Репозиторий Университета

© 2021 Spandidos Publications. All rights reserved. Malignant melanomas within the eye present different types of metabolic and metastatic behavior. Uveal melanoma (UM) affects a quarter of a million individuals in the USA; however, the molecular pathogenesis is not well understood. Although UV radiation is a risk factor in cutaneous melanomas, it is not crucial for UM progression. Apart from chromosomal abnormalities, numerous major tumorigenic signaling pathways, including the PI3K/Akt, MAPK/ERK, Ras-association domain family 1 isoform A and Yes-associated protein/transcriptional co-activator with PDZ-binding motif signaling pathways, are associated with intraocular tumors. The present review describes the current insights regarding these signaling pathways that regulate the cell cycle and apoptosis, and could be used as potential targets for the treatment of UMs.

© 2019, © 2019 Informa UK Limited, trading as Taylor  &  Francis Group. The recent developments in Cathepsin protease research have unveiled a number of key observations which are fundamental to further our understanding of normal cellular homeostasis and disease. By far, the most interesting and promising area of Cathepsin biology stems from how these proteins are linked to the fate of living cells through the phenomenon of Lysosomal Leakage and Lysosomal Membrane Permeabilisation. While extracellular Cathepsins are generally believed to be of central importance in tumour progression, through their ability to modulate the architecture of the Extracellular Matrix, intracellular Cathepsins have been established as being of extreme significance in mediating cell death through Apoptosis. With these two juxtaposed key research areas in mind, the focus of this review highlights recent advancements in how this fast-paced area of Cathepsin research has recently evolved in the context of their mechanistic regulation in cancer research. Abbreviations : ECM, Extracellular Matrix; MMP, Matrix Metalloproteases; LL, Lysosomal Leakage; LMP, Lysosomal Membrane Permeabilisation; LMA, Lysosomorphic Agents; BC, Breast Cancer; ASM, Acid Sphingomyelinase; TNF-α, Tumor Necrosis Factor-alpha; LAMP, Lysosomal Associated membrane Protein; PCD, Programmed Cell Death; PDAC, Pancreatic Ductal Adenocarcinoma; ROS, Reactive Oxygen Species; aa, amino acids.

© 2018 Medknow Publications. All rights reserved. 2-Amino-4H-chromene derivatives possess anticancer property proved on different in vivo and in vitro models of malignancies such breast, nasopharyngeal, bladder, ovary carcinomas, astrocytoma, and osteosarcoma. We assumed it might be effective to apply one of the derivatives as promising approach to lung carcinoma treatment.To evaluate how novel 4-Aryl substituted 2-Amino-4H-chromene derivative AX-554 impacts tumor growth and progression, as well as possible mechanisms for anticancer effect development on in vivo patient-derived heterotopic xenograft model of lung carcinoma in mice. This was an experimental in vivo study. 40 nu/nu BALB/c female mice were randomly allocated into four equal groups: Intact, control, reference, and main group. Animals of three latter groups were ingrafted with human-derived lung adenocarcinoma. Antitumor and antimetastatic action of AX-554 novel aminochromone derivative as a substance were studied. Mice survival was registered. Kinase of anaplastic lymphoma (ALK), tubulin Beta-3 (TUBB3), and c-mesenchymal-epithelial transition (MET) concentrations in the prime tumor nodes homogenates were determined by quantitative enzyme-linked immunosorbent assay. Dannet's parametric criterion and the nonparametric exact Fisher test were used. The normality of the distribution was determined using ANOVA. The survival curve was analyzed using Gehan's criterion with the Yates's correction. Aminochromone derivative possesses an inhibitory effect on human lung adenocarcinoma transplanted into nu/nu BALB/c female mice, as well as significant antimetastatic activity. About 50 mg/kg/day AX-554 intragastric course increases animals' life expectancy of more than 3.3 times when compared with the control and induces remission in 60% of cases. The anticancer effect of the derivative is due to anti-ALK-mediated activation of tumor cells apoptosis and suppression TUBB3-dependent cell proliferation.

© 2018 Elsevier Inc. Oxidative stress is a major contributor to secondary injury signaling cascades following traumatic brain injury (TBI). The role of lipid peroxidation in the pathophysiology of a traumatic insult to neural tissue is increasingly recognized. As the methods to quantify lipid peroxidation have gradually improved, so has the understanding of mechanistic details of lipid peroxidation and related signaling events in the injury pathogenesis. While free-radical mediated, non-enzymatic lipid peroxidation has long been studied, recent advances in redox lipidomics have demonstrated the significant contribution of enzymatic lipid peroxidation to TBI pathogenesis. Complex interactions between inflammation, phospholipid peroxidation, and hydrolysis define the engagement of different cell death programs and the severity of injury and outcome. This review focuses on enzymatic phospholipid peroxidation after TBI, including the mechanism of production, signaling roles in secondary injury pathology, and temporal course of production with respect to inflammatory response. In light of the newly identified phospholipid oxidation mechanisms, we also discuss possible therapeutic targets to improve neurocognitive outcome after TBI. Finally, we discuss current limitations in identifying oxidized phospholipids and possible methodologic improvements that can offer a deeper insight into the region-specific distribution and subcellular localization of phospholipid oxidation after TBI.

© 2018 Wolters Kluwer Health, Inc. All rights reserved. This work presents the results of in-vitro biological activity studies of three novel anticancer agents, phosphonium salts based on the 3-hydroxypyridine scaffold, including one derivative of 4-deoxypyridoxine. Proliferation and viability of cells treated with these compounds was assessed by the colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of the compounds on apoptosis and cell cycle were studied by flow cytometry using annexin V-FITC/propidium iodide and propidium iodide staining, respectively. The influence of the compounds on mitochondrial membrane potential and intracellular reactive oxygen species was evaluated using tetramethyl rhodamine ethyl and DCFHA staining. Western blot analysis was used to study the changes in the expression of Bcl-xL, Bax, and caspase-3 apoptotic proteins. The treatment of ovarian adenocarcinoma cells OVCAR-4 with the tested compounds inhibited the growth and induced cell cycle arrest in the G1 phase. 3-Hydroxypyridine derivatives induced apoptosis by hyperexpression of Bax and caspase-3, whereas 4-deoxypyridoxine derivative induced cell death partly by reactive oxygen species generation and caspase-3 hyperexpression. These results indicate that the quaternary phosphonium salts studied represent potential therapeutic agents for the treatment of ovarian cancer.

© 2017, Springer Science+Business Media, LLC, part of Springer Nature. Since the 1990s, when it was demonstrated by Hammel and others that liver fibrosis is reversible, researchers and physicians actively search for new antifibrotic therapies. In recent years, knowledge of liver fibrosis pathophysiology has greatly advanced and new cellular and molecular mechanisms were described. The cells that determine extracellular matrix components distribution are myofibroblasts, but their origin is diverse. They can be activated hepatic stellate cells (HSCs), portal fibroblasts (PF), or circulating mesenchymal stem cells of the bone marrow. Among large number of substrates to inhibit activation, to inhibit proliferation of myofibroblasts, and to induce their apoptosis we, chose curcumin and gliotoxin. Primarily, in the current work, we optimized the explantation culture method for isolation of hepatic myofibroblasts and received two different cultures—myofibroblasts of HSC and PF origin. Exposition of 50 μM curcumin and 0.1 μM gliotoxin was the most optimal; we observed suppression of hepatic myofibroblast activation and inhibition of their proliferation. These results extend the current knowledge of the cells within the liver fibrogenic populations and prove inhibitory influence of biologically active substances (curcumin and gliotoxin) on portal myofibroblasts.

© 2018 Elsevier Ltd  Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53 + cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53 + H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53 +/+ HCT116 cells in much lower concentration range compared to p53 −/− HCT116 cells.

© 2018 Copyright SPIE. The paper presents the results of the studies of influence of optical radiation with wavelengths of 520 and 780 nm on human glial cells (U251) at the range of exposure times ∼ 1-15 min. It was found that after the first minute of irradiation at the wavelength of 780 nm, the relative number of apoptotic cells significantly increased. The result corroborates the concept of biological hazard of optical radiation for tumor cells, and suggests that the approach has a great potential in clinical application for the treatment of human glioma.

© Izdatel'stvo Meditsina. All rights reserved.  Introduction. Single-walled carbon nanotubes (SWCNTs) can create risks to human health when they enter the body by oral route when used in packaging materials, as promising agrochemicals and pesticides. The aim of the study. Evaluation of the subacute oral toxicity of SWCNT in rats. Material and methods. In the 92-days of the experiment, the SWCNTs were administered to rats along with drinking water at doses of 0 (control); 0.01; 0.1; 1.0 and 10 mg/kg body weight (BW) in the groups 1-5, respectively. Hematological indices of blood, apoptosis of hepatocytes, levels of pro- and anti-inflammatory cytokines in blood plasma and their production by cells of the spleen ex vivo, the content of the main and transient components of the intestinal microbiocenosis in the cecum were studied. There were determined hematological blood counts, hepatocyte apoptosis, levels of pro- and anti-inflammatory cytokines in blood plasma and their production by spleen cells ex vivo, content in the cecum of the main and transient components of the intestinal microbiocenosis. Results. At the SWCNT dose of 0.01 mg/kg BW there was a decrease in the number of neutrophils and basophils, an increase in the number of lymphocytes, and a decrease in the number and volume of platelets. At a dose of 0.1 mg/ kg bw there was noted a decrease in the number of cells in the early stage of apoptosis and the total number of cells in apoptosis, as well as a significant decrease in the levels of cytokines IL-10, IL-2, IL-4, IL-13, chemokine MIP-3a, TGF-β isoform 1; at a dose of 1.0 mg/kg IL-12p70, and TGF-β isoforms 1 and 3. TGF- β 2 level was significantly elevated in group 5. The suppressive effect was noted for SWCNTs on the mold flora in intestinal contents at all doses of nanomaterial used, whereas the number of yeasts increased at 1 mg/kg BW. The immunization of rats with ovalbumin had a clear modulating effect on the immunotropic effects of SWCNTs administered at a dose of 0.1 mg/kg BW in a 28-days experiment. Discussion. The mechanisms of the observed changes development are likely to be associated with both systemic anti-inflammatory effects and with a decrease in the effect of SWCNT on the permeability of the intestinal barrier to protein antigens and microbial toxins. Conclusion. SWCNTs exhibit a number of effects in relation to the studied indices that do not demonstrate a monotonic dependence on the dose of nanomaterial, which, apparently, is related to the processes of aggregation of the SWCNT.

This paper presents a literature review considering the role and mechanism of apoptosis in the pathogenesis of ischemic stroke (IS). The authors introduce a new concept: the functional request of the patient as a set of external (the nature and intensity of rehabilitation measures, characteristics of everyday life, diet, etc.) and internal (genetic factors, internal picture of the disease, availability of rental and other psychological facilities and etc.) attributes. This concept allows a new angle in understanding the pathogenesis of IS and creates fundamental and clinical potential for more successful approaches to therapy and rehabilitation after IS.