Publications by authors named "Dagmara Mirowska-Guzel"

66 Publications

Early exposure to paracetamol reduces level of testicular testosterone and changes gonadal expression of genes relevant for steroidogenesis in rats offspring.

Drug Chem Toxicol 2021 Mar 3:1-8. Epub 2021 Mar 3.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology CePT, Warsaw, Poland.

In this study, we investigated the effects of early paracetamol treatment on the testicular level of testosterone and expression of genes important for steroid biosynthesis and reproduction in male rats offspring. Rats were continuously exposed to paracetamol at doses of 5 or 15 mg/kg b.w. during pregnancy and the first two months of the postpartum development. Testosterone level was determined by ELISA. Profile of gene expression for the testicular steroidogenic factors were evaluated using the Real-Time PCR. Our results showed that paracetamol reduces testicular testosterone level and causes compensatory transactivation of genes important for steroidogenesis and reproductive capacity. We have observed significant over-expression of several genes involved in cholesterol transport and steroid biosynthesis e.g., genes for steroidogenic acute regulatory protein, hydroxysteroid dehydrogenases, luteinizing hormone subunit beta, gonadotropin and androgen receptors. Up-regulation of these genes with parallel testosterone reduction in the testicles could be the possible mechanism that maintains and prevents the loss of the steroidogenic function.
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http://dx.doi.org/10.1080/01480545.2021.1892941DOI Listing
March 2021

Antiplatelet drugs and liver fibrosis.

Platelets 2021 Feb 12:1-10. Epub 2021 Feb 12.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT , Warsaw, Poland.

Liver fibrosis results from an imbalance between extracellular matrix formation and degradation. The background of liver fibrosis is chronic inflammation and subsequent microcirculation disturbance including microthrombosis. Platelets actively participate in liver fibrosis not only as a part of the clotting system but also by releasing granules containing important mediators. In fact, platelets may play a dual role in the pathophysiology of liver fibrosis as they are able to stimulate regeneration as well as aggravate the destruction of the liver. Recent studies revealed that antiplatelet therapy correlates with inhibition of liver fibrosis. However, liver impairment is associated with extensive coagulation disorders thus the safety of antiplatelet therapy is an area for detailed exploration. In this review, the role of platelets in liver fibrosis and accompanying hemostatic disorders are discussed. Additionally, results of animal and human studies on antiplatelet drugs in liver disorders and their potential therapeutic utility are presented.
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http://dx.doi.org/10.1080/09537104.2021.1883574DOI Listing
February 2021

Aspalathus linearis infusion affects hole-board test behaviour and amino acid concentration in the brain.

Neurosci Lett 2021 03 30;747:135680. Epub 2021 Jan 30.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology CePT, Banacha 1b, 02-097, Warsaw, Poland.

Rooibos tea, brewed using Aspalathus linearis leaves, is a popular South African herbal infusion, but its everyday intake is not fully described in terms of the neuropsychopharmacological outcomes. The cell-protective activity of A. linearis is connected with the ability of reducing glycaemia, inflammation as well as oxidative stress. It was already shown that "fermented" rooibos herbal tea (FRHT), which is rich in phenolic compounds, improves the cognitive performance of rats in the water maze and impacts dopaminergic striatal transmission. The present research was taken to extend the knowledge about the feasible behavioural and neurochemical implications of sustained oral FRHT consumption. We hypothesized that it might affect brain amino acid content and thus induce behaviour and neuroprotection. FRHTs of different leaf to water ratios (1:100, 2:100 and 4:100), analysed by chromatographic methods as regards their flavonoid characteristics, were given to rats as only liquid for 3 months. Their behaviour was evaluated in the hole-board test (HBT). Brain amino acids concentration was analysed in the striatum, hippocampus and prefrontal cortex by HPLC-ECD. The rats drinking rooibos tea presented increased motor activity defined as time spent on moving in the HBT. Their exploration measured by head-dipping and rearing was enhanced. Longer time of the testing-box central zone occupation indicated to reduction in anxiety-related behaviour. Excitatory amino acids (aspartate and glutamate) content was decreased in the striatum of animals drinking the infusions whereas taurine level was increased both in the striatum and hippocampus. In conclusion we suggest that long-term FRHT intake affects exploration and anxiety-related behaviour of the rats as well as exerts biochemical outcomes in the brain that support the neuroprotective impact of rooibos tea.
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http://dx.doi.org/10.1016/j.neulet.2021.135680DOI Listing
March 2021

The Importance of Non-Coding RNAs in Neurodegenerative Processes of Diabetes-Related Molecular Pathways.

J Clin Med 2020 Dec 23;10(1). Epub 2020 Dec 23.

Centre for Preclinical Research and Technology, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 02-091 Warsaw, Poland.

Diabetes mellitus (DM) is a complex condition and serious health problem, with growing occurrence of DM-associated complications occurring globally. Persistent hyperglycemia is confirmed as promoting neurovascular dysfunction leading to irreversible endothelial cell dysfunction, increased neuronal cell apoptosis, oxidative stress and inflammation. These collaboratively and individually result in micro- and macroangiopathy as well as neuropathy demonstrated by progressive neuronal loss. Recently, major efforts have been pursued to select not only useful diagnostic and prognostic biomarkers, but also novel therapeutic approaches. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a class of non-coding RNAs identified in most of the body fluids i.e., peripheral blood, cerebrospinal fluid, brain tissue and neurons. Numerous miRNAs, lncRNAs and their target genes are able to modulate signaling pathways known to play a role in the pathophysiology of progressive neuronal dysfunction. Therefore, they pose as promising biomarkers and treatment for the vast majority of neurodegenerative disorders. This review provides an overall assessment of both miRNAs' and lncRNAs' utility in decelerating progressive nervous system impairment, including neurodegeneration in diabetic pathways.
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http://dx.doi.org/10.3390/jcm10010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793080PMC
December 2020

Effect of protocatechuic acid on cognitive processes and central nervous system neuromodulators in the hippocampus, prefrontal cortex, and striatum of healthy rats.

Nutr Neurosci 2020 Dec 21:1-12. Epub 2020 Dec 21.

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Warsaw, Poland.

Objective: : This study aimed to investigate the influence of protocatechuic acid (PCA) on learning, memory, and central nervous system (CNS) neuromodulators in healthy rats, to analyse whether the procognitive effects of PCA found in animal models of memory impairment and described in the literature occur in healthy individuals.

Methods: : PCA was administered for 48 days at doses of 50 or 100 mg/kg body weight. The cognitive performance was analysed in behavioural tests (open field, novel object recognition, water maze). Then the animals were sacrificed and their hippocampi, prefrontal cortices and striata removed to measure the level of serotonin, dopamine (DA), noradrenaline, their metabolites and amino acids (taurine, histidine, serine, glutamic acid, aspartic acid, γ-aminobutyric acid, alanine) using high-performance liquid chromatography.

Results: : No obvious behavioural changes were observed. Post-mortem quantification of monoamines showed that the turnover of DA in the striatum was significantly increased by PCA. Moreover, hippocampal, and cortical levels of histidine were influenced by PCA and significantly decreased.

Conclusion: : Despite many beneficial effects of PCA in experimentally developed cognitive impairments, it has no sharp effect on memory performance in healthy rats. The influence on the turnover of striatal DA and modulation of the amino acid system by affecting the concentration of histidine deserves a deeper examination due to the role of histamine in neuropsychiatric disorders as well as the functional interactions between histidine and DA metabolism in the brain.
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http://dx.doi.org/10.1080/1028415X.2020.1859728DOI Listing
December 2020

Long Non-coding RNAs as Promising Therapeutic Approach in Ischemic Stroke: a Comprehensive Review.

Mol Neurobiol 2021 Apr 24;58(4):1664-1682. Epub 2020 Nov 24.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B str., Warsaw, 02-097, Warsaw, Poland.

In recent years, ischemic stroke (IS) has been one of the major causes of disability and mortality worldwide. The general mechanism of IS is based on reduced blood supply to neuronal tissue, resulting in neuronal cell damage by various pathological reactions. One of the main techniques for acute IS treatment entails advanced surgical approaches for restoration of cerebral blood supply but this is often associated with secondary brain injury, also known as ischemic reperfusion injury (I/R injury). Many researches have come to emphasize the significant role of long non-coding RNAs (lncRNAs) in IS, especially in I/R injury and their potential as therapeutic approaches. LncRNAs are non-protein transcripts that are able to regulate cellular processes and gene expression. Further, lncRNAs have been shown to be involved in neuronal signaling pathways. Several lncRNAs are recognized as key factors in the physiological and pathological processes of IS. In this review, we discuss the role of lncRNAs in neuronal injury mechanisms and their association with brain neuroprotection. Moreover, we identify the lncRNAs that show the greatest potential as novel therapeutic approaches in IS, which therefore merit further investigation in preclinical research. Graphical Abstract.
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http://dx.doi.org/10.1007/s12035-020-02206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932985PMC
April 2021

Are adipokines associated with atrial fibrillation in type 2 diabetes?

Endokrynol Pol 2020 ;71(1):34-41

1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.

Introduction: The potential effect of adipokines on the development of AF is yet to be established. The aim of this study was to investigate the association of baseline serum adipokines with 1) the presence of AF at baseline and 2) future risk of AF development.

Material And Methods: The current study is a sub-analysis of the prospective, randomised AVOCADO (Aspirin Vs./Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes) trial. The AVOCADO study included patients with type 2 DM burdened with at least two additional cardiovascular risk factors and receiving acetylsalicylic acid. In patients included in the current analysis adipokines and inflammatory biomarker levels were measured. Information on the subsequent AF diagnosis was collected after a median of 5.4 years of follow-up.

Results: A total of 273 patients with type 2 DM (median age 68 years; 52% male) were included in the initial analysis comparing patients with and without AF at baseline. Patients with diagnosed AF (12%) had higher levels of serum resistin [8.5 (5.8-10.5) vs. 6.9 (5.6-8.7) ng/mL; p = 0.034], adiponectin [6.9 (5.6-8.7) vs. 2.7 (1.8-4.2) ng/mL; p = 0.032], and N-terminal pro-B-type natriuretic peptide [336 (148-473) vs. 108 [45-217]; p < 0.001) than non-AF patients. There were no significant differences in serum leptin, IL-6, and TNF-alpha concentrations between the two groups. From subjects without known AF at study entry, 19% developed AF at follow-up. In logistic regression analysis, baseline adipokine levels did not predict AF development.

Conclusion: In type 2 DM, patients with AF have higher resistin and adiponectin concentrations than patients with no AF. None of the studied adipokines proved a predictor of future AF development.
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http://dx.doi.org/10.5603/EP.a2019.0059DOI Listing
January 2020

Are adipokines associated with atrial fibrillation in type 2 diabetes?

Endokrynol Pol 2020 ;71(1):34-41

1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.

Introduction: The potential effect of adipokines on the development of AF is yet to be established. The aim of this study was to investigate the association of baseline serum adipokines with 1) the presence of AF at baseline and 2) future risk of AF development.

Material And Methods: The current study is a sub-analysis of the prospective, randomised AVOCADO (Aspirin Vs./Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes) trial. The AVOCADO study included patients with type 2 DM burdened with at least two additional cardiovascular risk factors and receiving acetylsalicylic acid. In patients included in the current analysis adipokines and inflammatory biomarker levels were measured. Information on the subsequent AF diagnosis was collected after a median of 5.4 years of follow-up.

Results: A total of 273 patients with type 2 DM (median age 68 years; 52% male) were included in the initial analysis comparing patients with and without AF at baseline. Patients with diagnosed AF (12%) had higher levels of serum resistin [8.5 (5.8-10.5) vs. 6.9 (5.6-8.7) ng/mL; p = 0.034], adiponectin [6.9 (5.6-8.7) vs. 2.7 (1.8-4.2) ng/mL; p = 0.032], and N-terminal pro-B-type natriuretic peptide [336 (148-473) vs. 108 [45-217]; p < 0.001) than non-AF patients. There were no significant differences in serum leptin, IL-6, and TNF-alpha concentrations between the two groups. From subjects without known AF at study entry, 19% developed AF at follow-up. In logistic regression analysis, baseline adipokine levels did not predict AF development.

Conclusion: In type 2 DM, patients with AF have higher resistin and adiponectin concentrations than patients with no AF. None of the studied adipokines proved a predictor of future AF development.
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http://dx.doi.org/10.5603/EP.a2019.0059DOI Listing
January 2020

The Relation of the Brain-Derived Neurotrophic Factor with MicroRNAs in Neurodegenerative Diseases and Ischemic Stroke.

Mol Neurobiol 2021 Jan 17;58(1):329-347. Epub 2020 Sep 17.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Banacha 1B Str., 02-097, Warsaw, Poland.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.
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http://dx.doi.org/10.1007/s12035-020-02101-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695657PMC
January 2021

Non-Vitamin K Oral Anticoagulants (NOAC) Versus Vitamin K Antagonists (VKA) for Atrial Fibrillation with Elective or Urgent Percutaneous Coronary Intervention: A Meta-Analysis with a Particular Focus on Combination Type.

J Clin Med 2020 Apr 14;9(4). Epub 2020 Apr 14.

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, 02097 Warsaw, Poland.

Background: Our study aims to perform a meta-analysis of benefits and risks associated with the use of non-vitamin K oral anticoagulants (NOAC) versus vitamin K antagonists (VKA) in patients with a percutaneous coronary intervention (PCI) with a particular focus on the combination type: dual vs. dual antithrombotic therapy (DAT: NOAC + single antiplatelet therapy (SAPT) vs. DAT: VKA + SAPT), dual vs. triple antithrombotic therapy (DAT: NOAC + SAPT vs. TAT: VKA + dual antiplatelet therapy (DAPT)) or triple vs. triple antithrombotic therapy (TAT: NOAC+DAPT vs. TAT: VKA+DAPT).

Methods: PubMed, EMBASE, and Cochrane databases were searched to identify randomized controlled trials comparing antithrombotic regimens. Four randomized studies (n = 10.969; PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI) were included. The primary outcome was the composite of major bleeding defined by the International Society on Thrombosis and Hemostasis (ISTH) and clinically relevant bleeding requiring medical intervention (CRNM). Secondary outcomes included all-cause mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and stent thrombosis (ST).

Results: Combination strategies with NOACs were associated with reduced risk of major bleeding events across different combination strategies as compared to VKA, with the most significant risk reduction when DAT was compared with TAT, namely DAT with NOAC + SAPT was associated with a 37% relative risk reduction (RRR) of major bleeding events as compared to TAT with VKA + DAPT (RR 0.63; 95% CI, 0.50-0.80). The reduction of major bleeding risks is a class effect of NOACs. Combination strategies of NOACs vs. VKAs resulted in a comparable risk of MACE, MI, stroke, ST, or death.

Conclusions: Antithrombotic combinations of NOACs (as DAT or TAT) are safer than VKAs with respect to bleeding risk and result in a satisfactory efficacy with no increase of ischemic or thrombotic events in patients undergoing PCI.
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http://dx.doi.org/10.3390/jcm9041120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230168PMC
April 2020

Demographic and clinical profile of patients with multiple sclerosis diagnosed over the last 30 years according to different diagnostic criteria.

Neurol Neurochir Pol 2020 3;54(2):169-175. Epub 2020 Apr 3.

Centre for Preclinical Research and Technology (CePT), Department of Experimental and Clinical Pharmacology, Medical University of Warsaw.

The aim of this study was to investigate the demographic and clinical characteristics of patients with multiple sclerosis (MS) diagnosed between 1986 and 2015. 333 patients with definite MS were divided into four subgroups according to the following diagnostic criteria: Group A) Poser (n = 145), Group B) McDonald 2000 (n = 66), Group C) McDonald 2005 (n = 62), and Group D) McDonald 2010 (n = 60). We investigated: 1) patient sex and age at diagnosis, 2) symptoms and number of relapses that prompted MS diagnosis, 3) time between first symptoms suggestive of MS and confirmed diagnosis, and 5) Expanded Disability Status Scale (EDSS) score at disease onset. The overall female-to-male ratio was 2.3:1, but in the subgroups it differed significantly (A - 1.9; B - 1.6; C - 4.7; D - 3.6). The mean age at diagnosis (in years) decreased from 39.6 ± 13.3 in Group A to 29.9 ± 9.3 in Group D, p < 0.001. Pyramidal signs remained the most common manifestation regardless of the diagnostic criteria, although an increased trend of visual dysfunction was observed (A - 16%, B - 14%, C - 19%, D - 23,3%; A vs D, p < 0.001). The number of relapses before diagnosis decreased from median 4.0 to 2.5 in Group A and Group D, p < 0.001. Time from the first symptom to diagnosis shortened from 88.9 ± 80.2 months (Group A) to 33.6 ± 68.2 months (Group D), p < 0.0001. Mean EDSS score at diagnosis also decreased: A - 4.4 ± 2.3; B - 3.1 ± 1.7; C - 2.7 ± 1.3; D - 2.8 ± 1.4, p < 0.001. Our study indicates significant differences in demographic and clinical characteristics of MS diagnosed according to the changing criteria.
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http://dx.doi.org/10.5603/PJNNS.a2020.0027DOI Listing
July 2020

The role of acetylsalicylic acid and circulating microRNAs in primary prevention of cardiovascular events in patients with Diabetes Mellitus Type 2 - A Review.

Ann Agric Environ Med 2019 Dec 31;26(4):512-522. Epub 2019 Jan 31.

Medical University, Warsaw, Poland.

Introduction: Type 2 diabetes mellitus (T2DM) is a common metabolic disorder, which carries a risk for atherosclerosis and cardiovascular impairment. The purpose of this review is to demonstrate the role of acetylsalicylic acid (ASA) in primary cardiovascular prevention in T2DM patients, as well as present an outline of microRNAs (miRNA) relevant to ASA therapy and should be evaluated as targets to improve treatment.

Brief Description Of State Of Knowledge: Although the etiology of hypercoagulable state in T2DM is considered multifactorial, attention mainly focuses on platelet disturbances. Platelets in T2DM not only demonstrate intensified adhesion, activation, aggregation, and thrombin generation, but are likely to deliver miRNAs at specific sites of action in the cardiovascular system, hence contributing to the pathogenesis of cardiovascular events.

Objective: Since cardiovascular disease (CVD) is currently the leading cause of mortality among T2DM patients, appropriate risk stratification and management is necessary to reduce morbidity and mortality in this group. A large number of T2DM patients show inadequate response to antiplatelet therapy, which currently revolves around ASA, despite compliance with treatment regimens proposed by the guidelines.

Conclusions: The review shows that the use of ASA for primary prevention is beneficial in patients at high cardiovascular risk. However, it is important to select patients in whom ASA therapy will bring the most beneficial outcome with minimal risk for adverse effects. This can be potentially achieved with the use of unique biomarkers. The biologically diverse characteristics of miRNA make them a promising novel biomarker and potential tool for better risk stratification, as well as antiplatelet therapy optimization.
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http://dx.doi.org/10.26444/aaem/100391DOI Listing
December 2019

Effects of ethyl alcohol on injuries severity according to injury severity scales in pedestrian fatal injury in traffic crashes.

Int J Inj Contr Saf Promot 2020 Jun 16;27(2):112-120. Epub 2019 Sep 16.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.

Introduction: The dominant cause of injuries in traffic crashes. A significant portion of them affects victims under the influence of ethyl alcohol. The goal of the studies was to assess the correlation between the state of sobriety and the severity of injuries expressed by injury severity scales in fatal pedestrian victims of traffic crashes. Research Material and Method: The data were obtained from the Warsaw Medical University's Department of Forensic Medicine. The analysis covered the data for 2009-2013 and included 200 fatal pedestrian victims hit by passenger cars. The assessment of the effect of risk factors on injury severity expressed in terms of injury severity scales such as Life Threat Indicator (LTI), International Classification based Injury Severity Score (ICISS), Injury Severity Score (ISS) and New Injury Severity Score (NISS), was made using adequately selected methods of statistical analysis.

Results: As alcohol concentration increases in women, the values of LTI, ICISS-10 and ICISS-15 decrease, which denotes more severe injuries. In the ISS and NISS, the effect of alcohol concentration on the severity of injuries turned out to be negligible. However, these injuries are significantly heavier in women than in men. According to all the scales used, the older the victims, the milder injuries cause their death.

Conclusions: The studies show that ethyl alcohol concentration may harm injury severity, especially in the case of women. The assessment of the severity of injuries in traffic crash victims is significantly influenced by their age and gender. The more risk factors the scale takes into consideration, the more precise is the assessment.
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http://dx.doi.org/10.1080/17457300.2019.1665551DOI Listing
June 2020

The effect of ethyl alcohol on the severity of injuries in fatal pedestrian victims of traffic crashes.

PLoS One 2019 10;14(9):e0221749. Epub 2019 Sep 10.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.

Introduction: A substantial percentage of traffic crashes involve people under the influence of ethyl alcohol. In such circumstances, we speak of the possible effect of ethanol upon trauma outcomes. The present research aimed to assess the state of sobriety fatal pedestrian victims and the correlation between the level of sobriety and the severity of injuries.

Research Material And Method: The data was obtained from the Warsaw Medical University's Department of Forensic Medicine. The analysis covered the data for the period of 2009-2013; it encompassed 158 fatal pedestrian victims hit by passenger cars. The appropriate methods of statistical analysis were applied.

Results: The majority of the fatal pedestrian victims were individuals under the influence of ethyl alcohol (72.15%). Significant correlations were observed between the concentration of ethyl alcohol and the victims' gender (p<0.0001) and age (p = 0.0026). The analysis showed that pedestrians under the influence of ethyl alcohol more often died on the scene (78.95%).

Conclusions: Pedestrians under the influence of ethyl alcohol are a significant group of victims of traffic crashes. Ethyl alcohol is not an independent factor affecting the severity of injuries. A higher percentage of pedestrian victims die on the scene, especially in rural areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736251PMC
March 2020

Are antimigraine drugs that influence CGRP levels justified?

Pharmacol Rep 2019 Aug 12;71(4):624-635. Epub 2019 Mar 12.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology CePT, Warszawa, Poland; 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warszawa, Poland.

Migraine is one of the most common disorders found in everyday clinical practice. Although migraines are not directly life-threatening or permanently disabling, the severity of the pain and symptoms that characterize a migraine attack often prevent normal work and cause difficulties in everyday life. Migraines also affect the patient's family, who often experience stress and depression in response to the patient's condition. Available therapy, used in both acute and chronic treatments, might not provide sufficient improvement. Due to problems like therapy inefficacy, side effects, and intolerance, patients often stop treatments. Recent studies have indicated that drugs that act through calcitonin gene-related peptide (CGRP) can significantly improve migraine therapy. Here, we review results from currently available clinical trials on CGRP receptor antagonists and anti-CGRP monoclonal antibodies.
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http://dx.doi.org/10.1016/j.pharep.2019.03.002DOI Listing
August 2019

EQ-5D studies in nervous system diseases in eight Central and East European countries: a systematic literature review.

Eur J Health Econ 2019 Jun 16;20(Suppl 1):109-117. Epub 2019 May 16.

Department of Health Economics, Corvinus University of Budapest, Fővám tér 8., H-1093, Budapest, Hungary.

Backround: Guidelines for economic analyses of health care technologies require local input data for reimbursement decisions in the countries of Central and Eastern Europe (CEE). The aim of this study was to systematically review and analyse the available empirical studies using the EQ-5D instrument as a measure of the health-related quality of life (HRQoL) in patients with neurological diseases.

Methods: A systematic literature search was performed up to 1st April 2018 to identify relevant studies in eight selected CEE countries. Original articles reporting on studies of neurological diseases using the EQ-5D instrument were analysed.

Results: Thirty-six articles, describing the results of 38 samples of patients and a total of 13,005 patients were included in the review. Most studies were from Hungary (44.4%) and none from Romania or Slovakia. EQ-5D utility scores were reported in 33 (91.7%) articles. In multiple sclerosis (MS) being the most represented disease, the average utility scores ranged from 0.49 in Austria to 0.80 in Poland with a weighted average of 0.69. EQ VAS scores for MS ranged from 39 in Czech Republic to 72.0 in Poland, with weighted average of 59.1. MS patients, together with epilepsy and essential tremor patients, estimated their HRQoL among the highest.

Conclusions: EQ-5D research activity in neurology has been increasing through the years in studied CEE countries. There are clinical areas with the significant social burden, such as a migraine or meningitis, that are completely lacking data, other areas, such as stroke or epilepsy, with very scarce data.
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http://dx.doi.org/10.1007/s10198-019-01068-9DOI Listing
June 2019

Long-term administration of Aspalathus linearis infusion affects spatial memory of adult Sprague-Dawley male rats as well as increases their striatal dopamine content.

J Ethnopharmacol 2019 Jun 16;238:111881. Epub 2019 Apr 16.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology CePT, Banacha 1b, 02-097, Warsaw, Poland. Electronic address:

Ethnopharmacological Relevance: Everyday use of the herbal tea rooibos, produced from Aspalathus linearis (Brum.f) Dahlg. (Fabaceae) is customary in South Africa, a continuation of its historical use by indigenous people. Although evidence of its traditional indications is anecdotal, rooibos tea is regarded as a general health tea.

Aims Of The Study: Available contemporary research indicates to broad cell protective activity of rooibos focusing on its antioxidative, anti-inflammatory, anti-hyperglycaemic and antithrombotic features affecting metabolic syndrome, cardiovascular risk and neuroprotection. Nevertheless little is known about its impact on brain functions. The present experiment aimed to evaluate the possible behavioural and neurochemical effects of long-term oral administration of "fermented" rooibos herbal tea (FRHT) infusions to adult male Sprague-Dawley rats.

Materials And Methods: Infusions, prepared using 1, 2 and 4 g of "fermented" (oxidised) A. linearis leaves for 100 ml of hot water, were characterised in terms of flavonoid content by ultra-high and high performance liquid chromatography (UHPLC-qTOF-MS, HPLC-DAD) and administered to rats as sole drinking fluid for 12 weeks. Spatial memory behaviour was assessed in a modified version of the Morris water maze. Dopamine, noradrenaline, serotonin and their metabolite levels (DOPAC, 3-MT, HVA, MHPG, 5-HIAA) were quantified in prefrontal cortex, hippocampus and striatum by HPLC-ECD. Body weight and blood glucose level were additionally estimated.

Results: All FRHT-treated rats showed improvement of long-term spatial memory defined as increased number of crossings over the previous platform position in SE quadrant of the water maze. It was not accompanied by excessive motor activity. Striatal dopamine and its metabolite 3-MT (3-methoxytyramine) levels were increased in treated rats. There were no differences in body weight gain between control and treated animals but blood glucose level was significantly lower in the latter ones.

Conclusion: The improvement of long-term memory in FRHT-treated rats and stimulating impact of FRHT on their dopaminergic striatal transmission support the wellness enhancing effect of rooibos tea, contributing to a better understanding of the neurological background of traditional habitual consumption of this herbal tea.
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http://dx.doi.org/10.1016/j.jep.2019.111881DOI Listing
June 2019

Administration of protocatechuic acid affects memory and restores hippocampal and cortical serotonin turnover in rat model of oral D-galactose-induced memory impairment.

Behav Brain Res 2019 08 9;368:111896. Epub 2019 Apr 9.

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha 1b, 02-097 Warsaw, Poland. Electronic address:

Protocatechuic acid (PCA) is a phenolic compound believed to have neuroprotective and procognitive activity. d-Galactose (D-Gal) is a sugar, which administered to mammals can induce cognitive deficits. The first aim of this study was to confirm the effectiveness of D-Gal administered orally in inducing cognitive impairment in rats and describe how it affects the concentration of neurotransmitters in rats' brain. The second aim was to evaluate the influence of PCA on learning, memory and neurotransmission in D-Gal-exposed rats. Memory impairment was induced by long-term administration of D-Gal (100 mg/kg body weight/day) directly via oral gavage. PCA (50 or 100 mg/kg body weight/day, respectively) was administered in drinking water. Morris Water Maze test (MWM) to assess learning and spatial memory was initiated after 38 days of treatment and lasted for 10 days. The concentrations of monoamines and their metabolites were evaluated in selected brain regions using high performance liquid chromatography. D-Gal significantly impaired cognitive performance during the acquisition and recall of MWM compared to control rats and changed concentrations of cortical serotonin as well as its cortical and hippocampal turnover. The turnover of dopamine was also influenced by D-Gal. Simultaneously, PCA was found to improve retrieval of acquired information in MWM and to restore brain serotonergic and dopaminergic turnover dysregulated by D-Gal. These findings confirm the usefulness of oral D-Gal in eliciting rat model of mild memory impairment and show that long-term administration of PCA can be beneficial in reversing detrimental changes related to cognitive deficiencies.
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http://dx.doi.org/10.1016/j.bbr.2019.04.010DOI Listing
August 2019

Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke.

Mol Med Rep 2019 Apr 25;19(4):3263-3272. Epub 2019 Feb 25.

Perioperative Genomics Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA.

The impact of rare and damaging variants in genes associated with platelet function in large‑vessel ischemic stroke (LVIS) remains unknown. The aim of this study was to investigate the contribution of some of these variants to the genetic susceptibility to LVIS in Polish patients using a deep re‑sequencing of 54 selected genes, coding for proteins associated with altered platelet function. Targeted pooled re‑sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of LVIS) and 500 age‑, smoking status‑, and sex‑matched controls (no history of any type of stroke), and from the same population as patients with LVIS. After quality control and prioritization based on allele frequency and damaging probability, individual genotyping of all deleterious rare variants was performed in patients from the original cohort, and stratified to concomitant cardiac conditions differing between the study and stroke groups. We demonstrated a statistically significant increase in the number of rare and potentially damaging variants in some of the investigated genes in the LVIS pool (an increase in the genomic variants burden). Furthermore, we identified an association between LVIS and 6 rare functional and damaging variants in the Kv7.1 potassium channel gene (KCNQ1). The predicted functional properties (partial loss‑of function) for the three most damaging variants in KCNQ1 coding locus were further confirmed in vitro by analyzing the membrane potential changes in cell lines co‑transfected heterogeneously with human muscarinic type 1 receptor and wild‑type or mutated KCNQ1 cDNA constructs using fluorescence imaging plate reader. The study demonstrated an increased rare variants burden for 54 genes associated with platelet function, and identified a putative role for rare damaging variants in the KCNQ1 gene on LVIS susceptibility in the Polish population.
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http://dx.doi.org/10.3892/mmr.2019.9987DOI Listing
April 2019

Effects of α-Synuclein Monomers Administration in the Gigantocellular Reticular Nucleus on Neurotransmission in Mouse Model.

Neurochem Res 2019 Apr 13;44(4):968-977. Epub 2019 Feb 13.

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B, 02-097, Warsaw, Poland.

The aim of the study was to examine the Braak's hypothesis to explain the spreading and distribution of the neuropathological changes observed in the course of Parkinson's disease among ascending neuroanatomical regions. We investigated the neurotransmitter levels (monoamines and amino acid concentration) as well as tyrosine hydroxylase (TH) and transglutaminase-2 (TG2) mRNA expression in the mouse striata (ST) after intracerebral α-synuclein (ASN) administration into gigantocellular reticular nucleus (Gi). Male C57BL/10 Tar mice were used in this study. ASN was administrated by stereotactic injection into Gi area (4 μl; 1 μg/μl) and mice were decapitated after 1, 4 or 12 weeks post injection. The neurotransmitters concentration in ST were evaluated using HPLC detection. TH and TG2 mRNA expression were examined by Real-Time PCR method. At 4 and 12 weeks after ASN administration we observed decrease of DA concentration in ST relative to control groups and we found a significantly higher concentration one of the DA metabolites-DOPAC. At these time points, we also noticed the increase in DA turnover determined as DOPAC/DA ratio. Additionally, at 4 and 12 weeks after ASN injection we noted decreasing of TH mRNA expression. Our findings corresponds with the Braak's theory about the presence of the first neuropathological changes within brainstem and then with time affecting higher neuroanatomical regions. These results obtained after administration of ASN monomers to the Gi area may be useful to explain the pathogenesis of Parkinson's disease.
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http://dx.doi.org/10.1007/s11064-019-02732-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437297PMC
April 2019

MicroRNAs as Diagnostic and Prognostic Biomarkers in Ischemic Stroke-A Comprehensive Review and Bioinformatic Analysis.

Cells 2018 Dec 6;7(12). Epub 2018 Dec 6.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, 02-097 Warsaw, Poland.

Stroke is the second-most common cause of death worldwide. The pathophysiology of ischemic stroke (IS) is related to inflammation, atherosclerosis, blood coagulation, and platelet activation. MicroRNAs (miRNAs) play important roles in physiological and pathological processes of neurodegenerative diseases and progression of certain neurological diseases, such as IS. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of IS. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique value as diagnostic and prognostic markers in IS. In this review, we focus on the role of miRNAs as diagnostic and prognostic biomarkers in IS. We discuss the most common and reliable detection methods available and promising tests currently under development. We also present original results from bioinformatic analyses of published results, identifying the ten most significant genes (HMGB1, YWHAZ, PIK3R1, STAT3, MAPK1, CBX5, CAPZB, THBS1, TNFRSF10B, RCOR1) associated with inflammation, blood coagulation, and platelet activation and targeted by miRNAs in IS. Additionally, we created miRNA-gene target interaction networks based on Gene Ontology (GO) information derived from publicly available databases. Among our most interesting findings, miR-19a-3p is the most widely modulated miRNA across all selected ontologies and might be proposed as novel biomarker in IS to be tested in future studies.
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http://dx.doi.org/10.3390/cells7120249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316722PMC
December 2018

Resistin is a prognostic factor for death in type 2 diabetes.

Diabetes Metab Res Rev 2019 02 13;35(2):e3098. Epub 2018 Dec 13.

1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.

Purpose: To investigate the association of leptin, resistin, and tumour necrosis factor α (TNF-α) with prognosis in type 2 diabetes (T2D).

Methods: Analysis included 284 T2D patients. Apart from routine laboratory parameters, baseline leptin, resistin, and TNF-α concentrations were measured. Patients were followed for a median of 5.4 years. The primary endpoint was all-cause death at follow-up. The secondary endpoint was a composite of death, acute coronary syndrome, and stroke or transient ischemic attack.

Results: At baseline, median age was 68 years, and 48% of patients were female. Data on the primary endpoint were obtained for all patients: 32 (11%) died during follow-up. Data on the secondary endpoint were available for 230 patients, of whom 45 (20%) reached the secondary endpoint. In univariate analyses, older age, heart failure, lower-glomerular filtration rate, and higher resistin, TNF-α and NT-proBNP concentrations were predictors of the study endpoints. Of these variables, only resistin remained an independent predictor of both study endpoints in multivariate models. In receiver-operating characteristic analysis, area under the curve for resistin was 0.7. Resistin concentration of greater than or equal to 11.4 ng/mL had sensitivity of 41% and specificity of 91% for prediction of death at follow-up (Youden's index).

Conclusions: Higher resistin is associated with reduced survival in T2D, irrespectively of TNF-α. Resistin concentration of above 11 ng/mL indicates T2D patients at an increased risk of unfavourable outcomes. Leptin was not a prognostic factor. These results suggest that in T2D, association of resistin with unfavourable outcomes might, at least in part, result from its pro-inflammatory properties.
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http://dx.doi.org/10.1002/dmrr.3098DOI Listing
February 2019

Carcinoembryonic antigen and matrix metalloproteinase 2 serum and peritoneal washes concentration in staging and prognosis in colorectal cancer patients.

Pol Przegl Chir 2018 Jun;90(5):36-43

Warszawski Uniwersytet Medyczny Wydział I Lekarski Katedra i Klinika Chirurgii Ogólnej, Gastroenterologicznej i Onkologicznej WUM.

Purpose: The aim of the study was to determine of carcinoembryonal antigen and matrix metalloproteinase 2 peritoneal washes and serum concentration in patients suffering from colorectal cancer concerning tumor staging and 5-year survival rate in these patients.

Methods: 80 patients who underwent curative surgery for colorectal cancer were included into the study. Preoperative serum and intraoperative peritoneal washes CEA and MMP-2 concentrations were measured.

Results: Concerning tumor penetration CEA-s and CEA-p concentration was higher in subsequent stages from T2 to T4. Both CEA-s and CEA-p concentration was lower in T2 comparing to T3 and T4. Significant difference of CEA-s and CEA-p was noted between T2 and T4 stages. MMP2-s concentration was higher in T3 comparing to T2, the highest MMP2-p concentration was in T4, with no statistical significance. Concerning nodular status significant difference of CEA-s was noted between N0 and N1. For CEA-p significance was found between N0 and N2 as between N1 and N2. MMP2-s concentration was the highest in N1, MMP2-p concentration was the highest in T4, with no statistical significance. 5-year survival rate for all patients was 63,53%. There were significant differences in CEA-s and CEA-p concentration between patients with negative and positive 5-year survival.

Conclusion: Intraoperative peritoneal washes concentration of CEA may potentially serve as an important factor for more precise colorectal cancer staging. CEA-p and CEA-s concentration correlates with survival rate in patients suffering from colorectal cancer and can be useful as an additional prognostic factor. Usefulness of MMP2 measurement still requires further studies.
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http://dx.doi.org/10.5604/01.3001.0012.1269DOI Listing
June 2018

Octanoic acid prevents reduction of striatal dopamine in the MPTP mouse model of Parkinson's disease.

Pharmacol Rep 2018 Sep 25;70(5):988-992. Epub 2018 Apr 25.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland.

Background: Parkinson's disease (PD) is a progressive neurodegenerative process leading to the loss of dopaminergic neurons and their projections. 1-methyl-4-phenol-1,2,5,6-tetrahydropyridine (MPTP) toxicity is a well-recognized animal model of PD. It is suggested that the impairment of mitochondrial function in the substantia nigra plays an important role in both the onset and the progression of PD. Octanoic acid (C8), a fatty acid that is the main constituent of the medium-chain triglyceride ketogenic diet, increases the metabolic activity of mitochondria; hence, it seemed interesting to investigate whether C8 exhibits neuroprotective effects in the MPTP model of PD and whether it affects mitochondria function in the striatum.

Methods: Therefore, we examined the possible protective effects of C8 in the mouse model of PD induced by MPTP. For this purpose, changes in the concentration of DA and its metabolites were determined. In addition, we investigated whether expression levels of PGC-1α and the PEPCK enzyme, markers of mitochondrial activity, are altered by C8.

Results: In this study, we observed for the first time that acute and, in particular, repeated administrations of C8 significantly reduced the impairment of dopaminergic neurotransmission in the striatum evoked by MPTP administration and resulted in a marked increase in PGC-1α expression and in both forms of PEPCK.

Conclusions: These results indicate that the C8 leads to an inhibition of the neurodegenerative processes seen after MPTP administration. Our results suggest that a probable mechanism of the neuroprotective action of C8 is related to an increase in metabolic activity in striatal mitochondria.
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http://dx.doi.org/10.1016/j.pharep.2018.04.008DOI Listing
September 2018

Octanoic acid prevents reduction of striatal dopamine in the MPTP mouse model of Parkinson's disease.

Pharmacol Rep 2018 Oct 25;70(5):988-992. Epub 2018 Apr 25.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology (CePT), Warszawa, Poland; Department of Neurochemistry, Institute of Psychiatry and Neurology, Warszawa, Poland.

Background: Parkinson's disease (PD) is a progressive neurodegenerative process leading to the loss of dopaminergic neurons and their projections. 1-methyl-4-phenol-1,2,5,6-tetrahydropyridine (MPTP) toxicity is a well-recognized animal model of PD. It is suggested that the impairment of mitochondrial function in the substantia nigra plays an important role in both the onset and the progression of PD. Octanoic acid (C8), a fatty acid that is the main constituent of the medium-chain triglyceride ketogenic diet, increases the metabolic activity of mitochondria; hence, it seemed interesting to investigate whether C8 exhibits neuroprotective effects in the MPTP model of PD and whether it affects mitochondria function in the striatum.

Methods: Therefore, we examined the possible protective effects of C8 in the mouse model of PD induced by MPTP. For this purpose, changes in the concentration of DA and its metabolites were determined. In addition, we investigated whether expression levels of PGC-1α and the PEPCK enzyme, markers of mitochondrial activity, are altered by C8.

Results: In this study, we observed for the first time that acute and, in particular, repeated administrations of C8 significantly reduced the impairment of dopaminergic neurotransmission in the striatum evoked by MPTP administration and resulted in a marked increase in PGC-1α expression and in both forms of PEPCK.

Conclusions: These results indicate that the C8 leads to an inhibition of the neurodegenerative processes seen after MPTP administration. Our results suggest that a probable mechanism of the neuroprotective action of C8 is related to an increase in metabolic activity in striatal mitochondria.
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http://dx.doi.org/10.1016/j.pharep.2018.04.008DOI Listing
October 2018

Serum Brain-Derived Neurotrophic Factor is Related to Platelet Reactivity and Metformin Treatment in Adult Patients With Type 2 Diabetes Mellitus.

Can J Diabetes 2019 Feb 3;43(1):19-26. Epub 2018 Feb 3.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.

Objectives: The aim of this study was to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with platelet reactivity and antidiabetes treatment, as well as serum adipocytokine concentrations.

Methods: This observational, open-label study enrolled 149 patients. Serum BDNF, hematologic, biochemical parameters and platelet reactivity were measured. Blood samples were taken after the last acetylsalicylic acid dose.

Results: Patients with high BDNF levels were younger (65.60±8.956 vs. 68.59±8.516) and smoked cigarettes more frequently (14.6% vs. 4.1%); they were more commonly being treated by metformin (77.3% vs. 54%); had higher platelet counts (245.81±68.85 10/mm vs. 206.61±44.48 10/mm); had shorter collagen-adenosine diphosphate closure time (CADP-CT) values (104.88±69.73 s vs. 140.93±86.63 s); had higher triglyceride concentrations (140.73±67.5 vs. 121.76±60.49) and had higher concentrations of serum thromboxane B2 (0.938±1.59 vs. 0.364±0.76). In univariate linear regression analyses, predictive factors for serum BDNF levels above the median were metformin treatment, current smoking, platelet count, triglyceride concentration, total cholesterol concentration and CADP-CT >74 s. In multivariate backward stepwise analysis CADP-CT >141 s; adiponectin concentration >4.22 µg/mL; total cholesterol and low-density lipoprotein levels were independently associated with serum BDNF levels above the median.

Conclusions: Our results suggest that BDNF may be associated with lipid metabolism and that increased production of BDNF may be related to metformin treatment. Moreover, we showed an association between BDNF levels and platelet reactivity; we found that serum BDNF levels in patients with type 2 diabetes who had high platelet reactivity were higher than in subjects with normal platelet reactivity despite antiplatelet therapy.
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http://dx.doi.org/10.1016/j.jcjd.2018.01.014DOI Listing
February 2019

Early paracetamol exposure decreases brain-derived neurotrophic factor (BDNF) in striatum and affects social behaviour and exploration in rats.

Pharmacol Biochem Behav 2018 05 13;168:25-32. Epub 2018 Mar 13.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Centre for Preclinical Research and Technology CePT, Banacha 1B, 02-097 Warsaw, Poland.

The biochemical and behavioral responses to prenatal and early postnatal exposure to paracetamol in rats are not well understood. The effect of daily maternal and early life administration of 5 mg/kg (group P5) or 15 mg/kg paracetamol (group P15) was evaluated in two-month old male rats, relative to control animals receiving tap water (Con). Social behavior and episodic memory were investigated with Social Interaction and Novel Object Recognition (NOR) tests. Quantification of brain-derived neurotrophic factor (BDNF) was determined in prefrontal cortex, hippocampus and striatum using enzyme-linked immunosorbent assay (ELISA). Control animals exhibited a higher total frequency of social interactions and greater frequency of sniffing compared to rats exposed to paracetamol, and we found a statistically significant increase in the occurrence of pinning in paracetamol-treated animals. Rats from the 15 mg/kg group exhibited a greater interest in objects in the NOR test and spent more time exploring objects during the familiarization and choice phases. Biochemical analysis showed significant differences in striatal BDNF between the groups, specifically, a nearly two-fold decrease in striatal BDNF in the paracetamol groups (P5: 6.78 ± 0.60 pg/mg; P15: 6.06 ± 0.46 pg/mg) relative to the control group (Con: 11.33 ± 2.00 pg/mg). These results indicate that paracetamol exposure induces changes in social behaviour and exploration in rats and results in a significant decrease of striatal BDNF.
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http://dx.doi.org/10.1016/j.pbb.2018.03.004DOI Listing
May 2018

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

Peptides 2018 04 7;102:68-74. Epub 2018 Mar 7.

Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, the Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration.
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http://dx.doi.org/10.1016/j.peptides.2018.03.004DOI Listing
April 2018

Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1-P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients.

Int J Mol Sci 2017 Dec 11;18(12). Epub 2017 Dec 11.

Perioperative Genomics Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA.

The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. The genes selected for re-sequencing consisted of 26 genes coding for proteins associated with the surface membrane of platelets. Targeted pooled re-sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of large-vessel IS) and 500 controls. After quality control and prioritization based on allele frequency and damaging probability, follow-up individual genotyping of deleterious rare variants was performed in patients from the original cohort. Gene-based analyses identified an association between IS and 6 rare functional and damaging variants in the purinergic genes ( and locus). The predicted properties of the most damaging rare variants in and were confirmed by using mouse fibroblast cell cultures transfected with plasmid constructs containing cDNA of mutated variants (FLIPR on FlexStation3). This study identified a putative role for rare variants in and genes involved in platelet reactivity on large-vessel IS susceptibility in a Polish population.
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http://dx.doi.org/10.3390/ijms18122678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751280PMC
December 2017

Antidiabetic Effect of Brain-Derived Neurotrophic Factor and Its Association with Inflammation in Type 2 Diabetes Mellitus.

J Diabetes Res 2017 14;2017:2823671. Epub 2017 Sep 14.

Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which plays an important role in the central nervous system, and systemic or peripheral inflammatory conditions, such as acute coronary syndrome and type 2 diabetes mellitus (T2DM). BDNF is also expressed in several nonneuronal tissues, and platelets are the major source of peripheral BDNF. Here, we reviewed the potential role of BDNF in platelet reactivity in T2DM and its association with selected inflammatory and platelet activation mediators. Besides that, we focused on adipocytokines such as leptin, resistin, and adiponectin which are considered to take part in inflammation and both lipid and glucose metabolism in diabetic patients as previous studies showed the relation between adipocytokines and BDNF. We also reviewed the evidences of the antidiabetic effect of BDNF and the association with circulating inflammatory cytokines in T2DM.
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http://dx.doi.org/10.1155/2017/2823671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618763PMC
June 2018