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Mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model.
Fernandez-Chas, M, Curtis, MJ, Niederer, SA
British journal of pharmacology. 2018;(5):763-781
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Abstract
BACKGROUND AND PURPOSE Doxorubicin (DOX) is an effective cancer therapeutic agent but causes therapy-limiting cardiotoxicity. The effects of DOX and its metabolite doxorubicinol (DOXL) on individual channels have been well characterized in isolation. However, it is unknown how the action and interaction of affected channels combine to generate the phenotypic cardiotoxic outcome. We sought to develop an in silico model that links drug effects on channels to action potential duration (APD) and intracellular Ca2+ concentration in order to address this gap in knowledge. EXPERIMENTAL APPROACH We first propose two methods to obtain, from published values, consensus drug effects on the currents of individual channels, transporters and pumps. Separately, we obtained equivalent values for APD and Ca2+ concentration (the readouts used as surrogates for cardiotoxicity). Once derived, the consensus effects on the currents were incorporated into established biophysical models of the cardiac myocyte and were refined adjusting the sarcoplasmic reticulum Ca2+ leak current (ILeak ) until the consensus effects on APD and Ca2+ dynamics were replicated. Using factorial analysis, we then quantified the relative contribution of each channel to DOX and DOXL cardiotoxicity. KEY RESULTS The factorial analysis identified the rapid delayed rectifying K+ current, the L-type Ca2+ current and the sarcoplasmic reticulum ILeak as the targets primarily responsible for the cardiotoxic effects on APD and Ca2+ dynamics. CONCLUSIONS AND IMPLICATIONS This study provides insight into the mechanisms of DOX-induced cardiotoxicity and a framework for the development of future diagnostic and therapeutic strategies.
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Ion Channel Modulators in Cystic Fibrosis.
Gentzsch, M, Mall, MA
Chest. 2018;(2):383-393
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Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains one of the most common life-shortening genetic diseases affecting the lung and other organs. CFTR functions as a cyclic adenosine monophosphate-dependent anion channel that transports chloride and bicarbonate across epithelial surfaces, and disruption of these ion transport processes plays a central role in the pathogenesis of CF. These findings provided the rationale for pharmacologic modulation of ion transport, either by targeting mutant CFTR or alternative ion channels that can compensate for CFTR dysfunction, as a promising therapeutic approach. High-throughput screening has supported the development of CFTR modulator compounds. CFTR correctors are designed to improve defective protein processing, trafficking, and cell surface expression, whereas potentiators increase the activity of mutant CFTR at the cell surface. The approval of the first potentiator ivacaftor for the treatment of patients with specific CFTR mutations and, more recently, the corrector lumacaftor in combination with ivacaftor for patients homozygous for the common F508del mutation, were major breakthroughs on the path to causal therapies for all patients with CF. The present review focuses on recent developments and remaining challenges of CFTR-directed therapies, as well as modulators of other ion channels such as alternative chloride channels and the epithelial sodium channel as additional targets in CF lung disease. We further discuss how patient-derived precision medicine models may aid the translation of emerging next-generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF.
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Associations between common ion channel single nucleotide polymorphisms and sudden cardiac death in adults: A MOOSE-compliant meta-analysis.
Liu, X, Shi, J, Xiao, P
Medicine. 2018;(38):e12428
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Abstract
BACKGROUND We sought to identify common ion channel single nucleotide polymorphisms (SNPs) associated with the occurrence of sudden cardiac death (SCD) to predict the incidence of SCD in clinical settings. METHODS This study involved a systematic review and meta-analysis of ion channel SNPs and risk of SCD in adults. We searched public databases for studies published up to September 19, 2017. We examined relationships between SNPs in common ion channel genes and the incidence of SCD. RESULTS We collected data for 22 trials that included a total of 4149 patients who experienced SCD or had a high risk of SCD and assessed these data in our meta-analysis. An allelic model showed that rs11720524 in SCN5A clearly protected against SCD (odds ratio [OR]: 0.76; 95% confidence interval [95% CI]: 0.67-0.85; P < .001). Subgroup analysis showed that rs11720524 in SCN5A protected against SCD in Europeans and Caucasians but not in Koreans. The allelic model indicated that rs12296050 in KCNQ1 also had significant protective effects against SCD (OR: 0.85; 95% CI: 0.76-0.96; P = .007). Moreover, this model demonstrated that rs2283222 in KCNQ1 had a significant negative relationship with SCD (OR: 0.73; 95% CI: 0.62-0.85; P < .001). Rs12296050 in KCNQ1 protected against SCD in Koreans and Americans. Our results also showed that rs790896 in RYR2 was negatively associated with SCD in a dominant model (OR: 0.66; 95% CI: 0.45-0.97; P = .033). CONCLUSIONS Rs11720524 in SCN5A is negatively related to SCD in Europeans and Caucasians, and rs12296050 and rs2283222 in KCNQ1 and rs790896 in RYR2 clearly have protective effects against SCD.
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Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors.
Sun, WH, Dai, SP
Advances in experimental medicine and biology. 2018;:49-64
Abstract
Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.
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The S-Type Anion Channel ZmSLAC1 Plays Essential Roles in Stomatal Closure by Mediating Nitrate Efflux in Maize.
Qi, GN, Yao, FY, Ren, HM, Sun, SJ, Tan, YQ, Zhang, ZC, Qiu, BS, Wang, YF
Plant & cell physiology. 2018;(3):614-623
Abstract
Diverse stimuli induce stomatal closure by triggering the efflux of osmotic anions, which is mainly mediated by the main anion channel SLAC1 in plants, and the anion permeability and selectivity of SLAC1 channels from several plant species have been reported to be variable. However, the genetic identity as well as the anion permeability and selectivity of the main S-type anion channel ZmSLAC1 in maize are still unknown. In this study, we identified GRMZM2G106921 as the gene encoding ZmSLAC1 in maize, and the maize mutants zmslac1-1 and zmslac1-2 harboring a mutator (Mu) transposon in ZmSLAC1 exhibited strong insensitive phenotypes of stomatal closure in response to diverse stimuli. We further found that ZmSLAC1 functions as a nitrate-selective anion channel without obvious permeability to chloride, sulfate and malate, clearly different from SLAC1 channels of Arabidopsis thaliana, Brassica rapa ssp. chinensis and Solanum lycopersicum L. Further experimental data show that the expression of ZmSLAC1 successfully rescued the stomatal movement phenotypes of the Arabidopsis double mutant atslac1-3atslah3-2 by mainly restoring nitrate-carried anion channel currents of guard cells. Together, these findings demonstrate that ZmSLAC1 is involved in stomatal closure mainly by mediating the efflux of nitrate in maize.
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[Advance in molecular genetic research on generalized epilepsies].
Zhang, K, Jiang, H, Li, N
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2018;(6):908-911
Abstract
Genetic generalized epilepsies (GGEs) are a group of epilepsy syndromes caused by genetic factors. A few of GGEs conform to the Mendelian patterns, while most of them show polygene inheritance. Researchers initially found that most of the genes associated with GGEs are related to ion channels including voltage-gated sodium channels, potassium channels, calcium channels and chloride channels, and ligand-gated gamma-aminobutyric acid receptor channels. Further researches have shown that certain non-ion channel genes are also related to GGEs, and that de novo mutations and copy number variants also play an important role in the pathogenesis of GGEs. Application of next- and third-generation sequencing promoted delineation of the molecular genetics of the GGEs, but also brought more challenges. Genetic findings have provided an important basis for the elucidation of the pathogenesis, clinical diagnosis and precise treatment of GGEs. This paper provided a review for recent progress made in molecular genetics of GGEs.
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[Genetically determined abnormal electrical activity of the brain and the heart].
Mańka-Gaca, I, Łabuz-Roszak, B, Machowska-Majchrzak, A
Wiadomosci lekarskie (Warsaw, Poland : 1960). 2018;(2 pt 2):413-416
Abstract
Mutations leading to disorders within ion (mainly potassium and sodium) channels, have different degrees of expression in the brain and in the heart, which can cause simultaneous occurrence of disorders in both organs. This is manifested by the occurrence of epileptic seizures and cardiac electrical disturbances, further exacerbated by stimulation of autonomic structures within the central nervous system. In all patients with unclear paroxysmal disorders, and in those with unexplained sudden cardiac death, consideration should be given to the possibility of occurrence of genetically determined disorders in the ion channels. This article concerns the most common genetically determined epilepsy syndromes and genetically determined cardiac diseases.
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Arrhythmic hazard map for a 3D whole-ventricle model under multiple ion channel block.
Okada, JI, Yoshinaga, T, Kurokawa, J, Washio, T, Furukawa, T, Sawada, K, Sugiura, S, Hisada, T
British journal of pharmacology. 2018;(17):3435-3452
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Abstract
BACKGROUND AND PURPOSE To date, proposed in silico models for preclinical cardiac safety testing are limited in their predictability and usability. We previously reported a multi-scale heart simulation that accurately predicts arrhythmogenic risk for benchmark drugs. EXPERIMENTAL APPROACH We created a comprehensive hazard map of drug-induced arrhythmia based on the electrocardiogram (ECG) waveforms simulated under wide range of drug effects using the multi-scale heart simulator described here, implemented with cell models of human cardiac electrophysiology. KEY RESULTS A total of 9075 electrocardiograms constitute the five-dimensional hazard map, with coordinates representing the extent of the block of each of the five ionic currents (rapid delayed rectifier potassium current (IKr ), fast (INa ) and late (INa,L ) components of the sodium current, L-type calcium current (ICa,L ) and slow delayed rectifier current (IKs )), involved in arrhythmogenesis. Results of the evaluation of arrhythmogenic risk based on this hazard map agreed well with the risk assessments reported in the literature. ECG databases also suggested that the interval between the J-point and the T-wave peak is a superior index of arrhythmogenicity when compared to the QT interval due to its ability to characterize the multi-channel effects compared with QT interval. CONCLUSION AND IMPLICATIONS Because concentration-dependent effects on electrocardiograms of any drug can be traced on this map based on in vitro current assay data, its arrhythmogenic risk can be evaluated without performing costly and potentially risky human electrophysiological assays. Hence, the map serves as a novel tool for use in pharmaceutical research and development.
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Periodic paralysis.
Fialho, D, Griggs, RC, Matthews, E
Handbook of clinical neurology. 2018;:505-520
Abstract
The periodic paralyses are a group of skeletal muscle channelopathies characterizeed by intermittent attacks of muscle weakness often associated with altered serum potassium levels. The underlying genetic defects include mutations in genes encoding the skeletal muscle calcium channel Cav1.1, sodium channel Nav1.4, and potassium channels Kir2.1, Kir3.4, and possibly Kir2.6. Our increasing knowledge of how mutant channels affect muscle excitability has resulted in better understanding of many clinical phenomena which have been known for decades and sheds light on some of the factors that trigger attacks. Insights into the pathophysiology are also leading to new therapeutic approaches.
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A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome.
Bonfiglio, F, Henström, M, Nag, A, Hadizadeh, F, Zheng, T, Cenit, MC, Tigchelaar, E, Williams, F, Reznichenko, A, Ek, WE, et al
Neurogastroenterology and motility. 2018;(9):e13358
Abstract
BACKGROUND Irritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. METHODS Based on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. KEY RESULTS Suggestive GWAS signals (P ≤ 5.0 × 10-6 ) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P = 3.1 × 10-10 ) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. CONCLUSION & INFERENCES Our results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.