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Functionality of a bicistronic construction containing HEXA and HEXB genes encoding β-hexosaminidase A for cell-mediated therapy of GM2 gangliosidoses

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Neural Regeneration Research 2022年第1期17卷 122-129页

作者： Alisa A.Shaimardanova Daria S.Chulpanova valeriya v.solovyeva Aleksandr M.Aimaletdinov Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia

Tay-Sachs disease and Sandhoff disease are severe hereditary neurodegenerative disorders caused by a deficiency ofβ-hexosaminidase A(HexA)enzyme,which results in the accumulation of GM2 gangliosides in the nervous system cells.In this work,we analyzed the efficacy and safety of cell-mediated gene therapy for Sandhoff disease and Sandhoff disease using a bicistronic lentiviral vector encoding cDNA of HexAα-andβ-subunit genes separated by the nucleotide sequence of a P2A peptide(HEXA-HEXB).The functionality of the bicistronic construct containing the HEXA-HEXB genetic cassette was analyzed in a culture of HEK293T cells and human umbilical cord blood mononuclear cells(hUCBMCs).Our results showed that the enzymatic activity of HexA in the conditioned medium harvested from genetically modified HEK293T-HEXA-HEXB and hUCBMCs-HEXA-HEXB was increased by 23 and 8 times,respectively,compared with the conditioned medium of native cells.Western blot analysis showed that hUCBMCs-HEXA-HEXB secreted both completely separated HEXA and HEXB proteins,and an uncleaved protein containing HEXA+HEXB linked by the P2A peptide.Intravenous injection of genetically modified hUCBMCs-HEXA-HEXB to laboratory Wistar rats was carried out,and the HexA enzymatic activity in the blood plasma of experimental animals,as well as the number of live cells of immune system organs(spleen,thymus,bone marrow,lymph nodes)were determined.A significant increase in the enzymatic activity of HexA in the blood plasma of laboratory rats on days 6 and 9(by 2.5 and 3 times,respectively)after the administration of hUCBMCsHEXA-HEXB was shown.At the same time,the number of live cells in the studied organs remained unchanged.Thus,the functionality of the bicistronic genetic construct encoding cDNA of the HEXA and HEXB genes separated by the nucleotide sequence of the P2A peptide was shown in vitro and in vivo.We hypothesize that due to the natural ability of hUCBMCs to overcome biological barriers,such a strategy can restore the activity of the missing enzyme in the ce

关键词： bicistronic vector cell-mediated gene therapy GM2 gangliosidosis P2A peptide Sandhoff disease Tay-Sachs disease umbilical cord blood mononuclear cells β-hexosaminidase

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Increasingβ-hexosaminidase A activity using genetically modified mesenchymal stem cells

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Neural Regeneration Research 2024年第1期19卷 212-219页

作者： Alisa A.Shaimardanova Daria S.Chulpanova valeriya v.Solovуeva Shaza S.Issa Aysilu I.Mullagulova Angelina A.Titova Yana O.Mukhamedshina Anna v.Timofeeva Alexander M.Aimaletdinov Islam R.Nigmetzyanov Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Department of Histology Cytology and EmbryologyKazan State Medical UniversityKazanRussia

GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorde rs.These diseases result from a deficiency of lysosomal enzymeβ-hexosaminidase A(HexA),which is responsible for GM2 ganglioside degradation.HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells,leading to severe progressive neurodegeneration and neuroinflammation.To date,there is no treatment for these diseases.Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses.This study aimed to evaluate the ability of genetically modified mesenchymal stem cells(MSCs-HEXA-HEXB)to restore HexA deficiency in Tay-Sachs disease patient cells,as well as to analyze the functionality and biodistribution of MSCs in vivo.The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon intera ction with MSCs-HEXA-HEXB.The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme,detectable in vivo,and intravenous injection of the cells does not cause an immune response in animals.These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses.

关键词： adeno-associated viral vectors cell therapy cell-mediated gene therapy gene therapy GM2 gangliosidosis Sandhoff disease Tay-Sachs disease β-hexosaminidase

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Extracellular vesicles in the diagnosis and treatment of central nervous system diseases

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Neural Regeneration Research 2020年第4期15卷 586-596页

作者： Alisa A.Shaimardanova valeriya v.solovyeva Daria S.Chulpanova victoria James Kristina v.Kitaeva Albert A.Rizvanov Institute of Fundamental Medicine and Biology Kazan Federal UniversityKazanRussia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry The Russian Academy of SciencesMoscowRussia School of veterinary Medicine and Science University of NottinghamSutton Bonington CampusLeicestershireUK

Extracellular vesicles,including exosomes and microvesicles,play a fundamental role in the activity of the nervous system,participating in signal transmission between neurons and providing the interaction of central nervous system with all body systems.In many neurodegenerative diseases,neurons pack toxic substances into vesicles and release them into the extracellular space,which leads to the spread of misfolded neurotoxic proteins.The contents of neuron-derived extracellular vesicles may indicate pathological changes in the central nervous system,and the analysis of extracellular vesicle molecular content contributes to the development of non-invasive methods for the diagnosis of many central nervous system diseases.Extracellular vesicles of neuronal origin can be isolated from various biological fluids due to their ability to cross the blood-brain barrier.Today,the diagnostic potential of almost all toxic proteins involved in nervous system disease pathogenesis,specificallyα-synuclein,tau protein,superoxide dismutase 1,FUS,leucine-rich repeat kinase 2,as well as some synaptic proteins,has been well evidenced.Special attention is paid to extracellular RNAs mostly associated with extracellular vesicles,which are important in the onset and development of many neurodegenerative diseases.Depending on parental cell type,extracellular vesicles may have different therapeutic properties,including neuroprotective,regenerative,and anti-inflammatory.Due to nano size,biosafety,ability to cross the blood-brain barrier,possibility of targeted delivery and the lack of an immune response,extracellular vesicles are a promising vehicle for the delivery of therapeutic substances for the treatment of neurodegenerative diseases and drug delivery to the brain.This review describes modern approaches of diagnosis and treatment of central nervous system diseases using extracellular vesicles.

关键词： biomarkers cell-mediated therapy central nervous system diseases diagnosis exosomes extracellular RNAs extracellular vesicles microRNAs microvesicles neurodegenerative diseases

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Change of photosensitizer fluorescence at its diffusion in viscous liquid flow

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Journal of Innovative Optical Health Sciences 2016年第2期9卷 25-30页

作者： valeriya S.Maryakhina vyacheslav v.Gun'kov Orenburg State University 13 Pobedy st. Orenburg 460018Russia

In this paper,the mathematical model of distribution of the injected compound in biological liquid flow has been described.It is considered that biological liquid contains a few phases such as water,peptides and cells.The injected compound(for example,photosensitizer)can interact with peptides and cells.At the time,viscosity of the biological liquid depends on pathology present in organism.The obtained distribution of the compound connects on changes of its fluorescence spectra which are registered during fluorescent diagnostics of tumors.It is obtained that the curves do not have monotonic nature.There is a sharp curves decline in the first few seconds after injection.Intensivity of curves rises after decreasing.It is especially pronounced for wavelength 590 nm and 580 nm(near the"transparency window"of biological tissues).Time of inflection point shifts from 8.4 s to 6.9 s for longer wavelength.However,difference between curves is little for di®erent viscosity means of the biological liquid.Thus,additional pathology present in organism does not impact to the results of in vivo biomedical investigations.

关键词： Fluorescence diffusion biomedical diagnostics photosensitizer viscosity

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Facile Synthesis of Amino Acid Decorated Water-Soluble Fullerene Derivatives with Anti-influenza Activity

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Chinese Journal of Chemistry 2023年第15期41卷 1803-1808页

作者： valeriya S.Bolshakova Ekaterina O.Sinegubova Yana L.Esaulkova Alexander S.Peregudov Ekaterina A.Khakina Nikita A.Slesarenko Alexander F.Shestakov vladimir v.Zarubaev Pavel A.Troshin Olga A.Kraevaya Federal Research Center for Problems of Chemical Physics and Medicinal Chemistry of RAS Academician Semenov ave.1Chernogolovka142432Russia Higher Chemical College of RAS D.1.Mendeleev University of Chemical Technology of RussiaMiusskaya square 9Moscow125047Russia St.Petersburg Pasteur Institute Mira st.14St.Petersburg197101Russia A.N.Nesmeyanov Institute of Organoelement compounds of RAS Vavylova St.28B-334Moscow119991Russia National Research University Higher School of Economics Vavylova St.7Moscow101000Russia Department of Fundamental Physics&Chemical Engineering M.V.Lomonosov Moscow State UniversityLeninskie Gory 1/51Moscow119991Russia Zhengzhou Research Institute Harbin Institute of TechnologyLongyuan East 7th 26Jinshui DistrictZhengzhouHenan 450003China Harbin Institute of Technology West Dazhi Street 92Nan Gang DistrictHarbinHeilongjiang 150001China

Comprehensive Summary Herein,we present a facile synthesis of amide-type water-soluble fullerene derivatives decorated with five residues of amino acids.As compared to the previously developed approaches,the proposed method enables usage of a broad range of amino acids,including those unstable under Friedel-Crafts reaction conditions.Furthermore,it is fully tolerant to the nature of the sixth addend X in C60R5X precursor compounds and allows one to obtain fullerene derivatives with X=Cl,H,alkyl.The synthesized amide-type water-soluble fullerene derivatives demonstrated promising antiviral activities against rimantadine-resistant influenzaА/Puerto Rico/8/34(Н1N1)virus in vitro.

关键词： Fullerenes Amino acids Regioselectivity Water-solublel Influenza Antiviral

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Expression of auxin synthesis gene tms1 under control of tuber-specific promoter enhances potato tuberization in vitro

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Journal of Integrative Plant Biology 2015年第9期57卷 734-744页

作者： Oksana O.Kolachevskaya valeriya v.Alekseeva Lidiya I.Sergeeva Elena B.Rukavtsova Irina A.Getman Dick vreugdenhil Yaroslav I.Buryanov Georgy A.Romanov Signaling Systems Laboratory Timiryazev Institute of Plant Physiology Russian Academy of Sciences Plant Biotechnology Laboratory Branch of Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences Laboratory of Plant Physiology Wageningen University Department of Molecular Basis of Ontogenesis Belozersky Institute of Physico-Chemical Biology Moscow State University

Phytohormones, auxins in particular, play an important role in plant development and productivity. Earlier data showed positive impact of exogenous auxin on potato (Solanum tuberosum L.) tuberization. The aim of this study was to generate potato plants with increased auxin level predominantly in tubers. To this end, a pBinB33-tms1 vector was constructed harboring the Agrobacterium auxin biosynthesis gene tms1 fused to tuber-specific promoter of the class I patatin gene (B33-promoter) of potato. Among numerous independently generated B33:tms1 lines, those without visible differences from control were selected for detailed studies. In the majority of transgenic lines, tms1 gene transcription was detected, mostly in tubers rather than in shoots. Indoleacetic acid (IAA) content in tubers and the auxin tuber-to-shoot ratio were increased in tms1-expressing transformants. The organ-specific increase in auxin synthesis in B33:tms1-transformants accelerated and intensified the process of tuber formation, reduced the dose of carbohydrate supply required for in vitro tuberization, and decreased the photoperiodic dependence of tuber initiation. Overall, a positive correlation was observed between tms1 expression, IAA content in tubers, and stimulation of tuber formation. The revealed properties of B33:tms1 transformants imply an important role for auxin in potato tuberization and offer prospects to magnify potato productivity by a moderate organ-specific enhancement of auxin content.

关键词： Auxin gene expression Solanum tuberosum tms1 transgenic potato tuberization tuber yield

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Features of structure of external layer of murine hair at different stages of malignant tumor development

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Journal of Innovative Optical Health Sciences 2015年第3期8卷 3-8页

作者： valeriya S.Maryakhina Larisa S.Scheglova Ksenia A.Anenkova Institute of Micro-and Nanotechnologies Orenburg State University 13 Pobedy st. Orenburg 460018Russia Molecular Physics Department M.v.Lomonosov Moscow State University 1 Leninskiye Gory Moscow 119991Russia

In the paper,the results of experimental investigations on the diferences of wool structure ofhealthy mice and mice with malignant tumor(s)are represented.It is shown that destruction ofwool structure happens during pathology development.Quantity of cells of external wool layerand their thickness decrease when the tumor capsule enlarges.Difference is seen even when thetumor is small.The obtained results can be used to improve optical techniques of biomedicaldiagnostics of cancer diseases.

关键词： Breast cancer hair optical biomedical diagnost ics atomic force microscopy dynamiclight scattering

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Berberine Attenuated Aging-Accelerating Effect of High Temperature in Drosophila Model

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American Journal of Plant Sciences 2014年第3期5卷 275-278页

作者： valeriya Navrotskaya Gregory Oxenkrug Lyudmila vorobyova Paul Summergrad Tufts University School of Medicine Tufts Med-ical Center Boston USA v. N. Karazin Kharkiv National University Kharkiv Ukraine

We have observed that berberine prolonged life span and improved viability of pupae and climbing activity of imagoes of wild-type Drosophila melanogaster maintained at 23°C. As a continuation of our studies of berberine effect on life span, we were interested to evaluate the effect of berberine of life span in flies maintained at a higher temperature (28°C) known to accelerate aging in wild type flies. Considering that genetically or pharmacologically induced deficiency of TRP conversion into KYN prolonged life span in a Drosophila model, we compared the effects of berberine, a powerful inhibitor of kynurenine (KYN) formation from tryptophan (TRP), on life span in wild type and in Drosophila melanogaster mutants (vermilion) with deficient TRP-KYN metabolism maintained at 23°C and 28°C. High (28°C) ambient temperature decreased life span in both wild type and vermilion flies. Aging accelerating effect of high temperature was more pronounced in Oregon than in vermilion flies (-60% vs. -40% decrease of mean life span, resp). Berberine attenuated the aging-accelerating effect of high temperature. Effect of berberine was more pronounced in Oregon (+46%) than in vermilion (+22%) flies. The obtained data suggested the possible involvement of TRP-KYN metabolism in the aging-acceleration effect of the high temperature and in protective effect of berberine.

关键词： Berberine Life Span Drosophila Melanogaster High Temperature Kynurenine

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The Effect of Quartz Window on Bistability of the Silicon Wafer in Lamp-Based Reactor

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Journal of Materials Science and Chemical Engineering 2020年第1期8卷 54-65页

作者： valeriya P. Prigara Aleksandr N. Kupriyanov vladimir v. Ovcharov valiev Institute of Physics and Technology of Russian Academy of Sciences Yaroslavl Branch Yaroslavl Russia

The effect of a quartz plate (window) on the silicon wafer temperature is studied in the conditions of the combined thermal transfer in a lamp-based chamber for the rapid thermal treatment (RTP) set up. The chamber for RTP is simulated by a radiative-closed thermal system including the influence of quartz window as a spectral filter of lamp emission and a source of emitted thermal radiation. Energy equations for thermal fluxes involved in the heat input and output from the working wafer and quartz window are solved in spectral approximation. The transfer characteristics that are defined by the temperature dependencies of the silicon wafer and the quartz window on the temperature of the heater are accounted. It is shown that temperature bistability in the silicon wafer initiates an induced bistability into the quartz window that does not reveal bistable behavior because of the linear temperature dependence of its total optical characteristics. A possibility for simulation of the quartz window by spectral restriction of the heater radiation is confirmed. The availability of the weak bistable effect in the mode of zero effective heat exchange coefficient of a non-radiative component of the thermal flux removed from the working wafer has been obtained.

关键词： Lamp-Based Rector Silicon Wafer Quartz Window Temperature and Optical Bistability Induced Bistability Effect

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