俄罗斯联邦卫生部

Lichens are producers of a number of unique secondary metabolites. The most numerous and structurally diverse group of compounds characteristic of lichens are depsidones. To date, approximately 237 compounds belonging to the depsidones group have been described in lichens. At the same time, one or another biological activity has been described only for less than 10

Dynamics of glial activity changes in the subacute and chronic stages of ischemic stroke after small focal injuries remains poorly understood due to complexity of the long-term animal monitoring and data interpretation. The aim of this study was to assess relationship between the delayed morphological changes in nervous tissue after experimental stroke and lesion parameters determined in vivo at various time points. For this purpose, photothrombotic ischemia of the cerebral cortex was induced in the C57BL/6J-Tg(Thy1-GCaMP6f)GP5.17Dkim/J mice, which express fluorescent calcium sensor protein GCaMP6f in cortical neurons. Lesion (ischemic core) size was determined using wide-field optical imaging (WFOI) through a cranial window via the GCaMP6f fluorescence at 3 min, 1 day, and 7 days post-photothrombosis. On day 19, brain sections were analyzed using Nissl staining and immunohistochemistry for microglial (Iba1) and astrocytic (GFAP) markers. It was found that the signs of neuroinflammation – changes in glial cell morphology and quantity – persist in the perifocal region even 19 days after ischemia induction, despite the small lesion volume. A significant linear relationship between microglial nuclear area and lesion size on day 7 was identified. Conversely, no significant correlation was found between the lesion sizes determined in the hyperacute phase (3 min) and acute phase (1 day) and cellular parameters (cell count, morphometric parameters). This indicates that the lesion formation in the acute phase is dynamic, and only the lesion size after its stabilization influences long-term stroke outcomes. Absence of a correlation between the delayed glial changes and ischemic core size during the hyperacute and acute phases suggests that therapeutic window for interventions modulating glial activity may extend to the later period after stroke, even with small lesion size. The results also allow us to conclude that it is not necessary to make an amendment for the initial lesion size in the studies of delayed neuroglial processes in preclinical models. In turn, the correlation between the lesion size on day 7 and microglial cell nucleus area on day 19 demonstrates that the lesion size at the end of the acute phase may be one of the prognostic factors for effectiveness of the post-stroke therapy.

Immunotherapeutic methods, such as the use of checkpoint inhibitors, CAR T cells, dendritic cell vaccines, etc., offer promising approach to the treatment of glioblastomas. Dendritic cell (DC)-based vaccines used in glioma therapy have been well studied and are effective in some cases. However, the use of DC vaccines for the treatment of patients with gliomas, though shows promising results, is still limited by the suboptimal choice of tumor antigen and the method of its loading, as well as the immunosuppressive nature of the tumor cell microenvironment. In this work, we showed that glioma cell lines express a broad spectrum of immune checkpoints, suppress the maturation of allogeneic DCs during direct co-culturing, and do not stimulate the proliferation of allogeneic lymphocytes. Lymphocytes primed with dendritic cells loaded with the corresponding tumor lysates effectively lysed only two of three glioma cell lines, T98G and U373 MG, whereas 1321N1 cells completely suppressed the cytotoxic activity of lymphocytes primed by co-culturing with DCs loaded with the lysate of these cells. Thus, the efficacy of DC vaccines may be related to the individual characteristics of glioma cells.

Macrophages are a heterogeneous cell population whose functional diversity is formed during their maturation and depends on factors of the microenvironment after their migration into the bloodstream or tissues. One such factor is the pro-inflammatory protein cyclophilin A (CypA, 18 kDa). Using a model of early human monocytic THP-1 cells, it was shown that recombinant human CypA (rhCypA) exerts a differentiating effect on these cells, inducing their maturation, adhesion, and spreading. Under the effect of rhCypA, the THP-1 cells developed an actin cytoskeleton characteristic of motile cells with numerous pseudopodia and podosomes, which ensure tight adhesion of the cells to the substrate and determine their migratory capabilities. Combination of low concentrations of rhCypA and other activators (phorbol myristate acetate) showed an additive effect and ensured effective monocyte differentiation. It was shown that rhCypA, along with other pro-inflammatory factors (IFNγ, TNFα), promotes cell fusion and induces formation of multinucleated macrophages, which are formed during osteoclast maturation under normal conditions as well as during granuloma formation in chronic inflammation (tuberculosis, Crohn’s disease). Multinucleated giant cells have significantly higher functional activity (phagocytosis, bactericidal, and pro-inflammatory activity) compared to the mononuclear forms. The study showed that rhCypA enhances expression of the CD147 molecule, an integral functional regulator of CD29 and CD98 molecules involved in the processes of cell adhesion and fusion. Elevated doses of CypA cause deterioration in macrophages, inducing their apoptosis, which may play a role in regulation of the immune response. The findings of this study determined the mechanisms by which secreted CypA mediates monocyte differentiation and maturation, as well as it showed functional role of macrophages in the development of the immune response, which could facilitate further development of therapeutic approaches for the treatment of infectious, autoimmune, and other diseases.

We performed a comprehensive analysis of changes in the functional state of human multipotent mesenchymal stromal cells derived from the umbilical cord tissue (UC-MSCs) after a 30-day simulated microgravity exposure. It was found that simulated microgravity induced changes in the expression of stromal markers and cell cycle regulators in UC-MSCs but did not alter their viability and expression of the cytoskeletal genes. We also observed shifts in the expression of adhesion molecules and enhanced secretion of proinflammatory cytokines. These findings indicate that microgravity modulates functional properties of MSCs and confirm the possibility of using these cells as a model system for studies of the molecular and cellular mechanisms underlying adaptation to microgravity during long-term spaceflights.