Search Results (178)

S-nitrosoglutathione (GSNO), a promising S-nitrosothiol, has been recognized for its ability to modulate vascular tone through its vasodilatory, antiplatelet, and antiproliferative effects. However, data on its vasodilatory effects in human vessels remain limited, and its mechanisms of action have yet to be fully elucidated. In this study, we aimed to investigate the vasorelaxant effect of GSNO and its underlying mechanisms, with particular focus on the soluble guanylate cyclase (sGC)/nitric oxide (NO) pathway and potassium channels in isolated human saphenous veins (SVs) obtained from patients undergoing coronary artery bypass grafting (CABG). GSNO (10⁻⁸–10⁻⁴ M) produced concentration-dependent relaxations in SV rings precontracted with phenylephrine. These relaxations were unaffected by NO synthase inhibition with L-NAME (10⁻⁴ M, 30 min) or NO scavenging with PTIO (10⁻⁴ M, 30 min), but were significantly reduced by the sGC inhibitor, ODQ (10⁻⁵ M, 30 min). Inhibition of ATP-sensitive (glibenclamid; 10⁻⁵ M, 30 min.), high-conductance Ca²⁺-activated (charybdotoxin; 10⁻⁷ M, 30 min), small-conductance Ca²⁺-activated (apamin; 10⁻⁶ M, 30 min), or voltage-dependent (4-aminopyridine; 10⁻³ M, 30 min) potassium channels did not alter the maximum relaxant responses to GSNO. Furthermore, pretreatment with GSNO (10⁻⁴ M, 30 min) significantly attenuated both the contractile response and sensitivity to phenylephrine. Collectively, these findings demonstrate that GSNO exerts acute vasorelaxant and modulatory effects in human SV primarily via cGMP-dependent mechanisms, highlighting its potential as a local therapeutic agent for preventing graft spasm in CABG. Full article

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K⁺] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K⁺]_o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K⁺-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

Novel derivatives of valproic acid with biologically active moieties, such as thiomorpholine, 4-aminopyridine, serine methyl ester, trolox and the cinnamic acid derivative [(E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid], were synthesized at satisfactory yields. The conjugation of these moieties was based on the rationale of design and evaluation of compounds with selected structural characteristics, aiming at derivatives with multiple targets. These compounds reduced acute inflammation considerably and, in most cases, more than several highly used, well-known, non-steroidal anti-inflammatory drugs. They also offered the inhibition of soybean lipoxygenase, and some of them (compounds 5 and 6) possessed radical scavenging and lipid peroxidation attenuating effects. Their antioxidant capacity was several times higher than that of the established antioxidant trolox. All the tested compounds decreased plasma lipid markers in tyloxapol-induced hyperlipidemia in rats. Compound 2 resulted in 71.1%, 52.8% and 79.1% decrease in total cholesterol, triglycerides and LDL-cholesterol, respectively, at 150 μmol/kg (i.p.). The effect on total and LDL cholesterol is comparable or equal to that of simvastatin, a hypocholesterolemic 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitor, however, with additionally great triglyceride-decreasing effect compared to simvastatin. Thus, the synthesized compounds may be a valuable addition to multi-functional agents acting against various degenerative disorders that implicate inflammation and lipid derangement. Full article

Background/Objectives: Carvacrol is a naturally occurring phenolic monoterpene that is one of the main constituents of the essential oils of oregano (Origanum vulgare) and other herbs. Carvacrol has anti-inflammatory and antinociceptive effects. Carvacrol can activate and inhibit several second messengers and ionic channels at the systemic level. However, there is no evidence of the peripheral antinociception of carvacrol and its mechanism of action. This study was designed to determine whether the opioid receptor-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-K⁺ channel pathway is involved in the local antinociception of carvacrol. Methods: Wistar rats were injected with 1% formalin subcutaneously on the dorsal surface of the right hind paw with the vehicle or carvacrol (100–300 µg/paw). To determine whether the opioid receptor-NO-cGMP-K⁺ channel pathway and a biguanide-dependent mechanism are responsible for the local antinociception induced by carvacrol, the effect of the injection (10 min before the 1% formalin injection) with the corresponding vehicles, metformin, naltrexone, NG-L-nitro-arginine methyl ester (L-NAME), 1 H-(1,2,4)-oxadiazolo (4,2-a) quinoxalin-1-one (ODQ), and K⁺ channel blockers on the antinociception induced by local carvacrol (300 µg/paw) was determined. Results: In both phases of the formalin test, carvacrol produced antinociception. Naltrexone, metformin, L-NAME, ODQ, glibenclamide and glipizide (both ATP-sensitive K⁺ channel blockers), tetraethylammonium and 4-aminopyridine (voltage-gated K⁺ channel blockers), and apamin and charybdotoxin (Ca²⁺-activated K⁺ channel blockers) reversed the carvacrol-induced peripheral antinociception. Conclusions: The local peripheral administration of carvacrol produced significant antinociception and activated the opioid receptor-NO-cGMP-K⁺ channel pathway. Full article

A binuclear Au-P complex [Au₂(2-bdppmapy)₂](PF₆)₂ (1) was synthesised by the reaction of 2-bdppmapy (N,N′-bis-(diphenylphosphanylmethyl-2-aminopyridine) with AuCN and [Cu(MeCN)₄]PF₆. The solid phase of 1 emitted bright yellow phosphorescence at λ_max = 580 nm under UV excitation (QY = 4.41%, τ = 1.88 μs), which shifted to green (λ_max = 551 nm, QY = 5.73%) after being pressurised under 5 MPa. This colour change was recoverable upon exposure to CH₂Cl₂ vapor. Similar mechanochromic photoluminescence behaviour was observed after grinding the crystals of 1. A filter paper impregnated with 1 demonstrated recyclable write/erase functionality for encrypted information transfer. Full article

This study utilized the Schiff base reaction as a chemical bonding method to successfully graft 2-aminopyridine onto oxidized sodium alginate, resulting in the formation of modified sodium alginate (OSM). Subsequently, the OSM/polyacrylic acid (OSM/PAA) hydrogel was synthesized via a thermally initiated free radical polymerization process and evaluated as an adsorbent for the removal of heavy metal ions from wastewater. Comprehensive characterization of the prepared samples was performed using FT-IR, SEM, and TGA. The influence of temperature, pH, adsorbent dosage, contact time, and heavy metal ion concentration on the adsorption capacity of the OSM/PAA adsorbent in simulated wastewater was thoroughly investigated. Additionally, a detailed analysis of the adsorption thermodynamics, kinetics, and mechanisms was conducted. Experimental results indicated that at 25 °C, pH 5.0, and an adsorbent dosage of 0.4 g/L, the maximum adsorption capacities of the OSM/PAA hydrogel for Cu(II), Zn(II), and Ni(II) were 367.64 mg/g, 398.4 mg/g, and 409.83 mg/g, respectively. These findings suggest that the adsorption of heavy metal ions by OSM/PAA is a spontaneous, heterogeneous chemical process with significant potential for practical applications in wastewater treatment. Full article

Elevated levels of homocysteine in the blood plasma (hyperhomocysteinemia, HHCY) positively correlate with migraine symptoms in patients. Experimental studies show a higher sensitivity of rats with prenatal HHCY (pHHCY) to migraine symptoms like allodynia, photophobia, anxiety, and a higher excitability of meningeal trigeminal afferents. In the present study, the roles of purinergic mechanisms in the homocysteine-induced hyperexcitability of the trigeminal ganglion (TG) system using electrophysiological recordings from the trigeminal nerve, Ca²⁺ imaging of cells isolated from TG, and mast cell staining in meninges were investigated. Experiments were performed using rats with pHHCY born from females fed with a high-methionine-containing diet before and during pregnancy. Firstly, we found that lower concentrations of 4-aminopyridine, a K⁺-channel blocker, were able to induce an increase in the nociceptive activity of trigeminal afferents, supporting the hypothesis of the higher excitability of the trigeminal nerve of rats with pHHCY. Trigeminal afferents of rats with pHHCY were more sensitive to the exogenous application of the nonspecific agonist of purinergic ATP receptors. In neurons and satellite glial cells of TG of rats with pHHCY ATP, ADP (an agonist of metabotropic P2Y receptors) and BzATP (an agonist of ionotropic P2X with especially high potency for the P2X7 receptor) induced larger Ca²⁺ transients. The incubation of TG neurons in homocysteine for 24 h increased the ratio of neurons responding simultaneously to ATP and capsaicin. Moreover, rats with pHHCY exhibit a higher rate of degranulation of mast cells and increased response to the agonist of the P2X7 receptor BzATP application. In addition, higher levels of calcitonin gene-related peptide (CGRP) were found in rats with pHHCY. Our results suggest that chronic elevated levels of homocysteine induce the upregulation of ionotropic or metabotropic ATP receptors in neurons, satellite glial cells, and mast cells, which further provide inflammatory conditions and the sensitization of peripheral afferents underlying pain. Full article

Using 5-methyl salicylaldehyde (2) as a reactant to react with different amines, 2-aminobenzimidazole (1a), 2-aminobenzothiazole (1b), and 2-aminopyridine (1c), respectively, three types of Schiff base fluorescent probes 3a–3c were designed and synthesized for selective detection of Al³⁺ in aqueous media. The structure of the compounds was acquired by ¹H NMR, ¹³C NMR, and X-ray single-crystal diffraction. Furthermore, their photochromic and fluorescent behaviors have been investigated systematically by fluorescence spectra. Compounds 3a–3c can exhibit high selectivity, sensitivity, and anti-interference properties towards Al³⁺ in aqueous media. Among them, the limit of detection (LOD) of probe 3b for Al³⁺ is 2.81 × 10⁻⁷ M. Notably, the response times of probes 3a–3c for Al³⁺ are 90 s, 80 s, and 80 s, respectively, which are much faster than most previously reported probes. The coordination stoichiometry between compounds 3a–3c and Al³⁺ has been verified to be 1:1 through the Job’s plot. After coordination with Al³⁺, the C=N isomerization of compounds 3a–3c is inhibited, leading to the closure of the excited state intramolecular proton transfer (ESIPT) effect. At the same time, the fluorescence intensity is significantly increased through chelation-enhanced fluorescence mechanism (CHEF), which is confirmed by density functional theory (DFT) calculations. In addition, probes 3a–3c can be potentially applied in the selective and high-precision detection of Al³⁺ in environmental systems. Full article

Two new Co(II) coordination compounds viz. [Co(H₂O)(bz)₂(μ-3-Ampy)₂]_n (1) and [Co(4-Mebz)₂(2-Ampy)₂] (2) (wherebz = benzoate, 4-Mebz = 4-Methylbenzoate and Ampy = Aminopyridine) were synthesized and characterized via elemental (CHN), electronic spectroscopy, FT-IR spectroscopy, and thermogravimetric analysis (TGA). The molecular structures were determined by single-crystal X-ray diffraction analysis, inferring that compound 1 crystallizes as a 3-Ampy bridged Co(II) coordination polymer, whereas compound 2 crystallizes as a mononuclear Co(II) compound. Compound 1 unfolds the presence of N–H⋯O, C–H⋯O, O–H⋯O, C–H⋯N and aromatic π⋯π interactions, while for compound 2, N–H⋯O, C–H⋯O, C–H⋯C and C–H⋯π interactions are observed. Both the compounds showcase scarcely reported chelate ring interactions involving the benzoate moiety (chelate ring⋯π in 1 and N–H⋯chelate ring in 2). We also conducted theoretical evaluations comprising of combined QTAIM/NCI plot analysis, DFT energy calculation and MEP surface analysis to analyze the supramolecular interactions present in the crystal structures. As per QTAIM parameters, the predominance of π-stacking interactions over hydrogen bonds in stabilizing the assembly in compound 1 is affirmed. Likewise, in compound 2, both hydrogen bonding (HBs) and C–H⋯π interactions are deemed pivotal in stabilizing the dimeric assemblies. The in vitro antiproliferative activities of compounds 1 and 2 were performed against Dalton’s lymphoma (DL) cancer cell lines through cytotoxicity and apoptosis assays, showcasing higher cytotoxicity of compound 1 (IC₅₀ = 28 μM) over compound 2 (IC₅₀ = 34 μM). Additionally, a molecular docking study investigated the structure–activity relationship of these compounds and allowed an understanding of the molecular behaviour after treatment. Full article

Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d bears an aminopyridine amide with an IC₅₀ of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog 7q has an IC₅₀ of 18.8 µM, with potency residing in the (R)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor (R)-7q with T_m = 50.2 °C and a K_i of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions. Full article

4-aminopyridine (4-AP) is a non-selective blocker of voltage-dependent K⁺ channels used to improve walking in multiple sclerosis patients, and it may be useful in the treatment of cerebellar diseases. In animal models, 4-AP is used as a convulsant agent. When administered intrahippocampally, 4-AP induces acute local glucose hypermetabolism and significant brain damage, while i.p. administration causes less neuronal damage. This study aimed to investigate the effects of a single i.p. administration of 4-AP on acute brain glucose metabolism as well as on neuronal viability and signs of neuroinflammation 3 days after the insult. Brain glucose metabolism was evaluated by [¹⁸F]FDG PET neuroimaging. [¹⁸F]FDG uptake was analyzed based on volumes of interest (VOIs) as well as by voxel-based (SPM) analyses. The results showed that independently of the type of data analysis used (VOIs or SPM), 4-AP induced acute generalized brain glucose hypometabolism, except in the cerebellum. Furthermore, the SPM analysis normalized by the whole brain uptake revealed a significant cerebellar hypermetabolism. The neurohistochemical assays showed that 4-AP induced hippocampal astrocyte reactivity 3 days after the insult, without inducing changes in neuronal integrity or microglia-mediated neuroinflammation. Thus, acute brain glucose metabolic and neuroinflammatory profiles in response to i.p. 4-AP clearly differed from that reported for intrahippocampal administration. Finally, the results suggest that the cerebellum might be more resilient to the 4-AP-induced hypometabolism. Full article

The objective of this work was to improve the solubility and discover a stable co-amorphous form of valsartan (VAL), a BCS class-II drug, by utilizing small molecule 2-Aminopyridine (2-AP) in varying molar ratios (2:1, 1:1, and 1:2), employing a solvent evaporation technique. Additionally, by way of a density functional theory (DFT)-based computational method with commercially available software, a new approach for determining the intermolecular connectivity of multi-molecular hydrogen bonding systems was proposed. The binary systems’ features were characterized by PXRD, DSC, FTIR, and Raman spectroscopy, while the equilibrium solubility and dissolution was determined in 0.1 N HCL and water conditions to investigate the dissolution advantage of the prepared co-amorphous systems. The results demonstrated that the co-amorphous system was successfully prepared in VAL/2-AP with a 1:2 molar ratio following solvent evaporation, whereby the hydrogen bonding sites of VAL were fully occupied. Physical stability studies were carried out under dry conditions at room temperature for 6 months. Furthermore, four possible ternary systems were constructed, and their vibrational modes were simulated by DFT calculations. The calculated infrared spectra of the four configurations varied widely, with trimer 1 showing the most resemblance to the experimental spectrum of the co-amorphous 1:2 system. Additionally, co-amorphous VAL/2-AP displayed significant improvement in the solubility and dissolution study. Notably, in the 1:2 ratio, there was almost a 4.5-fold and 15.6-fold increase in VAL’s solubility in 0.1 N HCL and water environments, respectively. In conclusion, our findings highlight the potential of co-amorphous systems as a feasible approach to improving the properties and bioavailabilities of insoluble drugs. The proposed simulation method provides valuable insights into determining the supramolecular structure of multi-molecular hydrogen bonding systems, offering a novel perspective for investigating such systems. Full article

Background: Apigenin (4′,5,7-trihydroxyflavone), a flavonoid with potential cardiovascular benefits, has unclear mechanisms of action. This study investigates its effects on vascular function in Spontaneously Hypertensive Rats (SHRs). Methods: Mesenteric vascular beds (MVBs) were isolated from SHRs and perfused with increasing doses of apigenin after pre-contraction with phenylephrine. To explore the mechanisms, different MVBs were pre-perfused with antagonists and inhibitors, including indomethacin, L-NAME, and potassium channel blockers (tetraethylammonium, a non-specific potassium channel blocker; glibenclamide, an ATP-sensitive potassium channel blocker; 4-aminopyridine, a voltage-gated potassium channel blocker; charybdotoxin a selective intermediate-conductance calcium-activated potassium channel blocker; and apamin, a selective small-conductance calcium-activated potassium channel blocker). Results: Apigenin induced a dose-dependent reduction in perfusion pressure in MVBs with intact endothelium, an effect abolished by endothelium removal. L-NAME reduced apigenin-induced vasodilation by approximately 40%. The vasodilatory effect was blocked by potassium chloride and tetraethylammonium. The inhibition of small and intermediate calcium-activated potassium channels with charybdotoxin and apamin reduced apigenin-induced vasodilation by 50%, and a combination of these blockers with L-NAME completely inhibited the effect. Conclusions: Apigenin promotes vasodilation in resistance arteries through endothelial nitric oxide and calcium-activated potassium channels. These findings suggest that apigenin could have therapeutic potential in cardiovascular disease, warranting further clinical research. Full article

High-yielding synthetic routes to five new extremely bulky aminopyridine pro-ligands were developed, viz. (C₅H₃N-6-Ar¹)N(H)Ar²-2; Ar¹ = Trip, Ar² = TCHP (HAmPy¹), Ar* (HAmPy²) or Ar^† (HAmPy³); Ar¹ = TCHP, Ar² = Ar* (HAmPy⁴) or Ar^† (HAmPy⁵) (Trip = 2,4,6-triisopropylphenyl, TCHP = 2,4,6-tricyclohexylphenyl, Ar* = C₆H₂(CHPh₂)₂Me-2,6,4, Ar^† = C₆H₂(CHPh₂)₂Prⁱ-2,6,4. Four of these were deprotonated with LiBuⁿ in diethyl ether to give lithium aminopyridinate complexes which were dimeric for the least bulky ligand, [{Li(AmPy¹)}₂] or monomeric for the bulkier aminopyridinates, i.e., in [Li(AmPy²⁻⁴)(OEt₂)]. One aminopyridine was deprotonated with MeMgI to give monomeric [Mg(AmPy³)I(OEt₂)₂]. When treated with sodium or potassium mirrors or 5% w/w Na/NaCl, over-reduction occurred, leading to the alkali metal aminopyridinates, [M(AmPy³)(η⁶-toluene)] (M = Na or K) or [{Na(AmPy³)}_∞]. An attempted reduction of [Mg(AmPy³)I(OEt₂)₂] with a dimagnesium(I) compound led only to partial loss of diethyl ether and the formation of [(AmPy³)Mg(μ-I)₂Mg(AmPy³)(OEt₂)]. All prepared complexes have potential as ligand transfer reagents in salt metathesis reactions with metal halide complexes. Full article