Репозиторий Университета

Adoptive cell therapy has received a great deal of interest in the treatment of advanced cancers that are resistant to traditional therapy. The tremendous success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells in the treatment of cancer, especially hematological cancers, has exposed CAR’s potential. However, the toxicity and significant limitations of CAR-T cell immunotherapy prompted research into other immune cells as potential candidates for CAR engineering. NK cells are a major component of the innate immune system, especially for tumor immunosurveillance. They have a higher propensity for immunotherapy in hematologic malignancies because they can detect and eliminate cancerous cells more effectively. In comparison to CAR-T cells, CAR-NK cells can be prepared from allogeneic donors and are safer with a lower chance of cytokine release syndrome and graft-versus-host disease, as well as being a more efficient antitumor activity with high efficiency for off-the-shelf production. Moreover, CAR-NK cells may be modified to target various antigens while also increasing their expansion and survival in vivo. Extensive preclinical research has shown that NK cells can be effectively engineered to express CARs with substantial cytotoxic activity against both hematological and solid tumors, establishing evidence for potential clinical trials of CAR-NK cells. In this review, we discuss recent advances in CAR-NK cell engineering in a variety of hematological malignancies, as well as the main challenges that influence the outcomes of CAR-NK cell-based tumor immunotherapies.

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. The wide use of cobalt (Co) in food, industry, and medical devices requires full elucidation of its biological effects on tissues and organs. The aim was to assess serum metabolic alterations in immature mice after subchronic exposure to CoCl2. Pregnant ICR mice were subjected to a daily dose of 75 mg cobalt chloride/kg body weight (CoCl2x6H2O) 2–3 days before they gave birth, and treatment continued until days 25 and 30 after delivery. The compound was dissolved in and obtained with regular tap water. ICP-DRC-MS analysis showed significantly elevated serum Co2+ and diverse alterations in metabolic parameters of 25- and 30-day-old pups after exposure to CoCl2. Cholesterol and urea levels were significantly elevated in day 25 mice while HDL-C and LDL-C were reduced. In day 30, Co-exposed mice LDL-C and triglycerides were significantly increased while the total cholesterol level remained unchanged. Alkaline phosphatase was significantly reduced in day 25 Co-exposed mice. Blood glucose level of Co-exposed mice remained close to the untreated controls. Total protein content was slightly increased in day 30 mice. Co-exposure reduced albumin content and albumin/globulin ratio but increased significantly globulin content. Co administration showed strong correlation with cholesterol, urea, and HDL-C in both day 25 and 30 mice. Inverse correlation was found with alkaline phosphatase and albumin for day 25 and with triglycerides, globulin, and total protein content in day 30 Co-exposed mice. Subchronic CoCl2 exposure of immature mice induced significant changes in key metabolic parameters suggesting possible further disturbances in energy metabolism, osteogenesis, and reproduction.

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. The wide use of cobalt (Co) in food, industry, and medical devices requires full elucidation of its biological effects on tissues and organs. The aim was to assess serum metabolic alterations in immature mice after subchronic exposure to CoCl2. Pregnant ICR mice were subjected to a daily dose of 75 mg cobalt chloride/kg body weight (CoCl2x6H2O) 2–3 days before they gave birth, and treatment continued until days 25 and 30 after delivery. The compound was dissolved in and obtained with regular tap water. ICP-DRC-MS analysis showed significantly elevated serum Co2+ and diverse alterations in metabolic parameters of 25- and 30-day-old pups after exposure to CoCl2. Cholesterol and urea levels were significantly elevated in day 25 mice while HDL-C and LDL-C were reduced. In day 30, Co-exposed mice LDL-C and triglycerides were significantly increased while the total cholesterol level remained unchanged. Alkaline phosphatase was significantly reduced in day 25 Co-exposed mice. Blood glucose level of Co-exposed mice remained close to the untreated controls. Total protein content was slightly increased in day 30 mice. Co-exposure reduced albumin content and albumin/globulin ratio but increased significantly globulin content. Co administration showed strong correlation with cholesterol, urea, and HDL-C in both day 25 and 30 mice. Inverse correlation was found with alkaline phosphatase and albumin for day 25 and with triglycerides, globulin, and total protein content in day 30 Co-exposed mice. Subchronic CoCl2 exposure of immature mice induced significant changes in key metabolic parameters suggesting possible further disturbances in energy metabolism, osteogenesis, and reproduction.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. 20-hydroxycholesterol is a signaling oxysterol with immunomodulating functions and, thus, structural analogues with reporter capabilities could be useful for studying and modulating the cellular processes concerned. We have synthesized three new 20-hydroxycholesterol-like pregn-5-en-3β-ol derivatives with fluorescent 7-nitrobenzofurazan (NBD) or Raman-sensitive alkyne labels in their side-chains. In silico computations demonstrated the compounds possess good membrane permeability and can bind within active sites of known 20-hydroxycholesterol targets (e.g. Smoothened and yeast Osh4) and some other sterol-binding proteins (human LXRβ and STARD1; yeast START-kins Lam4S2 and Lam2S2). Having found good predicted membrane permeability and binding to some yeast proteins, we tested the compounds on microorganisms. Fluorescent microscopy indicated the uptake of the steroids by both Saccharomyces cerevisiae and Yarrowia lipolytica, whereas only S. cerevisiae demonstrated conversion of the compounds into 3-O-acetates, likely because 3-O-acetyltransferase Atf2p is present only in its genome. The new compounds provide new options to study the uptake, intracellular distribution and metabolism of sterols in yeast cells as well as might be used as ligands for sterol-binding proteins.

© 2019 Elsevier B.V. S-Methyl methanethiosulfonate (MMTS) is used in experimental biochemistry for alkylating thiol groups of protein cysteines. Its applications include mainly trapping of natural thiol-disulfide states of redox-sensitive proteins and proteins which have undergone S-nitrosylation. The reagent can also be employed as an inhibitor of enzymatic activity, since nucleophilic cysteine thiolates are commonly present at active sites of various enzymes. The advantage of using MMTS for this purpose is the reversibility of the formation of methylthio mixed disulfides, compared to irreversible alkylation using conventional agents. Additional benefits include good accessibility of MMTS to buried protein cysteines due to its small size and the simplicity of the protection and deprotection procedures. In this study we report examples of MMTS application in experiments involving oxidoreductase (glyceraldehyde-3-phosphate dehydrogenase, GAPDH), redox-regulated protein (recoverin) and cysteine protease (triticain-α). We demonstrate that on the one hand MMTS can modify functional cysteines in the thiol enzyme GAPDH, thereby preventing thiol oxidation and reversibly inhibiting the enzyme, while on the other hand it can protect the redox-sensitive thiol group of recoverin from oxidation and such modification produces no impact on the activity of the protein. Furthermore, using the example of the papain-like enzyme triticain-α, we report a novel application of MMTS as a protector of the primary structure of active cysteine protease during long-term purification and refolding procedures. Based on the data, we propose new lines of MMTS employment in research, pharmaceuticals and biotechnology for reversible switching off of undesirable activity and antioxidant protection of proteins with functional thiol groups.

© Copyright © 2019 Poddubskaya, Bondarenko, Boroda, Zotova, Glusker, Sletina, Makovskaia, Kopylov, Sekacheva, Moisseev and Baranova. Non-small cell lung carcinoma (NSCLC) is the major cause of cancer-associated mortality. Identification of rearrangements in anaplastic lymphoma kinase (ALK) gene is an effective instrument for more effective targeted therapy of NSCLC using ALK inhibitors dramatically raising progression-free survival in the ALK-mutated group of patients. However, the tumors frequently develop resistance to ALK inhibitors. We describe here a case of 48 y.o. male patient with ALK-positive NSCLC who was clinically managed for 6.5 years from the diagnosis. The tumor was surgically resected, but 8 months later multiple brain metastases were discovered. The patient started receiving platinum-based chemotherapy and then was enrolled in a clinical trial of second-generation ALK inhibitor ceritinib, which resulted in a 21 months stabilization. Following disease relapse, the patient was successfully managed for 33 months with different lines of chemo- and local ablative therapies. Chemotherapy regimens, including off-label combination of crizotinib + bevacizumab + docetaxel, were selected using the cancer transcriptome data-guided bioinformatical decision support system Oncobox. These therapies led to additional stabilization for 22 months. Survival of our patient after developing resistance to ALK inhibitor was longer for 16 months than previously reported average survival for such cases. This case shows that transcriptomic-guided sequential personalized prescription of targeted therapies can be effective in terms of survival and quality of life in ALK-mutated NSCLC.

© 2019 by the authors. Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium's acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of Laurus nobilis L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel's response to physiologically-relevant stimuli of pH 6.5-6.85 with IC50 range 150-9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund's adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Modern antimicrobial preservatives authorized for use in dosage form technology are reviewed. The nomenclature and various classifications of preservatives according to chemical nature, mechanism and spectrum of antimicrobial action, optimum effective concentrations for antimicrobial activity, and separate factors affecting the activity of antimicrobial preservatives in various dosage forms, e.g., optimum solution pH values and specific adsorbents reducing preservative activity, are presented. Antimicrobial preservatives used widely in pharmaceutical technology, i.e., parabens, sorbic acid and its salts, benzoic acid and its salts, and benzalkonium chloride, are discussed in detail. Ascience-based approach to selecting antimicrobial preservatives is shown to produce the most stable and safest medicines.

© 2018 MDPI AG. All rights reserved. Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus Niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

© 2018, Innovare Academics Sciences Pvt. Ltd. All rights reserved. Objective: The objective of the present study is to evaluate the electronic ultraviolet (UV) absorption spectra of herbal pharmaceutical substances (70% ethanol extracts) prepared from medicinal plant material of two snowdrop species – Galanthus woronowii Losinsk and Galanthus nivalis L. Methods: The groups of biologically active substances were investigated by UV-spectrophotometry including special sample preparation for flavonoids and alkaloids. Results: In the present study, data were obtained characterizing the composition of the main biologically active compounds of the genus Galanthus L., received its “spectrophotometric profiles.” On the basis of spectral characteristics of G. woronowii and G. nivalis flavonoids and alkaloids, we confirm feasibility for using galantamine, lycorine, quercetin, and its glycosides (hyperoside et al.) state standard samples in standardization analysis. Conclusion: It is shown that this method can be used to assess the quality of herbal pharmaceutical substances, serve to prove their identity in pharmacopoeial monograph.

© 2018 Elsevier Ltd A nickel oxyhydroxide [NiO(OH)] anode was exploited to develop a new synthetic route for the electrocatalytic N-N homocoupling of N-alkylaminopyrazoles in an alkaline aqueous medium. The advantages of this green electrochemical methodology include low cost, atom economy and high yields.

© 2018 IEEE. The work is focused on the research of urea elimination possibilities out of the waste dialysis solution by its electro-oxidation on the surface of platinum group metals and carbon materials. The work includes findings of experimental tests of various electrode materials for the specific urea elimination rate in a model solution.

BACKGROUND: total hip replacement has long ago become the «golden standard» for the treatment of dysplastic coxarthrosis in thousands of the patients receiving it every year. In the meantime, the analysis of the specialized literature gives evidence of the lack of a systematic and personified approach to the rehabilitation treatment. AIM: The objective of the present study was to improve medical rehabilitation of the patients following the total hip replacement and to develop the personalized programs for walking modality reconstruction taking into consideration the age and the body weight of the patients. PATIENTS AND METHODS: A total of 240 patients were available for the observation including 184 women and 56 men. They were divided into three study groups and one control group, with the differentiation into the following three subgroups: one comprised of the patients of moderate acerage age and body weight, the other containing the obese patients (BMI>35), and the third one involving the elderly patients (age >70 years); each subgroup consisted of 20 patients. All the patients received the early basic rehabilitation treatment, those in the study groups had to perform in addition the robotic training based on the use of hardware techniques supplemented by passive mechanotherapy and electromyostimulation designed to restore the walking stereotype with three types of devices: body weight unloading, video-reconstruction associated with biological feedback and robototherapy. RESULTS: The comparative analysis of the effectiveness of various methods of gait reconstruction has demonstrated the high effectiveness of the application of the hardware technique in the patients of moderate acerage age and body weight. At the same time, the elderly patients had a significantly higher rate of successful walking reconstruction efficiency under the influence of the video-associated training with biological feedback (3 times that achieved with training using the device for unloading the body weight and 4 times compared with the result of a course of robotic walk. The evaluation of the application of the techniques for the gait stereotype reconstruction in the obese patients gave evidence of the advantage of the Lokomat robotic trainings that produced 6 times better results than unloading of the body weight and 5 times better ones than the video-associated training with biological feedback. DISCUSSION: The results of the present study are on the whole comparable with the data reported by other authors although its design was different from that of the majority of the published studies in that our patients were allocated to different subgroups for the further personalization of the methods applied to restore the gait stereotype. The factors limiting the use of the results of this study include the medium-high level of the patients' welfare most of whom are residents of the city of Moscow and Moscow region characterized by a relatively high quality and accessibility of health care. It means that the results of such studies as the one described in the present article are directly related to the quality and accessibility of health care and can be extrapolated only to the socially safe and well-to-do patients. CONCLUSIONS: All the hardware techniques are equally effective in the patients of moderate average age and body weight. The elderly patients showed the best results using the video-reconstruction associated with biological feedback, while the Locomat technique was especially useful for the obese patients.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Echocardiographic parameters were assessed in patients with non-ST segment elevation acute coronary syndrome, who underwent emergency percutaneous coronary intervention followed by various outpatient physical cardiac rehabilitation programs. The patients underwent physical rehabilitation for 3 months under conditions of diagnostic centre in the rehabilitation unit according to the standard program including in treadmill or bicycle exercise in the exercise therapy room or with Nordic walking in the main training block. After rehabilitation course, the left ventricular mass index significantly decreased and systolic volume and left ventricular ejection fraction significantly increased in both groups. Nordic walking training for 3 months non-ST segment elevation acute coronary syndrome induced similar positive shifts in the parameters of intracardiac hemodynamics, as standard treadmill or bicycle training program, which allows considering it as an alternative cardiac rehabilitation method.