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Epigenetic regulation of gene expression in cells is a complex and dynamic process that remains incompletely understood. The architecture of the chromatin itself and its level of condensation can greatly impact the expression of genes as well as the sensitivity of the DNA to damage. The compact nature of heterochromatin typically results in gene silencing and resistance to DNA-damaging agents, while less compact euchromatin results in gene expression and increased sensitivity to injury. There are diverse ways in which the chromatin structure, and therefore the sensitivity of cells to damage, can be regulated, including post-translational modifications to both the histones within the chromatin and the DNA itself. These modifications are tightly controlled and correspond to various factors such as metabolism and cell cycle. When these processes are dysregulated, as in cancer cells, the chromatin structure is also altered, ultimately changing the gene expression profile as well as the susceptibility of cells to DNA-damaging agents commonly used for cancer treatments. Recent studies have shown that manipulating the various players involved in regulating post-translational modifications to chromatin and exploiting differences in metabolism may prove to be effective methods for modifying cancer and normal cell sensitivity to damaging agents. In this review we discuss various ways of regulating chromatin structure and how these changes can influence cellular sensitivity to damage as well as the implications of these relationships for improving the efficacy and safety of cancer treatments.

Alpha-toxin is a major virulence factor of Staphylococcus aureus. Monomer binding to host cell membranes results in the formation of heptameric transmembrane pores. Among human model airway epithelial cell lines, A549 cells were most sensitive toward the toxin followed by 16HBE14o- and S9 cells. In this study we investigated the processes of internalization of pore-containing plasma membrane areas as well as potential pathways for heptamer degradation (lysosomal, proteasomal) or disposal (formation of exosomes/micro-vesicles). The abundance of toxin heptamers upon applying an alpha-toxin pulse to the cells declined both in extracts of whole cells and of cellular membranes of S9 cells, but not in those of 16HBE14o- or A549 cells. Comparisons of heptamer degradation rates under inhibition of lysosomal or proteasomal degradation revealed that an important route of heptamer degradation, at least in S9 cells, seems to be the lysosomal pathway, while proteasomal degradation appears to be irrelevant. Exosomes prepared from culture supernatants of toxin-exposed S9 cells contained alpha-toxin as well as low amounts of exosome and micro-vesicle markers. These results indicate that lysosomal degradation of internalized toxin heptamers may be the most important determinant of toxin-resistance of some types of airway epithelial cells.

In this study, the cellular sensitivity of white blood cells in vitro to interferon-α2 in children with EBV-infection in the acute period of the disease in terms of the 1, 6, 12 months after a previous infection. Found that children in the dynamics of the EBV-infection, preservation of cell sensitivity at the same level at 1 month after the disease is seen in 40,5% children, 6 months – 27,8% patients. Lack of cell sensitivity to interferon-α2 blood leukocytes in 12 months after undergoing a EBV-infection observed in 88,9% of children. During repeated courses interferon-therapy to study cellular sensitivity of blood leukocytes for individual selection of the drug.

• M. aeruginosa in late lag phase held higher metabolic activity than that in exponential phase. • M. aeruginosa in late lag phase could be more effective inactivated by CuSO 4. • This effective inactivation was partially due to its higher sensitivity to CuSO 4 exposure. • The higher sensitivity was the inherent characteristic of M. aeruginosa in late lag phase. • M. aeruginosa control in late lag phase can reduce the risk of cyanotoxin release. Cyanobacterial blooms are always treated in exponential phase, which demands high dosages of algicides (e.g., CuSO 4). Actually, cyanobacterial blooms in late lag phase exhibit low cell-density and specific physiological/biochemical characteristics, implying the possibility of controlling blooms in a more efficient and economical way with CuSO 4 treatment if cyanobacterial cells in late lag phase can be treated. In this study, the outbreakof a Microcystis bloom was simulated, and Microcystis samples in late lag and exponential phases were treated with CuSO 4. The results showed that M. aeruginosa in late lag phase had a higher ratio of dividing-cells, F v /F m and intracellular total organic carbon content (TOC) than that in exponential phase, indicating that its metabolic activity was vigorous. M. aeruginosa in late lag phase could more easily be blocked, since a higher decrease in chlorophyll-a, F v /F m and membrane integrity occurred under the same dosages of CuSO 4 exposure compared to M. aeruginosa in exponential phase. Meanwhile, microcystin release in late lag phase was less than that in exponential phase. Moreover, higher sensitivity in late lag phase was confirmed at the individual level, as the photosynthesis related genes psaB and rbcL were more down-regulated than those in exponential phase. In general, cyanobacteria in late lag phase exhibited higher sensitivity to CuSO 4 , indicating that CuSO 4 treatments in late lag phase can achieve a higher control efficiency and fewer release of microcystin with low-dosages algicide. Hence, it is a more environmentally friendly strategy to control cyanobacterial blooms than the traditional strategy applied in exponential phase. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The correlation between time dependent viabilities, after applying two radiation qualities and two alkylating agents on HTB140 melanoma cells, has been studied. Irradiations were performed with γ-rays and 62MeV protons, close to the Bragg peak maximum, delivering doses of 8–24Gy. Treatments with fotemustine (FM) and dacarbazine (DTIC) were carried out with concentrations of 0.05–2mM. High radio-resistance of HTB140 cells revealed by a clonogenic assay was confirmed by microtetrasolium and sulforhodamine B, through the surviving fraction at 2Gy (SF2), being 0.961–0.956 for γ-rays and 0.931–0.887 for protons. A better efficiency of protons was illustrated by relative biological effectiveness at 2Gy (RBE), ranging from 1.69 to 1.89. A kinetic study of concentration dependent cytotoxicity indicated that the best effect of the drugs, estimated as the concentration that produces 50% of growth inhibition (IC50), was obtained at 48h, having values of 76μM for DTIC and 145μM for FM. The cytostatic ability of the drugs pointed out that the presence of DTIC at 24h, compared to FM, was insufficient to produce an effect. Protons and FM demonstrated their pro apoptotic capacity. Cross-resistance between treatments applied to the HTB140 cells was observed, protons being the most efficient, while DTIC, FM and γ-rays demonstrated a lower level of cell inactivation. [Copyright &y& Elsevier]

Abstract: Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1, 2-[bis (1,2-Benzisoselenazolone-3 (2H) -ketone)]ethane (BBSKE), a novel TrxR inhibitor, were investigated on A549, HeLa, Bel-7402, BGC823 and KB cell lines. After treated with BBSKE, a good linear correlation coefficient (r≥0.989) between TrxR activity and cell viability exists in each cell line together with cell growth/proliferation inhibition and apoptosis through Bcl-2/Bax and Caspase-3 pathways. These results suggest that there exists some relationship between TrxR inactivation and growth/proliferation inhibition or apoptosis in the investigated cell lines. [Copyright &y& Elsevier]

Abstract: We have derived cells from the Chinese hamster V79 cell line by conditioning them with repeated low doses of hydrogen peroxide (H2O2). This mimics the physiological condition where cells are repeatedly exposed to low levels of oxidants. In an attempt to characterize such cells, we have exposed both conditioned cells (V79C) and the parental V79 cells (V79P) to different types of cytotoxic agents and compared their sensitivity to cell killing. The V79C cells were found to be stably resistant to killing by agents that produced toxicity through oxidative stress, e.g. H2O2 and cisplatin. It was also found that the lipid peroxidation produced by these agents were considerably lower in the V79C cells. Thus, the difference in sensitivity could be due to lesser extent of damage to these cells. V79C cells had greater antioxidant defense through higher GSH content and greater activity of enzymes such as Cu–Zn superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), which provided protection from damage. Enzyme activities were also assayed at different times after treatment with various cytotoxic agents; there was a relatively large increase in SOD activity which perhaps plays a key role in determining the resistance of the V79C cells to killing. [Copyright &y& Elsevier]

Objective: To investigate the function of primary cilia in regulating the cellular response to temozolomide (TMZ) and ionizing radiation (IR) in glioblastoma (GBM)., Methods: GBM cells were treated with TMZ or X-ray/carbon ion. The primary cilia were examined by immunostaining with Arl13b and γ-tubulin, and the cellular resistance ability was measured by cell viability assay or survival fraction assay. Combining with cilia ablation by IFT88 depletion or chloral hydrate and induction by lithium chloride, the autophagy was measured by acridine orange staining assay. The DNA damage repair ability was estimated by the kinetic curve of γH2AX foci, and the DNA-dependent protein kinase (DNA-PK) activation was detected by immunostaining assay., Results: Primary cilia were frequently preserved in GBM, and the induction of ciliogenesis decreased cell proliferation. TMZ and IR promoted ciliogenesis in dose- and time-dependent manners, and the suppression of ciliogenesis significantly enhanced the cellular sensitivity to TMZ and IR. The inhibition of ciliogenesis elevated the lethal effects of TMZ and IR via the impairment of autophagy and DNA damage repair. The interference of ciliogenesis reduced DNA-PK activation, and the knockdown of DNA-PK led to cilium formation and elongation., Conclusion: Primary cilia play a vital role in regulating the cellular sensitivity to TMZ and IR in GBM cells through mediating autophagy and DNA damage repair., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Disseminated superficial actinic porokeratosis (DSAP), skin lesions of which are known to he induced by ultraviolet (UV) light, does not develop into skin cancer as frequently as other types of porokeratosis (PK). To establish the cellular basis of this characteristic of DSAP, we examined the colony-forming ability of UVC light- or X-ray-irradiated cultured fibroblasts derived from DSAP patients' skin. Sensitivity to the lethal effects of UV light was not significantly different between 3 DSAP and 5 control cell strains. In contrast, DSAP cell strains were significantly hypersensitive to the lethal effects of X-radiation, although the sensitivity was less than that of cell strains from other types of PK patients. The results indicate that the actinic character of DSAP is not reflected in the cellular response to the lethal effects of UV light, but suggest that DSAP shares X-ray sensitivity, which is probably associated with the cancer-prone nature of PK. [ABSTRACT FROM AUTHOR]

Alpha-toxin is a major virulence factor of Staphylococcus aureus. Monomer binding to host cell membranes results in the formation of heptameric transmembrane pores. Among human model airway epithelial cell lines, A549 cells were most sensitive toward the toxin followed by 16HBE14o- and S9 cells. In this study we investigated the processes of internalization of pore-containing plasma membrane areas as well as potential pathways for heptamer degradation (lysosomal, proteasomal) or disposal (formation of exosomes/micro-vesicles). The abundance of toxin heptamers upon applying an alpha-toxin pulse to the cells declined both in extracts of whole cells and of cellular membranes of S9 cells, but not in those of 16HBE14o- or A549 cells. Comparisons of heptamer degradation rates under inhibition of lysosomal or proteasomal degradation revealed that an important route of heptamer degradation, at least in S9 cells, seems to be the lysosomal pathway, while proteasomal degradation appears to be irrelevant. Exosomes prepared from culture supernatants of toxin-exposed S9 cells contained alpha-toxin as well as low amounts of exosome and micro-vesicle markers. These results indicate that lysosomal degradation of internalized toxin heptamers may be the most important determinant of toxin-resistance of some types of airway epithelial cells. [ABSTRACT FROM AUTHOR]