| 1. |
- Biktimirov, Artur, et al.
(författare)
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Neuromodulation as a basic platform for neuroprotection and repair after spinal cord injury
- 2021
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Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; , s. 269-300
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Bokkapitel (refereegranskat)abstract
- Spinal cord injury (SCI) is one of the most challenging medical issues. Spasticity is a major complication of SCI. A combination of spinal cord stimulation, new methods of neuroprotection and biomedical cellular products provides fundamentally new options for SCI treatment and rehabilitation. The paper attempts to critically analyze the effectiveness of using these procedures for patients with SCI, suggesting a protocol for a step-by-step personalized treatment of SCI, based on continuity of modern conservative and surgical methods. The study argues the possibility of using neuromodulation as a basis for rehabilitating patients with SCI.
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| 2. |
- Bryukhovetskiy, Igor, et al.
(författare)
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Glioblastoma : What can we do for these patients today and what will we be able to do in the future?
- 2021
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Ingår i: NANOMEDICINE AND NEUROPROTECTION IN BRAIN DISEASES. - : ELSEVIER ACADEMIC PRESS INC. - 9780323901628 ; , s. 99-118
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is an extremely aggressive primary human brain tumor. The median survival of GBM patients is 15 months in case of completing the modern complex treatment protocol. Chemotherapy can help to extend the life expectancy of patients. GBM treatment resistance is associated with cancer stem cells (CSCs). The present paper analyses the main reasons for ineffectiveness of the existing GBM treatment methods and suggests treating CSCs as a complex phenomenon, resulting from the coordinated interaction of normal stem cells and cancer cells (CCs) in immunosuppressive microsurroundings. The GBM treatment strategy is suggested not for only suppressing strategically important signaling pathways in CCs, but also for regulating interaction between normal stem cells and cancer cells. The paper considers the issue of controlling penetrability of the blood-brain barrier that is one of the main challenges in neuro-oncology. Also, the paper suggests the ways of extending life expectancy of GBM patients today and prospects for the near future.
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| 3. |
- Bryukhovetskiy, Igor, et al.
(författare)
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Personalized therapy and stem cell transplantation for pro-inflammatory modulation of cancer stem cells microenvironment in glioblastoma : Review
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 67-98
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor in humans. The prognosis for patients with GBM is unfavorable and treatment is largely ineffective, where modern treatment regimens typically increase survival by 15 months. GBM relapse and progression are associated with cancer stem cells (CSCs). The present review provides a critical analysis of the primary reasons underlying the lack of effectiveness of modern CSC management methods. An emphasis is placed on the role of the blood-brain barrier in the development of treatment resistance. The existing methods for increasing the efficiency of antitumor genotoxic therapy are also described, and a strategy for personalized regulation of CSC based on post-genome technologies is suggested. The hypothesis that GBM cells employ a special mechanism for DNA repair based on their interactions with normal stem cells, is presented and the function of the tumor microenvironment in fulfilling the antitumor potential of normal stem cells is explained. Additionally, the mechanisms by which cancer stem cells regulate glioblastoma progression and recurrence are described based on novel biomedical technologies.
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| 4. |
- Bryukhovetskiy, Igor, et al.
(författare)
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Transforming growth factor-beta mimics the key proteome properties of CD133- differentiated and CD133+ cancer stem cells in glioblastoma
- 2020
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Ingår i: Novel therapeutic advances in glioblastoma. - : Elsevier BV. - 9780128211144 ; , s. 219-242
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme is the most aggressive type of primary brain tumor in humans. Its invasive growth is associated with cluster of differentiation (CD)133 cancer stem cells (CSCs) and CD133(-) differentiated glioblastoma cells (DGCs) with aggressive phenotype, which are developed under the influence of transforming growth factor (TGF)-beta. The present study aimed to compare the proteomes of CD133 CSCs and CD133(-) DGCs stimulated by TGF-beta, as well as the expression levels of the main proteins responsible for activating the signaling pathway of receptor interactions with the extracellular matrix (ECM). The U87MG GBM cell line was used in this study. CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of CD133 (CD133); CD133(-) DCGs served as a control. CD133(-) DGCs of the U87-MG cell line were treated with 10ng/mL TGF-beta 1, and cell proliferation and migration were analyzed via real-time quantitative microscopy. High-performance liquid chromatography mass spectrometry was used for proteome analysis. The results revealed 589 proteins with significantly changes in expression among CD133 CSCs compared with those in CD133(-) DGCs (P < 0.05). Bioinformatics analysis allowed to attribute 134 differentially expressed proteins to 15 signaling pathways; among these proteins, 14 were involved in signaling cascades associated with the interaction between CSCs and the ECM, and were upregulated > twofold, while four proteins activated this signaling cascade. TGF-beta-stimulation increased the mobility, suppressed the proliferation and transformed the proteome profile of CD133(-) DGCs. Were identified 13 key proteins that activate the signaling pathway of receptor interaction with the ECM and three proteins activating this signaling pathway in CD133(-) DGCs which had the same values as those of CD133 CSCs. In conclusion, TGF-beta increased the expression of proteins that activate the signaling pathway of receptor interaction with the ECM in CD133(-) DGCs to the level of those in CD133 CSCs.
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| 5. |
- Giordano, Luca, et al.
(författare)
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Essential Role of Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) for Acute Pulmonary Oxygen Sensing
- 2022
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier. - 0005-2728 .- 1879-2650. ; 1863:Supplement
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) is essential for acute oxygen sensing and signaling in pulmonary arterial smooth muscle cells (PASMCs) by triggering the production of superoxide during acute hypoxia [1]. However, the molecular mechanism underlying Cox4i2-dependent oxygen sensing remains elusive. We analysed oxygen-dependent respiration by high resolution respirometry, redox changes of the electron transport chain (ETC) by RAMAN spectroscopy, and supercomplex formation by blue native gel analysis of PASMCs isolated from wild type (WT) and Cox4i2-/- mice. To understand the role of Cox4i2-specific cysteine residues we determined hypoxia-induced superoxide production and oxygen affinity in a mouse epithelial cell line (CMT167 cells) overexpressing either Cox4i1, or WT Cox4i2, or Cox4i2 mutants (C41S, C55A, C109S). Respiration and supercomplex formation were similar in WT and Cox4i2-/- PASMCs. Interestingly, hypoxia-induced reduction of ETC components (NADH, ubiquinol, and reduced cytochrome c) was prevented in Cox4i2-/- PASMCs. CMT167 cells expressing either Cox4i1, or Cox4i2 mutants lacked hypoxia-induced superoxide release, which was detected only in cells expressing WT Cox4i2. In contrast, overexpression of Cox4i1, or Cox4i2, or Cox4i2 mutants did not affect oxygen affinity. Our findings suggest that Cox4i2 does not alter superoxide production by rearrangement of supercomplexes, whereas its specific cysteines are needed for the superoxide release. In conclusion, Cox4i2 plays a major role in the hypoxia-induced reduction of ETC components, likely mediated through its redox-active cysteine residues.
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| 6. |
- Pak, Oleg, et al.
(författare)
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Effectiveness of bortezomib and temozolomide for eradication of recurrent human glioblastoma cells, resistant to radiation
- 2021
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Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; , s. 195-209
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Bokkapitel (refereegranskat)abstract
- Background: Glioblastoma multiforme (GBM) is a primary human brain tumor with the highest mortality rate. The prognosis for such patients is unfavorable, since the tumor is highly resistant to treatment, and the median survival of patients is 13 months. Chemotherapy might extend patients' life, but a tumor, that reappears after chemoradiotherapy, is resistant to temozolomide (TMZ). Using postgenome technologies in clinical practice might have a positive effect on the treatment of a recurrent GBM.Methods: T98G cells of human GBM have been used. Radiation treatment was performed with Rokus-M gamma-therapeutic system, using Co-60 as a source of radionuclide emissions. High-performance liquid chromatography-mass spectrometry was used for proteome analysis. Mass spectrometry data were processed with MaxQuant (version 1.6.1.0) and Perseus (version 1.6.1) software, Max Planck Institute of Biochemistry (Germany). Biological processes, molecular functions, cells locations and protein pathways were annotated with a help of PubMed, PANTHER, Gene Ontology and KEGG and STRING v10 databases. Pharmaceutical testing was performed in vitro with a panel of traditional chemotherapeutic agents.Results: GBM cells proliferation speed is inversely proportional to the irradiation dose and recedes when the dosage is increased, as expected. Synthesis of ERC1, NARG1L, PLCD3, ROCK2, SARNP, TMSB4X and YTHDF2 in GBM cells, treated with 60Gy of radiation, shows more than a fourfold increase, while the synthesis level of PSMA2, PSMA3, PSMA4, PSMB2, PSMB3, PSMB7, PSMC3, PSMD1, PSMD3 proteins increases significantly. Traditional chemotherapeutic agents are not very effective against cancer cells of the recurrent GBM. Combination of TMZ and CCNU with a proteasome inhibitor-bortezomib-significantly increases their ability to eradicate cells of a radioresistant GBM.Conclusions: Bortezomib and temozolomide effectively destroy cells of a radioresistant recurrent human glioblastoma; proteome mapping of the recurrent GBM cancer cells allows to identify new targets for therapy to improve the treatment results.
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| 7. |
- Shevchenko, Valeriy, et al.
(författare)
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Molecular determinants of the interaction between glioblastoma CD133(+) cancer stem cells and the extracellular matrix
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 155-169
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Bokkapitel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common primary tumor of the human brain. It is characterized by invasive growth and strong resistance to treatment, and the median survival time of patients is 15 months. The invasive growth of this tumor type is associated with tumor cells with an aggressive phenotype, while its treatment resistance is attributed to cancer stem cells (CSCs). It remains unclear if CSCs have a more invasive nature than differentiated glioblastoma cells (DGCs), and what contribution CSCs make to the aggressive phenotype of GBM. Interaction with the extracellular matrix (ECM) is a key factor in the development of invasion. The aim of the present study was to compare the expression levels of signaling pathway proteins involved in interaction of receptors with the ECM in CSCs and DGCs. The U-87MG GBM cell line was used in the present study CSCs were extracted from gliomaspheres through magnetic-activated cell sorting based on the expression of cluster of differentiation 133 (CD133); CD133-negative DCGs were used as a control. HPLC and mass spectrometry were also used, and biological and molecular functions, signaling pathways and protein-protein interactions were analyzed using publicly available databases. Increased expression levels of the following 10 proteins involved in interaction with the ECM were identified in CSCs, compared with expression levels in DGCs: COL6A1, COL6A3, FN1, ITGA2, ITGA5, ITGAV, ITGB1, ITGB3, LAMB1 and LAMC1. The proteome of CSCs was observed to have >2-fold higher expression of these key proteins, when compared with the DGC proteome. Increased expression levels of four proteins (FERMT2, LOXL2, HDAC2 and FBN1) involved in activating signaling in response to receptor interaction with the ECM was also observed, indicating that CSCs may have highly invasive nature. LOXL2 expression level was >9-fold higher in CSCs compared to DGCs, suggesting that this protein may have potential as an marker for CSCs and as a target for this cell type in GBM.
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| 8. |
- Shevchenko, Valeriy, et al.
(författare)
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Proteins of Wnt signaling pathway in cancer stem cells of human glioblastoma
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 185-200
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Bokkapitel (refereegranskat)abstract
- Rationale: Glioblastoma multiforme (GBM) is the most aggressive primary glial brain tumor. The prognosis for GBM patients is not favorable, with the median survival time being 15 months. Its treatment resistance is associated with GBM cell population having cancer stem cells (CSCs). Wnt/beta-catenin signaling pathway is a strategically important molecular mechanism, providing proliferation of stem cells of all types. This study compares the expression levels of signaling pathway proteins in CD133(+) CSCs and CD133 (-) differentiated glioblastoma cells (DGCs). Materials and methods: the present study used U-87MG cells of human glioblastoma, the material was tested for mycoplasma contamination. High-performance liquid chromatography (HPLC) mass spectrometry was used for proteome analysis. Biological and molecular functions, signaling pathways and protein-protein interactions were analyzed using free-access databases: PubMed, PANTHER, Gene Ontology, Swiss-Prot and KEGG. Protein-protein interactions (PPIs) were analyzed using the STRING database (version 10). Results: There were identified 589 proteins with significantly changed expression in CD133+ CSCs, as compared with CD133-DGCs (P < 0.05). Bioinformatics analysis allowed to attribute 134 differentially expressed proteins to 16 signaling pathways. A significant increase in expression of eight Wnt signaling pathway proteins (APC, CSNK1E, CSNK1A, CSNK2A2, CSNK2B, CTNNB1, DVL1, RUVBL) was detected, as well as four proteins of the non-canonical Wnt pathway-RHOA, ROCK2, RAC2, DAAM1. Special attention should be paid to beta-catenin (CTNNB1) with more than 13.98-fold increase of expression in CSCs and Disheveled-associated activator of morphogenesis 1 (DAAM1) with 6.15-fold higher upregulation level. Conclusion: proteins of Wnt/beta-catenin signaling cascade are a prospective target for regulating CSCs activity.
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| 9. |
- Sommer, Natascha, et al.
(författare)
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Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 6:16
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.
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| 10. |
- Zaitsev, Sergei, et al.
(författare)
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Pro-inflammatory modification of cancer cells microsurroundings increases the survival rates for rats with low differentiated malignant glioma of brain
- 2020
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Ingår i: NOVEL THERAPEUTIC ADVANCES IN GLIOBLASTOMA. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 253-279
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Bokkapitel (refereegranskat)abstract
- Rationale: Glioblastoma multiforme (GBM) is one of the most aggressive human brain tumors. The prognosis is unfavorable with a median survival of 15 months. GBM aggressive nature is associated with a special phenotype of cancer cells that develops because of the transforming growth factor beta (TGF-beta). The study was aimed at providing experimental justification in vivo of a possibility to suppress TGF-beta production in a tumor via pro-inflammatory modification of cancer cell microenvironment, using CD45+ mononuclear cells of the red bone marrow. Materials and methods: The experiment used animals with transplanted C6 glioma. The animals were divided into 4 groups: (I) control (N = 60); (II) group of rats (N = 30) that received granulocyte colony-stimulating factor (G-CSF) to recruit CD45+ bone marrow mononuclear cells into their systemic circulation (G-CSF group); (III) group of rats (N = 30) that received pro-inflammatory therapy to trigger systemic inflammatory reaction by injecting bacterial lipopolysaccharides (LPS) and interferon-gamma (IFN gamma); (IV) rats (N = 30), stimulated with G-CSF, followed by pro-inflammatory therapy. Stereotaxic modeling of a brain tumor in experimental animals, as well as a combination of morphological, immunocytochemical analyses and immunosorbent assay were used. Results: TGF-beta 1 production in the tumor tissue resulted being inversely proportional to the intensity of proliferation processes and directly proportional to the size of necrosis areas, peaking on the 28th day of the experiment. Stimulation of experimental animals with G-CSF recruits CD45+ mononuclear stem and progenitor cells into the systemic circulation of experimental animals with C6 glioma, accompanied by intensification of microglial proliferation in the tumor and infiltration of the tumor tissue with microglial cells. Pro-inflammatory therapy against G-CSF stimulation results in polarization of microglia/macrophages population together with intensified antigen presentation, lower production of TGF-beta and IL10, increased synthesis of pro-inflammatory cytokines TNF alpha and IL1 in the tumor lesion and adjacent brain matter, remodeling of tumor matrix and higher survival rates for the experimental animals. Conclusions: Pro-inflammatory inflammatory modification of cancer cell microenvironment suppresses TGF beta production in a tumor and increases survival rates of the rats with transplanted poorly differentiated malignant brain glioma.
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