ABSTRACT
The free-radical theory of aging, advanced more than 50 years ago by D.Harman, remains popular today. The review analyzes age-related changes in the main endogenous mechanisms of reactive oxygen species (ROS) production and antioxidant defense mechanisms. With age, ROS generation by mitochondria, peroxisomes, and NAD(P)H oxidases is enhanced, while the transcriptional activity of the important system Keap1/Nrf2/ARE maintaining redox balance decreases. In old animals, autophagy activity is also low, which removes damaged organelles and aggregated structures from cells. The age-related shift of the redox balance towards oxidative stress can cause the development of age-associated neurodegenerative, autoimmune and inflammatory pathologies.
Subject(s)
Aging , Oxidative Stress , Animals , Antioxidants , Autophagy , Humans , Kelch-Like ECH-Associated Protein 1 , NADPH Oxidases , NF-E2-Related Factor 2 , Oxidation-Reduction , Peroxisomes , Reactive Oxygen SpeciesABSTRACT
ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Two-fold intraperitoneal injections of doxorubicin in a cumulative dose of 8 mg/kg were followed by inhibition of tumor growth by 49.5%. Combined treatment with TS-13 and doxorubicin suppressed the tumor growth by 55.4%. In contrast to doxorubicin, TS-13 inhibited NO generation by peritoneal macrophages. The results show the prospect of studying TS-13 in the context of overcoming drug-resistance of tumors.
Subject(s)
Antioxidants/pharmacology , Doxorubicin/pharmacology , Phenols/pharmacology , Thiosulfonic Acids/pharmacology , Animals , Carcinoma, Lewis Lung/metabolism , Female , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred C57BL , Reactive Oxygen Species/metabolismABSTRACT
Nrf2 transcription factor plays a key role in maintaining cellular redox balance under stress and is a perspective target for oxidative stress-associated diseases. Under normal conditions, Nrf2 transcriptional activity is low due to its rapid ubiquitination and degradation in the 26S proteasome, as well as through various modifications of amino acid residues of this transcription factor that regulate its transport to the nucleus and binding to DNA. Continuous activation of Nrf2 is possible due to autophagy and epigenetic regulation that may underlie the increased resistance of tumor cells to radiotherapy and chemotherapy. This review deals with the mechanisms of regulation of Nrf2 transcriptional activity and its main elements, and pharmacological approaches to activation of the Keap1/Nrf2/ARE system.
Subject(s)
Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , NF-E2-Related Factor 2/metabolism , Neoplasm Proteins/metabolism , Oxidative Stress , Transcription, Genetic , Animals , Autophagy , Humans , Kelch-Like ECH-Associated Protein 1/biosynthesis , Kelch-Like ECH-Associated Protein 1/genetics , NF-E2-Related Factor 2/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Proteasome Endopeptidase Complex , Radiation Tolerance/genetics , UbiquitinationABSTRACT
Many plant phenols (stilbenes, curcumins, catechins, flavonoids, etc.) are effective antioxidants and protect cells during oxidative stress. Extensive clinical studies on the potential of phenolic compounds for treatment of cardiovascular, neurodegenerative, oncological, and inflammatory diseases are now being conducted. In addition to direct antioxidant effect, plant phenols may provide a protective effect via activation of the Keap1/Nrf2/ARE redox-sensitive signaling system and regulation of autophagy. In this review, mechanisms of effects of the most common plant phenols on autophagy are presented.
Subject(s)
Autophagy/drug effects , Phenols/pharmacology , Plants/metabolism , Animals , Antioxidants/chemistry , Antioxidants/metabolism , Curcumin/chemistry , Curcumin/pharmacology , Humans , Phenols/chemistry , Plant Proteins/metabolism , Plants/chemistry , Resveratrol , Signal Transduction/drug effects , Stilbenes/chemistry , Stilbenes/pharmacologyABSTRACT
Effects of water-soluble phenolic antioxidant sodium 3-(3'-tret-butyl-4'-hydroxyphenyl)-propyl thiosulfonate (TS-13), potassium 3,5-dimethyl-4-hydroxybenzyl thioetanoate (BEP-11-K) and potassium 3-(3',5'-ditretbutyl-4'-hydroxyphenyl)-propionate (potassium phenosan) on tumor cells proliferative activity and the role of redox-dependent and calcium-dependent signaling mechanisms in realization of tumor cell response to the antioxidant action were studied. Potassium phenosan and BEP-11-K were found to stimulate proliferation and ARE-inducing phenolic antioxidant TS-13 was found to inhibit tumor cell growth in culture. The tumor cell growth rate depended on the rate of intracellular reactive oxygen species production and was decreased by apocynin (a NADPH-oxidase inhibitor) and antimycin A (an ubiquinol-cytochrome c oxidoreductase inhibitor). TS-13 action on tumor cells was accompanied by a transient increase in intracellular reactive oxygen species production and the intracellular calcium concentration, whereas cell incubation with potassium phenosan and BEP-11-K did not influence the reactive oxygen species level and intracellular calcium ions. Cyclosporine A blocked the inhibitory effect of TS-13. Thus, it can be reasonably speculated that phenolic antioxidant TS-13 starts mitochondria-dependent apoptosis in tumor cells by the opening of permeability transition pores.
Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Mitochondria/metabolism , Response Elements , Thiosulfonic Acids/pharmacology , Cell Line, Tumor , Humans , Mitochondria/pathology , NADPH Oxidases/antagonists & inhibitors , NADPH Oxidases/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms , Reactive Oxygen Species/metabolismABSTRACT
A model for the redox regulation of the functional state of the cell has been constructed on the basis of representation of electron transfer processes by equivalent electric circuits. The mechanism of action of redox active molecules on biosystems has been discussed in terms of circuit theory. A method for determining the parameters of cellular redox sensors has been proposed. It has been established that the concentration and redox potential of compounds entering the cell are the main regulatory parameters of redox signals for the cell. It has been experimentally shown that the calcium response to hydrogen peroxide in rat C6 glioma cells and human FL amnion cells depends on the redox buffer capacity of cells.
Subject(s)
Calcium Signaling/drug effects , Hydrogen Peroxide/pharmacology , Models, Biological , Oxidants/pharmacology , Oxidative Stress/drug effects , Animals , Cell Line, Tumor , Humans , Oxidation-Reduction/drug effects , RatsABSTRACT
The parameters of the acid-base state and redox state of erythrocytes have been studied with the use of the fluorescent probes 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein and 2',7'-dichlorodihydrofluorescein. It has been found that the value of redox state parameters in erythrocytes depends both on the extracellular and intracellular concentrations of hydrogen ions. It has been shown that hydrogen peroxide induces a decrease in the value of the intracellular pH. The interrelation of cellular homeostasis parameters characterizing the acid-base and redox states of erythrocytes has been theoretically and experimentally substantiated.
Subject(s)
Erythrocytes/chemistry , Fluorescent Dyes/chemistry , Hydrogen/chemistry , Cations, Monovalent/chemistry , Humans , Hydrogen-Ion Concentration , Oxidation-ReductionABSTRACT
Effects of ascorbic acid on calcium homeostasis of human laryngeal carcinoma cells were studied. Intracellular concentration of free calcium and intracellular pH were measured by fluorescent analysis. Ascorbic acid in concentrations of 3-10 mM caused pH drop and sharply increased concentrations of free Ca ions in HEp-2 cells. Intracellular concentration of free Ca ions resulted from Ca ion release from the thapsigargin-sensitive Ca depots.
Subject(s)
Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Calcium Signaling/drug effects , Calcium/metabolism , Carcinoma/drug therapy , Laryngeal Neoplasms/drug therapy , Antioxidants/administration & dosage , Ascorbic Acid/administration & dosage , Carcinoma/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Extracellular Space/drug effects , Fluorescence , Humans , Hydrogen Peroxide/pharmacology , Hydrogen-Ion Concentration , Intracellular Space/drug effects , Intracellular Space/metabolism , Laryngeal Neoplasms/metabolism , Oxidants/pharmacology , Thapsigargin/pharmacology , Time FactorsABSTRACT
Recent achievements of biophysics and physiology resulted to remarkable progress in the understanding of role of redox processes in cell vital function. It was established that oxidizing and reducing agents participate in processes of differentiation, proliferation and apoptosis. Representations about an existence of definite balance between oxidation and reduction processes in cells or a redox homeostasis were formed. Recent data about mechanisms of regulation of redox homeostasis were considered in the review. The correlation between redox homeostasis and metabolism were in detail analyzed. The special interest is given to a problem of quantitative description of redox phenomena in biological systems.
Subject(s)
Cell Physiological Phenomena , Homeostasis/physiology , Oxidation-Reduction , Animals , HumansABSTRACT
The introduction of the parameters characterizing the redox state of the cell, such as the effective redox potential and the redox buffer capacity has been theoretically substantiated. A comparative study of the parameters of the redox state of erythrocytes from healthy donors and patients with diabetes and acute coronary syndrome has been performed. It was found that the redox buffer capacity in erythrocytes from patients with diabetes and acute coronary syndrome was reduced by 30-40% in comparison with the redox buffer capacity of erythrocytes from healthy donors. The largest change in the effective redox potential was observed for erythrocytes from patients with diabetes, which indicates a more expressed oxidative stress in this pathology.
Subject(s)
Acute Coronary Syndrome/metabolism , Diabetes Mellitus/metabolism , Erythrocytes/metabolism , Oxidative Stress , Acute Coronary Syndrome/pathology , Diabetes Mellitus/pathology , Erythrocytes/pathology , Female , Humans , Male , Oxidation-ReductionABSTRACT
The method for determination of intracellular oxidants content has been proposed. The method is based on the analysis of changes of 2,7-dichlorodihydrofluorescein oxidation. The theoretical model of hydrogen peroxide diffusion and its consumption in the cell and quantitative determination of hydrogen peroxide gradient through the cellular membrane has been built taking into account the experimental data. The coefficient for H2O2 permeability through the plasma membrane of human amnion cells is (2.1 +/- 0.1) x 10(-4) cm x c(-1).
Subject(s)
Cell Membrane Permeability/physiology , Cell Membrane/metabolism , Hydrogen Peroxide/metabolism , Amnion/cytology , Cell Membrane Permeability/drug effects , Cells, Cultured , Fluoresceins/pharmacology , Humans , Hydrogen Peroxide/pharmacology , Oxidation-Reduction/drug effects , Spectrometry, Fluorescence/methodsABSTRACT
Recent achievement of molecular biology and neurophysiology resulting in remarkable progress in the understanding of processes of neurodifferentiation, playing the relevant role both in an ontogenesis and working of adult brain. New representations have been formed about a role of cytoskeletal proteins in mechanisms of neurites growth. In the review we discussed recent data regarding mechanisms of neuronal differentiation regulation. The special interest is given to a problem of influence of electrical fields on neuronal growth and differentiation. The mechanisms of signal transduction from a cell surface to nuclear are in detail analyzed. The classification of the physical and chemical factors of growth neurites regulation is given.
