Day: December 6, 2022

Goldfracht, Idit published the artcileGenerating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes, Quality Control of 21829-25-4, the main research area is pluripotent stem cell cardiomyocyte heart tissue engineering ventricle atria.

The functions of the heart are achieved through coordination of different cardiac cell subtypes (e.g., ventricular, atrial, conduction-tissue cardiomyocytes). Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer unique opportunities for cardiac research. Traditional studies using these cells focused on single-cells and utilized mixed cell populations. Our goal was to develop clin.-relevant engineered heart tissues (EHTs) comprised of chamber-specific hPSC-CMs. Here we show that such EHTs can be generated by directing hPSCs to differentiate into ventricular or atrial cardiomyocytes, and then embedding these cardiomyocytes in a collagen-hydrogel to create chamber-specific, ring-shaped, EHTs. The chamber-specific EHTs display distinct atrial vs. ventricular phenotypes as revealed by immunostaining, gene-expression, optical assessment of action-potentials and conduction velocity, pharmacol., and mech. force measurements. We also establish an atrial EHT-based arrhythmia model and confirm its usefulness by applying relevant pharmacol. interventions. Thus, our chamber-specific EHT models can be used for cardiac disease modeling, pathophysiol. studies and drug testing.

Nature Communications published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Quality Control of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Pfeiffer-Kaushik, Emily R. published the artcileElectrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms, Quality Control of 21829-25-4, the main research area is arrhythmia cardiomyocyte nifedipine mexiletine voltage sensitive optical sensor; Action potential; Cardiac electrophysiology; Comprehensive in vitro proarrhythmia assay (CiPA); ICH S7B; Methods; Safety pharmacology; Stem cell-derived cardiomyocyte; Torsades de pointes (TdP) arrhythmia; Voltage-sensitive optical sensors; hERG.

Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclin. cardiac electrophysiol. assays. Three com. and one academic laboratory completed a limited study of the effects of 8 blinded compounds on the electrophysiol. of 2 com. lines of human induced pluripotent stem-cell derived cardiomyocytes (hSC-CMs). Acquisition technologies included CMOS camera and photometry; fluorescent voltage sensors included di-4-ANEPPS, FluoVolt and genetically encoded QuasAr2. The exptl. protocol was standardized with respect to cell lines, plating and maintenance media, blinded compounds, and action potential parameters measured. Serum-free media was used to study the action of drugs, but the exact composition and the protocols for cell preparation and drug additions varied among sites. Baseline AP waveforms differed across platforms and between cell types. Despite these differences, the relative responses to four selective ion channel blockers (E-4031, nifedipine, mexiletine, and JNJ 303 blocking IKr, ICaL, INa, and IKs, resp.) were similar across all platforms and cell lines although the absolute changes differed. Similarly, four mixed ion channel blockers (flecainide, moxifloxacin, quinidine, and ranolazine) had comparable effects in all platforms. Differences in repolarization time course and response to drugs could be attributed to cell type and exptl. method differences such as composition of the assay media, stimulated vs. spontaneous activity, and single vs. cumulative compound addition In conclusion, VSOs represent a powerful and appropriate method to assess the electrophysiol. effects of drugs on iPSC-CMs for the evaluation of proarrhythmic risk. Protocol considerations and recommendations are provided toward standardizing conditions to reduce variability of baseline AP waveform characteristics and drug responses.

Journal of Pharmacological and Toxicological Methods published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Quality Control of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Zeng, Haoyu published the artcileResolving the reversed rate effect of calcium channel blockers on human-induced pluripotent stem cell-derived cardiomyocytes and the impact on in vitro cardiac safety evaluation, Synthetic Route of 21829-25-4, the main research area is calcium channel blocker pluripotent stem cell cardiomyocyte heart safety.

Calcium channel blockers (CCBs), such as diltiazem, nifedipine, and verapamil, cause tachycardia effects on several com. available human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), when tested in culture media provided by suppliers, rather than bradycardia effects, as seen in vivo. We found that in test conditions where Na+ current of hiPSC-CMs was reduced to certain threshold by either specific Na+ channel blocker tetrodotoxin (TTX), or by voltage-dependent inactivation using elevated extracellular potassium concentrations, CCBs produced bradycardia effects on hiPSC-CMs. However, elevated extracellular potassium concentrations or the presence of TTX did not change other pharmacol. responses of hiPSC-CMs, including CCBs’ effects on contraction intensity and duration; beating rate change by calcium channel opener FPL64176, HCN blocker ivabradine, and β-adrenergic agonist isoproterenol; and action potential duration prolongation by hERG channel blocker dofetilide. We concluded that action potentials of hiPSC-CMs, with regards to the CCB phenotype, were Na+ current driven. When Na+ channel availability was reduced to a critical level, their action potentials became Ca2+ current driven, and their responses to CCBs correlated well to those seen in vivo. Importantly, the corrected bradycardia effect of calcium channel block with our defined conditions will provide more reliable results in cardiac safety readouts of test compounds that integrate multiple effects including calcium channel inhibition.

Toxicological Sciences published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Synthetic Route of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Jaeger, Karoline Horgmo published the artcileImproved computational identification of drug response using optical measurements of human stem cell derived cardiomyocytes in microphysiological systems, Product Details of C17H18N2O6, the main research area is microphysiol system human stem cell optical measurement; cardiac action potential model; cardiac ion channel blockade; computational identification of drug response; computational inversion; computational maturation; human induced pluripotent stem cell derived cardiomyocytes; voltage sensitive dye.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells’ electrophysiol. properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodol. to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca2+ transients made in stem cell derived cardiac microtissues. This methodol. quantifies ion channel changes through the inversion of data into a math. model, and maps this response to an adult phenotype through the assumption of functional invariance of fundamental intracellular and membrane channels during maturation. Here, we utilize an updated action potential model to represent both hiPSC-CMs and adult cardiomyocytes, apply an IC50-based model of dose-dependent drug effects, and introduce a continuation-based optimization algorithm for anal. of dose escalation measurements using five drugs with known effects. The improved methodol. can identify drug induced changes more efficiently, and quantitate important metrics such as IC50 in line with published values. Consequently, the updated methodol. is a step towards employing computational procedures to elucidate drug effects in adult cardiomyocytes for new drugs using stem cell-derived exptl. tissues.

Frontiers in Pharmacology published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Product Details of C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Jiang, Lin published the artcileCRISPR activation of endogenous genes reprograms fibroblasts into cardiovascular progenitor cells for myocardial infarction therapy, Formula: C17H18N2O6, the main research area is CRISPR fibroblast cardiovascular progenitor cell myocardial infarction therapy; CRISPR; cardiovascular progenitor cells; cell reprogramming; heart regeneration; myocardial infarction.

Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic anal. showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a pos. feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.

Molecular Therapy published new progress about Action potential. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Yamada, Makiko published the artcileCritical impact of drug-drug interactions via intestinal CYP3A in the risk assessment of weak perpetrators using physiologically based pharmacokinetic models, Formula: C18H19Cl2NO4, the main research area is drug interaction intestinal CYP3A physiol pharmacokinetic model.

A great deal of effort has been being made to improve the accuracy of the prediction of drug-drug interactions (DDIs). In this study, we addressed CYP3A-mediated weak DDIs, in which a relatively high false prediction rate was pointed out. We selected 17 orally administered drugs that have been reported to alter area under the curve (AUC) of midazolam, a typical CYP3A substrate, 0.84-1.47 times. For weak CYP3A perpetrators, the predicted AUC ratio mainly depends on intestinal DDIs rather than hepatic DDIs because the drug concentration in the enterocytes is higher. Thus, DDI prediction using simulated concentration-time profiles in each segment of the digestive tract was made by physiol. based pharmacokinetic (PBPK) modeling software GastroPlus. Although mechanistic static models tend to overestimate the risk to ensure the safety of patients, some underestimation is reported about PBPK modeling. Our in vitro studies revealed that 16 out of 17 tested drugs exhibited time-dependent inhibition (TDI) of CYP3A, and the subsequent DDI simulation that ignored these TDIs provided false-neg. results. This is considered to be the cause of past underestimation. Inclusion of the DDI parameters of all the known DDI mechanisms, reversible inhibition, TDI, and induction, which have opposite effects on midazolam AUC, to PBPK model was successful in improving predictability of the DDI without increasing false-neg. prediction as trade-off. This comprehensive model-based anal. suggests the importance of the intestine in assessing weak DDIs via CYP3A and the usefulness of PBPK in predicting intestinal DDIs. Although drug-drug interaction (DDI) prediction has been extensively performed previously, the accuracy of prediction for weak interactions via CYP3A has not been thoroughly investigated. In this study, we simulate DDIs considering drug concentration-time profile in the enterocytes and discuss the importance and the predictability of intestinal DDIs about weak CYP3A perpetrators.

Drug Metabolism & Disposition published new progress about Drug interactions. 72509-76-3 belongs to class pyridine-derivatives, name is 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C18H19Cl2NO4, Formula: C18H19Cl2NO4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Chen, Xin published the artcileGCN-BMP: Investigating graph representation learning for DDI prediction task, Formula: C17H18N2O6, the main research area is GCN BMP graph convolutional network; DDI; Graph representation learning; Interpretability; Robustness; Scalability.

One drug’s pharmacol. activity may be changed unexpectedly, owing to the concurrent administration of another drug. It is likely to cause unexpected drug-drug interactions (DDIs). Several machine learning approaches have been proposed to predict the occurrence of DDIs. However, existing approaches are almost dependent heavily on various drug-related features, which may incur noisy inductive bias. To alleviate this problem, we investigate the utilization of the end-to-end graph representation learning for the DDI prediction task. We establish a novel DDI prediction method named GCN-BMP (Graph Convolutional Network with Bond-aware Message Propagation) to conduct an accurate prediction for DDIs. Our experiments on two real-world datasets demonstrate that GCN-BMP can achieve higher performance compared to various baseline approaches. Moreover, in the light of the self-contained attention mechanism in our GCN-BMP, we could find the most vital local atoms that conform to domain knowledge with certain interpretability.

Methods (Amsterdam, Netherlands) published new progress about Drug interactions. 21829-25-4 belongs to class pyridine-derivatives, name is Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and the molecular formula is C17H18N2O6, Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Armaghan, Mahsa published the artcileIsolation of first row transition metal-carboxylate zwitterions, Synthetic Route of 24484-93-3, the main research area is first row transition metal carboxylate zwitterion hydroxymethylpyridylbenzoate preparation; crystal structure first row transition metal carboxylate zwitterion hydroxymethylpyridylbenzoate.

Zwitterionic 3d metal carboxylates of Zn(II), Cu(II), Ni(II) and Co(II) were isolated and structurally authenticated by x-ray crystallog. 2-Hydroxymethylpyridine-carboxylate ligands with different sizes and shapes demonstrate variable coordination modes with first row transition metals under different conditions, yielding a class of 17 complexes, predominantly zwitterions. The nature of the ligands permits the carboxylates to be uncoordinated, anionic and conjugated, thereby balancing the pos. charges on the metal centers.

RSC Advances published new progress about Crystal structure. 24484-93-3 belongs to class pyridine-derivatives, name is Methyl 4-chloropicolinate, and the molecular formula is C7H6ClNO2, Synthetic Route of 24484-93-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Norman, Mark H. published the artcileStructural elucidation of an oxazolo[5,4-b]pyridine: an alternative cyclization product related to nevirapine, Recommanded Product: 2-Chloro-4-methylpyridin-3-amine, the main research area is mol structure oxazolopyridine; nevirapine derivative; pyridooxazole structure; crystal structure oxazolopyridine.

An unexpected cyclization product was isolated in the final step of the synthesis of nevirapine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. Based on IR spectrometry, mass spectrometry, and a number of two-dimensional NMR experiments, the structure of this product was assigned to be 2-((2-cyclopropylamino)-3-pyridyl)-7-methyloxazolo[5,4-b]pyridine. Results of a single crystal X-ray anal. confirmed this structural assignment. This product arises from cyclization of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamine)-3-pyridinecarboxamide, 8, by displacement of the chlorine with the amide carbonyl oxygen. A competitive reaction occurs when 8 is deprotonated prior to cyclization to form nevirapine, 11-cyclopropyl-5,11-dihydro-4-methyl-6H- dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one.

Journal of Heterocyclic Chemistry published new progress about Crystal structure. 133627-45-9 belongs to class pyridine-derivatives, name is 2-Chloro-4-methylpyridin-3-amine, and the molecular formula is C6H7ClN2, Recommanded Product: 2-Chloro-4-methylpyridin-3-amine.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Gardner, Evan J. published the artcileTris(pyrazolyl)borate Copper Hydroxide Complexes Featuring Tunable Intramolecular H-Bonding, Application In Synthesis of 24484-93-3, the main research area is crystal structure copper pyrazolylborate pendant heterocycle arm; copper pyridyl pyrimidyl pyrazolylborate preparation intramol hydrogen bonding.

A modular synthesis provides access to new tris(pyrazolyl)borate ligands XpyMeTpK that possess a single functionalized pendant pyridyl (py) or pyrimidyl (pyd) arm designed to engage in tunable intramol. H-bonding to metal-bound functionalities. To illustrate such H-bonding interactions, [XpyMeTpCu]2(μ-OH)2 (6a-6e) complexes were synthesized from the corresponding XpyMeTpCu-OAc (5a-5e) complexes. Single crystal x-ray structures of three new dinuclear [XpyMeTpCu]2(μ-OH)2 complexes reveal H-bonding between the pendant heterocycle and bridging hydroxide ligands while the donor arm engages the Cu center in an unusual monomeric DMAPMeTpCu-OH complex. Vibrational studies (IR) of each bridging hydroxide complex reveal reduced νOH frequencies that tracks with the H-bond accepting ability of the pendant arm. Reversible protonation studies that interconvert [XpyMeTpCu]2(μ-OH)2 and [XpyMeTpCu(OH2)]OTf species indicate that the acidity of the corresponding aquo ligand decreases with increasing H-bond accepting ability of the pendant arm.

Inorganic Chemistry published new progress about Crystal structure. 24484-93-3 belongs to class pyridine-derivatives, name is Methyl 4-chloropicolinate, and the molecular formula is C7H6ClNO2, Application In Synthesis of 24484-93-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem