Day: November 30, 2022

Ramirez-Sagredo, Andrea published the artcilePolycystin-1 regulates cardiomyocyte mitophagy, HPLC of Formula: 21829-25-4, the main research area is mitochondrial dysfunction cardiomyocyte mitophagy Polycystin1 Hsp70 NDUFB8 FoxO1; FoxO1; cardiomyocyte; mitochondrial dynamics; mitochondrial metabolism; mitophagy; polycystin-1.

Polycystin-1 (PC1) is a transmembrane protein found in different cell types, including cardiomyocytes. Alterations in PC1 expression have been linked to mitochondrial damage in renal tubule cells and in patients with autosomal dominant polycystic kidney disease. However, to date, the regulatory role of PC1 in cardiomyocyte mitochondria is not well understood. The anal. of mitochondrial morphol. from cardiomyocytes of heterozygous PC1 mice (PDK1+/-) using transmission electron microscopy showed that cardiomyocyte mitochondria were smaller with increased mitochondria d. and circularity. These parameters were consistent with mitochondrial fission. We knocked-down PC1 in cultured rat cardiomyocytes and human-induced pluripotent stem cells (iPSC)-derived cardiomyocytes to evaluate mitochondrial function and morphol. The results showed that downregulation of PC1 expression results in reduced protein levels of sub-units of the OXPHOS complexes and less functional mitochondria (reduction of mitochondrial membrane potential, mitochondrial respiration, and ATP production). This mitochondrial dysfunction activates the elimination of defective mitochondria by mitophagy, assessed by an increase of autophagosome adapter protein LC3B and the recruitment of the Parkin protein to the mitochondria. siRNA-mediated PC1 knockdown leads to a loss of the connectivity of the mitochondrial network and a greater number of mitochondria per cell, but of smaller sizes, which characterizes mitochondrial fission. PC1 silencing also deregulates the AKT-FoxO1 signaling pathway, which is involved in the regulation of mitochondrial metabolism, mitochondrial morphol., and processes that are part of cell quality control, such as mitophagy. Together, these data provide new insights about the controls that PC1 exerts on mitochondrial morphol. and function in cultured cardiomyocytes dependent on the AKT-FoxO1 signaling pathway.

FASEB Journal published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (MTCO1). 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, HPLC of Formula: 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Li, Congwei published the artcileSpectroscopic methodology and molecular docking studies on changes in binding interaction of felodipine with bovine serum albumin induced by cocrystallization with β-resorcylic acid, Safety of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is felodipine bovine serum albumin beta resorcylic acid mol docking; binding interaction; bovine serum albumin; cocrystal; felodipine; molecular docking; β-resorcylic acid.

In the present study, a novel cocrystal of felodipine (FEL) and β-resorcylic acid (βRA) was developed. We specially focused on the change of binding pattern with bovine serum albumin (BSA) induced by cocrystn. of FEL with βRA. The solid characterizations and d. functional theory (DFT) simulation verified that FEL-βRA cocrystal formed in equimolar ratio (1 : 1 M ratio) through C=O···H-O hydrogen bond between C=O group in FEL and O-H group in βRA. The binding interactions between FEL-βRA system and BSA were studied using fluorescence spectral and mol. docking methods. Two guest mol. systems, including a phys. mixture of FEL and βRA and FEL-βRA cocrystal were performed binding to BSA in mol. docking. Mol. docking simulation suggested that FEL and its cocrystal inserted into the subdomain IIIA (site II’) of BSA. The interactions between FEL and BSA including hydrogen bonding with ASN390 residue and intermol. hydrophobic interactions with LEU429 and LEU452 residues. However, the size of supramol. FEL-βRA better matched that of active cavity of BSA; the cocrystal is closely bound to BSA through hydrogen bonding with ASN390 residue and intermol. hydrophobic interactions with LEU429, VAL432, LEU452 and ILE387 residues. This change on binding affinity of FEL to BSA induced by cocrystn. with βRA provided theor. basis to evaluate the transportation, distribution and metabolism of cocrystal drug.

Chemical & Pharmaceutical Bulletin published new progress about Density functional theory. 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, Safety of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Holt, Kimberly published the artcilePrediction of tissue-plasma partition coefficients using microsomal partitioning: incorporation into physiologically based pharmacokinetic models and steady-state volume of distribution predictions, Formula: C18H19Cl2NO4, the main research area is plasma partition coefficient protein binding microsomal partitioning PBPK model.

Drug distribution is a necessary component of models to predict human pharmacokinetics. A new membrane-based tissue-plasma partition coefficient (Kp) method (Kp,mem) to predict unbound tissue to plasma partition coefficients (Kpu) was developed using in vitro membrane partitioning [fraction unbound in microsomes (fum)], plasma protein binding, and log P. The resulting Kp values were used in a physiol. based pharmacokinetic (PBPK) model to predict the steady-state volume of distribution (Vss) and concentration-time (C-t) profiles for 19 drugs. These results were compared with Kp predictions using a standard method [the differential phospholipid Kp prediction method (Kp,dPL)], which differentiates between acidic and neutral phospholipids. The Kp,mem method was parameterized using published rat Kpu data and tissue lipid composition The Kpu values were well predicted with R2 = 0.8. With one outlier removed for Kp,mem and two for Kp,dPL, the Vss predictions for R2 were 0.80 and 0.79 for the Kp,mem and Kp,dPL methods, resp. The C-t profiles were also predicted and compared. Overall, the Kp,mem method predicted the Vss and C-t profiles equally or better than the Kp,dPL method. An advantage of using fum to parameterize membrane partitioning is that fum data are used for clearance prediction and are, therefore, generated early in the discovery/development process. Also, the method provides a mechanistically sound basis for membrane partitioning and permeability for further improving PBPK models.

Drug Metabolism & Disposition published new progress about Adipose tissue. 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

Zarybnicky, Tomas published the artcileThe selection and validation of reference genes for mRNA and microRNA expression studies in human liver slices using RT-qPCR, Product Details of C18H19Cl2NO4, the main research area is insulin YWHAZ ACTB B2M CYP3A4 CYP1A2 miR165p biomarker steatosis; RT-qPCR; human liver; mRNA; miRNA; precision-cut liver slices; reference gene.

The selection of a suitable combination of reference genes (RGs) for data normalization is a crucial step for obtaining reliable and reproducible results from transcriptional response anal. using a reverse transcription-quant. polymerase chain reaction. This is especially so if a three-dimensional multicellular model prepared from liver tissues originating from biol. diverse human individuals is used. The mRNA and miRNA RGs stability were studied in thirty-five human liver tissue samples and twelve precision-cut human liver slices (PCLS) treated for 24 h with DMSO (controls) and PCLS treated with β-naphthoflavone (10μM) or rifampicin (10μM) as cytochrome P 450 (CYP) inducers. Validation of RGs was performed by an expression anal. of CYP3A4 and CYP1A2 on rifampicin and β-naphthoflavone induction, resp. Regarding mRNA, the best combination of RGs for the controls was YWHAZ and B2M, while YWHAZ and ACTB were selected for the liver samples and treated PCLS. Stability of all candidate miRNA RGs was comparable or better than that of generally used short non-coding RNA U6. The best combination for the control PCLS was miR-16-5p and miR-152-3p, in contrast to the miR-16-5b and miR-23b-3p selected for the treated PCLS. Our results showed that the candidate RGs were rather stable, especially for miRNA in human PCLS.

Genes published new progress about Biomarkers. 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, Product Details of C18H19Cl2NO4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Alvebratt, Caroline published the artcileAn in vitro dissolution-digestion-permeation assay for the study of advanced drug delivery systems, Category: pyridine-derivatives, the main research area is felodipine oral drug delivery system lipid digestion colorectal cancer; Advanced drug delivery systems; Caco-2 cells; Digestion; Dissolution; Lipid-based formulations; Permeation.

Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a μFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution-digestion-permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC anal. The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.

European Journal of Pharmaceutics and Biopharmaceutics published new progress about Colorectal neoplasm. 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, Category: pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Henze, Laura J. published the artcileDevelopment and evaluation of a biorelevant medium simulating porcine gastrointestinal fluids, Application of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is gastrointestinal fluid dissolution intestinal medium; Animal model; Bile salts; Biorelevant media; Dissolution test; FaSSIF; FaSSIFp; Gastrointestinal fluid; Pigs; Pre-clinical model; phospholipids.

During drug product development preclin. animal models are also required to assess drug product performance, and there is a need to develop species specific intestinal media to similarly predict in vivo pharmacokinetic profiles in each preclin. model. Pigs, are increasingly being used in preclin. drug development, however to date there is a lack of quant. information about the composition of porcine gastrointestinal (GI) fluids. GI fluid samples, were collected from landrace pigs, and characterized. Fasted State Simulated Intestinal Fluid of pigs (FaSSIFp) was developed based on the physiol. composition of the GI fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. This study demonstrated that FaSSIFp was superior at predicting the solubility of the six model drugs in porcine intestinal fluids (PIF). A markedly high correlation (r2 0.98) was observed between the solubility obtained in PIF and FaSSIFp, whereas poor correlation (r2 0.12) was found for the solubility of the model drugs between human FaSSIF and PIF. This confirms that species specific biorelevant intestinal media are crucial to provide more accurate predictions of pharmacokinetic studies in preclin. models. Addnl., the availability of a species specific intestinal medium offers the potential to improve in vitro-in silico approaches to predict in vivo absorption and to reduce the overall number of animals needed in oral drug product development testing.

European Journal of Pharmaceutics and Biopharmaceutics published new progress about Dissolution. 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, Application of 3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Fernandes, Hugo J. R. published the artcileSingle-Cell Transcriptomics of Parkinson’s Disease Human In Vitro Models Reveals Dopamine Neuron-Specific Stress Responses, COA of Formula: C18H19Cl2NO4, the main research area is transcriptomics Parkinsons disease dopamine neuron iPSC; Cholesterol biosynthesis; Dopamine neurons; ER stress; Felodipine; Human iPSC; Oxidative stress; PD GWAS; Parkinson’s disease; SNCA-A53T; Single-cell transcriptomics.

The advent of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized Parkinson’s disease (PD) research, but single-cell transcriptomic anal. suggests unresolved cellular heterogeneity within these models. Here, we perform the largest single-cell transcriptomic study of human iPSC-derived dopaminergic neurons to elucidate gene expression dynamics in response to cytotoxic and genetic stressors. We identify multiple neuronal subtypes with transcriptionally distinct profiles and differential sensitivity to stress, highlighting cellular heterogeneity in dopamine in vitro models. We validate this disease model by showing robust expression of PD GWAS genes and overlap with postmortem adult substantia nigra neurons. Importantly, stress signatures are ameliorated using felodipine, an FDA-approved drug. Using isogenic SNCA-A53T mutants, we find perturbations in glycolysis, cholesterol metabolism, synaptic signaling, and ubiquitin-proteasomal degradation Overall, our study reveals cell type-specific perturbations in human dopamine neurons, which will further our understanding of PD and have implications for cell replacement therapies.

Cell Reports published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (DAn1). 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, COA of Formula: C18H19Cl2NO4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Zhang, Shutao published the artcileFelodipine blocks osteoclast differentiation and ameliorates estrogen-dependent bone loss in mice by modulating p38 signaling pathway, Quality Control of 72509-76-3, the main research area is osteoclast differentiation bone loss estrogen p38 signaling felodipine; Felodipine; MAPK; Osteoclast differentiation; Osteoporosis; RNA-Seq.

Postmenopausal osteoporosis is one of the most common types of osteoporosis resulting from estrogen deficiency in elderly women. In addition, hypertension is another common disease in the elderly, and it has become an independent risk factor for osteoporosis and osteoporotic fractures. Here, we report for the first time that felodipine, a first-line antihypertensive agent, significantly prevents postmenopausal osteoporosis in addition to its vasodilation properties. Quant. RT-PCR anal. revealed that treatment with felodipine significantly downregulated the genes associated with osteoclast differentiation. RNA-sequencing and western blotting suggested that felodipine could inhibit bone resorption by suppressing MAPK pathway phosphorylation. Moreover, micro-CT scanning and histol. anal. in an ovariectomy (OVX)-induced bone-loss mouse model indicated that felodipine might be a potent drug for preventing osteoporotic fractures. Therefore, this study proposes an attractive and promising agent with vasodilation properties to treat postmenopausal osteoporosis.

Experimental Cell Research published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (TRAP). 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, Quality Control of 72509-76-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Lorigo, Margarida published the artcileUV-B filter octylmethoxycinnamate impaired the main vasorelaxant mechanism of human umbilical artery, HPLC of Formula: 21829-25-4, the main research area is UV B filter octylmethoxycinnamate vasorelaxant mechanism human umbilical artery; Calcium channels; Endocrine disruptor compound; Nitric oxide; Personal care product; Pregnancy hypertensive disorders; Vascular homeostasis.

Personal care products (PCPs) are a group of diverse substances widely used daily for health, beauty, and cleanliness. More than 90% of all PCPs contain the UV-B filter octylmethoxycinnamate (OMC) as a protective function, however, their safety has recently been questioned. The purpose of the present work was to understand how the long-term exposure of UV-filter OMC, used daily by pregnant women, disrupts their vascular homeostasis, altering vascular responses of proteins and channels involved in contractile processes. The long-term effects of 24 h of exposure to OMC (1, 10, and 50μmol/L) were evaluated on contractile responses of human umbilical arteries (HUA) to serotonin and potassium chloride. Since OMC altered vascular homeostasis of arteries, its vascular mode of action was explored in more detail through the anal. of the activity of cGMP and Ca2+-channels, two pathways involved in their relaxation and contraction, resp. Our findings showed that long-term exposure of UV-filter OMC impaired the main vasorelaxant mechanism of HUA, once OMC altered the vasorelaxant response pattern of sodium nitroprusside and nifedipine. Results also showed that long-term exposure to OMC induced a decreased vasorelaxation response on HUA due to an interference with the NO/sGC/cGMP/PKG pathway. Moreover, OMC seems to modulate the L-type Ca2+ channels, the BKCa 1.1 α-subunit channels, and the PKG. Overall, since OMC compromises the vascular homeostasis of pregnant women it can be an inductor of pregnancy hypertensive disorders.

Chemosphere published new progress about Animal gene Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (BKCa β1). 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, HPLC of Formula: 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Evdokimovskii, Edward V. published the artcileRole of α2-adrenoceptor subtypes in suppression of L-type Ca2+ current in mouse cardiac myocytes, COA of Formula: C17H18N2O6, the main research area is cardiac myocyte a2AAR a2BAR a2CAR L type calcium current; ARC 239; BRL 44408; G-protein coupled receptors; JP 1302; cell signaling; guanabenz; left ventricle.

Sarcolemmal α2 adrenoceptors (α2-AR), represented by α2A, α2B and α2C isoforms, can safeguard cardiac muscle under sympathoadrenergic surge by governing Ca2+ handling and contractility of cardiomyocytes. Cardiomyocyte-specific targeting of α2-AR would provide cardiac muscle-delimited stress control and enhance the efficacy of cardiac malfunction treatments. However, little is known about the specific contribution of the α2-AR subtypes in modulating cardiomyocyte functions. Herein, we analyzed the expression profile of α2A, α2B and α2C subtypes in mouse ventricle and conducted electrophysiol. antagonist assay evaluating the contribution of these isoforms to the suppression of L-type Ca2+ current (ICaL). Patch-clamp electro-pharmacol. studies revealed that the α2-agonist-induced suppression of ICaL involves mainly the α2C, to a lesser extent the α2B, and not the α2A isoforms. RT-qPCR evaluation revealed the presence of adra2b and adra2c (α2B and α2C isoform genes, resp.), but was unable to identify the expression of adra2a (α2A isoform gene) in the mouse left ventricle. Immunoblotting confirmed the presence only of the α2B and the α2C proteins in this tissue. The identified α2-AR isoform-linked regulation of ICaL in the mouse ventricle provides an important mol. substrate for the cardioprotective targeting.

International Journal of Molecular Sciences published new progress about Adenosine A2B receptors Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, COA of Formula: C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem