Репозиторий Университета

© 2020 Elsevier B.V. Herein, the synthesis, design, and the physicochemical characterization of phosphorus functionalized thiazolotriazole (PFT) compound are presented. The PFT tests on the biological activity revealed butyrylcholinesterase inhibition that was confirmed and explained with molecular docking studies. The pronounced reduction of optical density and biological activity was found as a result of irradiation of the PFT water solution with laser beam at wavelength 266 nm. The observed phenomenon was explained on the base of molecular dynamics, docking, and density functional theory modeling by the formation of PFT conformers via laser-induced phosphonate group twisting. The reorganization of the PFT geometry was found to be a reason of butyrylcholinesterase inhibition mechanism change and the site-specificity loss. These results demonstrate that PFT combines photoswitching and bioactive properties in one molecule that makes it promising as a molecular basis for the further design of bioactive substances with photosensitive properties based on the mechanism of the phosphonate group phototwisting.

© 2019 Elsevier B.V. A high-performance thin-layer chromatography (HPTLC) method combined with effect-directed-analysis (EDA) was developed to screen the antioxidant, neuroprotective and antidiabetic effects in essential oils derived from lavender flower, lemon myrtle, oregano, peppermint, sage, and rosemary leaves (Lamiaceae family). HPTLC hyphenated with microchemical (DPPH•, p-anisaldehyde, and ferric chloride) derivatizations, was used to evaluate antioxidant activity, presence of phytosterols and terpenoids, and polyphenolic content, while the combination with biochemical (α-amylase and acetylcholine esterase (AChE) enzymatic) derivatizations was used to asses α-amylase and AChE inhibitory activities. The superior antioxidant activity of oregano leaf extract is attributed to the presence of high levels of aromatic compounds, like polyphenolic acids. The strongest α-amylase inhibition was observed in lemon myrtle and rosemary plus extracts due to the presence of monoterpenes. Rosemary and sage extracts exhibit the highest AChE inhibition activity, with 1 μL essential oils being more potent than the recommended daily dose of donepezil. This superior neuroprotection was attributed to the presences of di- and triterpenes that displayed strong AChE inhibition and antioxidant potential in DPPH• free radical assay. Antioxidant activity was related to phenolic content (R = 0.49), while α-amylase inhibitory activity was positively related to antioxidant activity (R = 0.20) and terpenoid/sterol content (R = 0.31). AChE inhibitory activity was correlated (R = 0.80) to the combined effect of phenolics and terpenoids. Thus, the superior AChE inhibitory and neuroprotection potential of rosemary and sage essential oils could be attributed to joint effects of main phenolic and terpene constituents. The hyphenated HPTLC method provided rapid bioanalytical profiling of highly complex essential oil samples.

© 2019 Federation of European Biochemical Societies Neurotoxins are among the main components of scorpion and snake venoms. Scorpion neurotoxins affect voltage-gated ion channels, while most snake neurotoxins target ligand-gated ion channels, mainly nicotinic acetylcholine receptors (nAChRs). We report that scorpion venoms inhibit α-bungarotoxin binding to both muscle-type nAChR from Torpedo californica and neuronal human α7 nAChR. Toxins inhibiting nAChRs were identified as OSK-1 (α-KTx family) from Orthochirus scrobiculosus and HelaTx1 (κ-KTx family) from Heterometrus laoticus, both being blockers of voltage-gated potassium channels. With an IC50 of 1.6 μm, OSK1 inhibits acetylcholine-induced current through mouse muscle-type nAChR heterologously expressed in Xenopus oocytes. Other well-characterized scorpion toxins from these families also bind to Torpedo nAChR with micromolar affinities. Our results indicate that scorpion neurotoxins present target promiscuity.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Objectives. To study the expression of various neurotransmitter transporters (glutamate, aspartate, lactate, choline) in cultures of astrocytes from different part of the brain (cortex, hippocampus, and brainstem) in rats aged three and 11 days. Materials and methods. An experimental study was performed using 24 Rattus norvegicus rats aged three (n = 12) and 11 days (n = 12). High-throughput sequencing results were analyzed. Results. Expression of the glutamate and aspartate transporters in the brainstem in three-day-old rats was greater than in other areas, though the reverse pattern was seen in rats aged 11 days. Expression of the lactate transporter with age was identical to that in the cortex. Conclusions. The data obtained here demonstrated the nature of neuroastrocyte relationships and the role of astrocytes in the process of signal transmission. The results of the study, carried out using original methods of investigating neurotransmitter transporters, allow them to be recommended for monitoring the processes of neurogenesis and neurohomeostasis, including in cerebrovascular and neurodegenerative diseases.

© 2018 Pharmascope Publications. All rights reserved. To study the function of the endothelium in conducting vascular pharmacological samples in normal and blocking the synthesis of nitric oxide by ultrasound examination of the velocity of central blood flow in the femoral artery in comparison with the changes in systemic hemodynamics and the linear velocity of microcirculatory flow using laser flowmetry. It was studied the parameters of the blood flow velocity (the maximum systolic and diastolic velocity, average systolic and diastolic velocity, Gosling index of pulsatility and resistance index by the Doppler ultrasound Minimax-Doppler-K), the parameters of central circulation ("Biopac-systems MP-150", AcqKnowledge 4.2, USA), and linear velocity of the microcirculatory flow of the musculus vastus medialis (Biopac MP-150, USA) in intact animals and rats with N-Ni-tro-L-arginine methyl ester (L-NAME) induced deficiency of nitric oxide. Quantitative evaluation of endothelial dysfunction in the conduct of pharmacological tests with endothelium-dependent (acetylcholine) and endothe-lium-independent (sodium nitroprusside) vasodilatation is most indicative in calculating the coefficient reflecting the ratio of vascular responses areas in intact rats with L-NAME induced deficiency of nitric oxide. Blood flow parameters (the maximum systolic velocity, the calculated difference between systolic and diastolic velocities) showed a high correlation, both with mean arterial pressure and a linear velocity of the microcirculatory flow. We conclude, that ultrasound Doppler were reflected in the systemic and local vascular response to the administration of vasodilators. It allows an assessment of endothelial function by using the Minimax-Doppler-K device.

© 2018 Zlobin, Mokrushina, Terekhov, Zalevsky, Bobik, Stepanova, Aliseychik, Kartseva, Panteleev, Golovin, Belogurov, Gabibov and Smirnov. Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70. Histidine residue acts as general base thus leading to attacking water molecule activation and subsequent SN2 inline hydrolysis resulting in BChE reactivation. This combination resembles canonical catalytic triad found in active centers of various proteases. Carboxyl group activates histidine residue by altering its pKa, which in turn promotes the activation of water molecule in terms of its nucleophilicity. Observed re-protonation of catalytic serine residue at position 198 from histidine residue at position 438 recovers initial configuration of the enzyme's active center, facilitating next catalytic cycle. We therefore suggest that utilization of uHTS platform in combination with deciphering of molecular mechanisms by QM/MM calculations may significantly improve our knowledge of enzyme function, propose new strategies for enzyme design and open new horizons in generation of catalytic bioscavengers against OP poisons.

© 2018, Media Sphera Publishing Group. All rights reserved. The main groups of neuroprotectors, which are active in preventing the processes of the death of the nerve cells of vascular, traumatic, toxic and other etiologies and can decrease the severity of cognitive impairment, include phosphatidylcholine, phosphatidylserine, preparations based on ginkgo biloba, group B vitamins, folic acid. Preparations based on ginkgo biloba have the same effect as synthetic nootropics. The antioxidant and membrane-stabilizing effects of neuroprotectors are highlighted. In view of practical applications, attention is given to the advantages of the combinations of different neuroprotectors. Cerebrovin as one of these drugs can be recommended for treatment of cognitive impairment in the elderly.

© 2018 Ima-Press Publishing House. All Rights Reserved. Objective: to investigate the effectiveness of cognitive and motor training as an additional method to basic therapy in patients with Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Patients and methods: The investigation enrolled 41 patients (15 women and 26 men; mean age. 73.59±6.3 years), including 32 patients with AD (mean age 74.94±5.15 years) and 9 patients with VCI (mean age, 72.31±4.98 years). Cognitive impairment (CI) corresponded to mild dementia in 15 patients (5 women and 10 men; mean age 74.6±2.8 years) and to moderate dementia in 29 (10 women and 19 men; mean age 72.1±3.2 years). The patients were randomly assigned to individual, group, and mixed (individual and then group) cognitive training groups. Quantitative scales were used to assess changes in CI and emotional and behavioral disorders after 1.5, 3, and 6 months of therapy. Results and discussion: During cognitive and motor training, all the groups showed a significant decrease in the severity of CI (p < 0.05), depression, anxiety, and apathy. The effectiveness of the training was further influenced by the severity of concomitant cardiovascular disease, the degree of apathy, adherence to the training, and the early initiation of basic symptomatic therapy. The greatest positive changes in anxiety and depressive disorders were noted in the patients receiving group cognitive and motor training. Conclusion: The results of the investigation allow group cognitive and motor training to be recommended as a mainstay in the therapy of patients with CI concurrent with emotional disorders.

© 2018 Ima-Press Publishing House. All rights reservbed. Dementia develops as a result of continuous long-term progression of less severe cognitive impairment (CI). Social and psychological methods (neurocognitive stimulation and neurocognitive training) are the mainstay of treatment for dementia. At the moment, there are no drugs both to cure dementia and to stop the degeneration of nerve tissue. Modern pharmacotherapy for dementia aims to maintain cognitive functions in the patient for as long as possible and to slow down disability, thus ensuring higher living standards. CI therapy most often consists of compensation for cognitive defect. Among the whole variety of pharmacological agents, the effective drugs to treat dementia are only two groups, such as acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. Atypical neuroleptics are employed for the treatment of psychotic disorders; antidepressants from a group of selective serotonin reuptake inhibitors are for depression. Cognitive behavioral therapy and cognitive stimulation deserve special attention. A high educational level and physical, social, and intellectual and activities can prevent dementia.

© Team of authors, 2018. Objective. To investigate the expression of transporters of different neurotransmitters (glutamate, aspartate, lactate, choline) in the culture of astrocytes isolated from different regions of the brain (cortex, hippocampus and brainstem) in 3- and 11-day rats. Material and methods. An experimental study was performed on 24 3-(n=12) and 11-days (n=12) old rats (Rattus norvegicus). The results of high-performance sequencing were analyzed. Results. The expression of glutamate and aspartate transporters in the brainstem of 3-day rats was higher than in other regions, however, an opposite effect was observed in 11-day rats. The expression of lactate transporters with age became identical to those of the cortex. Conclusion. The data demonstrate the particular qualities of neuro-astrocytic connections and the important role of astrocytes in signal transmission. Results of the study performed by using genetic methods developed by the authors for the study of neurotransmitter transporters make it possible to recommend these methods to control the neurogenesis and neurohomeostasis, including in cerebrovascular and neurodegenerative diseases.

© 2018 Izdatel'stvo Meditsina. All rights reserved. The problem of childbearing in patients with myasthenia gravis (MG) is extremely important, since the disease most often affects women in the reproductive period. Has not yet been determined neither the prognostic criteria for myasthenia exacerbation during pregnancy, nor the predictors for the development of the transient neonatal myasthenia gravis (TNM). The article analyzes the literature data from the first descriptions of pregnancy in patients with myasthenia and TNM until the present days. The evolution of the concept of the role of a high titer of antibodies to acetylcholine receptors (anti-AChR Ab) in the development of exacerbations of MG in the mother and TNM in her newborn is shown. The role of Ab against γ-subunits of AChR in the development of arthrogryposis and THM is discussed. The importance of planning the pregnancy in myasthenic mothers is emphasized. These observations show that the same woman has either a favorable course of MG with the birth of a healthy child, or has a severe exacerbation until the postpartum myasthenic crisis with the birth of baby with TNM depending on quality of remission before pregnancy. Based on the literature data and own experience, the indisputable role of thymectomy in the prevention of exacerbations of MG and TNM is shown. Own observation of cases of TNM demonstrates the crucial role of neostigmine test in the recognizing of «floppy baby» syndrome. For the first time in Russia, a study of anti-fetal/anti-adult AChR Ab ratio in the umbilical cord blood was conducted. For the first time in the world, a unique case of the birth of a healthy child in a couple of patients with juvenile MG is presented. The husband suffering of the severe refractory MG with elevated titre of anti-AChR Ab up to 20.8 nmol/l and a lot of congenital stigmas of dysembryogenesis. The wife had a mild course of MG. She was carefully prepared for pregnancy by thymectomy and glucocorticoid-therapy and had a stable condition for more than 10 years at the time of pregnancy. The titer of anti-AChR Ab was relatively low (9.0 nmol/L), however, the pool of anti-AChR Ab in the umbilical cord blood mainly contained anti-fetal AChR AB (92%). This example shows that it is the quality of remission of the mother's MG at the time of pregnancy determines the course of the disease during pregnancy and the risks of TNM. This case allows us to consider genetic factors as secondary and once again emphasizes the autoimmune nature of myasthenia gravis.

© 2018 Ima-Press Publishing House. All rights reserved. Chronic cerebral ischemia (CCI) is one of the most common diagnoses in middle-aged and elderly patients in the practice of an outpatient neurologist. Unfortunately, the diagnosis of CCI in these patients is often established only on the basis of complaints of headache, dizziness, instability during walking, and lower mood. At the same time, other diseases that cause these symptoms are not diagnosed, patients do not receive treatment, which considerably worsens quality of life and leads to anxiety and depression. A variety of diseases, such as headache, peripheral vestibular vertigo, depression, Alzheimer's disease, and Parkinson's syndrome, are frequently hidden under the diagnosis of CCI. The leading neurological syndrome in CCI is cognitive impairment that can be both moderate and reach the level of dementia. Approximately 40% of patients with chronic cerebrovascular disease complain of headache that is usually caused by mixed primary headache. The management tactics for a CCI patient suffering from headache is aimed at treating primary headache, modifying vascular risk factors, and managing cognitive impairment. The paper discusses the use of choline alphoscerate in patients diagnosed with CCI.

© 2018 Park-media, Ltd. In this paper, we, for the first time, describe the interaction between the butyrylcholinesterase enzyme and echothiophate, a popular model compound and an analogue of the chemical warfare agents VX and VR, at the atomistic level. Competition between the two echothiophate conformations in the active site was found using molecular modeling techniques. The first one is close to the mode of binding of the substrates of choline series (butyrylcholine and butyrylthiocholine) and is inhibitory, since it is unable to react with the enzyme. The second one is characterized by a significantly worse estimated binding affinity and is reactive. Thus, echothiophate combines the features of two types of inhibitors: competitive and suicidal. This observation will help clarify the kinetic reaction scheme in order to accurately assess the kinetic constants, which is especially important when designing new butyrylcholinesterase variants capable of full-cycle hydrolysis of organophosphorus compounds.

© 2018 by the Serbian Biological Society. The aim of this study was to assess the effects of DL-homocysteine (DL-Hcy) and DL-homocysteine thiolactone (DL-Hcy TLHC) on selected serum biochemical parameters, markers of oxidative stress and the activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)) in the plasma, as well as on acetylcholinesterase (AChE) activity in the cardiac tissue homogenate in the rat. Male Wistar rats were divided into three groups as follows: control group (1 mL 0.9% NaCl, intraperitoneal (i.p.) injection), DL-Hcy group (8 mmol/kg body mass (b.m.), i.p.) or DL-Hcy TLHC group (8 mmol/kg b.m., i.p.). One hour after administration, the rats were euthanized, whole blood was collected for biochemical analysis, and the heart was excised. Following the i.p. administration of DL-Hcy and DL-Hcy TLHC, the activities of antioxidant enzymes were mostly significantly increased, while plasma malondialdehyde (MDA) was decreased. Administration of DL-Hcy and DL-Hcy TLHC significantly inhibited AChE activity in rat cardiac tissue. Our findings suggest that DL-Hcy and DL-Hcy TLHC exerted prooxidant effects; however, the decrease in MDA points to an inverse response to the increase in antioxidant enzyme activities. While both substances inhibited AChE activity in rat cardiac tissue, DL-Hcy TLHC induced stronger effects than DL-Hcy.

Acetylcholinesterase inhibitors are widely used for a variety of medical, agricultural and public health purposes. Consequently, exposure is highly possible during lifetime. However, their systematic use raises concerns for the potential impact on the fetus and newborn since these substances may affect angiogenesis, the neonatal and maternal intensive care, neuroimmune function and response, mammary growth/lactation via cholinergic/non-cholinergic central and peripheral neuroendocrine pathways. New methodologies, neuroscientific technologies and research studies are needed to harness existing knowledge along with the proper management, availability for new acetylcholinesterase inhibitors, with stable pharmacodynamics and clinical outcomes.

Acetylcholinesterase inhibitors are widely used for a variety of medical, agricultural and public health purposes. Consequently, exposure is highly possible during lifetime. However, their systematic use raises concerns for the potential impact on the fetus and newborn since these substances may affect angiogenesis, the neonatal and maternal intensive care, neuroimmune function and response, mammary growth/lactation via cholinergic/non-cholinergic central and peripheral neuroendocrine pathways. New methodologies, neuroscientific technologies and research studies are needed to harness existing knowledge along with the proper management, availability for new acetylcholinesterase inhibitors, with stable pharmacodynamics and clinical outcomes.