NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers.

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Reactive oxygen species (ROS) are well known to be implicated in various important cellular processes including signaling, regulation of homeostasis, or induction of death. Oxidative stress resulting from increased ROS production and impaired free radical scavenging systems can cause severe damage to biological macromolecules, affecting cell proliferation and causing genomic instability and cellular senescence. Although ROS are involved in a wide range of cellular processes, a limited number of studies have examined the generation and function of ROS in stem cells. It is known that ROS may enhance differentiation of stem cells and facilitate reprogramming into induced pluripotent stem cells (iPSCs), but on the other hand, they are also associated with malignant transformation or premature aging. Stem cells have also been shown to possess defective DNA repair machinery, which may have serious consequences for cells exposed to extensive oxidative stress. Since stem cells are considered as a promising tool in regenerative medicine, it is crucial to know and better understand all the processes related to ROS to prevent potential generation of mutations causing genomic instability and to avoid unwanted ROS-driven differentiation. Thus, the mechanisms by which genomic integrity of stem cells is maintained under oxidative stress and the role of ROS should be elucidated before stem cells finally find their place in clinical applications.The paper by C.-J. Li et al. demonstrates that treatment with antioxidants not only increases proliferation and mitochondrial integrity of human mesenchymal stem cells (hMSCs) but also enhances the therapeutic potential of hMSCs by promoting the formation of tunneling nanotubes (TNTs) between hMSCs and oxidatively injured cells in a coculture system. The authors demonstrate that TNTs enable hMSCs to "export" their healthy mitochondria to the injured cells and hence decrease their oxidative stress and stabilize the mitochondrial membrane potential of the injured cells. Concurrently, the rescued cells also show enhanced mitophagy, implicating that their damaged mitochondria are eliminated in order to maintain normal cell physiology. The findings highlight that antioxidants enhance mitochondrial transfer from hMSCs to the injured cells and provide them with a repair mechanism.A similar topic is presented by Y.-C. Chuang et al. who show that Wharton's jelly mesenchymal stem cells (WJMSCs) are able to transfer healthy mitochondria to cybrid cells from a patient with myoclonus epilepsy associated with ragged-red fibers (MERRF) through intercellular connections. This mitochondrial transfer is found to be

Abstract:The biological activity of nanosize silver particles towards oral epithelium-derived carcinoma seems to be still underinvestigated. We evaluated the influence of low doses of nanosize scale silver particles on the proliferation and viability of malignant oral epithelial keratinocytes in vitro, alone and in conjunction with the plant alkaloid berberine. Cells of human tongue squamous carcinoma SCC-25 (ATCC CRL-1628), cultivated with the mixture of Dulbecco's modified Eagle's medium, were exposed to silver nanoparticles alone (AgNPs, concentrations from 0.31 to 10 µg/mL) and to a combination of AgNPs with berberine chloride (BER, 1/2 IC 50 concentration) during 24 h and 48 h. The cytotoxic activity of AgNPs with diameters of 10 nm˘4 nm was measured by 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cell cycle analysis was performed by treating cells with propidium iodide followed by flow-activated cell sorting. RT-QPCR reaction was used to assess expression of anti-apoptotic proteins Bcl-2 and pro-apoptotic protein Bcl-2-associated X protein Bax genes expression. Monodisperse silver nanoparticles at a concentration of 10 µg/mL arrested SCC-25 cells cycle after 48 h at the G0/G1 phase in a dose-and time-dependent manner through disruption G0/G1 checkpoint, with increase of Bax/Bcl-2 ratio gene expression. AgNPs exhibit cytotoxic effects on SCC-25 malignant oral epithelial keratinocytes, which is diminished when combined with BER. The AgNPs concentration required to inhibit the growth of carcinoma cells by 50% (IC 50 ) after 48 h was estimated at 5.19 µg/mL. AgNPs combined with BER increased the expression of Bcl-2 while decreasing the ratio of Bax/Bcl-2 in SCC-25 cells. Silver particles at low doses therefore reduce the proliferation and viability of oral squamous cell carcinoma cells. SCC-25 cells are susceptible to damage from AgNPs-induced stress, which can be regulated by the natural alkaloid berberine, suggesting that nanoparticles may be potentially used in a chemoprevention/chemotherapy by augmentation of action of standard anti-cancer drugs.

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The aim of this study was to assess the influence of cisplatin and an extremely low frequency electromagnetic field (ELF-EMF) on antioxidant enzyme activity and the lipid peroxidation ratio, as well as the level of DNA damage and reactive oxygen species (ROS) production in AT478 carcinoma cells. Cells were cultured for 24 and 72 h in culture medium with cisplatin. Additionally, the cells were irradiated with 50 Hz/1 mT ELF-EMF for 16 min using a solenoid as a source of the ELF-EMF. The amount of ROS, superoxide dismutase (SOD) isoenzyme activity, glutathione peroxidase (GSH-Px) activity, DNA damage, and malondialdehyde (MDA) levels were assessed. Cells that were exposed to cisplatin exhibited a significant increase in ROS and antioxidant enzyme activity. The addition of ELF-EMF exposure to cisplatin treatment resulted in decreased ROS levels and antioxidant enzyme activity. A significant reduction in MDA concentrations was observed in all of the study groups, with the greatest decrease associated with treatment by both cisplatin and ELF-EMF. Cisplatin induced the most severe DNA damage; however, when cells were also irradiated with ELF-EMF, less DNA damage occurred. Exposure to ELF-EMF alone resulted in an increase in DNA damage compared to control cells. ELF-EMF lessened the effects of oxidative stress and DNA damage that were induced by cisplatin; however, ELF-EMF alone was a mild oxidative stressor and DNA damage inducer. We speculate that ELF-EMF exerts differential effects depending on the exogenous conditions. This information may be of value for appraising the pathophysiologic consequences of exposure to ELF-EMF.

Free radicals generated by mitochondria are candidates for mediating long-lasting effects of radiation on cells, including genetic instability. To better understand the significance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in these long-term effects we assayed ROS and RNS levels, the mitochondrial membrane potential and mass, and the frequency of DNA strand breaks, apoptosis and necrosis in human leukemic cells (K562 and HL60) after 12 Gy of X irradiation. An increase in intracellular ROS level was observed immediately post-irradiation, and about 24 h later a second increase of ROS was accompanied by increase in nitrogen oxide, mitochondrial potential and mitochondrial mass in both cell types. The second peak of ROS level was partially inhibited by rotenone, an inhibitor of mitochondrial complex I, in K562 but not in HL60 cells suggesting that the sources of ROS differed in the two cell types. The frequency of DNA breaks showed kinetics similar to ROS levels, with a sharp peak immediately after irradiation and a second increase 24 and 48 h later, which was significantly higher in K562 cells. Forty-eight hours after irradiation an increase in the frequency of apoptotic cells was observed in both cell lines, which became larger and statistically significant in K562 cells after inhibition of mitochondrial complex I. Our results show that ionizing radiation activates cellular processes which produce long-lasting ROS and RNS radicals, which may have different sources in different cell types and could participate in cellular signaling networks important for radiosensitivity and mode of cell death.

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