calcium handling

BACKGROUND: In heart failure, signaling downstream the β2-adrenergic receptor is critical. Sympathetic stimulation of β2-adrenergic receptor alters cAMP (cyclic adenosine 3',5'-monophosphate) and triggers PKA (protein kinase A)-dependent phosphorylation of proteins that regulate cardiac function. cAMP levels are regulated in part by PDEs (phosphodiesterases). Several AKAPs (A kinase anchoring proteins) regulate cardiac function and are proposed as targets for precise pharmacology...

Pleckstrin homology domain-containing family M member 2 (PLEKHM2) is an essential adaptor for lysosomal trafficking and its homozygous truncation have been reported to cause early onset dilated cardiomyopathy (DCM). However, the molecular mechanism of PLEKHM2 deficiency in DCM pathogenesis and progression is poorly understood. Here, we generated an in vitro model of PLEKHM2 knockout (KO) induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the potential pathogenic mechanism of PLEKHM2-deficient cardiomyopathy...

Many challenges remain in the preclinical evaluation, adjudication, and prioritization of novel compounds in therapeutic discovery pipelines. These obstacles are evident by the large number of candidate or lead compounds failing to reach clinical trials, significantly due to a lack of efficacy in the disease paradigm of interest and/or the presence of innate chemical toxicity. The consequential compound attrition in discovery pipelines results in added monetary and time costs, potential danger to patients, and a slowed discovery of true therapeutics...

C18ORF25 was recently shown to be phosphorylated at S67 by AMP-activated protein kinase (AMPK) in the skeletal muscle, following acute exercise in humans. Phosphorylation was shown to improve the ex vivo skeletal muscle contractile function in mice, but our understanding of the molecular mechanisms is incomplete. Here, we profiled the interactome of C18ORF25 in mouse myotubes using affinity purification coupled to mass spectrometry. This analysis included an investigation of AMPK-dependent and S67-dependent protein/protein interactions...

Raw liquid anaerobic digestate was synthesised into nutrient-dense solid digestates via acidification and evaporation. Acidification retained ammonium in the digestate whilst also donating the anion to free ammonium to form an ammonium salt. Digestate was treated with the addition of sulphuric, nitric, and phosphoric acid resulting in the formation of ammonium sulphate, ammonium nitrate and ammonium phosphate, respectively then evaporated into a solid fertiliser product. FTIR, XRD and SEM-EDS collectively confirm that the addition of acids completely converted the free ammonium in the raw digestate into their respective ammonium salt counterparts...

Birch reduction and similar dissolved metal-type transformations hold significant importance in the organic synthesis toolbox. Historically, the field has been dominated by alkali metal reductants. In this study, we report that largely neglected, low-reactive alkaline earth metals can become powerful and affordable reductants when used in a ball mill under essentially solvent-free conditions, in the presence of ethylenediamine and THF as liquid additives. Calcium can reduce both electron-deficient and electron-rich arenes, with yields of products similar to those obtained with lithium metal...

INTRODUCTION: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs)...

There is still much uncertainty surrounding the approach to diagnosing and managing a sport-related concussion (SRC). Neurobiological recovery may extend beyond clinical recovery following SRC, highlighting the need for objective physiological parameters to guide diagnosis and management. With an increased understanding of the connection between the heart and the brain, the utility of assessing cardiovascular functioning following SRC has gained attention. As such, this review focuses on the assessment of cardiovascular parameters in the context of SRC...

We previously reported a novel compound called S-nitroso-N-pivaloyl-D-penicillamine (SNPiP), which was screened from a group of nitric oxide (NO) donor compounds with a basic chemical structure of S-nitroso-N-acetylpenicillamine (SNAP), to activate the non-neuronal acetylcholine (NNA) system. SNPiP-treated mice exhibited improved cardiac output and enhanced diastolic function, without an increase in heart rate. The NNA-activating effects included increased resilience to ischemia, modulation of energy metabolism preference, and activation of angiogenesis...

Heart failure (HF) is recognized as an epidemic in the contemporary world, impacting around 1%-2% of the adult population and affecting around 6 million Americans. HF remains a major cause of mortality, morbidity, and poor quality of life. Several therapies are used to treat HF and improve the survival of patients; however, despite these substantial improvements in treating HF, the incidence of HF is increasing rapidly, posing a significant burden to human health. The total cost of care for HF is USD 69.8 billion in 2023, warranting a better understanding of the mechanisms involved in HF...

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females...

BACKGROUND: Germline HRAS gain-of-function pathogenic variants cause Costello syndrome (CS). During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. This study investigated how overactive HRAS activity triggers arrhythmogenesis in atrial-like cardiomyocytes (ACMs) derived from human-induced pluripotent stem cells bearing CS-associated HRAS variants. METHODS: HRAS Gly12 mutations were introduced into a human-induced pluripotent stem cells-ACM reporter line...

Genetically encoded calcium indicators (GECIs) enable imaging techniques to monitor changes in intracellular calcium in targeted cell populations. Their large signal-to-noise ratio makes GECIs a powerful tool for detecting stimulus-evoked activity in sensory neurons. GECIs facilitate population-level analysis of stimulus encoding with the number of neurons that can be studied simultaneously. This population encoding is most appropriately done in vivo. Dorsal root ganglia (DRG), which house the soma of sensory neurons innervating somatic and visceral structures below the neck, are used most extensively for in vivo imaging because these structures are accessed relatively easily...

Caries is one of the most prevalent human diseases, resulting from demineralization of tooth hard tissue caused by acids produced from bacteria, and can progress to pulpal inflammation. Filling restoration with dental resin composites (DRCs) is currently the most common treatment for caries. However, existing DRCs suffer from low fracture strength and lack comprehensive anti-caries bioactivity including remineralization, pulp protection, and anti-cariogenic bacteria effects. In this study, inspired by plant roots' ability to stabilize and improve soil, fluorinated urchin-like hydroxyapatite (FUHA) with a three-dimensional whisker structure and bioactive components of calcium, phosphorus, and fluorine was designed and synthesized by a dynamic self-assembly method...

Oxidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidants in a cell. In the heart, oxidative stress may deteriorate calcium handling, cause arrhythmia, and enhance maladaptive cardiac remodeling by the induction of hypertrophic and apoptotic signaling pathways. Consequently, dysregulated ROS production and oxidative stress have been implicated in numerous cardiac diseases, including heart failure, cardiac ischemia-reperfusion injury, cardiac hypertrophy, and diabetic cardiomyopathy...

A variety of changes in mineral metabolism aiming to restore acid-base balance occur in acid loading and metabolic acidosis. Phosphate plays a key role in defense against metabolic acidosis, both as an intracellular and extracellular buffer, as well as in the renal excretion of excess acid in the form of urinary titratable acid. The skeleton acts as an extracellular buffer in states of metabolic acidosis, as the bone matrix demineralizes, leading to bone apatite dissolution and the release of phosphate, calcium, carbonate, and citrate into the circulation...

Taurine (2-aminoethanesulfonic acid) is a free amino acid found ubiquitously and abundantly in mammalian tissues. Taurine content in the heart is approximately 20 mM, which is approximately 100 times higher than plasma concentration. The high intracellular concentration of taurine is maintained by the taurine transporter (TauT; Slc6a6). Taurine plays various roles, including the regulation of intracellular ion dynamics, calcium handling, and acting as an antioxidant in the heart. Some species, such as cats and foxes, have low taurine biosynthetic capacity, and dietary taurine deficiency can lead to disorders such as dilated cardiomyopathy and blindness...

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for atrial structural remodeling and atrial fibrillation (AF). Calpain activity is hypothesized to promote atrial remodeling and AF. OBJECTIVE: To investigate the role of calpain in diabetes-associated atrial fibrillation, fibrosis, and calcium handling dysfunction. METHODS: DM-associated AF was induced in wildtype mice and in mice overexpressing the calpain inhibitor calpastatin (CAST-OE) using high-fat diet (HFD) feeding followed by low dose streptozotocin injection (STZ, 75 mg/kg)...

Experimental in vivo and in vitro studies showed that electric currents applied during the absolute refractory period can modulate cardiac contractility. In preclinical studies, cardiac contractility modulation (CCM) was found to improve calcium handling, reverse the foetal myocyte gene programming associated with heart failure (HF), and facilitate reverse remodeling. Randomized control trials and observational studies have provided evidence about the safety and efficacy of CCM in patients with HF. Clinically, CCM therapy is indicated to improve the 6-min hall walk, quality of life, and functional status of HF patients who remain symptomatic despite guideline-directed medical treatment without an indication for cardiac resynchronization therapy (CRT) and have a left ventricular ejection fraction (LVEF) ranging from 25 to 45%...

The brain is spatially organized and contains unique cell types, each performing diverse functions and exhibiting differential susceptibility to neurodegeneration. This is exemplified in Parkinson's disease with the preferential loss of dopaminergic neurons of the substantia nigra pars compacta. Using a Parkinson's transgenic model, we conducted a single-cell spatial transcriptomic and dopaminergic neuron translatomic analysis of young and old mouse brains. Through the high resolving capacity of single-cell spatial transcriptomics, we provide a deep characterization of the expression features of dopaminergic neurons and 27 other cell types within their spatial context, identifying markers of healthy and aging cells, spanning Parkinson's relevant pathways...