Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O2•-) and hydrogen peroxide (H2O2). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO- (O2•- + NO• → ONOO-) and maintains the physiologically relevant level of nitric oxide (NO•), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., β-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.
- Keywords
- Antioxidant enzymes, Chronic disease, Enzyme mimics, Low-molecular antioxidants, Oxidative stress, ROS,
- MeSH
- Anthocyanins metabolism pharmacology MeSH
- Antioxidants * pharmacology metabolism MeSH
- Chronic Disease MeSH
- Peroxynitrous Acid pharmacology MeSH
- Humans MeSH
- Neoplasms * MeSH
- Nitric Oxide MeSH
- Oxidative Stress MeSH
- Hydrogen Peroxide MeSH
- Reactive Oxygen Species metabolism MeSH
- Superoxide Dismutase metabolism MeSH
- Superoxides MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Anthocyanins MeSH
- Antioxidants * MeSH
- Peroxynitrous Acid MeSH
- Nitric Oxide MeSH
- Hydrogen Peroxide MeSH
- Reactive Oxygen Species MeSH
- Superoxide Dismutase MeSH
- Superoxides MeSH
Cobalt intoxication can occur after its release from metal-based prostheses, which is generally clinically severe. Therefore, there is a need for the development of a cobalt chelator since there are currently no approved drugs for cobalt intoxication. As flavonoids are known for their metal chelating properties and safety, the screening of cobalt chelating properties was performed in a total of 23 flavonoids by our recently developed new spectrophotometric assay. Further assessment of positive or negative consequences of cobalt chelation was performed both in vitro and ex vivo. Six and thirteen flavonoids significantly chelated cobalt ions at pH 7.5 and 6.8, respectively. Baicalein demonstrated a significant activity even at pH 5.5; however, none of the flavonoids showed chelation at pH 4.5. In general, baicalein and 3-hydroxyflavone were the most active. They also mildly decreased the cobalt-triggered Fenton reaction, but baicalein toxicity toward red blood cells was strongly increased by the addition of cobalt. Quercetin, tested as an example of flavonoid unable to chelate cobalt ions significantly, stimulated both the cobalt-based Fenton reaction and the lysis of erythrocytes in the presence of cobalt. Therefore, 3-hydroxyflavone can serve as a potential template for the development of novel cobalt chelators.
- Publication type
- Journal Article MeSH
Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.
- Keywords
- anti-oxidant activity, cancer, cardiovascular disease, dysfunction, flavonoids, genoprotection, injury, mitochondrial function, mitochondrial impairment, mitochondriopathy, natural substances, neurodegeneration, patient stratification, phytochemicals, predictive preventive personalized medicine (PPPM/3PM), stress, tumorigenesis,
- MeSH
- Antioxidants pharmacology therapeutic use MeSH
- Cytoprotection drug effects MeSH
- Flavonoids pharmacology therapeutic use MeSH
- Precision Medicine methods MeSH
- Humans MeSH
- Mitochondrial Diseases diagnosis prevention & control MeSH
- Mitochondria drug effects metabolism MeSH
- Mitophagy drug effects MeSH
- Oxidative Stress drug effects MeSH
- Prognosis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Antioxidants MeSH
- Flavonoids MeSH
Background: Oxidative stress is a key factor in the pathophysiology of many diseases. This study aimed to verify the antioxidant activity of selected plant phenolics in cell-based assays and determine their direct or indirect effects. Methods: The cellular antioxidant assay (CAA) assay was employed for direct scavenging assays. In the indirect approach, the influence of each test substance on the gene and protein expression and activity of selected antioxidant enzymes was observed. One assay also dealt with activation of the Nrf2-ARE pathway. The overall effect of each compound was measured using a glucose oxidative stress protection assay. Results: Among the test compounds, acteoside showed the highest direct scavenging activity and no effect on the expression of antioxidant enzymes. It increased only the activity of catalase. Diplacone was less active in direct antioxidant assays but positively affected enzyme expression and catalase activity. Morusin showed no antioxidant activity in the CAA assay. Similarly, pomiferin had only mild antioxidant activity and proved rather cytotoxic. Conclusions: Of the four selected phenolics, only acteoside and diplacone demonstrated antioxidant effects in cell-based assays.
- Keywords
- CAA, Nrf2-ARE, antioxidants, catalase, glucose toxicity, plant phenolics, superoxide dismutase,
- MeSH
- Antioxidant Response Elements MeSH
- Antioxidants chemistry pharmacology MeSH
- Biomarkers MeSH
- Gene Expression MeSH
- NF-E2-Related Factor 2 genetics metabolism MeSH
- Phenols chemistry pharmacology MeSH
- Glucose MeSH
- Humans MeSH
- Molecular Structure MeSH
- Oxidative Stress MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Plant Extracts chemistry pharmacology MeSH
- Superoxide Dismutase-1 genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antioxidants MeSH
- Biomarkers MeSH
- NF-E2-Related Factor 2 MeSH
- Phenols MeSH
- Glucose MeSH
- NFE2L2 protein, human MeSH Browser
- Antineoplastic Agents MeSH
- Plant Extracts MeSH
- SOD1 protein, human MeSH Browser
- Superoxide Dismutase-1 MeSH
Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review.
- Keywords
- flavonoids, iron ions, metallocomplexes,
- MeSH
- Antioxidants chemistry pharmacology MeSH
- Chelating Agents chemistry pharmacology MeSH
- Flavonoids chemistry MeSH
- Heme chemistry MeSH
- Ions chemistry metabolism MeSH
- Coordination Complexes chemistry MeSH
- Humans MeSH
- Molecular Structure MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Iron chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Antioxidants MeSH
- Chelating Agents MeSH
- Flavonoids MeSH
- Heme MeSH
- Ions MeSH
- Coordination Complexes MeSH
- Iron MeSH
Vanadium compounds increased the content and release of distinct isoflavones in a Trifolium pratense suspension culture. Regarding transport-mechanism inhibitors, the process was mostly facilitated by ABC proteins and vesicular transport. The transport of isoflavones and other secondary metabolites is an important part of metabolism within plants and cultures in vitro regarding their role in defence against various abiotic and biotic stressors. This research focuses on the way how to increase production and exudation of isoflavones by application of chemical elicitor and the basic identification of their transport mechanisms across cell membranes. The release of five isoflavones (genistin, genistein, biochanin A, daidzein, and formononetin) into a nutrient medium was determined in a Trifolium pratense var. DO-8 suspension culture after two vanadium compound treatments and cultivation for 24 and 48 h. The NH4VO3 solution caused a higher concentration of isoflavones in the medium after 24 h. This increased content of secondary metabolites was subsequently suppressed by distinct transport-mechanism inhibitors. The transport of isoflavones in T. pratense was mostly affected by ABC inhibitors from the multidrug-resistance-associated protein subfamily, but the genistein concentration in the medium was lower after treatment with multidrug-resistance protein subfamily inhibitors. Brefeldin A, which blocks vesicular transport, also decreased the concentration of some isoflavones in the nutrient medium.
- Keywords
- Abiotic elicitation, Plasma-membrane transport, Red clover, Secondary metabolites,
- MeSH
- Biological Transport drug effects MeSH
- Cell Membrane drug effects metabolism MeSH
- Isoflavones metabolism MeSH
- Trifolium drug effects metabolism MeSH
- Vanadium pharmacology MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Isoflavones MeSH
- Vanadium MeSH
Beer, the most popular beverage containing hops, is also frequently consumed by cancer patients. Moreover, non-alcoholic beer, owing to its nutritional value and high content of biological active compounds, is sometimes recommended to patients by oncologists. However, the potential benefits and negatives have to date not been sufficiently evaluated. The present study was designed to examine the effects of four main hop-derived prenylflavonoids on the viability, reactive oxygen species (ROS) formation, activity of caspases, and efficiency of the chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (OxPt) and irinotecan (IRI) in colorectal cancer cell lines SW480, SW620 and CaCo-2. All the prenylflavonoids exerted substantial antiproliferative effects in all cell lines, with xanthohumol being the most effective (IC50 ranging from 3.6 to 7.3 µM). Isoxanthohumol increased ROS formation and the activity of caspases-3/7, but 6-prenylnaringenin and 8-prenylnaringenin exerted antioxidant properties. As 6-prenylnaringenin acted synergistically with IRI, its potential in combination therapy deserves further study. However, other prenylflavonoids acted antagonistically with all chemotherapeutics at least in one cell line. Therefore, consumption of beer during chemotherapy with 5-FU, OxPt and IRI should be avoided, as the prenylflavonoids in beer could decrease the efficacy of the treatment.
- Keywords
- 5-fluorouracil, caspase activity, colorectal carcinoma cells, irinotecan, isoxanthohumol, naringenin, oxaliplatin, prenylflavonoids,
- MeSH
- Antioxidants MeSH
- Caco-2 Cells MeSH
- Drug Combinations MeSH
- Flavanones pharmacology therapeutic use MeSH
- Flavonoids pharmacology therapeutic use MeSH
- Fluorouracil therapeutic use MeSH
- Antineoplastic Agents, Phytogenic pharmacology therapeutic use MeSH
- Humulus chemistry MeSH
- Irinotecan therapeutic use MeSH
- Caspases metabolism MeSH
- Colorectal Neoplasms drug therapy metabolism MeSH
- Drug Interactions * MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Oxaliplatin therapeutic use MeSH
- Beer * adverse effects MeSH
- Propiophenones pharmacology therapeutic use MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Reactive Oxygen Species metabolism MeSH
- Plant Extracts pharmacology therapeutic use MeSH
- Feeding Behavior MeSH
- Treatment Outcome MeSH
- Xanthones pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 6-prenylnaringenin MeSH Browser
- 8-prenylnaringenin MeSH Browser
- Antioxidants MeSH
- Drug Combinations MeSH
- Flavanones MeSH
- Flavonoids MeSH
- Fluorouracil MeSH
- Antineoplastic Agents, Phytogenic MeSH
- Irinotecan MeSH
- isoxanthohumol MeSH Browser
- Caspases MeSH
- Oxaliplatin MeSH
- Propiophenones MeSH
- Antineoplastic Agents MeSH
- Reactive Oxygen Species MeSH
- Plant Extracts MeSH
- xanthohumol MeSH Browser
- Xanthones MeSH
The family Fabaceae traditionally serves as a food and herbal remedies source. Certain plants serve for treatment of menopausal symptoms based on a presence of typical secondary metabolites, isoflavones. Beside soybean and clovers, other plants or cultures in vitro can produce these molecules. A cultivation in vitro can be enhanced by elicitation that stimulates metabolites biosynthesis via stress reaction. Vanadium compounds have been already described as potential elicitors, and the aim of this study was to determine the impact of NH₄VO₃ and VOSO₄ solutions on isoflavones production in Genista tinctoria L. cell cultures. The significant increase of isoflavones content, such as genistin, genistein, or formononetin, was measured in a nutrient medium or dry mass after NH₄VO₃ treatment for 24 or 48 h. The possible transport mechanism of isoflavones release as a result of elicitation was further evaluated. An incubation with different transport inhibitors prior to elicitation took effect on isoflavones content in the medium. However, there was a non-ended result for particular metabolites such as genistein and daidzein, where ATP-binding cassette (ABC) or, alternatively, multidrug and toxin extrusion (MATE) proteins can participate. Possible elicitation by some inhibitors was discussed as a result of their pleiotropic effect. Despite this outcome, the determination of the transport mechanism is an important step for identification of the specific transporter.
- Keywords
- Dyer’s Greenweed, elicitation, heavy metals, plasma membrane transport,
- MeSH
- Cell Culture Techniques methods MeSH
- Genista chemistry cytology drug effects MeSH
- Isoflavones chemistry MeSH
- Secondary Metabolism drug effects MeSH
- Vanadium Compounds pharmacology MeSH
- Vanadates pharmacology MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ammonium metavanadate MeSH Browser
- Isoflavones MeSH
- Vanadium Compounds MeSH
- Vanadates MeSH
- vanadyl sulfate MeSH Browser
Interaction of flavonoids with transition metals can be partially responsible for their impact on humans. Stoichiometry of the iron/copper complex with a flavonoid glycoside isoquercitrin, a frequent component of food supplements, was assessed using competitive and non-competitive methods in four (patho)physiologically-relevant pH values (4.5. 5.5, 6.8, and 7.5). Isoquercitrin chelated all tested ions (Fe2+, Fe3+, Cu2+, and Cu⁺) but its affinity for Cu⁺ ions proved to be very low. In general, the chelation potency dropped with pH lowering. Metal complexes of 1:1 stoichiometry were mostly formed, however, they were not stable and the stoichiometry changed depending on conditions. Isoquercitrin was able to reduce both Cu2+ and Fe3+ ions at low ratios, but its reducing potential was diminished at higher ratios (isoquercitrin to metal) due to the metal chelation. In conclusion, this study emphasizes the need of using multiple different methods for the assessment of chelation potential in moderately-active metal chelators, like flavonoids.
- Keywords
- Job’s method, chelator, copper, iron, quercetin-3-O-β-glucopyranoside, reduction, stoichiometry,
- MeSH
- Chelating Agents chemistry MeSH
- Flavonoids chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Copper chemistry MeSH
- Quercetin analogs & derivatives chemistry MeSH
- Iron chemistry MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Chelating Agents MeSH
- Flavonoids MeSH
- isoquercitrin MeSH Browser
- Copper MeSH
- Quercetin MeSH
- Iron MeSH
Silybum marianum (milk thistle) is a medicinal plant used for the treatment of various liver disorders. This study examined whether the main flavonolignans from S. marianum (i.e. silybin, silychristin, silydianin) and their 2,3-dehydro derivatives (i.e. 2,3-dehydrosilybin, 2,3-dehydrosilychristin, 2,3-dehydrosilydianin) activate the Nrf2 pathway, which regulates the expression of genes encoding many cytoprotective enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). After 48h of exposure, 2,3-dehydrosilydianin at concentrations of 25μM and higher significantly elevated the activity of NQO1 in murine hepatoma Hepa1c1c7 cells. In contrast, other tested compounds at non-cytotoxic concentrations had a mild or negligible effect on the NQO1 activity. Using a luciferase reporter assay, 2,3-dehydrosilydianin was found to significantly activate transcription via the antioxidant response element in stably transfected human AREc32 reporter cells. Moreover, 2,3-dehydrosilydianin caused the accumulation of Nrf2 and significantly induced the expression of the Nqo1 gene at both the mRNA and protein levels in Hepa1c1c7 cells. We found that 2,3-dehydrosilydianin also increased to some extent the expression of other Nrf2 target genes, namely of the heme oxygenase-1 gene (Hmox1) and the glutamate-cysteine ligase modifier subunit gene (Gclm). We conclude that 2,3-dehydrosilydianin activates Nrf2 and induces Nrf2-mediated gene expression in Hepa1c1c7 cells.
- Keywords
- Flavonolignans, NQO1, Nrf2, Silybin, Silybum marianum, Silymarin,
- MeSH
- Gene Expression drug effects MeSH
- NF-E2-Related Factor 2 metabolism MeSH
- Glutamate-Cysteine Ligase genetics metabolism MeSH
- Heme Oxygenase-1 genetics metabolism MeSH
- Humans MeSH
- Membrane Proteins genetics metabolism MeSH
- Molecular Structure MeSH
- Mice MeSH
- NAD(P)H Dehydrogenase (Quinone) genetics metabolism MeSH
- Cell Line, Tumor MeSH
- Silybum marianum chemistry MeSH
- Silybin MeSH
- Silymarin pharmacology MeSH
- Up-Regulation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- NF-E2-Related Factor 2 MeSH
- GCLM protein, mouse MeSH Browser
- Glutamate-Cysteine Ligase MeSH
- Heme Oxygenase-1 MeSH
- Hmox1 protein, mouse MeSH Browser
- Membrane Proteins MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- NFE2L2 protein, human MeSH Browser
- Nqo1 protein, mouse MeSH Browser
- Silybin MeSH
- silidianin MeSH Browser
- silychristin MeSH Browser
- Silymarin MeSH
