Day: November 30, 2022

Zhong, Weixia published the artcileCentral and peripheral emetic loci contribute to vomiting evoked by the Akt inhibitor MK-2206 in the least shrew model of emesis, Product Details of C17H18N2O6, the main research area is Akt inhibitor central peripheral emetic locus vomiting emesis; Akt; Emesis; Least shrew; MK-2206; PI3K; Perifosine.

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), resp. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg, s.c. (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacol. inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.

European Journal of Pharmacology published new progress about 5-HT3 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, Product Details of C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Vella, Stephen A. published the artcileThe role of potassium and host calcium signaling in Toxoplasma gondii egress, Product Details of C17H18N2O6, the main research area is Toxoplasma gondii egress potassium calcium signaling; Calcium signaling; GCaMP6f; GeneticallyEncoded Calcium Indicators; R-GECO; Toxoplasma egress; Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite and replicates inside a parasitophorous vacuole (PV) within the host cell. The membrane of the PV (PVM) contains pores that permits for equilibration of ions and small mols. between the host cytosol and the PV lumen. Ca2+ signaling is universal and both T. gondii and its mammalian host cell utilize Ca2+ signals to stimulate diverse cellular functions. Egress of T. gondii from host cells is an essential step for the infection cycle of T. gondii, and a cytosolic Ca2+ increase initiates a Ca2+ signaling cascade that culminates in the stimulation of motility and egress. In this work we demonstrate that intracellular T. gondii tachyzoites are able to take up Ca2+ from the host cytoplasm during host cell signaling events. Both intracellular and extracellular Ca2+ sources are important in reaching a threshold of parasite cytosolic Ca2+ needed for successful egress. Two peaks of Ca2+ were observed in egressing single parasites with the second peak resulting from Ca2+ entry. We patched infected host cells to allow the delivery of precise concentrations of Ca2+ for the stimulation of motility and egress. Using this approach of patching infected host cells, allowed us to determine that increasing the host cytosolic Ca2+ to a specific concentration can trigger egress, which is further accelerated by diminishing the concentration of potassium (K+).

Cell Calcium published new progress about Calcium channels 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, Product Details of C17H18N2O6.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Wu, Ling published the artcileCalcium Channel Blocker Nifedipine Suppresses Colorectal Cancer Progression and Immune Escape by Preventing NFAT2 Nuclear Translocation, Related Products of pyridine-derivatives, the main research area is nifedipine calcium channel blocker colorectal cancer immune nuclear translocation; colorectal cancer; nifedipine; nuclear factors of activated T cells 2; tumor immune; tumor metastasis.

Abnormal activation of calcium channels has been shown to play crucial roles in tumor occurrence and development. However, the role of inhibitors targeting calcium channels in tumor progression and immune regulation remains unclear, and their clin. applications are still limited. We show that nifedipine (NIFE), a calcium channel blocker, inhibits calcium influx to impair nuclear factor of activated T cell 2 (NFAT2) dephosphorylation, activation, and nuclear translocation, thus preventing transcriptional activation of downstream signaling mols. to suppress colorectal cancer (CRC) proliferation and metastasis. In addition, NIFE decreases expression of programmed death-ligand 1 (PD-L1) on CRC cells and programmed death-1 (PD-1) on CD8+ T cells and reactivates tumor immune monitoring, which may stimulate or enhance PD-1-based antitumor immunotherapy. Our findings provide direct evidence that NIFE is a promising clin. therapy to treat patients with advanced CRC by affecting the tumor itself and tumor immunity. NIFE may be a promising therapeutic option to enhance effectiveness of immune checkpoint blockade therapy in CRC.

Cell Reports published new progress about Calcium channels 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, Related Products of pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Malecot, Claire O. published the artcileLow voltage-activated channels in rat pulmonary vein cardiomyocytes: coexistence of a non-selective cationic channel and of T-type Ca channels, Application of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is pulmonary vein cardiomyocyte cationic channel Ttype Ca; Basic science research; Electrophysiology; Ion channels/membrane transport.

Abstract: In rat pulmonary vein (PV) cardiomyocytes (CM), norepinephrine (NE) induces an automatic activity consisting of bursts of slow action potentials which depend on Ca2+ (upstroke) and Na+ (inter-burst) channels. Our objective was to characterize low voltage-activated (LVA) currents in rat PVCM susceptible to trigger this activity. Whole-cell ICa (5 mM Ca2+) was recorded from – 100 mV with classical Na+- and K+-free solutions A fast LVA ICa (FLVA-ICa), present in â‰?56% of PVCM between âˆ?- 50 to – 20 mV, was blocked by 10μM TTX and markedly increased by addition of NaCl (1 or 3 mM) or KCl (5 or 10 mM). Permeability ratios P’Ca/PNa and P’Ca/PK calculated for bi-ionic conditions were resp. 2.25 ± 0.51 and 1.88 ± 0.25, and not different from a value of 2. FLVA-ICa was increased by 10μM NE and 300 nM BayK8644, decreased by 5μM nifedipine but not blocked by ranolazine (10μM). NiCl2 (40μM) and TTA-A2 (10 or 100 nM) increased FLVA-ICa. Similar results were obtained in left atrial (LA) CM. Neither Ba2+ nor Sr2+ alone could permeate the FLVA channel or block Ca2+ influx but revealed a large slower activating and inactivating LVA Ca2+ current (SLVA-ICa), present in 10 out of 80 PVCM, absent in LACM, and partially inhibited by 100 nM TTA-A2. Therefore, the ionic channel underlying FLVA-ICa is likely a fast voltage-gated non-selective channel with a dihydropyridine binding site. SLVA-ICa might correspond to Ca2+ influx through Cav3.x channels and contribute to triggering NE-induced automatic activity in the PV myocardial sleeve.

Pfluegers Archiv published new progress about Calcium channels 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, Application of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Rembetski, Benjamin E. published the artcileContribution of Cav1.2 Ca2+ channels and store-operated Ca2+ entry to pig urethral smooth muscle contraction, COA of Formula: C17H18N2O6, the main research area is urethral smooth muscle contraction nifedipine Cav12 SERCA calcium; Ca2+ stores; lower urinary tract; store-operated Ca2+ entry; urethra; urinary continence.

However, recent findings in the mouse have suggested that USM tone is voltage independent, relying on Ca2+ influx through Orai channels via store-operated Ca2+ entry (SOCE). We explored if this pathway also occurred in the pig using isometric tension recordings of USM tone. Pig USM strips generated myogenic tone, which was nearly abolished by the Cav1.2 channel antagonist nifedipine and the ATP-dependent K+ channel agonist pinacidil. Pig USM tone was reduced by the Orai channel blocker GSK-7975A. Elec. field stimulation (EFS) led to phentolamine-sensitive contractions of USM strips. Contractions of pig USM were also induced by phenylephrine. Phenylephrine-evoked and EFS-evoked contractions of pig USM were reduced by �0-75% by nifedipine and �0% by GSK-7975A. Inhibition of Ano1 channels had no effect on tone or EFS-evoked contractions of pig USM. In conclusion, unlike the mouse, pig USM exhibited voltage-dependent tone and agonist/EFS-evoked contractions. Whereas SOCE plays a role in generating tone and agonist/neural-evoked contractions in both species, this dominates in the mouse. Tone and agonist/EFS-evoked contractions of pig USM are the result of Ca2+ influx primarily through Cav1.2 channels, and no evidence was found supporting a role of Ano1 channels in modulating these mechanisms.

American Journal of Physiology published new progress about Anoctamins, Ano1 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

Lu, Ping published the artcileOscillating calcium signals in smooth muscle cells underlie the persistent basal tone of internal anal sphincter, Application In Synthesis of 21829-25-4, the main research area is smooth muscle internal sphincter calcium signal oscillation; Internal anal sphincter; Ion channels; calcium oscillations; phasic contraction; sustained contraction.

A persistent basal tone in the internal anal sphincter (IAS) is essential for keeping the anal canal closed and fecal continence; its inhibition via the rectoanal inhibitory reflex (RAIR) is required for successful defecation. However, cellular signals underlying the IAS basal tone remain enigmatic. Here we report the origin and mol. mechanisms of calcium signals that control the IAS basal tone, using a combination approach including a novel IAS slice preparation that retains cell arrangement and architecture as in vivo, 2-photon imaging, and cell-specific gene-modified mice. We found that IAS smooth muscle cells generate two forms of contractions (i.e., phasic and sustained contraction) and Ca2+ signals (i.e., synchronized Ca2+ oscillations [SCaOs] and asynchronized Ca2+ oscillations [ACaOs]) that last for hours. RyRs, TMEM16A, -type Ca2+ channels, and gap junctions are required for SCaOs, which account for phasic contraction and 75% of sustained contraction. Nevertheless, only RyRs are required for ACaOs, which contribute 25% of sustained contraction. Nitric oxide, the primary neurotransmitter mediating the RAIR, blocks both types of Ca2+ signals, leading to IAS’s full relaxation. Our results show that the oscillating nature of Ca2+ signals generates and maintains the basal tone without causing cytotoxicity to IAS. Our study provides insight into fecal continence and normal defecation.

Journal of Cellular Physiology published new progress about Anoctamins, Ano1 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, Application In Synthesis of 21829-25-4.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Danielsson, Jennifer published the artcileAgonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone, Related Products of pyridine-derivatives, the main research area is asthma airway smooth muscle TMEM16A antagonist antiasthmatic agent; ANO1; Eact; flexiVent; organ bath.

TMEM16A (anoctamin 1) is an important calcium-activated chloride channel in airway smooth muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have proposed TMEM16A antagonists as novel therapies for asthma treatment. The TMEM16A agonist Eact induced a significant contraction of human ASM and guinea pig tracheal rings in an ex vivo organ bath model. Pretreatment with two different TMEM16A antagonists, benzbromarone or T16Ainh-A01, completely attenuated these Eact-induced contractions. Pretreatment of A/J mice in vivo with nebulized Eact caused an augmentation of methacholine-induced increases in airway resistance measured by the forced oscillatory technique (flexiVent). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in airway resistance. In in vitro cellular studies, TMEM16A was found to be expressed more abundantly in ASM compared with epithelial cells in culture (8-fold higher in ASM). Eact caused an increase in intracellular calcium in human ASM cells that was completely attenuated by pretreatment with benzbromarone. Eact acutely depolarized the plasma membrane potential of ASM cells, which was attenuated by benzbromarone or nifedipine. The TMEM16A agonist Eact modulates ASM contraction in both ex vivo and in vivo models, suggesting that agonism of TMEM16A may lead to clin. relevant bronchospasm.

American Journal of Physiology published new progress about Anoctamins, Ano1 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, Related Products of pyridine-derivatives.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Tran, Gael published the artcileBase-Controlled Completely Selective Linear or Branched Rhodium(I)-Catalyzed C-H ortho-Alkylation of Azines without Preactivation, Application of 3-Chloro-4-(trifluoromethyl)pyridine, the main research area is base controlled rhodium catalyzed regioselective alkylation azine acrylate acrylamide; C−H activation; homogeneous catalysis; nitrogen heterocycles; regioselectivity.

A [RhI]/bisphosphine/base catalytic system for the ortho-selective C-H alkylation of azines by acrylates and acrylamides is reported. This catalytic system features an unprecedented complete linear or branched selectivity that is solely dependent on the catalytic base that is used [e.g., 3-(trifluoromethyl)pyridine + N,N-dimethylacrylamide �linear product I when KOPiv was used as base vs. branched product II when K3PO4 was used under otherwise identical conditions]. Complete branched selectivity is even achieved for Et methacrylate, which enables the introduction of a quaternary carbon center. Excellent functional group compatibility is demonstrated for both linear and branched alkylations. The operational simplicity and broad scope of this transformation allow for rapid access to functionalized azines of direct pharmaceutical and agrochem. relevance.

Angewandte Chemie, International Edition published new progress about Alkenes Role: RCT (Reactant), RACT (Reactant or Reagent) (acrylates and acrylamides). 81565-19-7 belongs to class pyridine-derivatives, name is 3-Chloro-4-(trifluoromethyl)pyridine, and the molecular formula is C6H3ClF3N, Application of 3-Chloro-4-(trifluoromethyl)pyridine.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Zolfaghari, Zahra published the artcileThymol provokes burst of action potentials in neurons of snail Caucasotachea atrolabiata, Safety of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, the main research area is Caucasotachea neuron thymol action potential calcium potassium current; Action potential; Burst firing; Calcium channels; Potassium channels; Snail neuron; Thymol.

Thymol, a phenolic monoterpene, is well known for its antimicrobial, antifungal and antioxidant properties. In spite of wide use in oral care products, pharmaceutical and cosmetic preparation and in food industry, the effects of thymol on the neuronal activity and intrinsic properties have not been well studied. We studied the effects of thymol on the spontaneous activity and action potential properties of central neurons of snail Caucasotachea atrolabiata. Thymol (1 mM) altered action potentials characteristics and provoked epileptiform burst firing in snail neurons, which were partially reversible after washout. Before burst firing, action potentials had lower amplitude and maximum rising slope, while the threshold voltage was raised. These results suggest the inhibition of ion channels underlying action potential initiation and upstroke. The maximum falling slope and afterhyperpolarization were also considerably reduced, suggesting the inhibition of potassium channels. Thymol (0.5 mM) that was not able to induce burst firing in snail neurons, synergistically acted with potassium channel blocker, tetra-Et ammonium, to induce burst firing, which also supports the importance of potassium channel inhibition, especially delayed rectifier potassium channels, to the thymol-induced alteration of firing pattern. The thymol-induced burst firing seems to be dependent on both sodium and calcium currents. Our findings provide evidences for the ability of thymol in altering the firing mode of central neurons of snail, which apparently involves the inhibition of calcium and potassium currents. These results further support the interaction of thymol with ion channels and emphasize on the vulnerability of nervous system to this compound

Comparative Biochemistry and Physiology, Part C: Toxicology & Pharmacology published new progress about Action potential 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, Safety of Dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem

Ding, Chunyong published the artcileExploration of Synthetic Approaches and Pharmacological Evaluation of PNU-69176E and Its Stereoisomer as 5-HT2C Receptor Allosteric Modulators, Quality Control of 24484-93-3, the main research area is modulator 5HT2C receptor PNU69176E stereoisomer preparation structure activity.

Allosteric modulators of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner with great potential as novel central nervous system probes and therapeutics. To date, PNU-69176E is the only reported selective pos. allosteric modulator for the 5-HT2CR. For the first time, an optimized synthetic route to readily access PNU-69176E (1) and its diastereomer 2 has been established in moderate to good overall yields over 10 steps starting from com. available picolinic acid. This synthetic approach not only enables a feasible preparation of a sufficient amount of 1 for use as a reference compound for secondary pharmacol. studies, but also provides an efficient synthesis of key intermediates to develop novel and simplified 5-HT2CR allosteric modulators. Compound 1 and its diastereomer 2 were functionally characterized in Chinese hamster ovary (CHO) cells stably transfected with the 5-HT2CR using an intracellular calcium (Cai2+) release assay. Compound 1 demonstrated efficacy and potency as an allosteric modulator for the 5-HT2CR with no intrinsic agonist activity. Compound 1 did not alter 5-HT-evoked Cai2+ in CHO cells stably transfected with the highly homologous 5-HT2AR. In contrast, the diastereomer 2 did not alter 5-HT-evoked Cai2+ release in 5-HT2AR-CHO or 5-HT2CR-CHO cells or exhibit intrinsic agonist activity.

ACS Chemical Neuroscience published new progress about 5-HT2A receptors Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 24484-93-3 belongs to class pyridine-derivatives, name is Methyl 4-chloropicolinate, and the molecular formula is C7H6ClNO2, Quality Control of 24484-93-3.

Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem