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Biomedicine & Pharmacotherapy =... Dec 2023Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether...
Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether lowering LCAC levels with the anti-ischemia compound 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB) protects brain mitochondrial function and improves neurological outcomes after transient middle cerebral artery occlusion (MCAO). The effects of 14 days of pretreatment with methyl-GBB (5 mg/kg, p.o.) on brain acylcarnitine (short-, long- and medium-chain) concentrations and brain mitochondrial function were evaluated in Wistar rats. Additionally, the mitochondrial respiration and reactive oxygen species (ROS) production rates were determined using ex vivo high-resolution fluorespirometry under normal conditions, in models of ischemia-reperfusion injury (reverse electron transfer and anoxia-reoxygenation) and 24 h after MCAO. MCAO model rats underwent vibrissae-evoked forelimb-placing and limb-placing tests to assess neurological function. The infarct volume was measured on day 7 after MCAO using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with methyl-GBB significantly reduced the LCAC content in brain tissue, which decreased the ROS production rate without affecting the respiration rate, indicating an increase in mitochondrial coupling. Furthermore, methyl-GBB treatment protected brain mitochondria against anoxia-reoxygenation injury. In addition, treatment with methyl-GBB significantly reduced the infarct size and improved neurological outcomes after MCAO. Increased mitochondrial coupling efficiency may be the basis for the neuroprotective effects of methyl-GBB. This study provides evidence that maintaining brain energy metabolism by lowering the levels of LCACs protects against ischemia-induced brain damage in experimental stroke models.
Topics: Rats; Animals; Rats, Wistar; Reactive Oxygen Species; Mitochondria; Brain; Brain Ischemia; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Hypoxia; Reperfusion Injury
PubMed: 37924790
DOI: 10.1016/j.biopha.2023.115803 -
International Journal of Molecular... Dec 2022A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different...
A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different positions of the benzene ring. The method consists of reacting appropriate aniline derivatives with 5,12-(dimethyl)thioquinantrenediinium bis-chloride. A series of new quinobenzothiazine derivatives was obtained with propyl, allyl, propargyl and benzyl substituents in 9, 10 and 11 positions, respectively. The structure of the obtained compounds was analyzed by 1H and 13C NMR (HSQC, HMBC) and X-ray analysis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). In addition, all the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. 9-Benzyloxy-5-methyl-12H-quino [3,4-b][1,4]benzothiazinium chloride (6j), 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6a) and 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6d) demonstrated high activity against the entire tested microbial spectrum. The activities of the compounds were comparable with oxacillin, tetracycline and ciprofloxacinagainst staphylococcal strains and with rifampicin against both mycobacterial strains. Compound 6j had a significant effect on the inhibition of bacterial respiration as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity, but also bactericidal activity. Preliminary in vitro cytotoxicity screening of the compounds performed using normal human dermal fibroblasts (NHDF) proved that the tested compounds showed an insignificant cytotoxic effect on human cells (IC50 > 37 µM), making these compounds interesting for further investigation. Moreover, the intermolecular similarity of novel compounds was analyzed in the multidimensional space (mDS) of the structure/property-related in silico descriptors by means of principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The distance-oriented structure/property distribution was related with the experimental lipophilic data.
Topics: Humans; Microbial Sensitivity Tests; Methicillin-Resistant Staphylococcus aureus; Chlorides; Anti-Bacterial Agents; Mycobacterium
PubMed: 36499402
DOI: 10.3390/ijms232315078 -
Acta Crystallographica. Section C,... Oct 2021The crystal structures of the hydrochloride salts of nine substituted tryptamines, namely, 1-methyltryptammonium chloride, CHN·Cl, (1), 2-methyl-1-phenyltryptammonium...
The crystal structures of the hydrochloride salts of nine substituted tryptamines, namely, 1-methyltryptammonium chloride, CHN·Cl, (1), 2-methyl-1-phenyltryptammonium chloride, CHN·Cl, (2), 5-methoxytryptammonium chloride, CHNO·Cl, (3), 5-bromotryptammonium chloride, CHBrN·Cl, (4), 5-chlorotryptammonium chloride, CHClN·Cl, (5), 5-fluorotryptammonium chloride, CHFN·Cl, (6), 5-methyltryptammonium chloride, CHN·Cl, (7), 6-fluorotryptammonium chloride, CHFN·Cl, (8), and 7-methyltryptammonium chloride, CHN·Cl, (9), are reported. The seven tryptamines with N-H indoles, (3)-(9), show very similar structures, with N-H...Cl hydrogen-bonding networks forming two-dimensional sheets in the crystals. These sheets are combinations of R(8) and R(18) rings, and C(4) and C(9) chains. Substitution at the indole N atom reduces the dimensionality of the hydrogen-bonding network, with compounds (1) and (2) demonstrating one-dimensional chains that are a combination of different rings and parallel chains.
PubMed: 34607984
DOI: 10.1107/S2053229621008950 -
Environmental Science and Pollution... Jun 2021Methyl mercury chloride "MMC" (CHClHg) is an ubiquitous environmental toxicant that causes a variety of adverse effects. In the present study, we investigated the...
Dietary exposure to methyl mercury chloride induces alterations in hematology, biochemical parameters, and mRNA expression of antioxidant enzymes and metallothionein in Nile tilapia.
Methyl mercury chloride "MMC" (CHClHg) is an ubiquitous environmental toxicant that causes a variety of adverse effects. In the present study, we investigated the effects of sub-chronic toxicity of MMC on Nile tilapia (Oreochromis niloticus) through the evaluation of growth performance and hematological, biochemical, and oxidative stress biomarkers. From 150 healthy fish, five equally sized treatment groups were created: a control (CT) group fed with a basal diet and four MMC treatment groups exposed to 0.5, 1, 1.5, and 2 mg of MMC per kg of basal diet for 60 days. MMC exposure significantly reduced the growth performance and survival of O. niloticus and decreased red blood cell count and hemoglobin concentration. Treated fish exhibited normocytic normochromic anemia in addition to leucopenia, lymphopenia, granulocytopenia, and monocytopenia. Moreover, MMC exposure significantly affected liver function, including a reduction in the total protein levels while increasing cholesterol and triglyceride levels. It also markedly increased the production of stress biomarkers such as glucose and cortisol levels. Furthermore, MMC significantly elevated the levels of hepatic enzymes, induced tissue damage, and caused inflammation, as indicated by the upregulation of mRNA expression of hepatic metallothionein. Finally, MMC exposure induced oxidative stress by altering the antioxidant status of the liver and downregulating the mRNA expression of superoxide dismutase, glutathione peroxidase, and glutathione S-reductase. In conclusion, MMC toxicity induced hematological and biochemical alterations, leading to an enhanced state of oxidative stress in O. niloticus.
Topics: Animals; Antioxidants; Cichlids; Diet; Dietary Exposure; Dietary Supplements; Hematology; Liver; Metallothionein; Methylmercury Compounds; Oxidative Stress; RNA, Messenger
PubMed: 33606169
DOI: 10.1007/s11356-021-13014-5 -
ACS Omega Dec 2022Amphiphilic aryl radicals generated upon visible light irradiation of arylazo sulfones have been exploited in the development of a solventylation strategy via hydrogen...
Amphiphilic aryl radicals generated upon visible light irradiation of arylazo sulfones have been exploited in the development of a solventylation strategy via hydrogen atom transfer (HAT). The present protocol succeeded in the versatile functionalization of various olefins with carbon-centered radicals deriving from acetone, acetonitrile, chloroform, methylene chloride, nitromethane, methyl acetate, and methyl formate under metal- and photocatalyst-free conditions. The direct addition of the aryl radicals onto the olefin substrates was suppressed under high dilution conditions.
PubMed: 36591128
DOI: 10.1021/acsomega.2c07172 -
ChemMedChem Oct 2021Recent studies have shown the involvement of GluN2A subunit-containing NMDA receptors in various neurological and pathological disorders. In the X-ray crystal structure,...
Recent studies have shown the involvement of GluN2A subunit-containing NMDA receptors in various neurological and pathological disorders. In the X-ray crystal structure, TCN-201 (1) and analogous pyrazine derivatives 2 and 3 adopt a U-shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π-interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane (5) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7, triazole 10 and benzamides 12. The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two-electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o-iodobenzamide 12 b with the highest similarity to TCN-201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 μM, 12 b reached 36 % of the inhibitory activity of TCN-201 (1). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN-201 binding site.
Topics: Animals; Dose-Response Relationship, Drug; Molecular Structure; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Xenopus laevis
PubMed: 34265163
DOI: 10.1002/cmdc.202100400 -
Life (Basel, Switzerland) Oct 2021High quality nucleic acids (with high integrity, purity, and biological activity) have become indispensable products of modern society, both in molecular diagnosis and...
High quality nucleic acids (with high integrity, purity, and biological activity) have become indispensable products of modern society, both in molecular diagnosis and to be used as biopharmaceuticals. As the current methods available for the extraction and purification of nucleic acids are laborious, time-consuming, and usually rely on the use of hazardous chemicals, there is an unmet need towards the development of more sustainable and cost-effective technologies for nucleic acids purification. Accordingly, this study addresses the preparation and evaluation of silica-based materials chemically modified with chloride-based ionic liquids (supported ionic liquids, SILs) as potential materials to effectively isolate RNAs. The investigated chloride-based SILs comprise the following cations: 1-methyl-3-propylimidazolium, triethylpropylammonium, dimethylbutylpropylammonium, and trioctylpropylammonium. All SILs were synthesized by us and characterized by solid-state C Nuclear Magnetic Resonance (NMR), Scanning Electron Microscopy (SEM), elemental analysis, and zeta potential measurements, confirming the successful covalent attachment of each IL cation with no relevant changes in the morphology of materials. Their innovative application as chromatographic supports for the isolation of recombinant RNA was then evaluated. Adsorption kinetics of transfer RNA (tRNA) on the modified silica-based materials were investigated at 25 °C. Irrespective to the immobilized IL, the adsorption experimental data are better described by a pseudo first-order model, and maximum tRNA binding capacities of circa 16 µmol of tRNA/g of material were achieved with silica modified with 1-methyl-3-propylimidazolium chloride and dimethylbutylpropylammonium chloride. Furthermore, the multimodal character displayed by SILs was explored towards the purification of tRNA from lysates, which in addition to tRNA contain ribosomal RNA and genomic DNA. The best performance on the tRNA isolation was achieved with SILs comprising 1-methyl-3-propylimidazolium chloride and dimethylbutylpropylammonium chloride. Overall, the IL modified silica-based materials represent a more efficient, sustainable, and cost-effective technology for the purification of bacterial RNAs, paving the way for their use in the purification of distinct biomolecules or nucleic acids from other sources.
PubMed: 34685465
DOI: 10.3390/life11101090 -
Respiratory Research Oct 2023The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional...
INTRODUCTION
The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.
METHODS
After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.
RESULTS
Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.
CONCLUSION
Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
Topics: Mice; Rats; Humans; Animals; Guinea Pigs; Bronchoconstriction; Methacholine Chloride; Amitriptyline; Histamine; Bronchodilator Agents; Serotonin; Acetylcholine; Sympathomimetics; 1-Methyl-3-isobutylxanthine; Dilatation; Lung; Asthma; Albuterol; Endothelins; Thromboxanes
PubMed: 37907918
DOI: 10.1186/s12931-023-02580-6 -
International Journal of Developmental... Feb 2022Maternal separation (MS) is a model to induce permanent alternations in the central nervous system (CNS) and is associated with increased levels of anxiety and cognitive...
Maternal separation (MS) is a model to induce permanent alternations in the central nervous system (CNS) and is associated with increased levels of anxiety and cognitive deficiencies. Since methyl donor choline (Ch) has been shown to play a significant role in learning and memory and enhance synaptic plasticity, the authors hypothesized that Ch may attenuate MS-induced impairments in synaptic plasticity and cognitive performance. Rat pups underwent an MS protocol for 180 min/day from postnatal day (PND) 1 to 21. Ch was administered subcutaneously (100 mg/kg, 21 days) to the choline chloride and MS + choline chloride groups from PND 29 to 49. Anxiety-like behaviour, recognition memory, and spatial and passive avoidance learning and memory were measured in the adolescent rats. In addition, evoked field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 region of the hippocampus. MS induced higher anxiety-like behaviour in the animals. It also impaired learning and memory. However, MS had no effect on locomotor activity. Subcutaneous administration of Ch attenuated MS-induced cognitive deficits and enhanced the learning and memory of MS rats. Ch also decreased anxiety-like behaviour in the open-field test. The present results showed that long-term potentiation (LTP) was induced in all groups except MS and MS + saline animals. However, Ch injection induced LTP and had maintenance in MS + choline chloride, but it was not statistically significant compared with the MS group. In summary, the present findings indicate that MS can interfere with normal animal's cognition and subcutaneous of Ch may be considered an appropriate therapeutic strategy for promoting cognitive dysfunctions in MS animals.
Topics: Animals; Avoidance Learning; Choline; Hippocampus; Long-Term Potentiation; Male; Maternal Deprivation; Maze Learning; Memory; Neuronal Plasticity; Rats
PubMed: 34727391
DOI: 10.1002/jdn.10155 -
Journal of Hazardous Materials Oct 2023Bisulfite-activated permanganate (S(IV)/Mn(VII)) process has proven to be a promising method for rapidly degrading micropollutants. Previous studies have shown that the...
Bisulfite-activated permanganate (S(IV)/Mn(VII)) process has proven to be a promising method for rapidly degrading micropollutants. Previous studies have shown that the treatment efficiency of the S(IV)/Mn(VII) process suffer from significant water matrix effects while the mechanism still remains unclear. This study systematically investigates the influence of chloride, which is a common water constituent, on the S(IV)/Mn(VII) process. Addition of chloride decreased the removal of methyl phenyl sulfoxide, phenol, benzoic acid and carbamazepine by the S(IV)/Mn(VII) process but increased dimethoxybenzene removal. The distribution of reactive species in the S(IV)/Mn(VII) process in the absence and presence of chloride was determined with relative rate method. The S(IV)/Mn(VII) process primarily relies on SO and reactive manganese species (RMnS) for pollutant abatement while dosing chloride decreased the concentration of these reactive species. Reactive chlorine species (RCS), such as Cl and ClO, are formed through the reaction of SO with chloride, and become more important at high concentrations of chloride. RMnS includes Mn(VI), Mn(V) and Mn(III), but none of these species are capable of oxidizing chloride. However, chloride retarded the consumption of bisulfite which reduced RMnS and RCS in turn. DOM inhibited pollutant removal by the S(IV)/Mn(VII) process while the impact mechanism was significantly altered by chloride. Additionally, the study observed a synergistic inhibition of DOM and chloride on the degradation of pollutants that are highly reactive towards Cl and ClO.
PubMed: 37531765
DOI: 10.1016/j.jhazmat.2023.132173