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6‐Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease 下载免费PDF全文
Dr. Vyacheslav E. Semenov Irina V. Zueva Dr. Marat A. Mukhamedyarov Dr. Sofya V. Lushchekina Dr. Alexandra D. Kharlamova Elena O. Petukhova Dr. Anatoly S. Mikhailov Dr. Sergey N. Podyachev Dr. Lilya F. Saifina Dr. Konstantin A. Petrov Oksana A. Minnekhanova Prof. Vladimir V. Zobov Prof. Evgeny E. Nikolsky Prof. Patrick Masson Prof. Vladimir S. Reznik 《ChemMedChem》2015,10(11):1863-1874
Novel 6‐methyluracil derivatives with ω‐(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron‐withdrawing substituents on the benzyl rings. The compounds are mixed‐type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10 000‐fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6‐methyluracil derivatives are able to penetrate the blood–brain barrier (BBB), inhibiting brain‐tissue AChE. The most potent AChE inhibitor, 3 d (1,3‐bis[5‐(o‐nitrobenzylethylamino)pentyl]‐6‐methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β‐amyloid peptide plaques in the brain. 相似文献
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Sofya A. Ionova Aysylu F. Murtazina Inna S. Tebieva Zalina K. Getoeva Elena L. Dadali Polina A. Chausova Olga A. Shchagina Andrey V. Marakhonov Sergey I. Kutsev Rena A. Zinchenko 《International journal of molecular sciences》2022,23(20)
Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002–0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis. 相似文献
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Arvind Mukundan Shih-Wei Feng Yu-Hsin Weng Yu-Ming Tsao Sofya B. Artemkina Vladimir E. Fedorov Yen-Sheng Lin Yu-Cheng Huang Hsiang-Chen Wang 《International journal of molecular sciences》2022,23(9)
In this study, n-type MoS2 monolayer flakes are grown through chemical vapor deposition (CVD), and a p-type Cu2O thin film is grown via electrochemical deposition. The crystal structure of the grown MoS2 flakes is analyzed through transmission electron microscopy. The monolayer structure of the MoS2 flakes is verified with Raman spectroscopy, multiphoton excitation microscopy, atomic force microscopy, and photoluminescence (PL) measurements. After the preliminary processing of the grown MoS2 flakes, the sample is then transferred onto a Cu2O thin film to complete a p-n heterogeneous structure. Data are confirmed via scanning electron microscopy, SHG, and Raman mapping measurements. The luminous energy gap between the two materials is examined through PL measurements. Results reveal that the thickness of the single-layer MoS2 film is 0.7 nm. PL mapping shows a micro signal generated at the 627 nm wavelength, which belongs to the B2 excitons of MoS2 and tends to increase gradually when it approaches 670 nm. Finally, the biosensor is used to detect lung cancer cell types in hydroplegia significantly reducing the current busy procedures and longer waiting time for detection. The results suggest that the fabricated sensor is highly sensitive to the change in the photocurrent with the number of each cell, the linear regression of the three cell types is as high as 99%. By measuring the slope of the photocurrent, we can identify the type of cells and the number of cells. 相似文献
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Julia D. Vavilova Anna A. Boyko Natalya V. Ponomareva Vitaly F. Fokin Ekaterina Y. Fedotova Maria A. Streltsova Sofya A. Kust Maria V. Grechikhina Ekaterina V. Bril Olga S. Zimnyakova Elena I. Kovalenko Alexander M. Sapozhnikov 《International journal of molecular sciences》2021,22(23)
Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson’s disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57+CD56− T cells and CD57+CD56+ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57+CD56− T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection. 相似文献
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Anastasia I. Palamarchuk Nadezhda A. Alekseeva Maria A. Streltsova Maria O. Ustiuzhanina Polina A. Kobyzeva Sofya A. Kust Maria V. Grechikhina Anna A. Boyko Olga A. Shustova Alexander M. Sapozhnikov Elena I. Kovalenko 《International journal of molecular sciences》2021,22(24)
Nowadays, the use of genetically modified NK cells is a promising strategy for cancer immunotherapy. The additional insertion of genes capable of inducing cell suicide allows for the timely elimination of the modified NK cells. Different subsets of the heterogenic NK cell population may differ in proliferative potential, in susceptibility to genetic viral transduction, and to the subsequent induction of cell death. The CD57−NKG2C+ NK cells are of special interest as potential candidates for therapeutic usage due to their high proliferative potential and certain features of adaptive NK cells. In this study, CD57− NK cell subsets differing in KIR2DL2/3 and NKG2C expression were transduced with the iCasp9 suicide gene. The highest transduction efficacy was observed in the KIR2DL2/3+NKG2C+ NK cell subset, which demonstrated an increased proliferative potential with prolonged cultivation. The increased transduction efficiency of the cell cultures was associated with the higher expression level of the HLA-DR activation marker. Among the iCasp9-transduced subsets, KIR2DL2/3+ cells had the weakest response to the apoptosis induction by the chemical inductor of dimerization (CID). Thus, KIR2DL2/3+NKG2C+ NK cells showed an increased susceptibility to the iCasp9 retroviral transduction, which was associated with higher proliferative potential and activation status. However, the complete elimination of these cells with CID is impeded. 相似文献
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Anatoly I. Romanenko Galina E. Yakovleva Vladimir E. Fedorov Sofya B. Artemkina Alexandra Yu. Ledneva Kamil R. Zhdanov Boris M. Kuchumov Vitalii A. Kuznetsov Hongchao Wang Sanjai Singh Shivani Saini Mi-Kyung Han Sung-Jin Kim 《Journal of the American Ceramic Society》2020,103(11):6289-6297
The thermoelectric properties of a series of the polycrystalline samples of titanium dichalcogenides with partial substitution of Ti for Nb and S for Se were investigated. It was found that sintering of the samples improved the thermoelectric efficiency (ZT), and the maximum ZT was achieved at sintering temperature of 600°C. A further increase in the sintering temperature (850°C and 950°C) led to the recrystallization of the samples, as a result, the Seebeck coefficient sharply decreased and electrical conductivity dramatically increased. The temperature dependences of electrical conductivity σ(T) in the temperature range from 4.2 to 300 K and Seebeck coefficient S(T) in the temperature range from 77 to 300 K were investigated in order to determine the nature of the observed improvements in thermoelectric properties due to double substitutions and sintering. Two-dimensionalization of electron transport properties of Ti1−xNbxS2−ySey solid solutions was found. The Fermi energy EF2D was estimated using the temperature dependences of Seebeck coefficient. The relationship between the Fermi energy EF2D and figure of merit ZT was established. The effect of sintering on parameters σ(T), S(T), charge carrier concentration (n2D), mobility (µ), and thermal conductivity (k) was found. The optimal value of Fermi energy EF2D in terms of figure of merit ZT = 0.31 at room temperature (T = 300 K) was found for Ti0.98Nb0.02S1.3Se0.7 sample sintered at 600°C. 相似文献