Репозиторий Университета

© ISUCT Publishing. The macrolide antibiotic oligomycin A (1), produced by actinomycetes Streptomyces,[1] is a well-known inhibitor of FO F1 ATP-synthase, which is regarded as a molecular target for new drugs in the treatment of tumors and infections. Oligomycin A (1) exhibits antifungal and cytotoxic activities, but Gram-negative and Gram-positive bacteria are resistant to 1 except actinobacteria.[2] In micromolar concentrations, oligomycin binds to FO c-subunit, blocks proton translocation and disrupts bioenergetic metabolism.[3] However, a clinical application of oligomycin A is limited by high cytotoxicity for mammalian cells. The searches of new derivatives of oligomycin A with more selective pharmacological activity and low toxicity for normal cells are of great interest. New semi-synthetic oligomycins also would be valuable for SAR studies and depicting the mechanism of FO F1 ATP-synthase inhibition. The complicity of oligomycin structure and its lability in basic conditions[4] significantly impede modifications and an applicability of this antibiotic. However, previously we have managed this challenge and developed some modifications of the side chain and chemical transformations of the lactone moiety of 1.[4-9] In this paper, throughout our research we describe synthesis and biological investigation of novel oligomycin A derivatives, namely 16,33-O,O-diformyl-16,17-dihydro-16(S),17(R)-dihydroxyoligomycin A (3) and 33-O-formyloligomycin A (4). First, we have studied Prilezhaev epoxidation of double bonds in core structure of oligomycin A. It was found that treatment 1 with m-CPBA at -17oC in dichloromethane led to 16,17-epoxyoligomycin (2). Unfortunately, all attempts for isolation of product 2 were failed due to its instability on silica gel, and, consequently, we were unable to determine the structure of 2 by direct physicochemical and spectral methods. The presence of epoxide at C16-C19 positions was confirmed by tandem mass spectrometry, but its exact localization was still elusive. We assumed that it might be at C16-C17 positions, because C18-C19 double bond is hindered by ethyl side chain at C20. In order to obtain a stable oligomycin A derivative we performed an epoxide ring-opening reaction by the treatment of the crude epoxyoligomycin 2 with formic acid. This acid-catalyzed opening of the epoxide accompanied with acylation of 33-OH group and led to16,33-O,O-diformyl-16,17-dihydro-16(S),17(R)-dihydroxyoligomycin A (3). The structure of 3 was confirmed by NMR spectroscopy and high resolution mass spectrometry. Configurations at C16 and C17 positions were determined by detecting correlations in1H-1H ROESY spectrum. Obtained results allowed to confirm an assumption about localization of the epoxide ring and establish the structure of 2 as (R,R)-16,17-epoxyoligomycin A, since inversion of configuration has taken place at the attacked carbon atom.[23] It is known that O-acyl derivatives of pharmacologically active agents are widely used as prodrugs.[24] Acylation of 2-hydroxypropyl side chain in 2 prompts us to examine the reaction of oligomycin A (1) with formic acid. Thus, stirring the solution of 1 in HCOOH (98 %) for 2 h at room temperature afforded 33-O-formyloligomycin A (4) in a good yield. The structure of 4 was confirmed by NMR-spectroscopy and high resolution mass spectrometry. Also, biological data of new derivatives were evaluated. The modification of C16-C17 positions of the macrocycle as well as acylation of C33 hydroxyl group led to the decreasing of activity against S. fradiae, Candida spp. and filamentous fungi. Obtained results were in agreement with docking studies. A simulation of an interaction of 1, 3 and 4 with the FO subunit of the ATP-synthase (PDB: 4f4s) revealed that these modifications led to a significant change in the solvation energy and an increase in the conformational capacity of the ligands during the binding with the target. This resulted in decrease of the binding affinity for derivatives 2, 3. However, 33-O-formyloligomycin A (4) showed similar antiproliferative activity against tumor cell lines (HCT-116 colon carcinoma, К562 myeloid leukemia cell lines and MDR K562/4 subline) as for 1, but less cytotoxic for non-malignant human cells.

© 2018 SPIE. Application of terahertz (THz) spectroscopy for biological tissues is strongly limited by the extremely low penetration depth due to THz absorption by tissue water. One of the possible solution of such problem is the usage of THz wave penetration-enhancing agents (PEA) for optical clearing of tissues. In the present paper, the transmission-mode THz spectroscopy of a set of PEAs (polyethylene glycol with different molecular weight, propylene glycol, ethylene glycol, and dimethyl sulfoxide) was performed in order to reconstruct their dielectric properties and compare them with that of water. The obtained results emphasize the feasibility of using PEG to enhance the depth of THz wave penetration into tissues.

© 2018 Interregional public organization Association of infectious disease specialists of Saint-Petersburg and Leningrad region (IPO AIDSSPbR). All rights reserved. Vaccination against pneumococcal infections by 13-va-lent conjugate vaccine (PCV13) can significantly reduce morbidity and mortality. The study has been aimed to evaluate the social and pharmacoeconomic aspects of PCV13 vaccination of 65-year-old patients with various risks of pneumococcal infection. Material and methods. Markov model with 5 and 15 years time horizon was used for the analysis from the position of the health care system. The analysis was carried out for 65-year-old citizens with low (absence of immunocompromized conditions and chronic diseases), moderate (patients with chronic diseases without immunodeficiency) and high (immunocompromized conditions) risk of pneumococcal infection as well as for the entire population of 65-year-old citizens, regardless of the risk level. In base-case assumption has been made that 1 dose of PCV13 should be administered for the patients from low and moderate risk groups and in the high-risk group 1 dose of PCV13 and in 8 weeks a dose of polysaccharide pneumococcal vaccine (PPV23) should be given. The treatment and physician visit costs have been calculated using CHI rates for St. Petersburg in 2018. Vaccination cost was calculated using the auction price to purchase PCV13 and PPV23 in 2018. Results. Vaccination of 1 cohort of 65-year-old citizens in Russian Federation within 5 years will result in prevention of 2200 deaths, 3900 cases of invasive pneumococcal diseases (IPD) and 48700 cases of community-acquired pneumonia. In 15 years prevention of about 4,3 thousand deaths, 6,6 thousand IPD and 101,1 thousand cases of CAP will be provided. Within 15-year horizon the cost-effectiveness ratio will be RUR 30,3, 82,4 and 410,0 thousand per QALY in high, moderate and low risk groups, respectively. Even if the time horizon is reduced to 5 years the PCV13 vaccination can be considered as an economically high-efficient intervention in moderate and high risk groups (cost-effectiveness ratio - RUR 279,2 and 221,7 thousand / QALY, respectively). In the 15-year-horizon noting the distribution of 65-year-olds by risk levels the cost-effectiveness ratio of PCV13 in population as a whole will be RUR 216,4 thousand / QALY. If moderate and high risk groups only are vaccinated, the average cost-effectiveness ratio will drop to RUR 67,6 thousand /QALY. At universal PCV13 vaccination of 65 years old in 5 year time horizon return of investment to the health care system budget will be 33.2% and at vaccination of persons with moderate and high risk return of investment will be 44.0%. With the assumption of vaccination during the planned physician visit (without additional visit) the return to the budget will be 46.8% and 60.9% for vaccination of all 65-year-olds and patients from the moderate and high risk groups, respectively. Conclusions. Vaccination of the 65-year-old persons against PCV13 pneumococcal infection in Russian Federation can be considered as a highly socially and economically effective intervention resulting in significant reduction of pneumococcal infection incidence and related mortality. The cost-effectiveness of vaccination is increasing along with the level of the risk. PCV13 vaccination of patients with moderate and high risk only provides a significant reduction in the burden for the health care budget in comparison with the vaccination of the entire population of 65-year-olds.

Chronic spontaneous urticaria (CSU) is a mast cell-driven disease that is defined as the recurrence of wheals, angioedema, or both for >6 weeks due to known or unknown causes. As of yet, disease diagnosis is purely clinical. Objective tools are needed to monitor the activity of CSU and the efficacy of treatment. Recently, several reports have suggested that blood parameters may be considered as potential disease-related biomarkers. To review available literature on blood biomarkers for CSU diagnosis, activity monitoring, duration, patient subgroups allocation or response to treatment. We performed a Pubmed, Google Scholar and Web of Science search and identified and analysed 151 reports published prior to January 2016. We found strong evidence for significant differences between CSU patients and healthy controls in blood levels or values of D-dimer, C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), mean platelet volume (MPV), factor VIIa, prothrombin fragment 1+2 (F1+2), tumor necrosis factor, dehydroepiandrosterone sulfate and vitamin D. Also, there is strong evidence for a significant association between CSU activity and blood levels or values of D-dimer, F1+2, CRP, IL-6 and MPV. Strong evidence for reduced basophil count and high levels of IgG anti-FcεRI in the subgroup of CSU patients with positive autologous serum skin test was shown. In contrast, the evidence for all reported blood biomarkers for differentiating CSU from other diseases, or a role in prognosis, is weak, inconsistent or non-existent. We identified ten biomarkers which are supported by strong evidence for distinguishing CSU patients from healthy controls, or for measuring CSU activity. There is a need for further research to identify biomarkers which predict outcome or treatment response in CSU. This article is protected by copyright. All rights reserved.

Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have emerged as a result of the arms race between plants and pathogens. However, the regulation of these processes is the same for all living organisms, including plants, and is controlled by proteases. Different families of plant proteases are involved in every type of immunity: some of the proteases that are covered in this review participate in MTI, affecting stomatal closure and callose deposition. A large number of proteases act in the apoplast, contributing to ETI by managing extracellular defense. A vast majority of the endogenous proteases discussed in this review are associated with the programmed cell death (PCD) of the infected cells and exhibit caspase-like activities. The synthesis of signal molecules, such as salicylic acid, jasmonic acid, and ethylene, and their signaling pathways, are regulated by endogenous proteases that affect the induction of pathogenesis-related genes and SAR or ISR establishment. A number of proteases are associated with herbivore defense. In this review, we summarize the data concerning identified plant endogenous proteases, their effect on plant-pathogen interactions, their subcellular localization, and their functional properties, if available, and we attribute a role in the different types and stages of innate immunity for each of the proteases covered. View Full-Text

Wild ducks are known to be able to carry avian influenza viruses over long distances and infect domestic ducks, which in their turn infect domestic chickens. Therefore, prevention of virus transmission between ducks and chickens is important to control the spread of avian influenza. Here we used a low pathogenic wild aquatic bird virus A/duck/Moscow/4182/2010 (H5N3) for prevention of highly pathogenic avian influenza virus (HPAIV) transmission between ducks and chickens. We first confirmed that the ducks orally infected with H5N1 HPAIV A/chicken/Kurgan/3/2005 excreted the virus in feces. All chickens that were in contact with the infected ducks became sick, excreted the virus, and died. However, the ducks orally inoculated with 10⁴ 50% tissue culture infective doses of A/duck/Moscow/4182/2010 and challenged 14 to 90 days later with H5N1 HPAIV did not excrete the challenge virus. All contact chickens survived and did not excrete the virus. Our results suggest that low pathogenic virus of wild aquatic birds can be used for prevention of transmission of H5N1 viruses between ducks and chickens.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.

Plant defense is achieved mainly through the induction of microbe-associated molecular patterns (MAMP)-triggered immunity (MTI), effector-triggered immunity (ETI), systemic acquired resistance (SAR), induced systemic resistance (ISR), and RNA silencing. Plant immunity is a highly complex phenomenon with its own unique features that have emerged as a result of the arms race between plants and pathogens. However, the regulation of these processes is the same for all living organisms, including plants, and is controlled by proteases. Different families of plant proteases are involved in every type of immunity: some of the proteases that are covered in this review participate in MTI, affecting stomatal closure and callose deposition. A large number of proteases act in the apoplast, contributing to ETI by managing extracellular defense. A vast majority of the endogenous proteases discussed in this review are associated with the programmed cell death (PCD) of the infected cells and exhibit caspase-like activities. The synthesis of signal molecules, such as salicylic acid, jasmonic acid, and ethylene, and their signaling pathways, are regulated by endogenous proteases that affect the induction of pathogenesis-related genes and SAR or ISR establishment. A number of proteases are associated with herbivore defense. In this review, we summarize the data concerning identified plant endogenous proteases, their effect on plant-pathogen interactions, their subcellular localization, and their functional properties, if available, and we attribute a role in the different types and stages of innate immunity for each of the proteases covered. View Full-Text

Wild ducks are known to be able to carry avian influenza viruses over long distances and infect domestic ducks, which in their turn infect domestic chickens. Therefore, prevention of virus transmission between ducks and chickens is important to control the spread of avian influenza. Here we used a low pathogenic wild aquatic bird virus A/duck/Moscow/4182/2010 (H5N3) for prevention of highly pathogenic avian influenza virus (HPAIV) transmission between ducks and chickens. We first confirmed that the ducks orally infected with H5N1 HPAIV A/chicken/Kurgan/3/2005 excreted the virus in feces. All chickens that were in contact with the infected ducks became sick, excreted the virus, and died. However, the ducks orally inoculated with 10⁴ 50% tissue culture infective doses of A/duck/Moscow/4182/2010 and challenged 14 to 90 days later with H5N1 HPAIV did not excrete the challenge virus. All contact chickens survived and did not excrete the virus. Our results suggest that low pathogenic virus of wild aquatic birds can be used for prevention of transmission of H5N1 viruses between ducks and chickens.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.