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Objectives: Coenzyme Q10, incorporated in DOPC lyposomes or naturally present in liver bovine mitochondria or in human blood plasma, was reacted with nitrogen dioxide •NO2 or with a •NO/•NO2 mixture. Methods and Results: The reaction course was monitored by Electron Paramagnetic Resonance (EPR) spectroscopy and in all cases the formation of a di-tert-alkyl nitroxide was observed, deriving from the addition of •NO2 to one of the double bonds, most likely the terminal one, of the isoprenic chain. The rate constant for nitroxide formation was also determined by EPR spectroscopy and an initial rate of ca. 7 × 10−8 M s−1 was obtained. [ABSTRACT FROM AUTHOR]

Glutathione is considered the major non‐protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs. The balance between its concentration and redox state is due to a complex series of interactions between biosynthesis, utilization, degradation, and transport. All these factors are of great importance to understand the significance of cellular redox balance and its relationship with physiological responses and pathological conditions. The purpose of this review is to give an overview on glutathione cellular compartmentalization. Information on its subcellular distribution provides a deeper understanding of glutathione‐dependent processes and reflects the importance of compartmentalization in the regulation of specific cellular pathways. © 2018 BioFactors, 45(2):152–168, 2019 [ABSTRACT FROM AUTHOR]

Liposomes are versatile platforms to carry anticancer drugs in targeted drug delivery; they can be surface modified by different strategies and, when coupled with targeting ligands, are able to increase cellular internalisation and organelle-specific drug delivery. An interesting strategy of antitumoral therapy could involve the use of lysosomotropic ligand-targeted liposomes loaded with molecules, which can induce lysosomal membrane permeabilization (LMP), leakage of cathepsins into the cytoplasm and subsequent apoptosis. We have previously demonstrated the ability of liposomes functionalised with a mannose-6-phosphate to reach lysosomes; in this research we compare the behaviour of M6P-modified and non-functionalised liposomes in MCF7 tumour cell and in HDF normal cells. With this aim, we first demonstrated by Western blotting the overexpression of mannose-6-phosphate/insulin-like growth factor (M6P/IGF-II) receptor in MCF7. Then, we prepared calcein-loaded liposomes and we revealed the increased uptake of M6P-functionalised liposomes in MCF7 cells respect to HDF cells by flow cytometry analysis. Finally, we loaded functionalised and not functionalised liposomes with N-hexanoyl-d-erythro-sphingosine (C6Cer), able to initiate LMP-induced apoptosis; after having studied the stability of both vesicles in the presence of serum by Dynamic Light Scattering and Spectrophotometric turbidity measurements, we showed that ceramide-loaded M6P-liposomes significantly increased apoptosis in MCF7 with respect to HDF cells. [ABSTRACT FROM AUTHOR]

The article focuses on investigating the impact of chrysotile asbestos fibers, specifically long (CHR-L) and short (CHR-S) fibers, on placental tissue differentiation and proliferation, with findings indicating that CHR-L fibers can induce irreversible DNA alterations and cell apoptosis.

H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology. H-RasV12 expressing cells also show premature senescence followed by cell death, induced by autophagy and apoptosis. In this context, we provide evidence that in H-RasV12 expressing cells, the premature senescence is associated with cellular redox imbalance as well as with altered post-translation protein modification. In particular, redox imbalance is due to a strong reduction of total antioxidant capacity, and significant decrease of glutathione level. As the reversible addition of glutathione to cysteinyl residues of proteins is an important post-translational regulative modification, we investigated S-glutathionylation in cells expressing active H-Ras. In this contest we observed different S-glutathionylation patterns in control and H-RasV12 expressing cells. Particularly, the GAPDH enzyme showed S-glutathionylation increase and significant enzyme activity depletion in H-Ras V12 cells. In conclusion, we proposed that antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A fundamental player in this fine balance is reduced glutathione (GSH), required for the scavenging of ROS as well as of the reactive 2-oxoaldehydes methylglyoxal (MGO). MGO is a cytotoxic compound formed constitutively as byproduct of nutrient catabolism, and in particular of glycolysis, detoxified in a GSH-dependent manner by the glyoxalase pathway consisting in glyoxalase I and glyoxalase II reactions. A physiological increase in ROS production (oxidative eustress, OxeS) is promptly signaled by the decrease of cellular GSH/GSSG ratio which can induce the reversible S-glutathionylation of key proteins aimed at restoring the redox balance. An increase in MGO level also occurs under oxidative stress (OxS) conditions probably due to several events among which the decrease in GSH level and/or the bottleneck of glycolysis caused by the reversible S-glutathionylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. In the present review, it is shown how MGO can play a role as a stress signaling molecule in response to OxeS, contributing to the coordination of cell metabolism with gene expression by the glycation of specific proteins. Moreover, it is highlighted how the products of MGO metabolism, S-D-lactoylglutathione (SLG) and D-lactate, which can be taken up and metabolized by mitochondria, could play important roles in cell response to OxS, contributing to cytosol-mitochondria crosstalk, cytosolic and mitochondrial GSH pools, energy production, and the restoration of the GSH/GSSG ratio. The role for SLG and glyoxalase II in the regulation of protein function through S-glutathionylation under OxS conditions is also discussed. Overall, the data reported here stress the need for further studies aimed at understanding what role the evolutionary-conserved MGO formation and metabolism can play in cell signaling and response to OxS conditions, the aberration of which may importantly contribute to the pathogenesis of diseases associated to elevated OxS. [ABSTRACT FROM AUTHOR]

Resveratrol (RES) is a stilbenoid polyphenol with interesting antitumor activity compromised by its poor solubility and bioavailability; thus, new approaches are necessary to improve its therapeutic effectiveness. In the present study, bovine serum albumin coated layered double hydroxide (LDH–BSA) was employed to encapsulate RES in order to overcome the above-mentioned usage limits. To evaluate the feasibility of neutral RES complexation with cationic LDH, we carried out molecular dynamics simulation in order to predict its structure and stability. In the supramolecular complex formed with LDH, RES disposes itself in the interlamellar region of LDH where it is stabilized by intermolecular interactions. The physico-chemical characteristics of the resulting nanocomplexes were studied by X-ray powder diffraction, transmission electron microscopy, and attenuated total reflection Fourier transform infrared spectroscopy. The encapsulation efficiency and drug release studies were also performed. The combined experimental and computational approach were highly effective in giving insight into the interaction mode of the neutral RES with the charged LDH. Finally, the nanohybrid's anticancer ability was evaluated in human lung cancer cell line (A549) resulting in higher activity with respect to bare RES. Overall, the results showed that the nanocomposites are suitable for biomedical applications as delivery agents of RES. [ABSTRACT FROM AUTHOR]

Abstract: Nanostructured lipid carriers (NLC) represent an emerging tool for drug delivery and are characterized by important features which promote increased bioavailability and epithelial penetration of lipophilic compounds. However, despite these advantages, their potential cytotoxicity should not be underestimated, especially under in vivo usage conditions. Here we analyzed the viability, intracellular reactive oxygen species (ROS), oxidative DNA damage and mitochondrial functionality in human dermal fibroblasts (HDF) in the presence of NLC either empty or loaded with the reduced or oxidized form of Coenzyme Q10. Experiments were carried out under standard culture conditions and under oxidative stress induced by UVA irradiation, where the latter treatment significantly affected all the endpoints tested above compared to the non-UVA condition. The data show that NLC alone, whether exposed or not exposed to UVA, produce a slight, though significant decrease in cell viability associated with enhanced oxidative stress, which did not however lead to oxidative DNA damage nor mitochondrial impairment. Reduced CoQ10-NLC, differently from oxidized CoQ10-NLC, were able to efficiently counteract UVA-associated mitochondrial depolarization suggesting a potential role of this molecule in antiageing cosmetological formulations. In conclusion, our results suggest that interactions of NLC with cells and biomolecules should be routinely assessed for understanding their compatibility and toxicity, not only under normal conditions, but also under any chemical or physical stress which these delivery systems might be subjected to during their employment. [Copyright &y& Elsevier]

Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches.

Objectives: Coenzyme Q 10 , incorporated in DOPC lyposomes or naturally present in liver bovine mitochondria or in human blood plasma, was reacted with nitrogen dioxide • NO 2 or with a • NO/ • NO 2 mixture. Methods and Results: The reaction course was monitored by Electron Paramagnetic Resonance (EPR) spectroscopy and in all cases the formation of a di- tert -alkyl nitroxide was observed, deriving from the addition of • NO 2 to one of the double bonds, most likely the terminal one, of the isoprenic chain. The rate constant for nitroxide formation was also determined by EPR spectroscopy and an initial rate of ca. 7 × 10 -8  M s -1 was obtained.