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- Manskikh, V. N., et al.
(författare)
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Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1
- 2015
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Ingår i: Histology and Histopathology. - 0213-3911 .- 1699-5848. ; 30:3, s. 353-360
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Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in mammalian hearts often result in cardiac hypertrophy and fibrosis that are preceded by inflammatory infiltration. In this paper, we show that lifelong treatment of BALB/c and C57BL/6 mice with the mitochondria-targeted antioxidant SkQ1 retards senescence-associated myocardial disease (cardiomyopathy), cardiac hypertrophy, and diffuse myocardial fibrosis. To investigate the molecular basis of the action of SkQ1, we have applied DNA microarray analysis. The global gene expression profile in heart tissues was not significantly affected by administration of SkQ1. However, we found some small but statistically significant modifications of the pathways related to cell-to-cell contact, adhesion, and leukocyte infiltration. Probably, SkQ1-induced decrease in leukocyte and mesenchymal cell adhesion and/or infiltration lead to a reduction in age-related inflammation and subsequent fibrosis. The data indicate a causative role of mitochondrial reactive oxygen species in cardiovascular aging and imply that SkQ1 has potential as a drug against age-related cardiac dysfunction.
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| 2. |
- Brezgin, S, et al.
(författare)
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Replenishment of Hepatitis B Virus cccDNA Pool Is Restricted by Baseline Expression of Host Restriction Factors In Vitro
- 2019
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is the major cause of viral persistence in patients with chronic HBV infection. Understanding the mechanisms underlying stability and persistence of HBV cccDNA in hepatocytes is critical for developing novel therapeutics and managing chronic hepatitis B. In this study, we observed an unexpected increase in HBV cccDNA levels upon suppression of transcription by de novo DNA methyltransferase DNMT3A and uncovered additional mechanisms potentially involved in HBV cccDNA maintenance. Methods: HBV-expressing cell lines were transfected with a DNMT3A-expressing plasmid. Real-time PCR and HBsAg assays were used to assess the HBV replication rate. Cell cycling was analyzed by fluorescent cell sorting. CRISPR/Cas9 was utilized to abrogate expression of APOBEC3A and APOBEC3B. Alterations in the expression of target genes were measured by real-time PCR. Results: Similar to previous studies, HBV replication induced DNMT3A expression, which in turn, led to reduced HBV transcription but elevated HBV cccDNA levels (4- to 6-fold increase). Increased levels of HBV cccDNA were not related to cell cycling, as DNMT3A accelerated proliferation of infected cells and could not contribute to HBV cccDNA expansion by arresting cells in a quiescent state. At the same time, DNMT3A suppressed transcription of innate immunity factors including cytidine deaminases APOBEC3A and APOBEC3B. CRISPR/Cas9-mediated silencing of APOBEC3A and APOBEC3B transcription had minor effects on HBV transcription, but significantly increased HBV cccDNA levels, similar to DNMT3A. In an attempt to further analyze the detrimental effects of HBV and DNMT3A on infected cells, we visualized γ-H2AX foci and demonstrated that HBV inflicts and DNMT3A aggravates DNA damage, possibly by downregulating DNA damage response factors. Additionally, suppression of HBV replication by DNMT3A may be related to reduced ATM/ATR expression. Conclusion: Formation and maintenance of HBV cccDNA pools may be partially suppressed by the baseline expression of host inhibitory factors including APOBEC3A and APOBEC3B. HBV inflicts DNA damage both directly and by inducing DNMT3A expression.
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| 3. |
- Nikiforova, Yulia A., et al.
(författare)
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Crystal structure and phase transitions at high pressures in the superconductor FeSe0.89S0.11
- 2021
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Ingår i: Journal of Alloys and Compounds. - : Elsevier. - 0925-8388 .- 1873-4669. ; 860
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Tidskriftsartikel (refereegranskat)abstract
- We report on the structural phase transitions in the FeSe0.89S0.11 superconductor with T-C = 11 K observed by powder synchrotron X-ray diffraction at high pressures up to 18.5 GPa under compression and decompression modes. It was found that at ambient pressure and room temperature, FeSe0.89S0.11 has a tetragonal structure (space group NM). Under compression, in the region of 10 GPa, a phase transition from the tetragonal into the orthorhombic structure (sp. gr . Pnma) is observed, which persists up to 18.5 GPa. Our results strongly suggest that, at decompression, as the applied pressure decreases to 6 GPa and then is completely removed, most of the sample recrystallizes into the hexagonal phase of the structural type NiAs (sp. gr . P6(3)/mmc). However, the other part of the sample remains in the high pressure orthorhombic phase (sp. gr . Pnma), while the tetragonal phase (sp. gr . P4/n) is not restored. These observations illustrate a strong hysteresis of the structural properties of FeSe0.89S0.11 during a phase transition under pressure. (C) 2020 Elsevier B.V. All rights reserved.
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| 8. |
- Kostyusheva, A, et al.
(författare)
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ATM and ATR Expression Potentiates HBV Replication and Contributes to Reactivation of HBV Infection upon DNA Damage
- 2019
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hepatitis B virus infection (CHB) caused by the hepatitis B virus (HBV) is one of the most common viral infections in the world. Reactivation of HBV infection is a life-threatening condition observed in patients with CHB receiving chemotherapy or other medications. Although HBV reactivation is commonly attributed to immune suppression, other factors have long been suspected to play a role, including intracellular signaling activated in response to DNA damage. We investigated the effects of DNA-damaging factors (doxorubicin and hydrogen peroxide) on HBV reactivation/replication and the consequent DNA-damage response. Dose-dependent activation of HBV replication was observed in response to doxorubicin and hydrogen peroxide which was associated with a marked elevation in the mRNA levels of ataxia-telangiectasia mutated (ATM) and ATM- and RAD3-related (ATR) kinases. Downregulation of ATM or ATR expression by shRNAs substantially reduced the levels of HBV RNAs and DNA. In contrast, transcriptional activation of ATM or ATR using CRISPRa significantly increased HBV replication. We conclude that ATM and ATR are essential for HBV replication. Furthermore, DNA damage leading to the activation of ATM and ATR transcription, results in the reactivation of HBV replication.
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| 9. |
- Lopachev, A. V., et al.
(författare)
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Comparative Action of Cardiotonic Steroids on Intracellular Processes in Rat Cortical Neurons
- 2018
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Ingår i: Biochemistry (Moscow). - : MAIK NAUKA/INTERPERIODICA/SPRINGER. - 0006-2979 .- 1608-3040. ; 83:2, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- Binding to Na+,K+-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouabain affects the activation of mitogen-activated protein kinases (MAP kinases) ERK1/2, p38, and JNK. In this study, we compared the effects of digoxin and bufalin, which belong to different subclasses of CTS, on primary culture of rat cortical cells. We found that CTS toxicity is not directly related to the degree of Na+,K+-ATPase inhibition, and that bufalin and digoxin, like ouabain, are capable of activating ERK1/2 and p38, but with different concentration and time profiles. Unlike bufalin and ouabain, digoxin did not decrease JNK activation after long-term incubation. We concluded that the toxic effect of CTS in concentrations that inhibit less than 80% of Na+,K+-ATPase activity is related to ERK1/2 activation as well as the complex profile of MAP kinase activation. A direct correlation between Na+,K+-ATPase inhibition and the degree of MAP kinase activation is only observed for ERK1/2. The different action of the three CTS on JNK and p38 activation may indicate that it is associated with intracellular signaling cascades triggered by protein-protein interactions between Na+,K+-ATPase and various partner proteins. Activation of MAP kinase pathways by these CTS occurs at concentrations that inhibit Na+,K+-ATPase containing the alpha 1 subunit, suggesting that these signaling cascades are realized via alpha 1. The results show that the signaling processes in neurons caused by CTS can differ not only because of different inhibitory constants for Na+,K+-ATPase.
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| 10. |
- Michnowski, S., et al.
(författare)
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Review of Relationships Between Solar Wind and Ground-Level Atmospheric Electricity : Case Studies from Hornsund, Spitsbergen, and Swider, Poland
- 2021
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Ingår i: Surveys in geophysics. - : Springer. - 0169-3298 .- 1573-0956. ; 42:3, s. 757-801
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Forskningsöversikt (refereegranskat)abstract
- This paper reviews individual cases of the relationships between variations of solar wind parameters and variations of the DC vertical atmospheric electric field, E-z, and current density, J(z), measured at ground level in the Arctic, at the S. Siedlecki Polish Polar Station Hornsund, Spitsbergen (Svalbard, Norway), and at the mid-latitude S. Kalinowski Geophysical Observatory in Swider (Poland). A considerable number of events from Hornsund confirmed previous observations of regularity of effects related to the station's position against the location of the potential bays of ionospheric convection and polar electrojets, observed in other polar locations, as well as effects of other polar cap current systems. This allowed us to conclude that the physical dependence of ground-level E-z and J(z) on solar wind changes produce measurable effects which do not require statistical analysis to be observed. We can also expect that the dependence does exist, especially in strongly disturbed circumstances, e.g., following solar flares and Earth-directed coronal mass ejections, at middle latitudes. However, further investigations of these physical relationships by this approach are practically almost impossible since a very large number of variable parameters simultaneously affect the recorded lower atmospheric variables. In addition, results of quantitative analysis of predicted and observed effects are not satisfactory. Future research studies require more efficient ways of investigation by theoretical treatment and modelling work using existing and novel observational data besides taking advantage of scientific progress in magnetospheric physics.
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