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Background Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. Results By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Conclusions Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

Changes in the antioxidant protection system of Larix sibirica Ledeb at different pollution levels caused by emissions from a large aluminum smelter (BrAS) have been studied. We revealed that the content of peroxide (H

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with relapsed and refractory classic Hodgkin lymphoma (rrHL). However, the optimal conditioning regimen and GVHD prophylaxis for rrHL remain undetermined. The aim of this study was to investigate outcomes of allo-HSCT with a fludarabine plus bendamustine (FluBe) conditioning regimen and GVHD prophylaxis with posttransplantation cyclophosphamide (PTCY) in patients with rrHL.Allo-HSCT results in 58 adult patients with rrHL were analyzed retrospectively.Three-year overall survival and event-free survival were 81% (95% CI 65-91) and 55% (95% CI 38-72), respectively. The cumulative incidence of relapse (CIR) at 3 years was 33% (95% CI 13-51). The cumulative incidence of aGVHD grade II-IV and severe aGVHD grade III-IV was 36% (95% CI 22-48) and 22% (95% CI 9-33), respectively. The cumulative incidence of cGVHD was 32% (95% CI 17-45), including moderate or severe cGVHD in 17% (95% CI 4-28). Patients who developed aGVHD after allo-HSCT had significantly lower CIR (24% vs 49%, p = 0.004). The use of PBSC as a graft source also significantly reduced CIR (4% vs 61%, p = 0.002).FluBe-PTCY allo-HSCT facilitates favorable outcomes, low toxicity, and mortality in rrHL.

Recently, mesenchymal stem/stromal cells (MSCs) therapy has become an emerging therapeutic modality for the treatment of inflammatory bowel disease (IBD), given their immunoregulatory and pro-survival attributes. MSCs alleviate dysregulated inflammatory responses through the secretion of a myriad of anti-inflammatory mediators, such as interleukin 10 (IL-10), transforming growth factor-β (TGFβ), prostaglandin E2 (PGE2), tumor necrosis factor-stimulated gene-6 (TSG-6), etc. Indeed, MSC treatment of IBD is largely carried out through local microcirculation construction, colonization and repair, and immunomodulation, thus alleviating diseases severity. The clinical therapeutic efficacy relies on to the marked secretion of various secretory molecules from viable MSCs via paracrine mechanisms that are required for gut immuno-microbiota regulation and the proliferation and differentiation of surrounding cells like intestinal epithelial cells (IECs) and intestinal stem cells (ISCs). For example, MSCs can induce IECs proliferation and upregulate the expression of tight junction (TJs)-associated protein, ensuring intestinal barrier integrity. Concerning the encouraging results derived from animal studies, various clinical trials are conducted or ongoing to address the safety and efficacy of MSCs administration in IBD patients. Although the safety and short-term efficacy of MSCs administration have been evinced, the long-term efficacy of MSCs transplantation has not yet been verified. Herein, we have emphasized the illumination of the therapeutic capacity of MSCs therapy, including naïve MSCs, preconditioned MSCs, and also MSCs-derived exosomes, to alleviate IBD severity in experimental models. Also, a brief overview of published clinical trials in IBD patients has been delivered.

Objectives Therapy of patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) after PD-1 inhibitors failure remains an unresolved issue. The aim of this study was to evaluate the efficacy and safety of the combination of nivolumab with brentuximab vedotin (Nivo + BV) after nivolumab monotherapy failure. Methods This study retrospectively analyzed 21 patients with r/r cHL who were treated with the combination of Nivo + BV after Nivo failure. The response was evaluated by PET–CT scan according to the LYRIC criteria. Adverse events (AEs) were assessed according to NCI CTCAE v.4.03. Results Median follow-up was 19 (9–47) months. The ORR was 57%. The median OS was not reached, 24 month OS was 80% (95% CI 50–93%). Median PFS was 12 months with 24 month PFS of 31% (95% CI 12–53%). Any grade AEs were observed in 12 patients (63%), 3–4 grade AEs in 2 patients (10%). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after Nivo + BV was performed in 8 (38%) patients. The median time between Nivo + BV and allo-HSCT was 8 (5–21) months. Conclusions Combination of Nivo + BV in r/r cHL after nivolumab monotherapy failure is potentially an effective and safe approach. Supplementary Information The online version contains supplementary material available at 10.1007/s10147-021-02085-6.

Changes in the fatty acid (FA) composition of total lipids of Pinus sylvestris needles at different pollution levels caused by emissions from a large aluminum smelter (BrAS) have been studied. In the needles of trees from unpolluted (background) territories, the FA spectrum is represented by 24 acids with prevalence of unsaturated FAs (71.6%). The main unsaturated FA are represented by oleic (C18: 1ω9), linoleic (C18: 2ω6), and α-linolenic (C18: 3ω3) acids. Under the influence of BrAS emissions, the total amount of identified FAs in the needles and the proportion of unsaturated FAs decrease, while the fraction of saturated FAs, on the contrary, increases from 25.4% in unpolluted needles to 33.2% in polluted ones. The content of palmitic FA (C16:0) in the needles exceeds background values by 1.5 times, behenic acid (C22:0) – by 1.6–2.5 times, arachidic acid (C20:0) – by 1.5 times, palmitic margaric acid (C17:0) – by 1.5–2.3 times. These FAs play the important role in the protection of plant membranes from the effects of abiotic stress factors, making them less permeable. The sum of short-chain saturated FAs (C12:0, C14:0, C15:0) increase by 4.8 times in needles of trees that are highly polluted. Pentadecanoic (C15:0) acid is found in the needles only in the background areas and at the low pollution level. With a more severe pollution, C15:0 is not identified, but lauric acid with the cis-configuration of double bonds in the structure (izo-C12:0) appears. The presence of “relict” ∆5-polymethylene FAs in the composition of pine needle membrane lipids is determined. In the background areas, they account for 12.9% of the total FAs. With the industrial pollution intensification, their total content increases and reaches 14.1%. ∆5-polymethylene FAs are also able to protect membranes against negative influences. Thus, changes in the quantitative and qualitative FA composition of pine needle total lipids indicate the activation of the stabilization mechanisms of membrane lipids due to their tight packing in a bilayer. It is one of the adaptive reactions of Pinus sylvestris in response to the impact of the aluminum industry emissions.

There are individual differences in the tolerance to hypoxia and stress. Stress can contribute to the development of various diseases, including inflammatory bowel disease. It was found that inflammatory bowel diseases in animals susceptible to hypoxia runs more severe course than in tolerant animals. We studied morphofunctional changes in the colon under conditions of modeled cold stress in male C57BL/6 mice susceptible and tolerant to hypoxia. The animals were daily subjected to cold stress (20 min at -20°C) for 2 weeks. Cold stress was followed by an increase in the volume fraction of goblet cells in the colon and production of mucins by these cells in mice tolerant to hypoxia and an increase in cell content in the lamina propria of the colon mucous membrane in animals susceptible to hypoxia. The number of serotoninproducing endocrine cells increased in both groups, but these changes were more pronounced in mice susceptible to hypoxia.

Element contents in assimilation organs of trees are an essential component of a comprehensive forest condition diagnosis. They allow conclusions about the current nutritional status of trees and estimate the main risks for a sustainable forest ecosystem management in the future. The purpose of this research was to study the effect of highly aggressive fluorine-containing emissions from a large aluminum smelter on the nutritional status of coniferous trees Larix sibirica and Pinus sylvestris. Studies carried out in the background areas showed that the both species have the main part of the elements in optimal quantities. A deficiency is noted for potassium. The content of N, K, Mg, Na, S, F, Cu, Co, and Cd in L. sibirica needles was 1.2–5.2 times higher than in P. sylvestris needles. Under the influence of the aluminum smelter emissions, fluorine concentration in the tree needles increases by 13.8–30.0 times; sulfur by 2.9–3.6 times; heavy metals by 2.0–5.1 times; and nitrogen, calcium, magnesium, and sodium by 1.2–3.6 times, especially in the industrial zone and 5 km far from it. With the increasing distance from the smelter, the content of pollutants in the tree needles decreases. Values close to background are observed at a distance of over 40 km. According to index biogeochemical transformation, the elemental composition of P. sylvestris needles undergoes greater changes than L. sibirica ones under the influence emissions from the aluminum smelter. Changes in the element concentration of the tree needles caused by the impact of industrial emissions lead to a restructuring of the elements accumulation rows, as well as to a violation of the element quantitative ratios. Change of N:P:K, Ca:K, Ca:P, P:S, P:F, Mn:F, and Mn:Fe ratios points to serious nutrient imbalances in coniferous trees, which may reduce their vitality and growth in the long run.

Glioblastoma multiforme (GBM) is one of the most aggressive glial cell tumors in adults. Although current treatment options for GBM offer some therapeutic benefit, median survival remains poor and does not generally exceed 14 months. Several genes, such as isocitrate dehydrogenase (IDH) enzyme and O6-methylguanine-DNA methyltransferase (MGMT), have been implicated in pathogenesis of the disease. Treatment is often adapted based on the presence of IDH mutations and MGMT promoter methylation status. Recent GBM cell line studies have associated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) expression with high-grade tumors. Increased Nrf2 expression is often found in tumors with IDH-1 mutations. Nrf2 is an important transcription factor with anti-apoptotic, antioxidative, anti-inflammatory, and proliferative properties due to its complex interactions with multiple regulatory pathways. In addition, evidence suggests that Nrf2 promotes GBM cell survival in hypoxic environment,by up-regulating hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Downregulation of Nrf2 has been shown to improve GBM sensitivity to chemotherapy drugs such as Temozolomide. Thus, Nrf2 could be a key regulator of GBM pathways and potential therapeutic target. Further research efforts exploring an interplay between Nrf2 and major molecular signaling mechanisms could offer novel GBM drug candidates with a potential to significantly improve patients prognosis.

The serotonin system of the brain plays key roles in regulating behavior and cognitive functions, as well as in energy metabolism. This involves serotoninergic neurons in the midbrain expressing the enzyme tryptophan hydroxylase type 2 (TPH-2), which catalyzes the synthesis of serotonin, and hypothalamic neurons expressing serotonin receptors. Changes in the expression and distribution of TPH-2 in midbrain neurons on obesity remain poorly studied. In addition, it has been suggested that serotonin may also be synthesized in hypothalamic neurons influencing the serotonin system of the hypothalamus, though no data on the expression and possible localization of TPH-2 in hypothalamic neurons have been obtained. The aim of the present work was to study TPH-2 expression in the midbrain and its distribution in neurons in the arcuate, paraventricular, and supraoptic nuclei of the hypothalamus in mice with diet-induced obesity (DIO) and in agouti mice with genetically determined melanocortin-type obesity. Expression of the TPH-2 gene in the hypothalamus of C57Bl/6J mice was demonstrated and double immunolabeling studies provided the first evidence that this enzyme is located in proopiomelanocortin (POMC)-immunopositive neurons in the arcuate nuclei and vasopressin-immunopositive neurons in the paraventricular and supraoptic nuclei. In both types of obesity, TPH-2-immunopositive granules in POMC- and vasopressin-immunopositive neurons increased, though expression of the Tph2 gene increased only in agouti mice. TPH-2 content in the midbrain of DIO mice decreased, while there was no change in agouti mice. These results provide evidence of the important role of serotonin synthesized in the hypothalamic which, along with serotonin arriving from the midbrain, is involved in compensatory changes in hypothalamus signaling in obesity. Detection of TPH-2-immunopositive hypothalamic neurons of different ergicities and able to synthesize serotonin points to the existence of novel mechanisms of autocrine and paracrine serotonin regulation in the hypothalamus, including in obesity.