Overexpression of Glyoxalase 2 in Human Breast Cancer Cells: Implications for Cell Proliferation and Doxorubicin Resistance.

Glyoxalase 2 (Glo2) is an enzyme of the glyoxalase system whose pathway parallels glycolysis and which aims to remove methylglyoxal (MGO). This study analyzed the possible additional roles of the Glo2 enzyme in breast cancer (MCF7) and non-cancer (HDF) cell lines, investigating its presence at the nuclear level and its potential involvement in cell proliferation and chemotherapy resistance. The results revealed that Glo2 is overexpressed in cancer cells, and its expression is higher during the proliferative (S and G2/M) phases of the cell cycle.

Mechanisms of action of mineral fibres in a placental syncytiotrophoblast model: An in vitro toxicology study.

Asbestos has been widely used due to its unique characteristics. It is known that exposure to asbestos causes serious damage to health but one species, chrysolite, is still used because it is considered less toxic and not biopersistent in some countries. The aim of our study was to investigate if cellular process underlying the proliferation, differentiation and cell death of placental tissues could be modify in presence of asbestos fibres (50 μg/ml final concentration), long chrysolite fibres (CHR-L) and short chrysolite fibres (CHR-S), using BeWo cell line, an in vitro model that mimics the syncytiotrophoblast (STB), the outer layer of placental villi.

Integration of Lipid-Functionalized Epigallocatechin-3-gallate into PLGA Matrix as a Novel Polyphenol-Based Nanoantioxidant.

The search for polyphenol-based materials with antioxidant activity is a growing research area in the biomedical field. To obtain an efficient and stable nanoantioxidant, a novel biosystem was designed by integrating a lipophilic derivative of epigallocatechin-3-gallate (named EGCG-C18) on the surface of poly(lactic--glycolic acid) (PLGA). Poly(vinyl alcohol) (PVA) and 1,2-distearoyl--glycero-3-phosphoethanolamine-poly(ethylene glycol) (DSPE-PEG) were selected as polymeric and lipidic stabilizers, respectively, and their influence on both physical properties and the antioxidant activity of nanoantioxidant was investigated by a combined in silico and experimental approach.

Glutathionyl Hemoglobin and Its Emerging Role as a Clinical Biomarker of Chronic Oxidative Stress.

Hemoglobin is one of the proteins that are more susceptible to S-glutathionylation and the levels of its modified form, glutathionyl hemoglobin (HbSSG), increase in several human pathological conditions. The scope of the present review is to provide knowledge about how hemoglobin is subjected to S-glutathionylation and how this modification affects its functionality. The different diseases that showed increased levels of HbSSG and the methods used for its quantification in clinical investigations will be also outlined.

Meldonium Inhibits Cell Motility and Wound-Healing in Trabecular Meshwork Cells and Scleral Fibroblasts: Possible Applications in Glaucoma.

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine-a main player in mitochondrial energy generation-thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension.

Glyoxalase 2: Towards a Broader View of the Second Player of the Glyoxalase System.

Glyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two enzymes glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) form the complete glyoxalase pathway, which utilizes glutathione as cofactor in eukaryotic cells.

Influence of a lipophilic edaravone on physical state and activity of antioxidant liposomes: An experimental and in silico study.

The influence of a lipophilic derivative of Edaravone (C18Edv) on a POPC liposomal bilayer has been investigated by a combined computational-experimental approach. The order and hydration degree of three different systems composed by 10%, 20% and 40% in w/w percentage of C18Edv respect to POPC were investigated through Molecular Dynamics (MD) simulations and fluorescence spectroscopy experiments. Dynamic Light Scattering measurements showed how the presence of different amounts of C18EdV determines differences on liposome size and stability.

Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer.

The epidermal growth factor receptor (EGFR) is one of the most well-studied molecular targets in non-small cell lung cancer (NSCLC) and tyrosine kinase inhibitors have been shown to be effective in the treatment of advanced NSCLC. Nevertheless, the efficacy of tyrosine kinase inhibitors could be compromised by additional mutations in EGFR and compensatory activations of other pathways. Epigallocatechin-3-gallate (EGCG), the main bioactive molecule in green tea, acts as a tyrosine kinase inhibitor toward cancer cells overexpressing EGFR (wild-type).

Tuning curvature and phase behavior of monoolein bilayers by epigallocatechin-3-gallate: Structural insight and cytotoxicity.

The use of glyceryl monooleate (GMO)-based nanoparticles has not yet been explored in overcoming the low bioavailability of Epigallocatechin-3-gallate (EGCG), a green tea polyphenol with a known anticancer activity. Since the inclusion of a guest molecule can affect the curvature and the supramolecular structure of fully hydrated GMO-based phase, the phase behavior of bulk and dispersed liquid crystalline systems containing EGCG were explored by Small Angle Neutron Scattering and X-Ray Diffraction experiments. Molecular Dynamic Simulations showed how the interaction of EGCG with polar heads of GMO strongly affects the curvature and packing of GMO phase.

Insights into the Antioxidant Mechanism of Newly Synthesized Benzoxazinic Nitrones: In Vitro and In Silico Studies with DPPH Model Radical.

Synthetic nitrone spin-traps are being explored as therapeutic agents for the treatment of a wide range of oxidative stress-related pathologies, including but not limited to stroke, cancer, cardiovascular, and neurodegenerative diseases. In this context, increasing efforts are currently being made to the design and synthesis of new nitrone-based compounds with enhanced efficacy. The most researched nitrones are surely the ones related to α-phenyl-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) derivatives, which have shown to possess potent biological activity in many experimental animal models.

Interplay among Oxidative Stress, Methylglyoxal Pathway and S-Glutathionylation.

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).

Protection of Polyphenols against Glyco-Oxidative Stress: Involvement of Glyoxalase Pathway.

Chronic high glucose (HG) exposure increases methylglyoxal (MGO)-derived advanced glycation end-products (AGEs) and is involved in the onset of pathological conditions, such as diabetes, atherosclerosis and chronic-degenerative diseases. Under physiologic conditions the harmful effects of MGO are contrasted by glyoxalase system that is implicated in the detoxification of Reactive Carbonyl Species (RCS) and maintain the homeostasis of the redox environment of the cell. Polyphenols are the most abundant antioxidants in the diet and present various health benefits.

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism.

Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response.

Monoalkylated Epigallocatechin-3-gallate (C18-EGCG) as Novel Lipophilic EGCG Derivative: Characterization and Antioxidant Evaluation.

Epigallocatechin-3-gallate (EGCG) has the highest antioxidant activity compared to the others catechins of green tea. However, the beneficial effects are mainly limited by its poor membrane permeability. A derivatization strategy to increase the EGCG interaction with lipid membranes is considered as one feasible approach to expand its application in lipophilic media, in particular the cellular absorption.

Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations.

Dicarbonyl stress is a dysfunctional state consisting in the abnormal accumulation of reactive α-oxaldehydes leading to increased protein modification. In cells, post-translational changes can also occur through S-glutathionylation, a highly conserved oxidative post-translational modification consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue. This review recapitulates the main findings supporting a role for dicarbonyl stress and S-glutathionylation in the pathogenesis of cerebrovascular diseases, with specific emphasis on cerebral cavernous malformations (CCM), a vascular disease of proven genetic origin that may give rise to various clinical signs and symptoms at any age, including recurrent headaches, seizures, focal neurological deficits, and intracerebral hemorrhage.

Encapsulation of a Neutral Molecule into a Cationic Clay Material: Structural Insight and Cytotoxicity of Resveratrol/Layered Double Hydroxide/BSA Nanocomposites.

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.

Effect of High Glucose-Induced Oxidative Stress on Paraoxonase 2 Expression and Activity in Caco-2 Cells.

(1) Background: Hyperglycemia leads to several biochemical and physiological consequences, such as the generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), which are involved in the development of several human diseases. Intestinal cells are continuously exposed to pro-oxidants and lipid peroxidation products from ingested foods, and also to glyco-oxidative damage. It has been reported that free radical generation may be linked to the development of inflammation-related gastrointestinal diseases.

Cushing Syndrome: The Role of MSCs in Wound Healing, Immunosuppression, Comorbidities, and Antioxidant Imbalance.

Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy.

Side Effects of Curcumin: Epigenetic and Antiproliferative Implications for Normal Dermal Fibroblast and Breast Cancer Cells.

Background: Curcumin is a yellow-orange pigment obtained from the plant , which is known to exert beneficial effects in several diseases, including cancer. However, at high doses, it may produce toxic and carcinogenic effects in normal cells. In this context, we studied the effects of curcumin on normal human dermal fibroblast (HDF) cells and breast cancer cells (MCF7).

Synthesis, Characterization and Antioxidant Properties of a New Lipophilic Derivative of Edaravone.

As part of a program aimed to obtain antioxidants able to interact with cell membrane, edaravone (EdV, 3-methyl-1-phenyl-2-pyrazolin-5-one), a well-known free radical scavenger, has been modified by alkylation at its allylic position (4) with a C-18 hydrocarbon chain, and the increased lipophilicity has been determined towards the interaction with liposomes. The obtained derivative has been studied by means of density functional theory (DFT) methods in order to characterize its lowest energy conformers and predict its antioxidant properties with respect to the parent compound EdV. The in vitro antioxidant activity of C18-edaravone was studied by means of the α,α-diphenyl-β-picrylhydrazyl (DPPH) assay and in lipid peroxidation experiments performed on artificial lipid membranes using water-soluble as well as lipid-soluble radical initiators.

Reaction of endogenous Coenzyme Q with nitrogen monoxide and its metabolite nitrogen dioxide.

Coenzyme Q, incorporated in DOPC lyposomes or naturally present in liver bovine mitochondria or in human blood plasma, was reacted with nitrogen dioxide NO or with a NO/NO mixture. The reaction course was monitored by Electron Paramagnetic Resonance (EPR) spectroscopy and in all cases the formation of a di--alkyl nitroxide was observed, deriving from the addition of NO 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.

Synthesis and metabolism of methylglyoxal, S-D-lactoylglutathione and D-lactate in cancer and Alzheimer's disease. Exploring the crossroad of eternal youth and premature aging.

Both cancer and Alzheimer's disease (AD) are emerging as metabolic diseases in which aberrant/dysregulated glucose metabolism and bioenergetics occur, and play a key role in disease progression. Interestingly, an enhancement of glucose uptake, glycolysis and pentose phosphate pathway occurs in both cancer cells and amyloid-β-resistant neurons in the early phase of AD. However, this metabolic shift has its adverse effects.

KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced -Glutathionylation of Distinct Structural and Regulatory Proteins.

Loss-of-function mutations in the KRIT1 gene are associated with the pathogenesis of cerebral cavernous malformations (CCMs), a major cerebrovascular disease still awaiting therapies. Accumulating evidence demonstrates that KRIT1 plays an important role in major redox-sensitive mechanisms, including transcriptional pathways and autophagy, which play major roles in cellular homeostasis and defense against oxidative stress, raising the possibility that KRIT1 loss has pleiotropic effects on multiple redox-sensitive systems. Using previously established cellular models, we found that KRIT1 loss-of-function affects the glutathione (GSH) redox system, causing a significant decrease in total GSH levels and increase in oxidized glutathione disulfide (GSSG), with a consequent deficit in the GSH/GSSG redox ratio and GSH-mediated antioxidant capacity.

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways.

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.