeutic agents.

Catecholamines-dopamine, noradrenaline and adrenaline are important biomarkers of neurotransmitter metabolism, indicating neuroendocrine tumors and neurodegenerative diseases. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical technique with unprecedented multiplexing capabilities. However, not all important analytes exhibit strong SERS signals on stable and robust nanostructured substrates. In this work, we propose a novel indicator system based on the formation of mixed ligand complexes with bispidine-based bis-azole ligands which can serve as pliers to trap Cu(II) ions and stabilize its complexes with catecholamines. Four synthesized ligands with different functional groups: carboxyl, amino, benzyl, and methoxybenzyl, were applied for forming stable complexes to shift maximum absorbance of catecholamines from the ultraviolet region to 570-600 nm. A new absorbance band in the visible range resonates with the local surface plasmon resonance (LSPR) band of metal nanoparticles and most used laser wavelengths. This match allowed use of Molecular Immobilization and Resonant Raman Amplification by Complex-Loaded Enhancers (MIRRACLE) methodology to measure intense Raman signals on a nanostructured silver-based SERS-active substrate. The synthesized plier-like ligands fixed and stabilized catecholamine complexes with Cu(II) on the SERS sensor surface, which facilitated the determination of dopamine in a 3.2 × 10-12-1 × 10-8 M concentration range.

Morphine plays a critical regulatory role in both simple and complex plant species. Dopamine is a critical chemical intermediate in the morphine biosynthetic pathway and may have served as a primordial agonist in developing catecholamine signaling pathways. While dopamine remains the preeminent catecholamine in invertebrate neural systems, epinephrine is the major product of catecholamine synthetic pathways in vertebrate species. Given that the enzymatic steps leading to the generation of morphine are similar to those constraining the evolutionary adaptation of the biosynthesis of catecholamines, we hypothesize that the emergence of these more advanced signaling pathways was based on conservation and selective "retrofitting" of pre-existing enzyme activities. This is consistent with observations that support the recruitment of enzymatically synthesized tetrahydrobiopterin (BH4), which is a cofactor for tyrosine hydroxylase, the enzyme responsible for dopamine production. BH4 is also an electron donor involved in the production of nitric oxide (NO). The links that coordinate BH4-mediated NO and catecholaminergic-mediated processes provide these systems with the capacity to regulate numerous downstream signaling pathways. We hypothesize that the evolution of catecholamine signaling pathways in animal species depends on the acquisition of a mobile lifestyle and motivationally driven feeding, sexual, and self-protective responses.

Recently, cilia defects have been proposed to contribute to scoliosis. Here, we demonstrate that Ccdc57 plays an essential role in straightening the body axis of zebrafish by regulating ciliary beating in the brain ventricle (BV). Zygotic ccdc57 (Zccdc57) mutant zebrafish developes scoliosis without significant changes in their bone density and calcification, and the maternal-zygotic ccdc57 (MZccdc57) mutant embryos display curved bodies since the long-pec stage. The expression of ccdc57 is enriched in ciliated tissues and immunofluorescence analysis reveals colocalization of Ccdc57-HA with acetylated α-tubulin, implicating it in having a role in ciliary function. Further examination reveals that it is the coordinated cilia beating of multiple cilia bundles (MCB) in the Mzccdc57 mutant embryos that is affected at 48 hours post fertilization (hpf), when the compromised cerebrospinal fluid (CSF) flow and curved body axis have already occurred. Either ccdc57 mRNA injection or epinephrine treatment reverses the spinal curvature in MZccdc57 mutant larvae from ventrally curly to straight or even dorsally curly and significantly upregulates urotensin signaling. This study reveals the role of ccdc57 in maintaining coordinated cilia beating of MCB in the BV.

Duodenal varices (DVs) are ectopic gastrointestinal varices (ECVs) associated with portal hypertension (PH). We present the case of an 82-year-old woman who presented with symptomatic anemia secondary to DV hemorrhage diagnosed on oesophagogastroduodenoscopy. This lesion was treated with endoscopic adrenaline injection and clip application. The patient re-presented on multiple occasions with bleeding recurrence localized to the duodenum, which was managed with intramuscular octreotide and oral beta-blockade resulting in sustained remission of bleeding. This case highlights a rare cause of upper gastrointestinal hemorrhage and highlights the value of somatostatin analogues for conservative treatment of DVs.

Cecal mucosal bleeding is an undocumented and rare cause of lower gastrointestinal (GI) bleeding. We present a case of a 73-year-old woman with end-stage renal disease and paroxysmal atrial fibrillation on apixaban who presented with lower gastrointestinal bleed. She was found to have symptomatic, acute chronic anemia requiring multiple packed red blood cell transfusions. Colonoscopy revealed a localized area of active, cecal mucosal bleeding without evidence of Dieulafoy lesion, ulcer, mass, arteriovenous malformation, or diverticula. Hemostasis was achieved with epinephrine injection and the use of bipolar electrocautery. She was later resumed on her therapeutic anticoagulation without recurrence of bleeding. Therapeutic anticoagulation in our patient with ESRD increased her risk for gastrointestinal bleeding. Had this transient, mucosal-limited bleeding not been active during endoscopic evaluation, the etiology of her massive gastrointestinal bleeding would have been missed. This case expands the differential of acute, lower GI bleeding to include cecal mucosal bleeding, which is a rare, intermittent, cause of bleeding that is amenable to endoscopic management.

This study aimed to investigate the association between changes in FABP4 concentration and hormones and metabolites levels during and after acute low- and moderate-intensity aerobic exercise in healthy men. Eleven healthy men (24.4 ± 1.4 years) were administered three trials in random order: 1) low-intensity aerobic exercise trial (LE trial; acute exercise at 40% peak oxygen uptake [Vo2peak] + bed rest), 2) moderate-intensity aerobic exercise trial (ME trial: acute exercise at 60%Vo2peak + bed rest), and 3) bed rest (Con trial). Expired gas and venous blood samples were collected at baseline, and immediately, 30 and 60 min after exercise, and substrate oxidation and hormone, metabolite, and FABP4 concentrations were measured. FABP4 concentration did not increase during aerobic exercise in LE and ME trials (p > 0.05) However, FABP4 concentration significantly increased after the acute aerobic exercise in both the LE and ME trials (p ≤ 0.003). Increased FABP4 concentration after acute exercise was not correlated with adrenaline, noradrenaline, other hormone, and metabolite concentration changes. These findings suggest that FABP4 concentration increases after acute aerobic exercise independently of exercise intensity. Furthermore, increased FABP4 concentration after acute aerobic exercise may not be involved in the magnitude of adrenaline, noradrenaline, and lipolytic response.