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Archives of Toxicology Oct 2023A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and... (Review)
Review
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Oxidative Stress; Chronic Disease
PubMed: 37597078
DOI: 10.1007/s00204-023-03562-9 -
Scientific Reports Sep 2023Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and...
Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (HO), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not HO primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.
Topics: Humans; Reactive Oxygen Species; Cell Death; Oxidative Stress; Iron Overload; Iron; Myocytes, Cardiac
PubMed: 37726294
DOI: 10.1038/s41598-023-42760-4 -
Cardiovascular Diabetology Sep 2023Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the... (Review)
Review
Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.
Topics: Humans; Endothelial Cells; Vascular Diseases; Diabetes Mellitus; Hyperglycemia; Oxidative Stress
PubMed: 37660030
DOI: 10.1186/s12933-023-01965-7 -
Cellular & Molecular Biology Letters Sep 2023During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS),... (Review)
Review
During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, and proinflammatory cytokines. This detrimental environment triggers cellular stress and subsequent dysfunction, which not only contributes to the development of associated diseases, that is, osteoporosis and osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated stress and reduce the overall tissue damage, cells possess diverse defense mechanisms. However, cellular antioxidative capacities are limited and thus ROS accumulation can lead to aberrant cell fate decisions, which have adverse effects on cartilage and bone homeostasis. In this narrative review, we address oxidative stress as a major driver of pathophysiologic processes in cartilage and bone, including senescence, misdirected differentiation, cell death, mitochondrial dysfunction, and impaired mitophagy by illustrating the consequences on tissue homeostasis and regeneration. Moreover, we elaborate cellular defense mechanisms, with a particular focus on oxidative stress response and mitophagy, and briefly discuss respective therapeutic strategies to improve cell and tissue protection.
Topics: Humans; Reactive Oxygen Species; Oxidative Stress; Osteoarthritis; Cell Differentiation; Osteoporosis; Cellular Senescence
PubMed: 37777764
DOI: 10.1186/s11658-023-00489-y -
Nature Communications Jul 2023Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars...
Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNr) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNr and SNr-targeted chemogenetic inhibition targeted to SNr rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.
Topics: Male; Animals; Mice; Hepatic Encephalopathy; Oxidative Stress; Antioxidants; Bile Ducts; Thioacetamide
PubMed: 37488119
DOI: 10.1038/s41467-023-40081-8 -
International Journal of Molecular... Jun 2023Skeletal muscle is continuously exposed during its activities to mechanical/oxidative damage [...].
Skeletal muscle is continuously exposed during its activities to mechanical/oxidative damage [...].
Topics: Oxidative Stress; Muscle, Skeletal
PubMed: 37373372
DOI: 10.3390/ijms241210227 -
International Journal of Molecular... Sep 2023An imbalance between the formation of reactive oxygen species (ROS) and the reaction of antioxidant proteins is referred to as oxidative stress [...].
An imbalance between the formation of reactive oxygen species (ROS) and the reaction of antioxidant proteins is referred to as oxidative stress [...].
Topics: Oxidative Stress; Reactive Oxygen Species; Antioxidants; Proteins
PubMed: 37833901
DOI: 10.3390/ijms241914455 -
International Journal of Molecular... Mar 2024Reactive oxygen species (ROS) and free radicals work to maintain homeostasis in the body, but their excessive production causes damage to the organism. The human body is... (Review)
Review
Reactive oxygen species (ROS) and free radicals work to maintain homeostasis in the body, but their excessive production causes damage to the organism. The human body is composed of a variety of cells totaling over 60 trillion cells. Each cell performs different functions and has a unique lifespan. The lifespan of cells is preprogrammed in their genes, and the death of cells that have reached the end of their lifespan is called apoptosis. This is contrary to necrosis, which is the premature death of cells brought about by physical or scientific forces. Each species has its own unique lifespan, which in humans is estimated to be up to 120 years. Elucidating the mechanism of the death of a single cell will lead to a better understanding of human death, and, conversely, the death of a single cell will lead to exploring the mechanisms of life. In this sense, research on active oxygen and free radicals, which are implicated in biological disorders and homeostasis, requires an understanding of both the physicochemical as well as the biochemical aspects. Based on the discussion above, it is clear to see that active oxygen and free radicals have dual functions of both injuring and facilitating homeostasis in living organisms.
Topics: Humans; Reactive Oxygen Species; Oxidative Stress; Free Radicals; Antioxidants; Apoptosis
PubMed: 38542335
DOI: 10.3390/ijms25063360 -
Frontiers in Endocrinology 2023
Topics: Humans; Hypoxia; Oxidative Stress; Endocrine Gland Neoplasms
PubMed: 37908751
DOI: 10.3389/fendo.2023.1268268 -
Biomolecules Dec 2023Recent years have seen an increased interest in the role of oxidative stress (OS) in pregnancy. Pregnancy inherently heightens susceptibility to OS, a condition fueled... (Review)
Review
Recent years have seen an increased interest in the role of oxidative stress (OS) in pregnancy. Pregnancy inherently heightens susceptibility to OS, a condition fueled by a systemic inflammatory response that culminates in an elevated presence of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the circulatory system. The amplified OS in pregnancy can trigger a series of detrimental outcomes such as underdevelopment, abnormal placental function, and a host of pregnancy complications, including pre-eclampsia, embryonic resorption, recurrent pregnancy loss, fetal developmental anomalies, intrauterine growth restriction, and, in extreme instances, fetal death. The body's response to mitigate the uncontrolled increase in RNS/ROS levels requires trace elements that take part in non-enzymatic and enzymatic defense processes, namely, copper (Cu), zinc (Zn), manganese (Mn), and selenium (Se). Determination of ROS concentrations poses a challenge due to their short half-lives, prompting the use of marker proteins, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione (GSH). These markers, indicative of oxidative stress intensity, can offer indirect assessments of pregnancy complications. Given the limitations of conducting experimental studies on pregnant women, animal models serve as valuable substitutes for in-depth research. This review of such models delves into the mechanism of OS in pregnancy and underscores the pivotal role of OS markers in their evaluation.
Topics: Animals; Female; Humans; Pregnancy; Antioxidants; Reactive Oxygen Species; Placenta; Oxidative Stress; Superoxide Dismutase; Catalase; Glutathione; Glutathione Peroxidase; Pregnancy Complications
PubMed: 38136639
DOI: 10.3390/biom13121768