17 results on '"Pomierny B"'
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2. Mitochondria-targeted hydrogen sulfide donor reduces atherogenesis by changing macrophage phenotypes and increasing UCP1 expression in vascular smooth muscle cells.
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Stachowicz A, Wiśniewska A, Czepiel K, Pomierny B, Skórkowska A, Kuśnierz-Cabala B, Surmiak M, Kuś K, Wood ME, Torregrossa R, Whiteman M, and Olszanecki R
- Abstract
Atherosclerosis is a leading cause of morbidity and mortality in the Western countries. Mounting evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (H
2 S) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of H2 S to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial H2 S donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE-/- ) mice. Our results indicated that AP39 reduced atherosclerosis in apoE-/- mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reduced proinflammatory M1-like macrophages and increased anti-inflammatory M2-like macrophages in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid β-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE-/- mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation. Taken together, mitochondrial H2 S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis., Competing Interests: Declaration of Competing Interest MW, RT, and MEW have intellectual property (patents awarded and pending) on slow-release sulfide-generating molecules and their therapeutic use. MW is CSO of MitoRx Therapeutics, Oxford, U.K, developing organelle-targeted molecules for clinical use., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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3. Disruption of Glutamate Homeostasis in the Brain of Rat Offspring Induced by Prenatal and Early Postnatal Exposure to Maternal High-Sugar Diet.
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Mizera J, Pomierny B, Sadakierska-Chudy A, Bystrowska B, and Pomierny-Chamiolo L
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- Animals, Brain metabolism, Diet, Diet, High-Fat, Female, Homeostasis, Humans, Male, Pregnancy, Rats, Sugars, Glutamic Acid metabolism, Prenatal Exposure Delayed Effects metabolism
- Abstract
A high-calorie diet has contributed greatly to the prevalence of overweight and obesity worldwide for decades. These conditions also affect pregnant women and have a negative impact on the health of both the woman and the fetus. Numerous studies indicate that an unbalanced maternal diet, rich in sugars and fats, can influence the in utero environment and, therefore, the future health of the child. It has also been shown that prenatal exposure to an unbalanced diet might permanently alter neurotransmission in offspring. In this study, using a rat model, we evaluated the effects of a maternal high-sugar diet on the level of extracellular glutamate and the expression of key transporters crucial for maintaining glutamate homeostasis in offspring. Glutamate concentration was assessed in extracellular fluid samples collected from the medial prefrontal cortex and hippocampus of male and female offspring. Analysis showed significantly increased glutamate levels in both brain structures analyzed, regardless of the sex of the offspring. These changes were accompanied by altered expression of the EAAT1, VGLUT1, and x
c - proteins in these brain structures. This animal study further confirms our previous findings that a maternal high-sugar diet has a detrimental effect on the glutamatergic system.- Published
- 2022
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4. Identification of optimal reference genes for gene expression studies in a focal cerebral ischaemia model-Spatiotemporal effects.
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Pomierny B, Krzyzanowska W, Jurczyk J, Strach B, Skorkowska A, Leonovich I, Budziszewska B, and Pera J
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- Actins genetics, Animals, Gene Expression, Gene Expression Profiling methods, Male, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Reference Standards, Brain Ischemia genetics, Glyceraldehyde-3-Phosphate Dehydrogenases genetics
- Abstract
A proper reference gene (RG) is required to reliably measure mRNA levels in biological samples via quantitative reverse transcription PCR (RT-qPCR). Various experimental paradigms require specific and stable RGs. In studies using rodent models of brain ischaemia, a variety of genes, such as β-actin (Actb), hypoxanthine phosphoribosyltransferase 1 (Hprt1), peptidyl-propyl isomerase A (Ppia) and glyceraldehyde-3-phosphate dehydrogenase (Gapdh), are used as RGs. However, most of these genes have not been validated in specific experimental settings. The aim of this study was to evaluate the time- and brain region-dependent expression of RG candidates in a rat model of transient middle cerebral artery occlusion (tMCAO). The following genes were selected: Actb, Hprt1, Ppia, Gapdh, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta (Ywhaz) and beta-2 microglobulin (B2m). Focal cerebral ischaemia was induced by 90 min of tMCAO in male Sprague-Dawley rats. Expression was investigated at four time points (12 and 24 h; 3 and 7 days) and in three brain areas (the frontal cortex, hippocampus and dorsal striatum) within the ischaemic brain hemisphere. The RT-qPCR results were analysed using variance analysis and the ΔCt, GeNorm, NormFinder and BestKeeper methods. Data from these algorithms were ranked using the geometric mean of ranks of each analysis. Ppia, Hprt1 and Ywhaz were the most stable genes across the analysed brain areas and time points. B2m and Actb exhibited the greatest fluctuations, and the results for Gapdh were ambiguous., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2022
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5. Pharmacokinetic/Pharmacodynamic Assessment of Selective Phosphodiesterase Inhibitors in a Mouse Model of Autoimmune Hepatitis.
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Świerczek A, Pomierny B, Wyska E, and Jusko WJ
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- 3',5'-Cyclic-AMP Phosphodiesterases, Animals, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Disease Models, Animal, Interleukin-17, Male, Mice, Mice, Inbred BALB C, Phosphodiesterase 3 Inhibitors, Tumor Necrosis Factor-alpha, Hepatitis, Autoimmune drug therapy, Phosphodiesterase Inhibitors pharmacology
- Abstract
Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment of autoimmune disorders. This study develops a pharmacokinetic/pharmacodynamic (PK/PD) model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH. The pharmacokinetics of the PDE inhibitors (PDEi) were assessed in male BALB/c mice after intraperitoneal administration. In pharmacodynamic studies, mice received PDEi and AIH was induced in these animals by intravenous injection of concanavalin A (ConA). Serum drug concentrations, tumor necrosis factor α (TNF α ), interleukin 17 (IL-17), and aminotransferase activities were quantified. The PK/PD analysis was performed using ADAPT5 software. The PK/PD model assumes inhibition of cAMP hydrolysis in T cells by PDEi, ConA-triggered formation of TNF α and IL-17, suppression of TNF α and IL-17 production by cAMP, and stimulatory effects of TNF α and IL-17 on the hepatic release of aminotransferases. Selective blockage of PDE4 leads to the highest inhibition of cAMP degradation in T cells and amelioration of disease outcomes. However, inhibition of both PDE3 and PDE7 also contribute to this effect. The proposed PK/PD model may be used to assess and predict the activities of novel PDEi and their combinations in ConA-induced hepatitis. A balanced suppression of different types of PDE appears to be a promising treatment option for AIH; however, this hypothesis warrants testing in humans based on translation of the PK/PD model into clinical settings. SIGNIFICANCE STATEMENT: A novel PK/PD model of PDE inhibitor effects in mice with ConA-induced autoimmune hepatitis was developed involving a mechanistic component describing changes in cAMP concentrations in mouse T cells. According to model predictions, inhibition of PDE4 in T cells causes the highest cAMP elevation in T cells, but suppression of PDE3 and PDE7 also contribute to this effect. A balanced inhibition of PDE3, PDE4, and PDE7 appears to be a promising treatment strategy for AIH., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
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- 2022
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6. Metabolic benefits of novel histamine H 3 receptor ligands in the model of excessive eating: The importance of intrinsic activity and pharmacokinetic properties.
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Mika K, Szafarz M, Bednarski M, Kuder K, Szczepańska K, Pociecha K, Pomierny B, Kieć-Kononowicz K, Sapa J, and Kotańska M
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- Adipose Tissue drug effects, Animals, Body Weight drug effects, C-Peptide blood, Carrier Proteins blood, Cholesterol blood, Energy Intake drug effects, Female, Glucose Tolerance Test, Histamine Agonists administration & dosage, Histamine Agonists chemistry, Histamine Antagonists administration & dosage, Histamine Antagonists chemistry, Injections, Intraperitoneal, Insulin blood, Insulin Resistance, Leptin blood, Ligands, Metformin administration & dosage, Metformin pharmacology, Models, Animal, Obesity drug therapy, Obesity metabolism, Rats, Wistar, Triglycerides blood, Rats, Feeding Behavior drug effects, Histamine Agonists pharmacokinetics, Histamine Agonists pharmacology, Histamine Antagonists pharmacokinetics, Histamine Antagonists pharmacology, Receptors, Histamine H3 metabolism
- Abstract
Aims: One of the therapeutic approaches in the treatment of obesity is the use of histamine H
3 receptor ligands. Histamine plays a significant role in eating behavior because it causes a loss of appetite and is considered to be a satiety signal released during food intake., Material and Methods: Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored., Results: Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders., Conclusion: The presented study proves that search among the active histamine H3 receptor ligands for the new therapeutic agents to treat obesity is justified. Compounds KSK-61 and KSK-63 can be considered as the leading structures., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2021
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7. The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H 2 S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia.
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Pomierny B, Krzyżanowska W, Jurczyk J, Skórkowska A, Strach B, Szafarz M, Przejczowska-Pomierny K, Torregrossa R, Whiteman M, Marcinkowska M, Pera J, and Budziszewska B
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- Animals, Brain Ischemia etiology, Brain Ischemia metabolism, Brain Ischemia pathology, Hydrogen Sulfide analysis, Male, Mitochondria drug effects, Organophosphorus Compounds administration & dosage, Protective Agents administration & dosage, Rats, Rats, Sprague-Dawley, Thiones administration & dosage, Brain Ischemia prevention & control, Hydrogen Sulfide metabolism, Infarction, Middle Cerebral Artery complications, Mitochondria metabolism, Organophosphorus Compounds pharmacology, Protective Agents pharmacology, Thiones pharmacology
- Abstract
Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H
2 S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2 S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2 S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR -sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.- Published
- 2021
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8. Evaluation of Biofilm Formation and Prevalence of Multidrug-Resistant Strains of Staphylococcus epidermidis Isolated from Neonates with Sepsis in Southern Poland.
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Skiba-Kurek I, Nowak P, Empel J, Tomczak M, Klepacka J, Sowa-Sierant I, Żak I, Pomierny B, and Karczewska E
- Abstract
Staphylococcus epidermidis strains play an important role in nosocomial infections, especially in the ones associated with biofilm formation on medical devices. The paper was aimed at analyzing the mechanisms of antibiotic resistance and confirming the biofilm-forming ability among S. epidermidis strains isolated from the blood of hospitalized newborns. Genetic analysis of resistance mechanism determinants included multiplex PCR detection of mecA , ermA , ermB, ermC , msrA , and mef genes. Biofilm analysis comprised phenotypic and genotypic methods including Christensen and Freeman methods and PCR detection of the ica ADB gene complex. Among the tested S. epidermidis strains, 89% of the isolates were resistant to methicillin, 67%-to erythromycin, 53%-to clindamycin, 63%-to gentamicin, and 23%-to teicoplanin, while all the strains were susceptible to vancomycin and linezolid. The mecA gene was detected in 89% of the isolates, the ermC gene was the most common and present among 56% of the strains, while the msrA gene was observed in 11% isolates. Eighty-five percent of the strains were described as biofilm-positive by phenotypic methods and carried the icaADB gene cluster. Multidrug resistance and the biofilm-forming ability in most of the strains tested may contribute to antimicrobial therapy failure ( p < 0.05).
- Published
- 2021
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9. MH-76, a Novel Non-Quinazoline α 1 -Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats.
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Kubacka M, Mogilski S, Zadrożna M, Nowak B, Szafarz M, Pomierny B, Marona H, Waszkielewicz A, Jawień W, Sapa J, Bednarski M, Knutelska J, and Kotańska M
- Abstract
Background: Quinazoline α
1 -adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1 -adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α1 -adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1 -adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats., Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed., Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307., Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.- Published
- 2021
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10. The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours.
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Chamera K, Kotarska K, Szuster-Głuszczak M, Trojan E, Skórkowska A, Pomierny B, Krzyżanowska W, Bryniarska N, and Basta-Kaim A
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- Animals, Antigens, CD metabolism, Brain metabolism, CX3C Chemokine Receptor 1 metabolism, Chemokine CX3CL1 metabolism, Female, Male, Pregnancy, Rats, Rats, Wistar, Receptors, Immunologic metabolism, Schizophrenia metabolism, Brain drug effects, Lipopolysaccharides pharmacology, Poly I-C pharmacology, Prenatal Exposure Delayed Effects metabolism, Signal Transduction drug effects
- Abstract
Background: The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes., Methods: We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student's t test., Results: We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40, Il-1β, Tnf-α, Arg1, Tgf-β and Il-10, as well as IBA1, IL-1β and IL-4, while after Poly I:C-generated MIA in levels of Cd40, iNos, Il-6, Tgf-β, Il-10, and IBA1, IL-1β, TNF-α, IL-6, TGF-β and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype., Conclusions: Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.
- Published
- 2020
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11. The impact of 3,4-methylendioxymetamphetamine (MDMA) abstinence on seeking behavior and the expression of the D 2 -like and mGlu 5 receptors in the rat brain using saturation binding analyses.
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Frankowska M, Miszkiel J, Pomierny-Chamiolo L, Pomierny B, Celeste Borelli A, Suder A, and Filip M
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- Amphetamine-Related Disorders physiopathology, Amphetamine-Related Disorders psychology, Animals, Brain metabolism, Brain physiopathology, Cues, Housing, Animal, Male, Rats, Wistar, Social Isolation, Amphetamine-Related Disorders metabolism, Behavior, Animal drug effects, Brain drug effects, Central Nervous System Stimulants pharmacology, Drug-Seeking Behavior drug effects, N-Methyl-3,4-methylenedioxyamphetamine pharmacology, Receptor, Metabotropic Glutamate 5 metabolism, Receptors, Dopamine D2 metabolism
- Abstract
The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D
2 -like and metabotropic glutamate type 5 (mGlu5 ) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2 -like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2 -like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2 -like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2 -like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.- Published
- 2020
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12. Preliminary study on Se-enriched Lentinula edodes mycelium as a proposal of new feed additive in selenium deficiency.
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Muszyńska B, Szacawa E, Bederska-Łojewska D, Dudek K, Pomierny B, Włodarczyk A, Kała K, Lazur J, Suchocki P, Budziszewska B, Bednarek D, and Pieszka M
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- Animals, Cattle, Soil, Animal Feed, Food, Fortified, Selenium, Shiitake Mushrooms
- Abstract
The presence of selenium in European soil is low and this causes its deficiency in livestock and, in consequence, in humans. This study aimed to obtain Lentinula (L.) edodes mycelium with the maximum content of selenium. This species was used for experiment based on its documented medicinal properties. Calves were fed with selenium-enriched L. edodes mycelium, and serum selenium concentration, average daily weight gains and selected immune parameters were estimated. The selenium-enriched mushroom was found to be safe based on cytotoxicity tests (MTT and LDH tests) and for this reason it was used for further experiments. The mean quantity of selenium in the serum of calves fed with selenium-enriched L. edodes mycelium was significantly higher than that of control calves. Additionally, the calves fed with selenium-enriched L. edodes mycelium had higher body weight gains than those of control calves. White blood cell counts and subpopulations of lymphocytes in the experimental and control calves were within the reference range. The administration of L. edodes enriched with selenium had a beneficial effect on state of health of the calves., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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13. Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia.
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Krzyżanowska W, Pomierny B, Bystrowska B, Pomierny-Chamioło L, Filip M, Budziszewska B, and Pera J
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- Acetylcysteine administration & dosage, Animals, Astrocytes drug effects, Astrocytes metabolism, Brain Ischemia genetics, Brain Ischemia pathology, Ceftriaxone administration & dosage, Frontal Lobe drug effects, Frontal Lobe metabolism, Gene Expression Regulation drug effects, Hippocampus drug effects, Hippocampus metabolism, Humans, Infarction, Middle Cerebral Artery, Rats, Synaptic Transmission drug effects, Amino Acid Transport Systems, Acidic genetics, Brain Ischemia drug therapy, Excitatory Amino Acid Transporter 2 genetics, Glutamic Acid metabolism
- Abstract
One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.
- Published
- 2017
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14. Existence of Brain 5-HT1A-5-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor-Receptor Interactions Regulating 5-HT1A Receptor Recognition.
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Borroto-Escuela DO, Li X, Tarakanov AO, Savelli D, Narváez M, Shumilov K, Andrade-Talavera Y, Jimenez-Beristain A, Pomierny B, Díaz-Cabiale Z, Cuppini R, Ambrogini P, Lindskog M, and Fuxe K
- Abstract
Studies on serotonin-selective reuptake inhibitors have established that disturbances in the ascending 5-HT neuron systems and their 5-HT receptor subtypes and collateral networks to the forebrain contribute to the etiology of major depression and are targets for treatment. The therapeutic action of serotonin-selective reuptake inhibitors is of proven effectiveness, but the mechanisms underlying their effect are still unclear. There are many 5-HT subtypes involved; some need to be blocked (e.g., 5-HT2A, 5-HT3, and 5-HT7), whereas others need to be activated (e.g., postjunctional 5-HT1A and 5-HT4). These state-of-the-art developments are in line with the hypothesis that the development of major depression can involve an imbalance of the activity between different types of 5-HT isoreceptors. In the current study, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5-HT1A-5-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET
2 ) assay. A high density of PLA-positive clusters visualizing 5-HT1A-5-HT2A isoreceptor complexes was demonstrated in the pyramidal cell layer of the CA1-CA3 regions of the dorsal hippocampus. A marked reduction in the density of PLA-positive clusters was observed in the CA1 and CA2 regions 24 h after a forced swim test session, indicating the dynamics of this 5-HT isoreceptor complex. Using a bioinformatic approach, previous work indicates that receptors forming heterodimers demonstrate triplet amino acid homologies. The receptor interface of the 5-HT1A-5-HT2A isoreceptor dimer was shown to contain the LLG and QNA protriplets in the transmembrane and intracellular domain, respectively. The 5-HT2A agonist TCB2 markedly reduced the affinity of the 5-HT1A agonist ipsapirone for the 5-HT1A agonist binding sites in the frontal lobe using the 5-HT1A radioligand binding assay. This action was blocked by the 5-HT2A antagonist ketanserin. It is proposed that the demonstrated 5-HT1A-5-HT2A isoreceptor complexes may play a role in depression through integration of 5-HT recognition, signaling and trafficking in the plasma membrane in two major 5-HT receptor subtypes known to be involved in depression. Antagonistic allosteric receptor-receptor interactions appear to be involved in this integrative process.- Published
- 2017
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15. Glutamate transporters in brain ischemia: to modulate or not?
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Krzyżanowska W, Pomierny B, Filip M, and Pera J
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- Amino Acid Transport Systems, Acidic metabolism, Animals, Brain metabolism, Brain pathology, Brain Ischemia metabolism, Brain Ischemia pathology, Glutamate Plasma Membrane Transport Proteins drug effects, Glutamate Plasma Membrane Transport Proteins metabolism, Humans, Synaptic Transmission drug effects, Treatment Outcome, Vesicular Glutamate Transport Proteins metabolism, Amino Acid Transport Systems, Acidic drug effects, Brain drug effects, Brain Ischemia therapy, Glutamic Acid metabolism, Ischemic Preconditioning, Neuroprotective Agents therapeutic use, Vesicular Glutamate Transport Proteins drug effects
- Abstract
In this review, we briefly describe glutamate (Glu) metabolism and its specific transports and receptors in the central nervous system (CNS). Thereafter, we focus on excitatory amino acid transporters, cystine/glutamate antiporters (system xc-) and vesicular glutamate transporters, specifically addressing their location and roles in CNS and the molecular mechanisms underlying the regulation of Glu transporters. We provide evidence from in vitro or in vivo studies concerning alterations in Glu transporter expression in response to hypoxia or ischemia, including limited human data that supports the role of Glu transporters in stroke patients. Moreover, the potential to induce brain tolerance to ischemia through modulation of the expression and/or activities of Glu transporters is also discussed. Finally we present strategies involving the application of ischemic preconditioning and pharmacological agents, eg β-lactam antibiotics, amitriptyline, riluzole and N-acetylcysteine, which result in the significant protection of nervous tissues against ischemia.
- Published
- 2014
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16. Potential neurotoxic effect of ethylene glycol ethers mixtures.
- Author
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Pomierny B, Starek A, Krzyżanowska W, Starek-Swiechowicz B, Smaga I, Pomierny-Chamioło L, Regulska M, and Budziszewska B
- Subjects
- Animals, Apoptosis drug effects, Caspase 3 metabolism, Cerebral Cortex metabolism, Frontal Lobe metabolism, Frontal Lobe pathology, Hippocampus metabolism, Lipid Peroxidation drug effects, Nerve Degeneration, Neurotoxicity Syndromes metabolism, Neurotoxicity Syndromes pathology, Oxidative Stress drug effects, Rats, Rats, Wistar, Cerebral Cortex drug effects, Ethers toxicity, Ethylene Glycols toxicity, Frontal Lobe drug effects, Hippocampus drug effects, Neurotoxicity Syndromes etiology
- Abstract
Background: Ethylene glycol ethers (EGEs) are widely used as mixtures in various industrial processes and in many household products. 2-Methoxyethanol and 2-ethoxyethanol primarily exert gonadotoxic effect, while 2-butoxyethanol and 2-isopropoxyethanol have potent hemolytic activity. EGEs can cross the blood-brain barrier, but their potential neurodegenerative action in vivo has not been investigated, yet. In the present work, we examined potential adverse effects of EGEs on some selected brain structures., Methods: A mixture of two compounds: one with stronger hydrophilic properties (2-methoxyethanol or 2-ethoxyethanol) and the second more lipophilic (2-butoxyethanol or 2-isopropoxyethanol) were administered sc for 4 weeks. Total antioxidant capacity, lipid peroxidation and caspase-3 activity were determined in the frontal cortex and hippocampus., Results: It has been found that 4-week administration of a mixture of two EGEs, with various intensity, decreased total antioxidant capacity, enhanced lipid peroxidation and increased caspase-3 activity in the frontal cortex and hippocampus of Wistar rat., Conclusion: The obtained results suggested that EGEs exerted adverse effects on the CNS cells and may contribute in pathogenesis of neurodegenerative disorders.
- Published
- 2013
- Full Text
- View/download PDF
17. Effects of ethylene glycol ethers on cell viability in the human neuroblastoma SH-SY5Y cell line.
- Author
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Regulska M, Pomierny B, Basta-Kaim A, Starek A, Filip M, Lasoń W, and Budziszewska B
- Subjects
- Cell Line, Tumor, Humans, Hydrogen Peroxide pharmacology, Hydrogen Peroxide toxicity, Neuroblastoma, Neurons physiology, Cell Survival drug effects, Ethylene Glycols pharmacology, Neurons drug effects
- Abstract
Ethylene glycol ethers (EGEs) are a class of chemicals used extensively in the manufacture of a wide range of domestic and industrial products, which may result in human exposure and toxicity. Hematologic and reproductive toxicity of EGEs are well known whereas their action on neuronal cell viability has not been studied so far. In the present study, we investigated the effects of some EGEs on cell viability and on the hydrogen peroxide-induced damage in the human neuroblastoma (SH-SY5Y) cells. It has been found that 2-phenoxyethanol in a concentration-dependent manner (5-25 mM, 24 h) increased the basal and H(2)O(2)-induced lactate dehydrogenase (LDH) release and 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction. 2-Butoxyethanol given alone did not affect LDH release and MTT reduction but concentration-dependently enhanced the cytotoxic effect of H(2)O(2). 2-Isopropoxyethanol significantly and concentration-dependently (1-25 mM) increased the basal LDH release and attenuated MTT reduction, but did not potentiate the cytotoxic effect of H(2)O(2). Contrary to this, 2-methoxyethanol did not show a cytotoxic effect while 2-ethoxyethanol at high concentrations intensified the hydrogen peroxide action. This study demonstrated that among the EGEs studied, 2-phenoxyethanol showed the most consistent cytotoxic effect on neurons in in vitro conditions and enhanced the hydrogen peroxide action. 2-Isopropoxyethanol had also a potent cytotoxic effect, but it did not enhance the hydrogen peroxide action, whereas 2-butoxyethanol only potentiated cytotoxic effect of H(2)O(2). It is concluded that the results of the present study should be confirmed in in vivo conditions and that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be responsible for initiation or exacerbation of neuronal cell damage.
- Published
- 2010
- Full Text
- View/download PDF
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