Cellular systems responsible for the formation and removal of reactive oxygen species (ROS), functioning within physiological limits, are essential for maintaining intracellular redox balance. This state is known as oxidative eustress. Key redox signaling molecules, such as superoxide anion radical (O2•-) and hydrogen peroxide (H2O2), operate at nanomolar concentrations and are produced by NADPH oxidases (regulated by various factors), the mitochondrial electron transport chain (ETC), and numerous enzymes. In addition, cell signaling is influenced by nitric oxide (NO•) and reactive lipid species. Disruption of ROS signaling can lead to oxidative stress, a harmful condition associated with many chronic diseases, including cancer. The dual nature of ROS is evident in premalignant and malignant cells at all stages of tumor development, including proliferation, migration/invasion, angiogenesis, inflammation, immune evasion, and metastasis. ROS can promote tumor formation by regulating immune cells, mitochondrial metabolism, DNA methylation, DNA damage [such as the DNA oxidation product, 8-oxo-dG, resulting from hydroxyl radical (•OH) attack], and other mechanisms. The tumor-promoting activity mediated by H2O2 manifests through the promotion of epithelial-to-mesenchymal transition (EMT) and the formation of the tumor microenvironment (TME) by tumor-associated macrophages. While ROS are vital for tumor initiation and growth, their excessive production can also have anticancer effects by inducing senescence, apoptosis, or necrosis. ROS-related anticancer mechanisms include mitochondrial dysfunction, p53-dependent apoptosis, iron-dependent ferroptosis, activation of endoplasmic reticulum stress, inhibition of growth signaling pathways (such as the epidermal growth factor pathway, EGF), among others. Tumor cells employ a range of adaptive mechanisms to effectively maintain ROS levels within a dynamic range that promotes proliferation while preventing cell death. This regulation is achieved by fine-tuning the effects of antioxidants throughout all stages of cancer. During early tumor development, characterized by increased oncogene-induced oxidative stress, cancer cells depend on glutathione (GSH) and upregulated antioxidant gene expression controlled by nuclear factor erythroid 2-related factor 2 (NRF2) to maintain redox balance. The opposing roles of certain antioxidant enzymes, such as Mn-SOD (SOD2), illustrate the same duality as ROS, acting as potential tumor suppressors during early carcinogenesis and as tumor promoters during metastasis. Low-molecular-weight antioxidants such as vitamins C (ascorbate) and E (tocopherols), carotenoids (e.g., lycopene, β-carotene), flavonoids (e.g., quercetin), and isoflavones demonstrate effective antioxidant activity in vitro, but their anticancer effects in clinical settings remain unproven. Understanding the influence of the antioxidant network and the redox threshold on epithelial-to-mesenchymal transition and key tumor microenvironment components could lead to more effective therapeutic strategies. This review explores the dual roles of ROS and antioxidants throughout different stages of cancer progression.

• Keywords
• Antioxidants, Cancer, Cell signaling, Oxidative stress, ROS, Tumorigenesis,
• Publication type
• Journal Article MeSH
• Review MeSH

Given the key importance played by the redox-active metals iron (Fe), copper (Cu), and manganese (Mn) in vital cellular processes, such as DNA synthesis, oxidative phosphorylation, the detoxification of reactive oxygen species (ROS), and angiogenesis, it is not surprising that their dysregulation plays a causative role in many human diseases. The same applies to redox-inactive zinc (Zn), which is involved in numerous biological functions, and serves as a structural element, a catalyst, and a participant in both intracellular and intercellular signaling and in maintaining immune system function. An imbalance in redox active (Fe, Cu, Mn) or redox inactive (Zn) metal ions, whether in excess or deficiency, is harmful and may disrupt the structural, regulatory, and catalytic roles of various antioxidant enzymes (superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPxs)), proteins, receptors, transporters, alter sulfhydryl homeostasis, generate high levels of ROS (e.g., hydroxyl radicals by the Fenton reaction), initiate lipid peroxidation, cause DNA damage, and lead to cell death via mechanisms such as ferroptosis, cuproptosis, cellular senescence, or inflammation. Maintaining redox homeostasis is essential for regulating numerous cellular signaling pathways. Redox-sensitive signaling pathways, such as the nuclear factor kappa B (NF-κB), mitogen-activated protein kinase kinase (MAPK), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, form an intricate network that governs cellular responses to redox metal-induced oxidative stress and inflammation. The Nrf2 pathway is primarily responsible for mediating antioxidant defenses, whereas the NF-κB and MAPK pathways play roles in proinflammatory and stress-related responses. Dysregulation of redox-active Fe, Cu, Mn, and redox-inactive Zn can alter epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The dyshomeostasis of metal ions is closely related to the pathogenesis of lung, renal, and gastrointestinal diseases, neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, and Huntington's disease), psychiatric conditions (schizophrenia), and various cancers. This review summarizes recent findings on the role of iron, copper, manganese, and zinc in maintaining physiological functions, redox homeostasis, and human diseases. See also the graphical abstract(Fig. 1).

• Keywords
• copper, human diseases, iron, manganese, oxidative stress, zinc,
• Publication type
• Journal Article MeSH
• Review MeSH

Myocardial infarction is a leading cause of death and morbidity in individuals with cardiovascular diseases. Natural antioxidants, such as those found in green tea leaves, are beneficial in preventing these diseases. This study evaluated the protective effects of green tea leaves powder against isoprenaline (ISO)-induced myocardial infarction in rats. Four groups of male Long Evans rats were used: Control, Control + green tea leaves powder, ISO, and ISO + green tea leaves powder. Organ and blood plasma samples were collected to measure oxidative stress biomarkers, biochemical parameters, and gene expressions. Furthermore, tissue sections were prepared and stained histologically. ISO-induced rats showed decreased cellular antioxidants (catalase activity and glutathione concentration) and elevated oxidative stress markers. Notable inflammatory cell infiltration and fibrosis were observed in the heart and kidneys of ISO-induced rats. Supplementation with green tea leaves powder significantly restored catalase activity and glutathione concentration (p < 0.05) in plasma and tissues. It also considerably reduced lipid peroxidation, nitric oxide, and advanced oxidation protein products (p < 0.05) in ISO-administered rats. Furthermore, green tea leaves powder supplementation halted inflammatory gene expression (p < 0.05), restored antioxidant genes (p < 0.05) such as Nrf-2-HO-1, and prevented cardiac fibrosis in ISO-administered rats. Green tea leaves powder supplementation may reduce oxidative stress, inflammation, and fibrosis in ISO-administered rats, potentially through the Nrf-2-HO-1-mediated restoration of antioxidant enzymes and prevention of heart inflammation.

• Keywords
• Camellia sinensis, Fibrosis, Inflammation, Isoprenaline, Myocardial infarction,
• MeSH
• Antioxidants * metabolism   pharmacology   MeSH
• Camellia sinensis * chemistry   MeSH
• NF-E2-Related Factor 2 * metabolism   MeSH
• Heme Oxygenase (Decyclizing) MeSH
• Myocardial Infarction * chemically induced   drug therapy   metabolism   pathology   MeSH
• Isoproterenol adverse effects   MeSH
• Catechin * pharmacology   MeSH
• Rats MeSH
• Myocardium pathology   metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Polyphenols * pharmacology   chemistry   MeSH
• Heart Injuries * chemically induced   drug therapy   metabolism   MeSH
• Rats, Long-Evans MeSH
• Powders MeSH
• Plant Extracts pharmacology   MeSH
• Signal Transduction drug effects   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antioxidants * MeSH
• NF-E2-Related Factor 2 * MeSH
• Heme Oxygenase (Decyclizing) MeSH
• Hmox1 protein, rat MeSH Browser
• Isoproterenol MeSH
• Catechin * MeSH
• Nfe2l2 protein, rat MeSH Browser
• Polyphenols * MeSH
• Powders MeSH
• Plant Extracts MeSH

Graphene-based materials (GBMs) have shown significant promise in cancer therapy due to their unique physicochemical properties, biocompatibility, and ease of functionalization. Their ability to target solid tumors, penetrate the tumor microenvironment (TME), and act as efficient drug delivery platforms highlights their potential in nanomedicine. However, the complex and dynamic nature of the TME, characterized by metabolic heterogeneity, immune suppression, and drug resistance, poses significant challenges to effective cancer treatment. GBMs offer innovative solutions by enhancing tumor targeting, facilitating deep tissue penetration, and modulating metabolic pathways that contribute to tumor progression and immune evasion. Their functionalization with targeting ligands and biocompatible polymers improves their biosafety and specificity, while their ability to modulate immune cell interactions within the TME presents new opportunities for immunotherapy. Given the role of metabolic reprogramming in tumor survival and resistance, GBMs could be further exploited in metabolism-targeted therapies by disrupting glycolysis, mitochondrial respiration, and lipid metabolism to counteract the immunosuppressive effects of the TME. This review focuses on discussing research studies that design GBM nanocomposites with enhanced biodegradability, minimized toxicity, and improved efficacy in delivering therapeutic agents with the intention to reprogram the TME for effective anticancer therapy. Additionally, exploring the potential of GBM nanocomposites in combination with immunotherapies and metabolism-targeted treatments could lead to more effective and personalized cancer therapies. By addressing these challenges, GBMs could play a pivotal role in overcoming current limitations in cancer treatment and advancing precision oncology.

• Keywords
• cancer, graphene, graphene oxide, nanomaterials, photodynamic therapy, photothermal therapy,
• MeSH
• Graphite * chemistry   therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Tumor Microenvironment * drug effects   MeSH
• Neoplasms * drug therapy   metabolism   MeSH
• Nanocomposites * chemistry   therapeutic use   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Graphite * MeSH
• Antineoplastic Agents MeSH

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

• Keywords
• Antioxidant enzymes, Heavy metals, Human disease, Oxidative stress, ROS, Toxicity,
• MeSH
• Antioxidants metabolism   MeSH
• Environmental Pollutants * toxicity   pharmacokinetics   MeSH
• Humans MeSH
• Heavy Metal Poisoning MeSH
• Oxidative Stress drug effects   MeSH
• Metals, Heavy * toxicity   pharmacokinetics   MeSH
• Environmental Exposure * adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antioxidants MeSH
• Environmental Pollutants * MeSH
• Metals, Heavy * MeSH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

• Keywords
• Antioxidant enzyme, Catalytic activity, Expression, Glutathione, Metabolic dysfunction-associated steatotic liver disease,
• MeSH
• Antioxidants * metabolism   MeSH
• Liver metabolism   pathology   MeSH
• Humans MeSH
• Oxidative Stress drug effects   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Fatty Liver * metabolism   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antioxidants * MeSH
• Reactive Oxygen Species MeSH