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Cited by 2,638Antioxidant Activity and Oxidative StressRedox biology and oxidative stressExercise and Physiological Responses

Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging

Open access
Jomova, Klaudia, Raptova, Renata, Alomar, Suliman Y., Alwasel, Saleh H., Nepovimova, Eugenie, Kuca, Kamil, Valko, Marian·2023·Archives of Toxicology
DOI 10.1007/s00204-023-03562-9PMC PMC10475008
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Abstract

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.

AI snapshot

Written from a shortened version of the paper’s full text (it is longer than we read).

TL;DR

This review argues that ROS/RNS at physiological levels support redox signaling (“oxidative eustress”), while excessive ROS/RNS cause oxidative stress (“distress”) that is a common denominator in chronic diseases and aging. It surveys ROS/RNS chemistry, antioxidant systems, oxidative-stress biomarkers, disease associations, and antioxidant interventions, concluding that antioxidant therapy has shown only limited and inconsistent clinical benefit.

Key findings

  • Oxidative stress is implicated as a shared feature of cancer, cardiovascular disease, diabetes, neurological disorders (Alzheimer’s and Parkinson’s diseases, Down syndrome), psychiatric disorders (depression, schizophrenia, bipolar disorder), renal disease, lung disease (COPD, lung cancer), and aging.
  • Antioxidant defense includes enzymes (SODs, catalase, GPx) and low-molecular-weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others); vitamin E is described as “the first line of defense against the peroxidation of lipids.”
  • Clinical antioxidant results are mixed: in the ATBC trial, β-carotene supplementation (20 mg/day for 5–8 years) was associated with an 18% increased incidence of lung cancer; the CHAOS trial found α-tocopherol reduced myocardial infarction but not cardiovascular mortality, while the HOPE trial failed.
  • Some interventions showed benefit in specific contexts: CoQ10 at 1200 mg/day delayed progression in early Parkinson’s disease; NAC (50 mg/kg IV plus 500 mg orally twice daily for 3 months) improved dopamine transporter binding by about 3.5–8.3% in Parkinson’s patients.

Methods

  • Narrative review of ROS/RNS chemistry, endogenous and exogenous sources, ROS-mediated signaling pathways, antioxidant systems, oxidative-stress biomarkers, and disease/aging associations.
  • Discusses evidence from in vitro experiments, animal models, and clinical trials, including selected trial doses and outcomes.
  • No systematic review search strategy, inclusion criteria, or quantitative meta-analysis is stated in the paper.

Limitations

  • The paper states that many in vitro antioxidant results cannot be simply translated to in vivo conditions, and that some antioxidants switch to prooxidant behavior or lose activity in vivo.
  • It states that whether oxidative stress is a cause or consequence of disease is impossible to conclude, and that “total antioxidant capacity” has serious limitations.
  • Evident from the text: as a narrative review, it does not provide a systematic search, risk-of-bias assessment, or pooled effect estimates, so the strength of disease-specific conclusions varies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00204-023-03562-9

Cites

672 of 672 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingreasoning

    SOD when present in the reaction mixture diminished DNA cleavage.

    “SOD is another agent which, when present in the reaction mixture, diminished DNA cleavage (Nandi et al. 2019).”
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  • Findingcitation

    Recent results using various cell types confirmed stochastic and transient formation of superoxide radicals, termed mitochondrial flash, from single or restricted clusters of interconnected mitochondria.

    “Recent results using various cell types confirmed the “stochastic and transient” formation of superoxide radicals, termed “mitochondrial” flash from either a single or restricted clusters of interconnected mitochondria (O-Uchi et al. 2018).”
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  • Findingcitation

    Hydroxyl radicals originating from the Fenton reaction might not be the main product when a physiological concentration of bicarbonate is present.

    “Interestingly, it has recently been reported that the hydroxyl radicals originating from the Fenton reaction might not be the main product when a physiological concentration of bicarbonate is present in the system (Illes et al. 2019).”
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  • Findingcitation

    ROS stimulated the oxidation of thioredoxin and its dissociation from ASK1.

    “It has been reported that ROS stimulated the oxidation of thioredoxin and its dissociation from ASK1 (Matsukawa et al. 2004).”
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  • Findingcitation

    Hydrogen peroxide was able to regulate the phosphorylation of 512 and 523 tyrosine residues of protein kinase C.

    “For example, hydrogen peroxide was able to regulate the phosphorylation of 512 and 523 tyrosine residues of protein kinase C (Aicart-Ramos et al. 2014).”
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    Findingcitation

    One puff of cigarette smoke contains approximately 10^15 free radicals of various origins.

    “It has been estimated that one puff of cigarette smoke contains approximately 1015 free radicals of various origins (Yang et al. 2008).”
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    Findingcitation

    Approximately 4-5% of oxygen in the human body is converted to ROS by biological reductants.

    “Approximately 4–5% of oxygen in the human body is converted to ROS by biological reductants.”
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    Interpretationnone given

    Certain antioxidants such as flavonoids with weak prooxidant properties may boost cellular antioxidant systems and act as preventive anticancer agents.

    “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.”
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    Premisecitation

    Free radicals contain at least one unpaired electron in the outer shell, which usually gives them high reactivity.

    “Free radicals are chemical entities containing at least one unpaired electron in the outer shell which usually gives them high reactivity.”
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    ROS/RNS are formed during electron transfer reactions by losing or accepting electrons.

    “ROS or RNS are formed during electron transfer reactions, by losing or accepting electron(s) (Halliwell and Gutteridge 2015).”
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    Premisenone given

    Vitamin E is one of the most effective low molecular weight antioxidants and first line of defense against lipid peroxidation.

    “Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids.”
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    Premisecitation

    Excessive formation of ROS disrupts redox homeostasis, leading to oxidative stress and damage to DNA, proteins, and membranes.

    “In contrast, excessive formation of ROS is responsible for disrupted redox homeostasis which in turn leads to oxidative stress and ROS-mediated damage to all important biomolecules including DNA, proteins, and membranes (Liguori et al. 2018).”
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    Interpretationnone given

    Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders, psychiatric diseases, renal disease, lung disease, and aging.

    “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.”
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    Singlet oxygen is a very efficient oxidizing agent in biological systems and can cause damage to all biomolecules including DNA.

    “Singlet oxygen is a very efficient oxidizing agent in biological systems and can cause damage to all biomolecules, including DNA.”
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    Ionizing radiation may cause radiolysis of water, accompanied by formation of hydroxyl radicals.

    “Ionizing radiation may cause radiolysis of water, accompanied by the formation of hydroxyl radicals (Nuszkiewicz et al. 2020).”
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    Efficient formation of hydroxyl radicals is achieved when stoichiometric quantities of redox metals are present and when a reducing agent (O2·−) that can recycle metal ions back to their active reduced form is present.

    “The efficient formation of hydroxyl radicals is achieved when stoichiometric quantities of redox metals are present and when a reducing agent (O2·−) that can recycle metal ions back to their active reduced form is present (Valko et al. 2005)8”
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    Premisecitation

    Under physiological conditions, the vast majority of superoxide radical is present as the radical anion O2·−, and approximately only 0.6% exists in the protonated form as hydroperoxyl radical HOO· (pKa = 4.8).

    “Under physiological conditions, a vast majority of superoxide radical is present in the form of the radical anion (O2·−), and approximately only 0.6% exists in the protonated form as hydroperoxyl radical HOO· (pKa = 4.8); O2·− is the conjugate base of a weak acid HOO· (de Grey 2002)1”
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    RNS are nitrogen-containing species of which the most significant representative is nitric oxide.

    “Reactive nitrogen species (RNS) are nitrogen-containing species of which the most significant representative example is nitric oxide (NO·) (Ignarro et al. 1987).”
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    Peroxisomes are dynamic and metabolically active subcellular compartments and a source of ROS including hydrogen peroxide and superoxide.

    “Another very important source of ROS, including hydrogen peroxide and superoxide anion radicals are dynamic and metabolically active subcellular compartments, peroxisomes (Phaniendra et al. 2015).”
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    Premisecitation

    The set of reactions resulting in formation of superoxide radicals is omnipresent and a critical component in biological systems.

    “The above set of reactions, resulting in the formation of superoxide radicals, has been shown to be omnipresent and a critical component in biological systems (Poole 2015; Adams et al. 1969; Davies et al. 2022).”
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    In neutral pH, metals (Fe or Cu) interact with carbonate and hydroperoxides resulting in carbonate radical anion CO3·−, which may dominate over hydroxyl radicals when bicarbonate concentration is higher than 100 μM.

    “In the course of this reaction, in neutral pH, metals (Fe or Cu) interact with carbonate and hydroperoxides resulting in the formation of carbonate radical anion CO3·−, which may dominate over the hydroxyl radicals when the concentration of bicarbonate is higher than 100 µM.”
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    Premisecitation

    Hydroxyl radical is one of the most reactive radicals in biological systems and causes damage to all important biomolecules including DNA, proteins, and membranes.

    “Hydroxyl radical is one of the most reactive radicals occurring in biological systems and causes damage to all important biomolecules involving DNA, proteins, and membranes (Valko et al. 2007).”
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    Production of ATP is tightly linked with formation of ROS, which may be involved in pathological states or physiological cell signaling.

    “Production of ATP is tightly linked with the formation of ROS which may be involved in the pathological states of an organism or physiological cell signaling (Valko et al. 2007).”
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    Premisecitation

    The endoplasmic reticulum is a complex dynamic structure with functions including calcium storage, lipid metabolism, and protein synthesis.

    “The endoplasmic reticulum (ER) is a complex dynamic structure possessing many functions in the cell, the most important ones include calcium storage, lipid metabolism, and protein synthesis (Cao et al. 2022).”
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    Premisecitation

    Hydrogen peroxide is a strong oxidant but the kinetics of its reaction with biomolecules is rather slow, so it can accumulate in cells in relatively high concentrations.

    “Hydrogen peroxide is a strong oxidant but the kinetics of its reaction with biomolecules is rather slow and therefore it can be accumulated in cells in relatively high concentrations (Andres et al. 2022).”
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    Molecular oxygen in a triplet state contains two unpaired electrons with parallel spin states in antibonding π* orbitals and is a biradical.

    “Molecular oxygen in a triplet state contains two unpaired electrons with parallel spin states (↑↑) in antibonding π* orbitals and therefore is a biradical.”
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    Singlet oxygen has a short half-life, about 10-6 s, depending on the media.

    “Singlet oxygen has a short half-life, about 10–6 s, depending on the media (Valko et al. 2004).”
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    Gastrointestinal problems involve Crohn's disease, reflux, esophagus cancer, and other disorders.

    “GI problems involve Crohn’s disease, reflux, esophagus cancer, and other disorders (Bhattacharyya et al. 2014).”
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    There are three main forms of superoxide dismutase present in humans: Cu,Zn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3).

    “There are three main forms of superoxide dismutase present in humans, Cu, Zn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) (Zelko et al. 2002).”
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    ERK plays important roles in cell growth, cell proliferation, and cell survival.

    “ERK plays important roles in the processes involving cell growth, cell proliferation, and cell survival (Lavoie et al. 2020).”
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    Antioxidant enzymes represent an important defense mechanism against ROS-induced oxidative stress, which causes damage to all cellular components.

    “Antioxidant enzymes represent an important defense mechanism against ROS-induced oxidative stress, causing damage to all cellular components (Mates et al. 1999).”
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    Red meat contains high content of iron which may catalyze ROS formation in the colon during digestion.

    “Red meat contains high content of iron which may catalyze ROS formation in the colon in the process of digestion (Valko et al. 2001).”
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    SOD was discovered in 1967 by Irwin Fridovich.

    “SOD was discovered in 1967 by Irwin Fridovich (McCord and Fridovich 1969).”
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    Four main MAPK cascades have been identified: ERK1/2, JNK, p38, and BMK1/ERK5.

    “Four main MAPK cascades have been identified: ERK1/2 (extracellular signal-regulated kinases), c-Jun N-terminal kinases (JNK), p38 (p38 kinase), and the BMK1/ERK5 (big MAP kinase 1) (Schaeffer and Weber 1999).”
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    SODs can be inhibited by copper chelators such as EDTA and cuprizone.

    “SODs can be inhibited also by copper chelators such as EDTA and cuprizone (a copper‐specific chelator) (Zhu et al. 2014).”
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    Acrylamide can interact with hemoglobin and increase ROS formation.

    “Acrylamide can interact with hemoglobin and increase ROS formation (Bergmark et al. 1993).”
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    P38 is a major pathway influencing cell proliferation, cell cycle, and apoptosis, and is activated in response to environmental stresses including inflammatory cytokines, oxidative and nitrosative stress, and DNA damage.

    “P38 is a major pathway influencing cell proliferation, cell cycle, and apoptosis, and is activated in response to various environmental stresses, involving inflammatory cytokines, oxidative and nitrosative stress, and DNA damage (Shahab and Jamesdaniel 2022; Zhang et al. 2016).”
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    The family of NF-κB consists of five structurally similar members: p50/p105, p52/p100, RelA, RelB, and c-Rel.

    “The family of NF-κB consists of five structurally similar members, involving p50/p105 (NF-κB1), p52/p100 (NF-κB2), RelA (p65), RelB, and c-Rel (Liu et al. 2017).”
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    Cells under a higher partial pressure of oxygen are permanently exposed to attack by ROS, which is balanced by the concerted action of a sophisticated antioxidant defense system.

    “Cells under a higher partial pressure of oxygen are permanently exposed to attack by ROS which is balanced by the concerted action of a sophisticated antioxidant defense system (Bandyopadhyay et al. 1999).”
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    A positive correlation between high consumption of red meat and incidence of colon cancer has been proposed.

    “A positive correlation between the high consumption of red meat and the incidence of colon cancer has been proposed (Valko et al. 2001).”
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    A very large gradient (≈10,000) of calcium ions exists across the plasma membrane.

    “A very large gradient (≈ 10,000) of calcium ions exists across the plasma membrane (Jomova et al. 2022).”
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    The IKK complex is a core component of NF-κB and a target of ROS, affecting NF-κB and S-glutathionylation and inhibited IKKβ activity.

    “In addition, I-κB-Kinase (IKK) complex is the core component of NF-κB and is a target of ROS, affecting thus NF-κB and S-glutathionylation and inhibited IKKβ activity (Reynaert et al. 2006).”
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    A key role of Ca2+ is ATP synthesis and mitochondrial ROS formation through oxidative phosphorylation and activation of enzymes.

    “The key role of Ca2+ is ATP synthesis and mitochondrial ROS formation through oxidative phosphorylation and activation of enzymes (Lewis et al. 2014).”
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    PI3K/AKT is an intracellular pathway involved in regulation of cell cycle growth, proliferation, apoptosis, protein synthesis, and drug resistance in response to growth factors, cytokines, and hormones.

    “The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) is an intracellular pathway involved in the regulation of a variety of critical cellular physiological processes involved in the cell cycle growth and proliferation and apoptosis, protein synthesis, and drug resistance in response to stimulation by growth factors, cytokines and hormones (Leslie and Downes 2002).”
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    SOD catalyzes the dismutation of superoxide anion radical very effectively by a Ping Pong mechanism with remarkably high reaction rates.

    “This enzyme catalyzes the dismutation of superoxide anion radical very effectively by a “Ping Pong” mechanism with remarkably high reaction rates according to the reaction (Zelko et al. 2002)12”
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    NF-κB is an important inducible transcription factor playing a key role in immune and inflammatory responses, cellular adhesion, differentiation, proliferation, and apoptosis.

    “The nuclear factor-κB (NF-κB) is an important inducible transcription factor playing a key role in processes of the immune and inflammatory responses, cellular adhesion, differentiation, proliferation, and apoptosis (Bonizzi and Karin 2004).”
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    The catalase reaction proceeds in two steps: reduction of the first H2O2 molecule forms oxyferryl species (FeIVO), and the second H2O2 molecule reduces FeIVO to O2, H2O, and free enzyme.

    “The reaction proceeds in two steps; the first step involves the reduction of the first molecule of H2O2 accompanied by the formation of oxyferryl species (FeIVO) and in the course of the second step, the FeIVO complex is reduced by the second molecule of H2O2 to O2, and H2O molecules and free enzyme (Lardinois 1995; Nandi et al. 2019)14and15”
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    The abundance of GSH is unusually high: cytosol concentration is ca 1-11 mM, mitochondria contain 6-10 mM, and nuclei 3-15 mM of GSH.

    “The abundance of GSH is unusually high, the cytosol concentration is ca 1–11 mM, mitochondria contain 6–10 mM, and nuclei 3–15 mM of GSH.”
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    Vitamin C is a water-soluble antioxidant present in the diet, supplements, and preservatives.

    “Vitamin C (ascorbic acid) is a water-soluble antioxidant present in the diet, supplements, and preservatives (Kazmierczak-Baranska et al. 2020).”
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    Manganese can oscillate between several oxidation states, making it suitable for accommodating superoxide radical anion and designing SOD mimetic compounds.

    “Manganese is a transition metal capable of oscillating between several oxidation states which makes it suitable for the accommodation of superoxide radical anion and the design of SOD mimetic compounds (Vincent et al. 2021).”
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    Prooxidant properties of vitamin C in the presence of redox-active metal ions and oxygen have been confirmed predominantly under in vitro conditions; occurrence under in vivo conditions has not been convincingly documented.

    “Prooxidant properties of vitamin C in the presence of redox-active metal ions and oxygen have been confirmed predominantly under in vitro conditions, occurrence under in vivo conditions has not been convincingly documented (Halliwell 1996).”
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    • cites Halliwell 1996 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The most representative examples of small molecular antioxidants involve vitamins C, E, and A, polyphenols of which about half are flavonoids, carotenoids, glutathione, curcumin, melatonin, and others.

    “The most representative examples of small molecular antioxidants involve vitamins C, E, and A, polyphenols of which about half are flavonoids, carotenoids, glutathione, curcumin, melatonin, and others (Niki 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Niki 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Catalase breaks down two molecules of hydrogen peroxide into two water molecules and one molecule of oxygen.

    “Catalase breaks down two molecules of hydrogen peroxide into two water molecules and one molecule of oxygen (Nandi et al. 2019)13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nandi et al. 2019 source

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  • May combine two claims.

    Premisecitation

    GPx-1 acts in the intracellular environment and maintains the physiological level of hydrogen peroxide, which is important in mitochondrial function, thiol redox homeostasis, and signal transduction.

    “GPx-1 acts in the intracellular environment and maintains the physiological level of hydrogen peroxide, which is important in mitochondrial function, thiol redox homeostasis, and signal transduction (Brigelius-Flohé and Maiorino 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brigelius-Flohé and Maiorino 2013 source

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  • May combine two claims.

    Premisecitation

    Sulfur-containing compounds are usually good antioxidants able to accommodate unpaired electron(s), forming thiyl radicals (GS·) with rather high lifetime and therefore very mild damage to biological molecules.

    “Compounds containing sulfur are usually good antioxidants able to accommodate unpaired electron(s), which in turn result in the formation of thiyl radicals (GS·), whose lifetime is rather high and therefore damage to biological molecules is very mild (Karoui et al. 1996)22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Karoui et al. 1996 source

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  • May combine two claims.

    Premisecitation

    Ebselen and its modified analog BXT-51072 delay neurological deficits and acute ischemic stroke, inhibit the inflammatory response, suppress oxidative damage, and have other beneficial oxidative stress-reducing properties.

    “This compound and its modified analog BXT-51072 were able to delay neurological deficits, and acute ischemic stroke, inhibit the inflammatory response, suppress oxidative damage, and other beneficial oxidative stress-reducing properties (Forman and Zhang 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Forman and Zhang 2021 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GPx reduces lipid hydroperoxides to alcohols and hydrogen peroxide to water.

    “GPx reduces lipid hydroperoxides to alcohols and hydrogen peroxide to water (Lubos et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lubos et al. 2011 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Deficiency of Vitamin E is related to neurological problems.

    “Deficiency of Vitamin E is related to neurological problems (National Institutes of Health 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites National Institutes of Health 2021

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ebselen possesses wide substrate specificity.

    “These involve among others, the Se-based organic compound ebselen, possessing a wide substrate specificity (Sies 1993a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sies 1993a

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A linear correlation between the reduction potentials of flavonoids and their antioxidant potential has been reported.

    “A linear correlation between the reduction potentials of flavonoids and their antioxidant potential has been reported (Lindgerg Madsen et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lindgerg Madsen et al. 2000

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  • May combine two claims.

    Premisecitation

    ERG reacts fast with hydroxyl radicals, and its reaction with hydrogen peroxide and superoxide radical anion is somewhat slower.

    “ERG reacts fast with hydroxyl radicals, and its reaction with hydrogen peroxide and superoxide radical anion is somewhat slower (Fahey 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fahey 2001 source

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  • May combine two claims.

    Premisecitation

    Low incidence of cardiovascular diseases has been linked to the consumption of red wine containing a high concentration of resveratrol, a multipurpose molecule possessing various beneficial and health-protecting properties, involving antioxidant and antitumor properties.

    “A low incidence of cardiovascular diseases has been linked to the consumption of red wine containing a high concentration of resveratrol, a multipurpose molecule possessing various beneficial and health-protecting properties, involving antioxidant, and antitumor properties.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Catalgol et al. 2012 source

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  • May combine two claims.

    Premisecitation

    Flavonoids can activate the synthesis of antioxidant enzymes and regenerate vitamins with higher electron reduction potential, such as vitamin E.

    “In addition, flavonoids can activate the synthesis of antioxidant enzymes and regenerate vitamins with higher electron reduction potential of the corresponding couples, such as vitamin E (Fig. 12) (Simunkova et al. 2019a, b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Simunkova et al. 2019a, b

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  • May combine two claims.

    Premisecitation

    Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant and neuroprotective activities in mice.

    “Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant (Nakamichi et al. 2016) and neuroprotective (Yang et al. 2012) activities in mice.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nakamichi et al. 2016 source

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    • cites Yang et al. 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melatonin is found in various tissues other than the pineal gland, involving the pancreas, liver, brain, lens, thyroid, and others.

    “Melatonin is found in various tissues other than the pineal gland, involving the pancreas, liver, brain, lens, thyroid, and others (Mahmood 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mahmood 2019 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Se is an essential component of many proteins, called selenoproteins.

    “Se is an essential component of many proteins, called selenoproteins (Zhang et al. 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhang et al. 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melatonin acts together with vitamin D as "light sensors" to meet the requirements for light and dark.

    “Melatonin acts together with vitamin D as “light sensors” to meet the requirements for light and dark (Minich et al. 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Minich et al. 2022 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ERG occurs in two tautomeric thione and thiol forms, with the thione form more abundant at physiological pH.

    “ERG occurs in two tautomeric thione and thiol forms, the thione form being more abundant at physiological pH (Borodina et al. 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Borodina et al. 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Resveratrol has been associated with the so-called "French paradox", based on epidemiological data from the French population known for the low incidence of cardiovascular diseases despite the consumption of a high-fat diet.

    “Resveratrol has been associated with the so-called “French paradox”, which has been reported in 1992, based on epidemiological data from the French population known for the low incidence of cardiovascular diseases despite the consumption of a high-fat diet (Catalgol et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Catalgol et al. 2012 source

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  • May combine two claims.

    Premisecitation

    ERG ameliorates oxidative stress at the sites of injuries and has been classified as an "adaptive antioxidant" because it does not interfere with the physiological function of ROS.

    “ERG ameliorates oxidative stress at the sites of injuries and has been classified as an “adaptive antioxidant” because it does not interfere with the physiological function of ROS (Halliwell et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Halliwell et al. 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Supplements containing Se help to boost the immune system; Se is sometimes combined with vitamins C and E.

    “Supplements containing Se help to boost the immune system, Se is sometimes combined with vitamins C and E (Shakoor et al. 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shakoor et al. 2021 source

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  • May combine two claims.

    Premisecitation

    ERG has been found to be an effective antioxidant in cardiovascular diseases, chronic pulmonary diseases, lung inflammatory diseases, and other pathologies.

    “ERG has been found to be an effective antioxidant in cardiovascular diseases (Servillo et al. 2017), chronic pulmonary diseases (Rahman 2012), lung inflammatory diseases (Repine and Elkins 2012), and other pathologies.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Servillo et al. 2017 source

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    • cites Rahman 2012 source

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    • cites Repine and Elkins 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ergothioneine (ERG) is a sulfur-histidine betaine amino acid possessing antioxidant properties.

    “Ergothioneine (ERG) is a sulfur-histidine betaine amino acid possessing antioxidant properties (Fig. 14) (Borodina et al. 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Borodina et al. 2020 source

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  • May combine two claims.

    Interpretationreasoning

    Carotenoids behave under normal conditions as antioxidants, but under high partial pressure of oxygen (and high concentration) they may lose antioxidant properties and behave as prooxidants.

    “Thus carotenoids behave under normal conditions as antioxidants, however, under a high partial pressure of oxygen (and high concentration) they may lose their antioxidant properties and behave as prooxidants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Supplementation by Se may help to improve thyroid function, but the results were not straightforward.

    “Since the thyroid gland contains a high amount of selenium, it has been expected that supplementation by Se may help to improve thyroid function. However, the results were not straightforward (Winther et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Winther et al. 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The concept of oxidative stress in greater detail was first defined by Prof. Sies in 1985.

    “The concept of oxidative stress in greater detail has been for the first time defined by Prof. Sies in 1985 (Sies 1985, 2018, 2020a).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sies 1985

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    • cites Sies 2018 source

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    • cites Sies 2020a

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Myeloperoxidase (MPO) is a heme-containing peroxidase released mainly by neutrophils.

    “Myeloperoxidase (MPO) is a heme-containing peroxidase released mainly by neutrophils (Davies and Hawkins 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Davies and Hawkins 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A more complex definition of oxidative stress, based on the disruption of redox signaling, has been proposed.

    “In view of this, a more complex definition of oxidative stress, based on the disruption of redox signaling has been proposed (Jones 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jones 2006 source

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  • May combine two claims.

    Premisecitation

    Xanthine oxidase catalyzes the oxidation of xanthine to uric acid (antioxidant) accompanied by the formation of superoxide radical anion, O2·−, and hydrogen peroxide.

    “Xanthine oxidase catalyzes the oxidation of xanthine to uric acid (antioxidant) accompanied by the formation of superoxide radical anion, O2·−, and hydrogen peroxide (McCord 1985).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McCord 1985 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Whether oxidative stress is a consequence or cause of the diseases is impossible to conclude.

    “There are many assays, which can be applied in the “quantification” of oxidative stress, however, whether oxidative stress is a consequence or cause of the diseases is impossible to conclude.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Additional supplementation with vitamin C did not increase the level of vitamin E, documenting that the in vitro redox recycling of vitamin E by vitamin C does not work in humans.

    “Contrary to expectations, additional supplementation with vitamin C did not increase the level of vitamin E, which documents, that the in vitro redox recycling of vitamin E by vitamin C does not work in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salonen et al. 2000 source

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  • May combine two claims.

    Premisecitation

    Since enhanced antioxidant status has not been shown to be effective in the alleviation of oxidative stress, a new approach based on the thiol redox pool has been proposed.

    “Since the enhanced antioxidant status has not been shown to be effective in the alleviation of oxidative stress, a new approach based on the thiol redox pool has been proposed (Jones 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jones 2006 source

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  • May combine two claims.

    Premisecitation

    Protein carbonyls are structurally stable and suitable for chemical detection.

    “These products are structurally stable and suitable for chemical detection (Stadtman 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stadtman 2004 source

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  • May combine two claims.

    Premisecitation

    Melatonin occurs in mitochondria in higher abundance compared to blood, due to higher requirements for an antioxidant pool in mitochondria containing electron transport chain.

    “Melatonin occurs in mitochondria in higher abundance compared to blood. This is due to the higher requirements for an antioxidant pool in mitochondria containing electron transport chain (Tan et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tan et al. 2015 source

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  • May combine two claims.

    Premisecitation

    Many natural antioxidants taken from diet or from supplements have very limited bioavailability and their in vitro antioxidant activity and ability to regenerate themselves have not been confirmed in cells or tissues.

    “Many natural antioxidants taken from diet or from supplements have very limited bioavailability and their in vitro antioxidant activity and ability to regenerate themselves have not been confirmed in cells or tissues (Jomova et al. 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jomova et al. 2019 source

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  • May combine two claims.

    Premisecitation

    Many in vitro experiments under different experimental conditions confirmed the good antioxidant activity of melatonin, however, levels of melatonin in certain body organs might not be high enough to exhibit antioxidant properties.

    “Many in vitro experiments under different experimental conditions confirmed the good antioxidant activity of melatonin, however, levels of melatonin in certain body organs might not be high enough to exhibit antioxidant properties (Sanchez-Barcelo et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sanchez-Barcelo et al. 2010 source

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  • May combine two claims.

    Premisecitation

    Cu,Zn-SOD is known to be increased as a response to certain therapies or in some diseases, therefore determination of activities of different SODs is necessary.

    “Cu, Zn-SOD is known to be increased as a response to certain therapies or in some diseases therefore determination of activities of different SODs is necessary (Crapo et al. 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crapo et al. 1992 source

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  • May combine two claims.

    Premisecitation

    Further studies documented the oxidation of vitamin E after the attack of ROS, however, the oxidation of vitamin E has not provided protection against lipids or damage to other biomolecules associated with chronic diseases.

    “Further studies documented the oxidation of vitamin E after the attack of ROS, however, the oxidation of vitamin E has not provided protection against lipids or damage to other biomolecules associated with chronic diseases (Niki and Noguchi 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Niki and Noguchi 2021 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    XDH can be converted to XO by the oxidation of thiols.

    “XDH can be converted to XO by the oxidation of thiols (Fig. 19) (Enroth et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Enroth et al. 2000 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The term oxidative stress in relation to biological systems appeared for the first time in the scientific literature in the early 70's.

    “The term oxidative stress in relation to biological systems appeared for the first time in the scientific literature in the early 70’s (Azzi 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Azzi 2022 source

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  • May combine two claims.

    Premisecitation

    Various disease states are characterized by disturbed metal homeostasis, such as hemochromatosis (iron overload), and flavonoids in the presence of iron (or other redox metals) behave as prooxidants, increasing the total amount of ROS.

    “Various disease states are characterized by disturbed metal homeostasis, such as hemochromatosis (iron overload) and flavonoids in the presence of iron (or other redox metals) behave as prooxidants, increasing the total amount of ROS (Valko et al. 2005).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Valko et al. 2005 source

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  • May combine two claims.

    Interpretationreasoning

    XO is one of the most important ROS-generating enzymes and can be used as a sensitive biomarker of oxidative stress.

    “Thus, XO is one of the most important ROS-generating enzymes and can be used as a sensitive biomarker of oxidative stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    While EGCG is a good antioxidant in various radical scavenging assays, in plasma its antioxidant activity is limited.

    “While EGCG is a good antioxidant in various radical scavenging assays, in plasma is its antioxidant activity limited (Rasaei et al. 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rasaei et al. 2021 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2020-2021 during the COVID-19 pandemic period, melatonin was the most sought-after supplement to optimize levels of cytokines linked with disturbed sleeping.

    “Interestingly, in 2020–2021, during the COVID-19 pandemic period, melatonin was the most sought-after supplement to optimize levels of cytokines linked with disturbed sleeping (Minich et al. 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Minich et al. 2022 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Catalase activity in the studied system is conversely proportional to the obtained signal.

    “Thus, the catalase activity in the studied system is conversely proportional to the obtained signal (Hadwan 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hadwan 2018 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melatonin and vitamin D act synergistically in skin protection.

    “Melatonin and vitamin D act synergistically in skin protection (Wacker and Holick 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wacker and Holick 2013 source

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  • May combine two claims.

    Premisecitation

    MPO converts hydrogen peroxide and chloride anions to hypochlorous acid and protects the organism against toxins and pathogens.

    “MPO converts hydrogen peroxide and chloride anions to hypochlorous acid and protects the organism against toxins and pathogens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Davies and Hawkins 2020 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxidative eustress 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.

    “Oxidative eustress means “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 (Forman et al. 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Forman et al. 2010 source

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  • May combine two claims.

    Interpretationown data

    In man, supplementation with high doses of antioxidants does not always ameliorate the oxidative stress component of various disease states of an organism or oxidative stress is not the only cause of the diseases.

    “The presented results indicate, that in man, supplementation with high doses of antioxidants does not always ameliorate the oxidative stress component of various disease states of an organism or oxidative stress is not the only cause of the diseases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Advanced glycation end products (AGEs) are heterogenous molecules originating from the nonenzymatic reaction of glucose or other saccharides with proteins or lipids.

    “Heterogenous molecules originating from the nonenzymatic reaction of glucose or other saccharides with proteins or lipids are termed advanced glycation end products (AGEs) (Perrone et al. 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Perrone et al. 2020 source

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  • May combine two claims.

    Premisecitation

    MPO-derived oxidant 3-Cl-Tyr occurs in high-density lipoprotein (HDL) and is a good biomarker of cardiovascular diseases.

    “MPO-derived oxidant 3-Cl-Tyr is occurring in high-density lipoprotein (HDL) and therefore is a good biomarker of cardiovascular diseases (Bergt et al. 2004)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bergt et al. 2004 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Protein carbonyls are protein modifications formed on side chains of proteins following the oxidation of proline, arginine, lysine, and threonine.

    “Protein carbonyls, [C=O], (aldehydes or ketones) are protein modifications, formed on side chains of proteins following the oxidation of proline, arginine, lysine, and threonine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stadtman 2004 source

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  • May combine two claims.

    Premisecitation

    The concept of "total antioxidant capacity" has serious limitations and cannot be simply transferred to in vivo conditions.

    “The concept of “total antioxidant capacity” has serious limitations and cannot be simply transferred to in vivo conditions (Sies 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sies 2007 source

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  • May combine two claims.

    Premisecitation

    Melatonin interferes with inflammatory processes by interacting with cyclooxygenase (COX2), which is a key mediator of inflammatory processes and promotes apoptosis in malignant cells.

    “Melatonin interferes with inflammatory processes by interacting with cyclooxygenase (COX2), which is a key mediator of inflammatory processes and promotes apoptosis in malignant cells (Favero et al. 2017; Chitimus et al. 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Favero et al. 2017 source

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    • cites Chitimus et al. 2020 source

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  • May combine two claims.

    Premisecitation

    More than 100 DNA adducts with ROS have been detected and the methods of their quantification have been well established.

    “To date, more than 100 DNA adducts with ROS have been detected and the methods of their quantification have been well established (Dizdaroglu et al. 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dizdaroglu et al. 2002 source

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  • May combine two claims.

    Premisecitation

    Increased oxidative stress causes modifications of all subcellular organelles, including oxidation of endoplasmic reticulum Ca2+-ATPase and contractile proteins, resulting in contractile dysfunction.

    “Increased oxidative stress causes modifications of all subcellular organelles, including oxidation of endoplasmic reticulum Ca2+-ATPase and contractile proteins (actin and myosin being the most important) resulting in contractile dysfunction (Steinberg 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Steinberg 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    About 20 various AGEs have been detected in blood and tissues, as well as in foods.

    “About 20 various AGEs have been detected in blood and tissues, as well as in foods.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Singh et al. 2001 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxidative stress has been related to many pathological states of an organism.

    “Oxidative stress has been related to many pathological states of an organism (Halliwell and Gutteridge 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Halliwell and Gutteridge 2015 source

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  • May combine two claims.

    Premisecitation

    Both peroxyl radicals and alkoxyl radicals are further cyclized and, depending on the type of polyunsaturated fatty acid, degraded into reactive aldehydes such as 4-hydroxynonenal or malondialdehyde.

    “Both peroxyl radicals and alkoxyl radicals are further cyclized and dependent on the type of polyunsaturated fatty acid, degraded into reactive aldehydes such as 4-hydroxynonenal (4-HNE) or malondialdehyde (MDA) (Fig. 21) (Ramana et al. 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ramana et al. 2014 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    JNKs play an important role in insulin resistance, and p38 MAPK has been shown to stimulate the uptake of glucose.

    “In addition, JNKs (c-Jun N-terminal kinase) play an important role in insulin resistance, and p38 MAPK (p38 mitogen-activated protein kinase) has been shown to stimulate the uptake of glucose (Bennett and Lawan 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bennett and Lawan 2020 source

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  • May combine two claims.

    Premisecitation

    In cells, the GSH/GSSG ratio is greater than 30, and in serum it is about 10 times lower.

    “In the cells, the GSH/GSS ratio is greater than 30, and in the serum is about 10 times lower (Hwang et al. 1992).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hwang et al. 1992 source

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  • May combine two claims.

    Premisecitation

    Lipid hydroperoxides react fast with Fe2+ to form alkoxyl radicals, and reaction with Fe3+ results in the formation of lipid peroxyl radicals, but the latter reaction is slower.

    “Lipid hydroperoxides react fast with Fe2+ to form alkoxyl radicals (LO·), and reaction with Fe3+ results in the formation of lipid peroxyl radicals (LOO·), however, the latter reaction is slower (Valko et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Valko et al. 2006 source

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  • May combine two claims.

    Premisecitation

    Peroxiredoxin 2 has been found to be secreted by inflammatory cells and is elevated in synovial fluids and serum in patients with rheumatoid arthritis.

    “PRX2 has been found to be secreted by inflammatory cells and is elevated in synovial fluids and serum in patients with rheumatoid arthritis (Szabo-Taylor et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Szabo-Taylor et al. 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glutathionylated hemoglobin detected in erythrocytes by mass spectrometry is a good marker of oxidative stress under various conditions, such as renal diseases, diabetes, or hyperlipidemia.

    “It has been proposed that glutathionylated hemoglobin detected in erythrocytes by Mass spectrometry (MS) is a good marker of oxidative stress under various conditions, such as renal diseases, diabetes, or hyperlipidemia (Ghezzi 2013).”
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    • cites Ghezzi 2013 source

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    Premisecitation

    Uncoupling of nitric oxide synthases results in a switch from nitric oxide to superoxide radical and peroxynitrite and suppressed bioavailability of nitric oxide and vasoconstriction.

    “Uncoupling of NOs results in a switch from nitric oxide to superoxide radical and peroxynitrite and suppressed bioavailability of nitric oxide and vasoconstriction (Santillo et al. 2015).”
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    • cites Santillo et al. 2015 source

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    Premisecitation

    Stimulated angiotensin II produces ROS which in turn causes mitochondrial dysfunction, mitochondrial DNA lesions, heart failure, fibrosis, and cardiac hypertrophy.

    “In addition, stimulated AngII produces ROS which in turn causes mitochondrial dysfunction, mitochondrial DNA lesions, heart failure, fibrosis, and cardiac hypertrophy (Dai et al. 2016).”
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    • cites Dai et al. 2016 source

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    Premisecitation

    Cardiovascular diseases have multifactorial origins and according to WHO are the major cause of death worldwide.

    “Cardiovascular diseases (CVD) have multifactorial origins and according to WHO are the major cause of death worldwide (Benjamin et al. 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Benjamin et al. 2017 source

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    Premisecitation

    Vascular NOXs are regulated by angiotensin II, which stimulates the formation of NOX-dependent ROS that in turn activate angiotensin II receptor type 1 with a self-strengthening effect.

    “Vascular NOXs are regulated by a peptide-hormone, Angiotensin II (AngII) that stimulates the formation of NOX-dependent ROS which in turn activate Angiotensin II receptor type 1 (AT1) with a self-strengthening effect (Santillo et al. 2015).”
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    • cites Santillo et al. 2015 source

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    Premisecitation

    Secretion of thioredoxin is a response to increased oxidative stress which can be inhibited by antioxidants.

    “It has been proposed that the secretion of TRX is a response to increased oxidative stress which can be inhibited by the antioxidants (Kondo et al. 2004).”
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    • cites Kondo et al. 2004 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Isoprostanes are specific prostaglandin-like molecules formed by the non-enzymatic ROS-mediated peroxidation of PUFAs, involving for example arachidonic acid.

    “Isoprostanes are specific prostaglandin-like molecules formed by the non-enzymatic ROS-mediated peroxidation of PUFAs, involving for example arachidonic acid (Milne et al. 2015).”
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    • cites Milne et al. 2015 source

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    Premisecitation

    The most abundant non-fluorescence AGEs involve carboxymethyl-lysine (CML) and carboxyethyl-lysine (CEL), while fluorescence AGEs involve methylglyoxal-lysine and pentosidine.

    “The most abundant non-fluorescence AGEs involve carboxymethyl-lysine (CML), and carboxyethyl-lysine (CEL). Fluorescence AGEs involve methylglyoxal-lysine and pentosidine (Singh et al. 2001).”
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    • cites Singh et al. 2001 source

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  • May combine two claims.

    Premisecitation

    Elevated levels of cysteinylated albumin detected by mass spectrometry have been associated with kidney diseases and diabetes, and in addition, hepatic diseases.

    “Elevated levels of cysteinylated albumin detected by MS have been associated with kidney diseases and diabetes, and in addition, hepatic diseases (Nagumo et al. 2014).”
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    • cites Nagumo et al. 2014 source

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    Premisecitation

    NOX activity has been found to be increased in patients with metabolic syndrome and increased plasma levels of oxidized LDL and nitrotyrosine.

    “NOX activity has been found to be increased in patients with metabolic syndrome and increased plasma levels of oxidized LDL and nitrotyrosine (Fortuno et al. 2006).”
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    • cites Fortuno et al. 2006 source

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    Premisecitation

    Vitamin C can reduce apoptosis in vascular smooth muscle cells and prevent the instability of plaques.

    “Vitamin C can reduce apoptosis in vascular smooth muscle cells and prevent the instability of plaques (Lehr et al. 1994).”
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    • cites Lehr et al. 1994 source

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    Premisecitation

    Vitamin D alone but more convincingly in combination with vitamin E decreased oxidative stress in cardiomyocytes, reduced inflammatory markers, and suppressed apoptosis, hypertrophy, and other ailments in obese rats.

    “Vitamin D alone but more convincingly in combination with vitamin E decreased oxidative stress in cardiomyocytes, reduced inflammatory markers, and suppressed apoptosis, hypertrophy, and other ailments in obese rats (Farhangi et al. 2017).”
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    • cites Farhangi et al. 2017 source

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    Premisecitation

    Mice supplemented with resveratrol exhibit prolonged survival, less frequently occurring cardiac fibrosis, and improved diastolic function.

    “Mice supplemented with resveratrol exhibit prolonged survival, less frequently occurring cardiac fibrosis, and improved diastolic function (Sung et al. 2015).”
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    • cites Sung et al. 2015 source

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    Premisecitation

    In a clinical trial, subjects drinking three cups of green tea for a period of four months restored endothelial dysfunction and reduced 8-iso-prostoglandin-F2α.

    “In a clinical trial, it has been reported that subjects drinking three cups of green tea for a period of four months have restored endothelial dysfunction and reduced 8-iso-prostoglandin-F2α, a useful oxidative stress marker.”
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    • cites Oyama et al. 2010 source

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  • May combine two claims.

    Premisecitation

    Intake of strawberries for 30 days can decrease levels of LDL cholesterol and triglycerides and provide partial protection against cardiovascular diseases.

    “Intake of strawberries for 30 days can decrease levels of LDL cholesterol and triglycerides and provide partial protection against cardiovascular diseases (Alvarez-Suarez et al. 2014).”
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    • cites Alvarez-Suarez et al. 2014 source

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    Premisecitation

    The CHAOS trial demonstrated that α-tocopherol is able to reduce the incidence of myocardial infarction, but failed to reduce mortality in cardiovascular diseases.

    “CHAOS trial demonstrated that α-tocopherol is able to reduce the incidence of myocardial infarction, however, failed to reduce the mortality in cardiovascular diseases (Stephens et al. 1996).”
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    • cites Stephens et al. 1996 source

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    Premisecitation

    High levels of ROS trigger cell cycle arrest and cancer cell death.

    “High levels of ROS have been shown to trigger cell cycle arrest and cancer cell death (Moon et al. 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Moon et al. 2010 source

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    Premisecitation

    ROS can either promote protumorigenic signaling supporting the proliferation and survival of cancer cells or conversely promote antitumorigenic signaling and oxidative stress-induced cancer cell death.

    “ROS can either (i) promote protumorigenic signaling supporting the proliferation and survival of cancer cells or (ii) conversely promote antitumorigenic signaling and oxidative stress-induced cancer cell death (Reczek and Chandel 2017).”
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    • cites Reczek and Chandel 2017 source

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  • May combine two claims.

    Premisecitation

    Vitamin C has the ability to prevent LDL oxidation and consequently slows down the peroxidation of lipids.

    “Vitamin C has the ability to prevent LDL oxidation and consequently slows down the peroxidation of lipids (Maeda et al. 2000).”
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    • cites Maeda et al. 2000 source

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  • May combine two claims.

    Interpretationreasoning

    Dysregulation of the PI3K/Akt pathway by excessive ROS production in various cancers is well established and is a critical target in anticancer therapy.

    “Thus, dysregulation of the PI3K/Akt pathway by excessive ROS production in various cancers is well established and is a critical target in anticancer therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Delphinidin possesses ROS scavenging properties and is able to prevent apoptosis of endothelial cells under in vitro conditions via interference with NO-signaling pathways.

    “Delphinidin, an anthocyanin, a primary plant pigment, containing 6 hydroxyl groups in its structure possesses ROS scavenging properties and is able to prevent apoptosis of endothelial cells under in vitro conditions via interference with NO-signaling pathways (Martin et al. 2003).”
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    • cites Martin et al. 2003 source

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  • May combine two claims.

    Premisecitation

    C-reactive protein is a good marker of inflammation and has been found to be reduced by vitamin E.

    “CRP is a good marker of inflammation and has been found to be reduced by vitamin E (Patrick et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Patrick et al. 2001

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  • May combine two claims.

    Premisecitation

    Compared to healthy cells, cancer cells are characterized by increased formation of ROS and therefore to avoid ROS-induced cell death, cancer cells restore their ROS homeostasis by increasing their antioxidant capacity.

    “Compare to healthy cells, cancer cells are characterized by increased formation of ROS and therefore to avoid ROS-induced cell death, cancer cells restore their ROS homeostasis by increasing their antioxidant capacity (Valko et al. 2006).”
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    • cites Valko et al. 2006 source

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    Premisecitation

    Oral administration of 2 g of vitamin C in healthy populations helped to reduce platelet aggregation and arterial stiffness, but the exact mechanism has not been fully explored.

    “Oral administration of 2 g of vitamin C in healthy populations helped to reduce aggregation platelet and arterial stiffness, however, the exact mechanism has not been fully explored (Wilkinson et al. 1999).”
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    • cites Wilkinson et al. 1999 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activated mutations within the Ras/Raf/MAPK/ERK pathway represent the most frequent oncogenic factor for many cancers.

    “Activated mutations within this pathway represent the most frequent oncogenic factor for many cancers (Khotskaya et al. 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Khotskaya et al. 2017 source

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  • May combine two claims.

    Premisecitation

    Vitamin E inhibits the protein kinase C pathway, NF-kappa B, and IkappaB degradation, all activated by oxidized low-density lipoprotein.

    “Vitamin E inhibits the protein kinase C pathway, NF-kappa B, and IkappaB degradation, all activated by oxidized low-density lipoprotein (LDL) (Goya et al. 2006).”
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    • cites Goya et al. 2006 source

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  • May combine two claims.

    Premisecitation

    Resveratrol has been found to activate eNOS which may prevent hypertension in obese mice.

    “Resveratrol has also been found to activate eNOS which may prevent hypertension in obese mice (Huang et al. 2018).”
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    • cites Huang et al. 2018 source

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  • May combine two claims.

    Premisecitation

    A diet enriched with fruits and vegetables or antioxidants in the form of supplements lowered the risk of incidence and mortality in patients suffering from cancer.

    “A diet enriched with fruits and vegetables or antioxidants in the form of supplements lowered the risk of incidence and mortality in patients suffering from cancer (Genkinger et al. 2004).”
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    • cites Genkinger et al. 2004 source

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    Premisecitation

    Vitamin E decreases monocyte recruitment as a result of suppressed formation of foam cells and reduces expression of scavenger receptors on macrophages.

    “Vitamin E has been reported to decrease monocyte recruitment as a result of suppressed formation of foam cells and reduce expression of scavenger receptors (SRs) on macrophages (Zapolska-Downar et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zapolska-Downar et al. 2000 source

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    Premisecitation

    Expressed mutant Parkin results in increased levels of carbonyls, peroxidation of lipids, and nitrated proteins.

    “Conversely, expressed mutant Parkin results in increased levels of carbonyls, peroxidation of lipids, and nitrated proteins (Hyun et al. 2002).”
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    • cites Hyun et al. 2002 source

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    Premisecitation

    Increased levels of iron have been confirmed in the PD midbrain, which results in iron-induced oxidative stress and neurodegeneration.

    “Increased levels of iron have been confirmed in the PD midbrain, which in turn results in iron-induced oxidative stress and neurodegeneration (Chinta and Andresen 2008).”
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    • cites Chinta and Andresen 2008

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  • May combine two claims.

    Interpretationreasoning

    Although various antioxidants have been shown to be effective in ameliorating symptoms of Alzheimer's disease, available data from pre-clinical studies are not very convincing to be applied in further studies.

    “In conclusion, although various antioxidants have been shown to be effective in ameliorating symptoms of AD, available data from pre-clinical studies are not very convincing to be applied in further studies.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Knocked down PINK1 in SHSY5Y cells results in inhibition of mDNA synthesis, disruption of mitochondrial activity, mitochondrial membrane potential, and suppressed production of ATP.

    “Knocked down PINK1 in SHSY5Y cells results in inhibition of mDNA synthesis, disruption of key indicators of mitochondrial activity, mitochondrial membrane potential, and suppressed production of ATP (Gegg et al. 2009).”
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    • cites Gegg et al. 2009 source

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    Premisecitation

    α-Synuclein causes dysfunction of mitochondrial complex I in PD, which increases ROS and oxidative stress.

    “α-Synuclein has been reported to cause dysfunction of mitochondrial complex I in PD which in turn increases levels of ROS and consequently ROS-induced oxidative stress (Winklhofer and Haass 2010).”
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    • cites Winklhofer and Haass 2010 source

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    Premisecitation

    Aminochrome is a highly reactive molecule capable of forming adducts with α-synuclein and ROS such as superoxide radical anion and depleting NADPH.

    “Aminochrome is a highly reactive molecule capable of forming adducts with α-synuclein and ROS such as superoxide radical anion and depleting NADPH (Norris et al. 2005).”
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    • cites Norris et al. 2005 source

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    Premisecitation

    SH-SY5Y cell line with overexpressing wild-type and mutant Parkin exhibits decreased levels of ROS and resistance to apoptosis induced by 6-hydroxydopamine.

    “This cell line with overexpressing wild-type and mutant Parkin exhibits decreased levels of ROS and resistance to apoptosis induced by 6-hydroxydopamine (Jiang et al. 2004).”
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    • cites Jiang et al. 2004 source

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    Premisecitation

    DJ-1 is expressed in neurons and glial cells and acts as a ROS scavenger and transcriptional co-activator and molecular chaperon.

    “DJ-1 is expressed in neurons and glial cells and acts as a ROS scavenger and transcriptional co-activator and molecular chaperon (Yokota et al. 2003).”
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    • cites Yokota et al. 2003 source

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    Premisecitation

    DJ-1 exposed to oxidative stress undergoes oxidation of Cysteine106 and translocates from cytoplasm to mitochondria or to the nucleus.

    “DJ-1 exposed to oxidative stress undergoes oxidation of Cysteine106 and translocates from cytoplasm to mitochondria or to the nucleus (Junn et al. 2009).”
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    • cites Junn et al. 2009 source

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    Premisecitation

    Biochemical disturbances result in dopamine oxidation to dopamine-quinones or 6-hydroxydopamine, both involved in neurodegeneration.

    “The above-described biochemical disturbances result in dopamine oxidation to dopamine-quinones or 6-hydroxydopamine, both involved in neurodegeneration (Hastings 2009).”
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    • cites Hastings 2009 source

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    Premisecitation

    Increased levels of redox metals act catalytically and contribute to the formation of damaging ROS and the occurrence of oxidative stress in the brain via the Fenton reaction.

    “Increased levels of redox metals act catalytically and contribute to the formation of damaging ROS and the occurrence of oxidative stress in the brain via the Fenton reaction (Valko et al. 2005)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Valko et al. 2005 source

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  • May combine two claims.

    Premisenone given

    ROS levels directly influence synaptic efficiency, characterized as the most important origin of neuronal dysfunction in Parkinson's disease.

    “ROS levels directly influence synaptic efficiency, characterized as the most important origin of neuronal dysfunction in PD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Significantly decreased levels of CoQ10 have been detected in cortex of post-mortem brain tissues of Parkinson's brains; level of oxidized form of ubiquinone increased compared to healthy subjects.

    “Significantly decreased levels of CoQ10 have been detected in the cortex of post-mortem brain tissues of Parkinson’s brains. In addition, the level of the oxidized form of ubiquinone has been found to be increased compared to healthy subjects (Sohmiya et al. 2004).”
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    • cites Sohmiya et al. 2004 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Alzheimer's disease is a multifactorial disease characterized by the degeneration of cells in the brain.

    “Alzheimer’s disease (AD) is a multifactorial disease characterized by the degeneration of the cells in the brain (Knopman et al. 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Knopman et al. 2021 source

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    Premisecitation

    Nigral dopaminergic neurons are less abundant with L-type Ca2+ channels, have low oscillations of Ca2+, more expressed calcium-binding proteins calbindins, and therefore exhibit lower susceptibility to damage in PD.

    “For example, nigral neurons are less abundant with the L-type Ca2+ channels and are characterized by low oscillations of Ca2+, more expressed calcium-binding proteins calbindins, and therefore exhibit lower susceptibility to damage in PD (Khaliq and Bean 2010).”
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    • cites Khaliq and Bean 2010 source

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    Premisecitation

    CoQ10 location close to membranes protects them from free radicals-induced damage and prevents peroxidation of lipids and DNA damage.

    “Its location close to the membranes protects them from free radicals-induced damage and prevents peroxidation of lipids and DNA damage (Crane 2001).”
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    • cites Crane 2001 source

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    Premisecitation

    Neurotoxic 6-hydroxydopamine and superoxide radical are able to release free iron from ferritin, which may participate in Fenton chemistry, forming ROS and initiating lipid peroxidation.

    “It has been declared, that neurotoxic 6-hydroxydopamine (and also superoxide radical) is able to release “free iron” from ferritin which in turn may participate in Fenton chemistry, forming ROS and initiating lipid peroxidation (Monteiro and Winterbourn 1989).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Monteiro and Winterbourn 1989 source

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  • May combine two claims.

    Premisenone given

    PINK1 mutations disturb kinase functions and neuroprotection.

    “PINK1 mutations disturb kinase functions and neuroprotection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GSH therapy improved performance of patients, with nearly half a decline in disability lasting about three months after interrupted therapy.

    “GSH therapy improved the performance of patients, with nearly half a decline in disability of patients which lasted for about three months after interrupted therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sechi et al. 1996 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Of 500 genes on chromosome 21, 18 genes influence gene expression, and more than 20 genes are involved in metabolic functioning.

    “Of 500 genes on chromosome 21, 18 genes influence gene expression, and more than 20 genes are involved in metabolic functioning (Sturgeon and Gardiner 2011).”
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    • cites Sturgeon and Gardiner 2011 source

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    Premisecitation

    Supplementation with antioxidants in patients with Down syndrome improves oxidative stress biomarkers and overall antioxidant status, but no improvements in cognitive performance or retardation of cognitive decline observed.

    “Although supplementation with antioxidants in patients with Down syndrome improves oxidative stress biomarkers and the overall antioxidant status of an organism. However, no improvements in cognitive performance or retardation of cognitive decline have been observed (Rueda Revilla et al. 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rueda Revilla et al. 2020 source

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    Premisecitation

    PD patients with badly controlled motor symptoms intravenously administered 1400 mg glutathione three times a week for four weeks had minor symptomatic improvement and well-tolerated glutathione.

    “In another study, PD patients with badly controlled motor symptoms were intravenously administrated 1400 mg of glutathione three times a week for four weeks. The outcome was a minor symptomatic improvement and well-tolerated glutathione (Hauser et al. 2009).”
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    • cites Hauser et al. 2009 source

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  • May combine two claims.

    Premisecitation

    Patients with neurological disorders such as PD have decreased plasma levels of vitamin C; level of vitamin C can be considered a biomarker of PD progression.

    “Patients suffering from neurological disorders such as PD have been reported to have decreased plasma levels of vitamin C; the level of vitamin C can be considered a biomarker of PD progression (Foy et al. 1999).”
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    • cites Foy et al. 1999 source

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    Premisecitation

    Analysis confirmed occurrence of glycation end products and process of glycoxidation triggered very early in prenatal life.

    “The analysis confirmed the occurrence of glycation end products and that the process of glycoxidation is triggered very early in prenatal life (Head et al. 2001).”
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    • cites Head et al. 2001 source

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    Premisecitation

    In trial with PD patients, GSH level monitored by MRI following intravenously administrated 150 mg/kg of NAC; in all studied subjects GSH increased, returned to original level after 120 min.

    “In a trial with patients suffering from PD was glutathione (GSH) level quantitatively monitored by Magnetic Resonance Imaging (MRI) following intravenously administrated 150 mg/kg of NAC. In all studied subjects the level of GSH increased, however, returned back to its original level after 120 min (Holmay et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Holmay et al. 2013 source

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  • May combine two claims.

    Premisecitation

    Carnosine is a dipeptide with metal-chelating, antioxidant, reducing, and radical scavenging properties, mainly peroxyl radicals causing damage to biological membranes.

    “Carnosine is a dipeptide (β-alanyine-L-histidine) with metal-chelating (contains several nitrogen donor atoms), antioxidant, reducing, and radical scavenging properties, mainly peroxyl radicals causing damage to biological membranes (Kohen et al. 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kohen et al. 1988 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NAC has been used for many years in clinical praxis to restore hepatic levels of glutathione after acetaminophen overdose.

    “N-Acetylcysteine has been used for many years in clinical praxis to restore hepatic levels of glutathione after acetaminophen overdose (Smilkstein et al. 1988).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smilkstein et al. 1988 source

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  • May combine two claims.

    Premisecitation

    Children and teenagers (7-15 years) with Down syndrome supplemented with vitamins E and C or α-lipoic acid showed suppressed signs of oxidative damage; vitamins C and E suppressed lipid peroxidation in blood.

    “Children and teenagers (7–15 years of age) with Down syndrome supplemented with vitamins E and C or α-lipoic acid explored suppressed signs of oxidative damage. Vitamins C and E were able to suppress lipid peroxidation in the blood (Parisotto et al. 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Parisotto et al. 2014 source

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  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Interpretationreasoning

    GSH slows down disease progression.

    “Based on these findings, it has been proposed that GSH slows down the disease progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although vitamins improved oxidative stress markers, cognitive functions were not improved.

    “Based on the various trials attempting to monitor the beneficial effect of antioxidant supplementation in patients suffering from Down syndrome, it can be concluded that although vitamins were able to improve oxidative stress markers, cognitive functions were not improved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary intake of vitamin C has been connected with reduced risk of PD, however two large cohort studies did not confirm this expectation.

    “Dietary intake of vitamin C has been connected with a reduced risk of PD, however, two large cohort studies did not confirm this expectation (Hughes et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hughes et al. 2016 source

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  • May combine two claims.

    Interpretationreasoning

    Longer treatment with higher doses of vitamins C and E is beneficial in reducing oxidative damage to lipids, however without cognitive improvements.

    “From this follows that longer treatment with higher doses of vitamins C and E is beneficial in reducing oxidative damage to lipids, however, without cognitive improvements.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Individuals taking 3000 mg of NAC every day for four weeks showed increased GSH/GSSG, but biomarkers of oxidative damage (lipid peroxidation) remained unchanged.

    “Individuals were taking 3000 mg of NAC every day for four weeks. The results have shown that the level of GSH/GSSG increased, however, the biomarkers of oxidative damage (peroxidation of lipids) remained unchanged (Coles et al. 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Coles et al. 2018 source

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  • May combine two claims.

    Premisecitation

    Post-mortem brains of Parkinson's patients revealed altered ratio between reduced and oxidized glutathione (GSH/GSSG ratio) and reduction of glutathione in substantia nigra.

    “Post-mortem brains of Parkinson’s patients revealed the altered ratio between the reduced and oxidized glutathione (GSH/GSSG ratio) and the reduction of glutathione in the substantia nigra (Sian et al. 1994).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sian et al. 1994 source

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  • May combine two claims.

    Premisecitation

    In recent study, 42 PD patients intravenously infused with NAC (50 mg/kg) plus oral NAC (500 mg twice a day) for 3 months showed improvement in dopamine transporter binding (cca 3.5-8.3%), suggesting NAC has positive clinical effects and improved symptoms.

    “In a very recent study, 42 patients with PD were intravenously infused with NAC (50 mg/kg) plus taking NAC orally (500 mg twice a day) for 3 months. Dopamine transporter binding was evaluated by using DaTscan imaging (DTscan is a radiopharmaceutical used in a brain scan (SPECT), to visualize striatal dopamine transporters). Improvement in dopamine transporter binding (cca 3.5–8.3%) suggests that N”
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    • cites Monti et al. 2019 source

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    Premisecitation

    In one trial lasting 2 years, antioxidant supplementation with vitamin C, vitamin E, and α-lipoic acid in subjects with Down syndrome did not prevent cognitive decline nor improved cognitive function.

    “In one of the trials lasting 2 years, antioxidant supplementation with vitamin C, vitamin E, and α-lipoic acid in subjects with Down syndrome did not prevent cognitive decline nor improved cognitive function (Lott et al. 2011).”
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    • cites Lott et al. 2011 source

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    Interpretationnone given

    Causal relationship between mental/psychiatric diseases and oxidative stress is problematic to reliably determine; difficult to determine if oxidative stress is cause or consequence.

    “Although many detailed studies have declared an association between mental/psychiatric diseases and oxidative stress, the causal relationship between them is problematic to reliably determine. In fact, it is difficult to determine, if oxidative stress is a cause or a consequence of the disease’s state.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Vitamin C deficiency is responsible for adverse mood and cognitive defects due to importance of vitamin C in modulating synthesis of neurotransmitters.

    “Vitamin C deficiency is responsible for adverse mood and cognitive defects. This is due to the importance of vitamin C in modulating the synthesis of neurotransmitters (Plevin and Galletly 2020).”
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    • cites Plevin and Galletly 2020 source

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    Premisecitation

    A diet containing high content of phenols, anthocyanins, and vitamin C improves symptoms of depression mainly by reducing level of oxidative damage, increasing levels and activity of antioxidant enzymes such as SOD and GPx, and increasing level of expression of glutathione.

    “A diet containing high content of phenols, anthocyanins, and vitamin C improves symptoms of depression mainly by reducing the level of oxidative damage (biomarkers) in the brain, increasing levels and activity of antioxidant enzymes such as SOD and GPx, and increasing the level of expression of glutathione (Dong et al. 2021).”
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    • cites Dong et al. 2021 source

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    Premisecitation

    Experiments using mice have shown that quercetin is able to make protection against anxiety and depression as well as improve memory by regulating mutually interacting cholinergic and serotonergic systems.

    “Experiments using mice have shown that quercetin is able to make a protection against anxiety and depression as well as improve memory by regulating mutually interacting cholinergic and serotonergic systems (Samad et al. 2018).”
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    • cites Samad et al. 2018 source

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    Premisecitation

    Among other pathologies, impaired neurotransmission, autoimmune dysfunction, abnormal neuronal development, and oxidative stress have been proposed in schizophrenia.

    “Among other pathologies, impaired neurotransmission, autoimmune dysfunction, abnormal neuronal development, and oxidative stress have been proposed (Kessler 1997; Salim 2014).”
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    • cites Kessler 1997 source

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    • cites Salim 2014 source

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  • Classified as probably not a substantial claim.

    Interpretationcitation

    Patients with schizophrenia should regularly take higher amounts of vitamin C (minimum 2 g/day) to reach normal plasma levels of vitamin C.

    “Therefore patients with schizophrenia should regularly take higher amounts of vitamin C (minimum 2 g/day) to reach normal plasma levels of vitamin C.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Significantly higher level of SOD has been observed among chronically ill patients taking antipsychotic drugs than in patients in first episode; this indicates level of oxidative stress occurs mainly in first episode characterized by fewer symptoms.

    “Significantly higher level of SOD has been observed among chronically ill patients taking antipsychotic drugs than in patients in the first episode. This observation indicates that the level of oxidative stress occurs mainly in the first episode characterized by fewer symptoms (Zhang et al. 2012).”
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    • cites Zhang et al. 2012 source

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    Premisecitation

    Increased levels of isoprostanes, predominantly 8-iso-PGF2α, have been detected in urine of patients, making analysis of isoprostanes a valuable and reliable marker of level of oxidative damage in schizophrenia patients.

    “Increased levels of isoprostanes, and predominantly 8-iso-prostaglandin (8-iso-PGF2α) have been detected in the urine of patients, making analysis of isoprostanes a valuable and reliable marker of the level of oxidative damage in schizophrenia patients (De Simone et al. 2023).”
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    • cites De Simone et al. 2023 source

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    Premisecitation

    Curcumin has strong antioxidant, antimutagenic, anti-inflammatory, and antimicrobial functions and reduces symptoms of patients with schizophrenia.

    “Curcumin has strong antioxidant, antimutagenic, anti-inflammatory, and antimicrobial functions and has been found to reduce the symptoms of patients with schizophrenia (Rabiee et al. 2023).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rabiee et al. 2023 source

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    Premisecitation

    Supplementation with high doses of vitamins C and E and fish oil improves clinical symptoms of patients with schizophrenia and partially restored levels of antioxidants.

    “Supplementation with high doses of vitamins C and E and fish oil has been found to improve clinical symptoms of patients with schizophrenia and partially restored levels of antioxidants (Pandya et al. 2013).”
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    • cites Pandya et al. 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Quercetin is one of the most abundant flavonoids in fruits and vegetables.

    “One of the most abundant flavonoids in fruits and vegetables is quercetin (Jomova et al. 2017).”
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    • cites Jomova et al. 2017 source

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    Premisecitation

    In three groups of treated and untreated patients with schizophrenia and healthy controls, GPx was significantly lowered in both groups of patients; untreated patients revealed decreased levels of CAT, GSH, and albumin; both groups showed significantly lowered non-enzymatic antioxidant capacity; antioxidant status was most significantly impaired in untreated patients, confirming level of抗氧化剂 in患者与

    “It was found that the enzyme glutathione peroxidase (GPx) was significantly lowered in both groups of patients. Untreated patients revealed decreased levels of catalase (CAT), glutathione (GSH), and albumin. Both groups of patients, treated and untreated showed significantly lowered non-enzymatic antioxidant capacity. Antioxidant status was most significantly impaired in untreated patients, confir”
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    • cites Goh et al. 2022 source

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    Premisecitation

    Lower serotonin levels may affect concentrations of norepinephrine to lower levels which in turn may trigger depression.

    “For example, lower serotonin levels may affect concentrations of norepinephrine (noradrenaline) to lower levels which in turn may trigger depression (Balmus et al. 2016).”
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    • cites Balmus et al. 2016 source

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    Premisecitation

    In another study, a group of 50 volunteers for 8 weeks consumed dark chocolate and blueberries; increased intake of flavonoids resulted in reduced symptoms of depression.

    “In another study, a group of 50 volunteers for 8 weeks consumed dark chocolate and blueberries (Kontogianni et al. 2020). Increased intake of flavonoids resulted in reduced symptoms of depression.”
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    • cites Kontogianni et al. 2020 source

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    Premisecitation

    Plasma glutathione peroxidase levels have been found to be lowered in schizophrenia patients as well as in psychotic children.

    “Plasma glutathione peroxidase levels have been found to be lowered in schizophrenia patients (Gawryluk et al. 2011) as well as in psychotic children (Golse et al. 1977).”
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    • cites Gawryluk et al. 2011 source

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    • cites Golse et al. 1977

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depression has a very high rate of suicides.

    “Depression has a very high rate of suicides (Bains and Abdijadid 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bains and Abdijadid 2021

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    Premisecitation

    Vitamin C affects dopaminergic system and its deficiency has been associated with schizophrenia.

    “Vitamin C is known to affect the dopaminergic system and its deficiency has been associated with schizophrenia (Plevin and Galletly 2020).”
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    • cites Plevin and Galletly 2020 source

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    Premisecitation

    Systematic review and meta-analysis of NAC in schizophrenia patients found individuals in acute phase were most responsive to treatment with NAC than those not in acute phase; considerable heterogeneity across subgroups noted.

    “A systematic review and meta-analysis of N-acetylcysteine in schizophrenia patients have been carried out (Kishi et al. 2023). Both subgroups, individuals in the acute phase and in the non-acute phase were supplied with N-acetylcysteine. Individuals with schizophrenia in the acute phase were most responsive to the treatment with N-acetylcysteine than those who were not in the acute phase. However,”
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    • cites Kishi et al. 2023 source

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    Premisecitation

    Patients with schizophrenia on medical treatment supplemented with extracts from Ginkgo Biloba had higher response rate and significant reduction score on scale of assessment of positive symptoms.

    “Patients with schizophrenia on medical treatment were supplemented with extracts from Ginko Biloba (Zhang et al. 2001). The outcome was very promising as measured by a higher response rate and significant reduction score on the scale of assessment of positive symptoms.”
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    • cites Zhang et al. 2001 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Incidence of bipolar disorder is between 1 and 3% of world's population with average age between 20 and 30 years.

    “The incidence of bipolar disorder is between 1 and 3% of the world’s population with average age between 20 and 30 years.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Andreazza et al. 2008 source

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    • cites Cecerska-Heryc et al. 2022 source

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  • May combine two claims.

    Premisecitation

    Post-mortem analysis of prefrontal cortex showed significantly increased levels of 8-OH-Gua which may affect aggregation of proteins.

    “Post-mortem analysis of the prefrontal cortex showed significantly increased levels of 8-OH-Gua (see also above) which may in turn affect the aggregation of proteins (Balmus et al. 2016).”
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    • cites Balmus et al. 2016 source

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    Premisecitation

    In patients with bipolar disorder, DNA oxidative damage is related to increased telomere shortening, translating into approximately 10-year acceleration of aging.

    “It has been reported that DNA oxidative damage is related to increased telomere shortening in patients with BD; this translates into an approx. 10-year acceleration of aging (Akarsu et al. 2018).”
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    • cites Akarsu et al. 2018 source

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    Premisecitation

    Oxidative DNA damage and telomere shortening have been found to be increased in patients with bipolar disorder which has been estimated to accelerate aging by about 10 years.

    “Interestingly, oxidative DNA damage and telomere shortening have been found to be increased in patients with bipolar disorder which in turn has been estimated to accelerate aging by about 10 years (Akarsu et al. 2018).”
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    • cites Akarsu et al. 2018 source

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    Premisecitation

    In RCT, 105 patients divided randomly into three groups, group 1 taking daily 500 mg vitamin C, group 2 receiving 600 IU vitamin E twice daily, group 3 placebo; results showed supplementation with vitamins C and E and antipsychotic drugs are effective in management of schizophrenia and alleviating symptoms.

    “The role of vitamins C and E in the management of schizophrenia has been studied by randomized control trials (Kouser et al. 2021). 105 patients were divided randomly into three groups, group 1 taking daily 500 mg of vitamin C, group 2 receiving 600 IU of vitamin E twice daily, and group 3 taking placebo on a daily basis. The results have shown that the supplementation of patients suffering from”
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    • cites Kouser et al. 2021

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  • The quote only partly states this claim.

    Premisecitation

    N-acetyl Cysteine (1 g twice daily for 24 weeks) significantly improved MADRS state in patients with bipolar disorder.

    “It has been reported that N-acetyl Cysteine significantly improved (based on the Montgomery Asberg Depression Rating Scale, MADRS) state of patients with bipolar disorder (Berk et al. 2008).”
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    • cites Berk et al. 2008 source

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    Premisecitation

    In patients with bipolar disorder, plasma levels of nitric oxide and nitrite are increased and correlate with disease severity.

    “Increased levels of nitric oxide and nitrite in plasma have been observed and the amount correlated well with the severity of the disease (Aydemir et al. 2014).”
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    • cites Aydemir et al. 2014 source

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    Premisecitation

    3-NT induces inflammation and may contribute to increased oxidative stress.

    “3-NT is known to induce inflammation and may contribute to increased oxidative stress (Andreazza et al. 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andreazza et al. 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Proteasomes can mildly degrade oxidized proteins, so protein oxidative damage can be considered temporary.

    “It is well known that proteasomes (complex intracellular proteases) are able to mildly degrade oxidized proteins (Dunlop et al. 2009) and therefore protein oxidative damage can be considered temporary.”
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    • cites Dunlop et al. 2009 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bipolar disorder is characterized by extreme swings in mood with emotional highs and lows.

    “Bipolar disorder (BD) or manic depression is a mental health disorder characterized by extreme swings in mood with emotional highs (mania or hypomania) and lows (depression) (Andreazza et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andreazza et al. 2008 source

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    Premisecitation

    In post-mortem hippocampus, damage to genetic material occurs in the cytoplasm of cells, affecting RNA more than DNA.

    “In a post-mortem study of the hippocampus, it was proved that damage to the genetic material in this region occurs in the cytoplasm of cells, so it affects RNA more than DNA (Palta et al. 2014).”
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    • cites Palta et al. 2014 source

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    Premisecitation

    Bipolar disorder is characterized by mutations to mtDNA and mitochondrial dysfunction caused predominantly by excess ROS.

    “Bipolar disorder is also characterized by mutations to mtDNA and mitochondrial dysfunction caused predominantly by excess ROS (Andreazza et al. 2018; Yager et al. 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Andreazza et al. 2018 source

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    • cites Yager et al. 2010 source

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    Premisecitation

    Coenzyme Q10 has been found effective in alleviating symptoms of bipolar disorder; in geriatric bipolar disorder patients, 200 mg/day improved vitality and energy.

    “Coenzyme Q10 (ubiquinone, see also above) is a substance produced naturally by the body and has been found to be effective in alleviating symptoms of bipolar disorder. In two studies, 29 patients suffering from geriatric bipolar disorder were taking a lower dose of 200 mg of coenzyme Q every day (Aiken 2018). The nutrient improved vitality and energy of patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aiken 2018

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    Premisecitation

    Chronic hyperglycemia results in suppressed activity of mTOR associated with AMPK-induced increase in ROS formation and enhanced expression of TXNIP.

    “Chronic hyperglycemia results in the suppressed activity of mTOR associated with AMP-activated protein kinase-induced increase in ROS formation and enhanced expression of thioredoxin interacting protein (TXNIP) a potential sensor of glucose and oxidative stress (Akpoveso et al. 2023).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Akpoveso et al. 2023 source

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    Premisecitation

    Vitamin E controls hyperglycemia and lowers HbA1c by suppressing oxidative stress in rats.

    “In another rat experiment, vitamin E has been shown to control hyperglycemia and lower glycated hemoglobin, and HbA1c, by suppressing the oxidative stress level (Ihara et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ihara et al. 2000 source

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  • May combine two claims.

    Interpretationcitation

    Antioxidants such as vitamins E and C, lipoic acid, and selenium have hypoglycemic effects, but supplementation of patients with these vitamins did not bring the desired effect.

    “Based on the discussed results, antioxidants such as vitamins E and C, lipoic acid, and selenium have hypoglycemic effects, however, supplementation of patients with these vitamins did not bring the desired effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rajendiran et al. 2018 source

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    Premisecitation

    Selenate is an efficient insulin-mimetic and reduces glucose level in streptozotocin-induced diabetes in laboratory animals.

    “Experimental evidence supports selenate as an efficient insulin-mimetic (Stapleton 2000). For example, selenate has been shown to reduce the glucose level in streptozotocin-induced diabetes in laboratory animals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stapleton 2000 source

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    Premisecitation

    In type 1 diabetic patients, vitamin E (1800 IU/day for 4 months) significantly increased serum vitamin E and improved HbA1c.

    “The results have shown that the serum level of vitamin E was significantly increased in both type 1 diabetic and control subjects. Glycated hemoglobin A1c (HbA1c) was improved by the vitamin E supply.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bursell et al. 1999 source

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    Premisecitation

    NOX-4 is involved in inflammation in diabetes and its deletion downregulates NF-κB signaling.

    “NOX-4 has been found to be involved in inflammation in diabetes and its deletion resulted in the downregulation of Nuclear factor-kappa B (NF-κB) signaling, an important mediator of inflammation (Jha et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jha et al. 2016 source

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  • The quote only partly states this claim.

    Premisecitation

    In patients with bipolar disorder, omega-3 fatty acids (about 10 g/day) for 4 months resulted in much longer periods of remission than placebo.

    “The results have shown that patients taking omega-3 fatty acids have much longer periods of remission than the untreated group (Stoll et al. 1999).”
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    • cites Stoll et al. 1999 source

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    Premisecitation

    In type 1 diabetic patients, retina blood flow was significantly lower than in non-diabetic subjects and significantly increased after vitamin E treatment to non-diabetic levels.

    “Retina blood flow was evaluated using fluorescein angiography and was significantly lower compared to that of non-diabetic subjects. After treatment with vitamin E retina blood flow significantly increased in the group of diabetic patients and reached the level of non-diabetic subjects.”
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    • cites Bursell et al. 1999 source

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    Premisecitation

    Oxidative stress plays a key role in organ complications of diabetes such as cardiovascular problems, stroke, diabetic retinopathy, nephropathy, and neuropathy; diabetic nephropathy is most common, affecting 28% of the diabetic population.

    “Regardless of whether excessive ROS formation is the primary initiator or accompanying factor in the pathogenesis of diabetes mellitus, oxidative stress plays a key role in the organ complications such as cardiovascular problems, neurological problems (stroke), diabetic retinopathy, nephropathy, and neuropathy; diabetic nephropathy being the most common, affecting 28% of the diabetic population (J”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jha et al. 2016 source

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    • cites Kleinschnitz et al. 2010 source

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    Premisecitation

    In non-insulin-dependent diabetic patients, vitamin C (2 g/day for 90 days) improved glycemic control, HbA1c, fasting blood glucose, cholesterol, and triglycerides.

    “Supplementation with vitamin C improved glycemic control in non-insulin-dependent diabetic patients as well as glycated hemoglobin (HA1c) and fasting blood glucose. In addition, supplementation with vitamin C improved the level of cholesterol and triglycerides showing the beneficial effect of vitamin C on glycemic control and lipids in non-insulin-dependent diabetic subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Eriksson and Kohvakka 1995 source

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    Premisecitation

    Alpha-lipoic acid scavenges ROS formed in lipid peroxidation and prevents diabetic complications such as cataract formation, polyneuropathy, and vascular damage.

    “Packer et al. reported that alpha-lipoic acid is capable of scavenging ROS formed in the course of lipid peroxidation and preventing diabetic complications such as cataract formation, polyneuropathy, and vascular damage (Packer et al. 2001).”
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    • cites Packer et al. 2001 source

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    Premisecitation

    Vitamin E significantly reduces blood glucose in diabetic rats compared to untreated, and the effect is dose-dependent.

    “It has been shown that vitamin E significantly reduced glucose levels in the blood compared to untreated rats. The beneficial effect of vitamin E on the hyperglycemic diabetic rats was found to be dose-dependent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Al Shamsi et al. 2004 source

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    Premisecitation

    HOCl is responsible for renal dysfunction among obese children, who show positive correlation between 8-iso-PGF2α and blood lipids, serum MPO, and insulin resistance.

    “HOCl has been found to be responsible for renal dysfunction among obese children. These children have shown a positive correlation between an isoprostane 8-iso-prostaglandin F2α (8-iso-PGF2α) and blood lipids, serum levels of MPO, and insulin resistance (Yu et al. 2013; Correia-Costa et al. 2016).”
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    • cites Yu et al. 2013

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    • cites Correia-Costa et al. 2016 source

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    Premisecitation

    Shorter HO-1 (GT)n alleles improve acute kidney injury and outcome after kidney transplantation in mouse models, at least partly due to increased HO-1 promoter activity.

    “Shorter HO-1 (GT)n alleles have been found to improve acute kidney injury and outcome after kidney transplantation in mouse models (Leaf et al. 2016), at least partly due to the increase in HO-1 promoter activity (Gill et al. 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Leaf et al. 2016 source

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    • cites Gill et al. 2018 source

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    Premisecitation

    Various autoantibodies against epithelial cells and against collagen have been reported in COPD patients, which increases disorder severity.

    “Various autoantibodies against epithelial cells and against collagen have been reported in COPD patients which in turn increases disorder severity (Byrne et al. 2019).”
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    • cites Byrne et al. 2019 source

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    Premisecitation

    In patients with renal lithiasis, coenzyme Q10 for 1 week significantly improved glomerular filtration and decreased albumin/creatinine ratio and β2-microglobulin levels.

    “A significant improvement in glomerular filtration and a decrease in the albumin/creatinine ratio and β2-microglobulin levels have been observed in the group taking coenzyme Q10 for 1 week.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carrasco et al. 2014 source

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    Premisecitation

    Bardoxolone methyl activates Nrf2-Keap1 pathway, inhibits NF-κB, and maintains normal kidney function.

    “Bardoxolone is known to activate the Nrf2-Keap1 pathway, which in turn inhibits the proinflammatory cytokine NF-κB and maintains normal kidney function (Pergola et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pergola et al. 2011 source

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    Premisecitation

    Crocin has antioxidant and reno-protective mechanisms by declining IL-18, Nox-4, and p53 and improving diabetic nephropathy.

    “The antioxidant and reno-protective mechanisms have been observed for the carotenoid molecule, crocin, by declining Interleukin-18 (IL-18), Nox-4, and p53 and improving diabetic nephropathy (Yaribeygi et al. 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yaribeygi et al. 2018 source

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  • May combine two claims.

    Interpretationreasoning

    In CKD patients, various endogenous and exogenous mechanisms lead to enhanced activity of oxidative enzymes XO, MPO, and NOX, resulting in mitochondrial dysfunction, eNOS uncoupling, secondary ROS, and disturbed metal metabolism.

    “In conclusion, various endogenous and exogenous pathophysiological mechanisms in patients with chronic kidney diseases lead to enhanced activity of oxidative enzymes such as xanthine oxidase (XO), myeloperoxidase (MPO), and the NADPH oxidase enzymes (NOX). Abnormally regulated homeostasis of enzymes results in mitochondrial dysfunction, eNOS uncoupling, formation of secondary ROS, and disturbed”
    Quote in the paperSubstantial claim

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    Premisecitation

    8-hydroxy-Gua is increased in the peripheral lungs of patients with COPD, confirming the occurrence of oxidative stress in the lungs.

    “A well-known biomarker of oxidative DNA damage, 8-hydroxy-Gua, is increased in the peripheral lungs of patients with COPD, confirming thus the occurrence of oxidative stress in the lungs (Caramori et al. 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Caramori et al. 2011 source

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    Premisecitation

    N-acystelyn inhibits hydrogen peroxide/superoxide radicals and increases intracellular glutathione in alveolar epithelial cells in smokers with COPD.

    “It has been reported that N-acystelyn inhibits hydrogen peroxide/superoxide radicals and increases intracellular glutathione in alveolar epithelial cells in smokers with chronic obstructive pulmonary disease (Gillissen et al. 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gillissen et al. 1997 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Other factors such as genetic predisposition, diet, silica, asbestos, high energy radiation, concentration of radon and other factors play a role in lung cancer.

    “About 85% of lung cancers are associated with smoking, however, lung cancer occurs also among non-smokers and represents the seventh most common cause of cancer mortality which indicates that other factors such as genetic predisposition, diet, silica, asbestos, high energy radiation, concentration of radon and other factors play a role.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: About 85% of lung cancers are associated with smoking.

  • May combine two claims.

    Interpretationreasoning

    Cyclic formation of ROS promotes chronic inflammation resulting in DNA damage, mutations, loss of repair, and inhibition of apoptosis, all contributing to lung cancer incidence.

    “Cyclic formation of ROS promotes chronic inflammation resulting in DNA damage, mutations, and loss of repair and inhibition of apoptosis, all contributing to lung cancer incidence.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Exogenous sources including tobacco smoke, asbestos, radon, and others increase ROS formation, which activates transcription factors NF-κB and AP-1.

    “Exogenous sources, involving tobacco smoke, asbestos, radon, and others increase ROS formation which consequently activates transcription factors NF-κB and activator protein AP-1.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Drost et al. 2005 source

      Not checked in the free run.

    • cites Federico et al. 2007 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intake of thiol or thiol-related mucolytic substances (cca. 300-600 mg twice a day) with radical scavenging/antioxidant properties reduces the incidence of respiratory exacerbations and improves the quality of life.

    “These trials suggest that intake of thiol or thiol-related mucolytic substances (cca. 300–600 mg twice a day) with radical scavenging/antioxidant properties reduces the incidence of respiratory exacerbations and improves the quality of life.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pretreatment of guinea pigs with Mn-based mimetic complex reduces both smoking-induced expression of IL-8 and activation of NF-κB.

    “Pretreatment of guinea pigs with Mn-based mimetic complex reduces both smoking-induced expression of IL-8 and activation of NF-κB (Nishikawa et al. 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nishikawa et al. 1999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A placebo-controlled trial of 124 patients with COPD receiving 300 mg of erdosteine twice a day for 8 months demonstrated improved quality of life and suppressed respiratory exacerbations.

    “A placebo-controlled trial containing 124 patients with chronic pulmonary obstructive disease received 300 mg of erdosteine twice a day for 8 months (Moretti et al. 2004). The results demonstrated improved quality of life and suppressed respiratory exacerbations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Moretti et al. 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diet supplemented with vitamin E and N-acetylcysteine resulted in increased tumor progression and suppressed survival in mouse models of KRAS and BRAF mutations in lung cancer.

    “In the work, of Sayin and his group, (Sayin et al. 2014) diet supplemented with vitamin E and N-acetylcysteine resulted in increased tumor progression and suppressed survival in mouse models of KRAS and BRAF mutations in lung cancer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sayin et al. 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gas phase tobacco contains cca 10^15 radicals, mostly short-lived carbon and oxygen-based with a lifetime <1 s.

    “Gas phase tobacco contains cca 1015 radicals, mostly shortly lived carbon and oxygen-based with a lifetime < 1 s. (Mousapasandi et al. 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mousapasandi et al. 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    N-acystelyn inhibits oxidative stress-mediated Interleukin-8 in alveolar epithelial A439 cells, confirming its anti-inflammatory effect.

    “N-acystelyn inhibits oxidative stress-mediated Interleukin-8, a chemokine produced in alveolar epithelial A439 cells, confirming thus the anti-inflammatory effect of N-acystelyn.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gillissen et al. 1997 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    If DNA damage escapes repair, permanent DNA mutations may lead to genomic instability, which is a first step to metabolic instability and suppressed synthesis of antioxidant enzymes.

    “If the damage escapes repair mechanism, permanent DNA mutations may lead to genomic instability which is a first step to metabolic instability and suppressed synthesis of antioxidant enzymes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Antioxidants have been found to interfere with signaling pathways and are able to overcome barriers against tumor progression.

    “Antioxidants have been found to interfere with signaling pathways and are able to overcome barriers against tumor progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Selenium supplementation enhances the synthesis of electrophilic cyclopentenone 15d-PGJ2, a potent Nrf2 agonist, significantly increasing the cellular antioxidant pool and anti-inflammatory properties.

    “Selenium supplementation enhances the synthesis of electrophilic cyclopentenone 15d-PGJ2, a very potent Nrf2 agonist, significantly increasing the cellular antioxidant pool and anti-inflammatory properties (Greene et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Greene et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One year of treatment with carbocisteine resulted in a decreased number of respiratory exacerbations and significantly improved quality of life.

    “Several observational studies confirmed that one year of treatment with carbocisteine resulted in a decreased number of respiratory exacerbations and significantly improved quality of life (Esposito et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Esposito et al. 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chalcones have been shown to reduce lung inflammation, but the effect on COPD is not known.

    “Chalcones have been shown to reduce lung inflammation, however, the effect on chronic pulmonary obstructive disease is not known (Lv et al. 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lv et al. 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These transcription factors are responsible for gene transcription of proinflammatory cytokines such as TNF-α and interleukins IL-8 and IL-6, which sequestrate leukocytes such as neutrophils and macrophages, forming part of an inflammatory pathway.

    “These transcription factors are responsible for the gene transcription of proinflammatory cytokines, such as tumor necrosis factor (TNF-α) and interleukins IL-8 and IL-6 which in turn sequestrate leukocytes such as neutrophils and macrophages forming thus a part of an inflammatory pathway (Drost et al. 2005; Federico et al. 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Drost et al. 2005 source

      Not checked in the free run.

    • cites Federico et al. 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Smoking and COPD are directly related and result in depleted sulfhydryls and antioxidant capacity in plasma.

    “Smoking and chronic obstructive pulmonary disease are directly related and result in depleted sulfhydryls and antioxidant capacity in plasma (Rahman 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rahman 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vitamin E and N-acetylcysteine act almost synergistically in tumor transcription profiles and enhance the proliferation of tumor cells accompanied by reduced expression of tumor suppressor protein p53 in human and mouse lung cancer cells.

    “Although vitamin E and N-acetylcysteine are structurally different molecules, interestingly, in cellular systems they act almost synergistically in tumor transcription profiles and enhance the proliferation of tumor cells accompanied by reduced expression of tumor suppressor protein p53 and other changes in human and mouse lung cancer cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sayin et al. 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations in the affinity of FOXO to DNA and modifications of transcriptional activity play a significant role in the pathology of chronic diseases such as cancer or diabetes and affect the lifespan of organisms by activation of longevity genes such as SIRT6 responsible for the synthesis of antioxidants and HSP chaperones.

    “Alterations in the affinity of FOXO to DNA and modifications of transcriptional activity play a significant role not only in the pathology of chronic diseases such as cancer or diabetes but also affect the lifespan of organisms by activation of longevity genes such as SIRT6 responsible for the synthesis of antioxidants and HSP chaperones (Merksamer et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Merksamer et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Caloric restriction explains longer lifespan by suppressed metabolic rate as a result of significantly reduced intake of food, which results in decreased rate of free radical damage.

    “Caloric restriction idea explains longer lifespan by suppressed metabolic rate as a result of significantly reduced intake of food (Heilbronn and Ravussin 2003), which in turn results in a decreased rate of free radical damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Heilbronn and Ravussin 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the cell senescence process, two main proteins, Rb and p53, are activated; their inactivation prevented senescence.

    “In the cell senescence process, two main proteins, a tumor suppressor protein and critical cell cycle regulator Retinoblastoma protein (Rb) and p53 tumor suppressor protein are activated; their inactivation prevented senescence (Kulju and Lehman 1995).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kulju and Lehman 1995 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In most studies, animal's intake of calories reduced by half of normal levels, and lifespan extended between 50 and 300%, depending on species.

    “In most of the studies animal’s intake of calories has been reduced by half of their normal levels. The results have shown that the lifespan has been extended between 50 and 300%, depending on the species (Grabski 2020; Flanagan et al. 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Grabski 2020

      Not checked in the free run.

    • cites Flanagan et al. 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 20% reduction of calories in mice diet resulted in increased expression of SIRT1, decreased levels of superoxide radical anion, and increased expression of superoxide dismutase.

    “It was also reported that a 20% reduction of calories in mice diet resulted in increased expression of SIRT1, decreased levels of superoxide radical anion, and increased expression of superoxide dismutase (Yzydorczyk et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yzydorczyk et al. 2019 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Caloric restriction may slow down the aging process and allow the organism to live longer.

    “From this follows that caloric restriction may slow down the aging process and allows the organism to live longer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Short-term caloric restriction in mice increases overexpression of telomerase reverse transcriptase (TERT), which reduces telomere erosion from various tissues such as muscles, kidney, and lungs.

    “Short-term caloric restriction in mice increases expression of all seven sirtuin (SIRT1-SIRT7) proteins (Maldonado et al. 2021) and overexpression of telomerase reverse transcriptase (TERT) which reduces telomere erosion from various tissues such as muscles, kidney, and lungs (Vera et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vera et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Significantly elevated p53 is directly associated with high ROS levels and the mechanism of apoptosis, whereas a mild increase in p53 expression is associated with cell senescence accompanied by a small increase in oxidative stress.

    “Whereas significantly elevated p53 is directly associated with high ROS levels and the mechanism of apoptosis, a mild increase in p53 expression is associated with cell senescence accompanied by a small increase in oxidative stress (Macip et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Macip et al. 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ROS-induced oxidative stress is involved in various steps of senescence signaling pathways, activating p53.

    “Based on these observations, ROS-induced oxidative stress is involved in various steps of senescence signaling pathways, activating thus p53.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sirtuins play an important role in antioxidant defense mechanisms and are known to prevent DNA damage, inflammatory reactions, and the formation of cancer cells.

    “Sirtuins play an important role in antioxidant defense mechanisms and are known to prevent DNA damage, inflammatory reactions, and the formation of cancer cells (Watroba and Szukiewicz 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Watroba and Szukiewicz 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACH1 activates transcription factors involved in triggering glycolysis, playing an important role in tumor growth promotion, metastasis, and chemoresistance in mouse and human lung cancer cells.

    “Subsequently, BACH1 activates transcription factors involved in the triggering process of glycolysis playing an important role in tumor growth promotion, metastasis, and chemoresistance in mouse and human lung cancer cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wiel et al. 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The concerted action of sirtuins stabilizes telomers and alleviates telomere-associated disorders.

    “In addition, the concerted action of sirtuins has been found to stabilize telomers and alleviate telomere-associated disorders (Amano et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Amano et al. 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cellular senescence is progressive irreversible cell cycle arrest controlled by mechanisms such as telomere shortening, oxidative stress, DNA replication stress, activation by oncogenes, and other factors.

    “Cellular senescence was observed in primary cells as progressive irreversible cell cycle arrest controlled by various mechanisms such as telomere shortening, oxidative stress, DNA replication stress, activation by oncogenes, and other factors (Devaraj et al. 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Devaraj et al. 2021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antioxidants suppress levels of free heme and stabilize transcription factor BACH1, important in heme homeostasis, maintenance of cell cycle, ROS formation, and other processes.

    “The antioxidants were responsible for suppressing levels of free heme and stabilization of transcription factor BACH1, important in heme homeostasis, maintenance of cell cycle, ROS formation, and other processes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wiel et al. 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The first line of antioxidant defense against ROS is very efficient and is predominantly represented by the intracellular antioxidant pool, consisting of antioxidant enzymes including Cu,Zn-SOD (SOD1), catalase, glutathione peroxidase (GPX), and peroxiredoxins (PRDx).

    “The first line of antioxidant defense against ROS is very efficient and is predominantly represented by the intracellular antioxidant pool, consisting of antioxidant enzymes, including Cu,Zn-SOD (SOD1), catalase, glutathione peroxidase (GPX), peroxiredoxins (PRDx).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Several transcription factors such as AP-1, NF-κB, and predominantly Nrf2 are involved in the induction of antioxidant enzymes.

    “Several transcription factors such as activator protein (AP-1), nuclear factor kappa B (NF-κB), and predominantly the nuclear factor erythroid 2–related factor 2 (Nrf2) are involved in the induction of antioxidant enzymes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The extracellular matrix of tissues contains the major extracellular antioxidant enzyme SOD (EC-SOD or SOD3).

    “The extracellular matrix of tissues contains the major extracellular antioxidant enzyme SOD (EC-SOD or SOD3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The kinetics of superoxide radical removal by SOD mimetic compounds is much less effective than by SOD enzymes.

    “However, the kinetics of superoxide radical removal by SOD mimetic compounds is much less effective than by SOD enzymes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cambinol inhibits NAD-dependent deacetylases implicated in the regulation of many biological processes including metabolic control.

    “Cambinol inhibits NAD-dependent deacetylases implicated in the regulation of many biological processes including metabolic control (Lugrin et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lugrin et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The activity of FOXO4 can be enhanced by resveratrol or inhibited by nicotinamide, an inhibitor of SIRT1.

    “The activity of FOXO4 can be enhanced by resveratrol or conversely inhibited by nicotinamide, an inhibitor of SIRT1 (Xia et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xia et al. 2013 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aging and age-related diseases have a multifactorial and multilayered origin, but one of the key factors is certainly oxidative damage.

    “Based on many published studies and some facts outlined above, it is clear that aging and age-related diseases have a multifactorial and multilayered origin (Luo et al. 2020), however, one of the key factors is certainly oxidative damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Luo et al. 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Honokiol can promote cell viability and endoplasmic reticulum stress modulation by SIRT1 expression.

    “Honokiol can promote cell viability and endoplasmic reticulum stress modulation by SIRT1 expression (Khatoon et al. 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Khatoon et al. 2022 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Extracellular antioxidant defense against ROS is also mediated by SOD mimetic compounds, capable of scavenging superoxide radicals and preventing formation of damaging peroxynitrite formed by reaction between superoxide and nitric oxide.

    “In addition to small-molecular antioxidants, extracellular antioxidant defense against ROS is also mediated by SOD mimetic compounds, capable of scavenging superoxide radicals and preventing the formation of damaging peroxynitrite, formed by the reaction between superoxide and nitric oxide.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Honokiol extends the lifespan of SOD1-G93A transgenic mice and improves their motor function and the viability of neuroblastoma/spinal cord NSC-34 hybrid cell lines and the morphology of mitochondria in SOD1-G93A cells.

    “Honokiol has been shown to extend the lifespan of SOD1-G93A transgenic mice and improve their motor function and the viability of neuroblastoma/spinal cord NSC-34 hybrid cell lines and the morphology of mitochondria in SOD1-G93A cells (Zhou et al. 2023).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhou et al. 2023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ex-527 acts as a SIRT1 and necroptosis inhibitor in animal models.

    “It has been reported that Ex-527 acts as a SIRT1 and necroptosis (an emerging mode of program cell death) inhibitor in animal models (Wang et al. 2012; Nikseresht et al. 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wang et al. 2012 source

      Not checked in the free run.

    • cites Nikseresht et al. 2019 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The structure of ergothioneine allows the chelation of redox metals which escaped from homeostasis and the upregulation of antioxidants via the Nrf2 pathway, which results in the prevention of the aging process.

    “The structure of ergothioneine allows the chelation of redox metals which escaped from homeostasis and the upregulation of antioxidants via the Nrf2 pathway which in turn results in the prevention of the aging process.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sirtuins play a central role in platelet aging, and inhibition of sirtuins restricts platelet life span and management of thrombosis.

    “In the study of anticancer properties of sirtuin inhibitors, it has been found, that sirtuins play a central role in platelet aging. This suggests that the process of sirtuins inhibition involves the restriction of platelet life span and management of thrombosis (Kumari et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kumari et al. 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of the ergothioneine transporter in C. elegans reduces their lifespan and increases their susceptibility to ROS-induced damage.

    “The knockdown of the ergothioneine transporter in C. elegans (a transparent 1 mm long nematode model organism) reduces their lifespan and increases their susceptibility to ROS-induced damage (Cheah et al. 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cheah et al. 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Cancer cells produce a high amount of ROS and therefore have to cope with enhanced oxidative stress.

    “For example, cancer cells produce a high amount of ROS and therefore they have to cope with enhanced oxidative stress.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The rate constants of ROS removal by low molecular weight antioxidants within cells are negligible compared to the scavenging activity of intracellular enzymes.

    “The rate constants of ROS removal by low molecular weight antioxidants within the cells are negligible compared to the scavenging activity of intracellular enzymes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ergothioneine is highly abundant in mushrooms and their consumption positively influences cognitive impairment in elderly people, confirming the importance of ergothioneine in healthy aging.

    “Ergothioneine (see also above) is highly abundant in mushrooms and their consumption has been found to positively influence cognitive impairment in elderly people, confirming the importance of ergothioneine in healthy aging (Feng et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Feng et al. 2019 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ergothioneine activates the mTOR pathway, which may activate neurotrophic factor signaling, the regulator of neuronal differentiation.

    “Contrary to these studies, it has been reported that ergothioneine activates the mTOR pathway which in turn may activate neurotrophic factor signaling, the regulator of neuronal differentiation (Ishimoto et al. 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ishimoto et al. 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Glutathione reductase (GR) in the presence of NADPH restores reduced glutathione (GSH) from its oxidized GSSG form.

    “In addition, glutathione reductase (GR) in the presence of NADPH restores reduced glutathione (GSH) from its oxidized GSSG form.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The second line of antioxidant defense involves the synthesis of a thioredoxin redox system in which reduced thioredoxin (TRX) catalyzes reduction of disulfides and is itself oxidized and subsequently reduced by thioredoxin reductase at the expense of NADPH.

    “The second line of antioxidant defense involves the synthesis of a thioredoxin redox system in which reduced thioredoxin (TRX) catalyzes the reduction of disulfides (–S–S–) and is itself oxidized and subsequently reduced by thioredoxin reductase at the expense of NADPH.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Organisms have evolved a complex and sophisticated system of defense against oxidative stress.

    “Organisms have evolved a complex and sophisticated system of defense against oxidative stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Resveratrol inhibits retrotransposition of Long Interspersed Nuclear Element-1 (LINE-1), comprising cca 17% of the human genome, which is related to SIRT6 and SIRT7.

    “Resveratrol has been found to inhibit retrotransposition of Long Interspersed Nuclear Element-1 (LINE-1), comprising cca 17% of the human genome (Lander et al. 2001), which in turn is related to SIRT6 and SIRT7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lander et al. 2001 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Ergothioneine is an agent suppressing the level of oxidative stress, modulating gene expression, and interfering with signal pathways, promoting longevity.

    “Taken together, ergothioneine is an agent suppressing the level of oxidative stress, modulating gene expression, and interfering with signal pathways, promoting thus longevity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Oxidative stress is responsible for disturbed signalling pathways, which in turn affect apoptosis induction, mitochondrial function, protein modification, and other mechanisms.

    “Oxidative stress is responsible for disturbed signalling pathways which in turn affects, for example, molecular mechanisms of apoptosis induction, impairment of mitochondrial function, protein modification, and other mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The defense system both boosts the capacity to detoxify oxidants and repairs oxidative damage.

    “The defense system not only boosts the capacity to detoxify oxidants but also repairs oxidative damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oxidative stress is a double-edged sword for living systems: it is important for physiological signaling mediated by physiological concentrations of ROS (from ~10^-12 M to ~10^-6 M), termed oxidative eustress, while it can be responsible for oxidative damage to biomolecules, termed oxidative distress, mediated by increased ROS concentration (>10^-6 M).

    “However, oxidative stress is a “double edge sword” for living systems, as it is important for physiological signaling mediated by physiological concentrations of ROS (from ~ 10−12 M to ~ 10−6 M), termed “oxidative eustress”, while it can be responsible for oxidative damage to biomolecules, a process termed “oxidative (di)stress”, mediated by increased ROS concentration (> 10−6 M) (Murphy et al. 2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Murphy et al. 2022

      Not checked in the free run.

    • cites Azzi 2022 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These compounds appear to be effective in extracellular space, where the concentration of antioxidant enzymes is usually much lower than in the intracellular environment.

    “These compounds appear to be effective in extracellular space, where the concentration of antioxidant enzymes is usually much lower than in the intracellular environment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    NRF2 signaling can be activated by flavonoids and antioxidants contained in tea, vegetables, and fruit extracts.

    “NRF2 signaling can be activated by flavonoids and antioxidants contained in tea, vegetables, and fruit extracts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The antioxidant status of an organism can be enhanced by NRF2 activators, which appear to represent a promising therapeutic approach.

    “The antioxidant status of an organism can be enhanced by the NRF2 activators which appear to represent a promising therapeutic approach.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Salen-based organic compounds possessing hydrogen peroxide scavenging activity have been prepared and tested as glutathione peroxidase mimetics.

    “In addition to SOD-mimetic compounds, Salen-based organic compounds, possessing hydrogen peroxide scavenging activity have been prepared and tested as Glutathione peroxidase mimetics.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The antioxidant network in living systems also includes low-molecular-weight antioxidants derived from the diet, probably the most important being vitamins C and E, carotenoids, and flavonoids (polyphenols).

    “The mosaic of the antioxidant network in living systems also includes low-molecular-weight antioxidants derived from the diet, probably the most important being vitamins C and E, carotenoids, and flavonoids (polyphenols).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    These compounds may show a lower degree of specificity and reduce other ROS/RNS species.

    “However, these compounds may show a lower degree of specificity and reduce other ROS/RNS species.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Metal-based SOD and SOD-catalase mimetic compounds are frequently studied, and several are currently undergoing clinical trials.

    “Frequently studied are metal-based SOD and SOD-catalase mimetic compounds of which several are currently undergoing clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Ergothioneine appears to be a promising antioxidant.

    “A promising antioxidant appears to be ergothioneine, however, double-blind placebo-controlled trials have to be conducted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    NRF2 activators are not restricted to a specific organ or tissue and therefore may exhibit various side effects and disruption of physiological mechanisms.

    “NRF2 activators are not restricted to a specific organ or tissue and therefore may exhibit various side effects and disruption of physiological mechanisms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Proteins are one of the most abundant biomolecules and are a frequent target of ROS attacks.

    “Proteins are one of the most abundant biomolecules and are a frequent target of ROS attacks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Activation of NRF2 results predominantly in the induction of antioxidant enzymes.

    “Activation of NRF2 results predominantly in the induction of antioxidant enzymes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Because redox metal manganese may exist in several oxidation states, attention has focused on Mn-cyclic polyamines, Mn-salen complexes, and Mn- and Fe-based metalloporphyrins.

    “Since redox metal manganese may exist in several oxidation states, attention has been focused on Mn-cyclic polyamines, Mn-salen complexes, and Mn- and Fe-based metalloporphyrins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Many NRF2 activators are Lewis acids capable of accepting electron pairs and/or donating protons.

    “Many of these activators are Lewis acids capable of accepting electron pairs and/or donating protons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Use of certain antioxidants (e.g., flavonoids) showing weak prooxidant properties may boost cellular antioxidant systems, involving antioxidant enzymes and synthesis of glutathione, and thus act as preventive anticancer agents.

    “Paradoxically promising appears to be the use of certain antioxidants (e.g. flavonoids) showing weak prooxidant properties, that may boost cellular antioxidant systems, involving antioxidant enzymes and synthesis of glutathione and thus act as preventive anticancer agents.”
    Quote in the paperSubstantial claim
297 of 297

  • The paper relies on this without support.

    Many chronic diseases are multifactorial in origin.

    “Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator.”

  • The paper relies on this without support.

    ROS are important players in cellular proliferation, differentiation, migration, apoptosis, and necrosis.

    “ROS are important players in cellular proliferation, differentiation, migration, apoptosis, and necrosis.”

  • The paper relies on this without support.

    Low to intermediate levels of ROS and RNS are necessary for the maintenance of many important physiological functions, redox homeostasis, and the regulation of key transcription factors.

    “Low to intermediate levels of ROS and RNS are necessary for the maintenance of many important physiological functions, redox homeostasis, and the regulation of key transcription factors.”

  • The paper relies on this without support.

    The level of oxidative stress, quantified by oxidative stress markers, is elevated in aging individuals or people with bad lifestyles, taking unhealthy food, smoking, drinking alcohol, lack of physical exercise, and genetic predisposition.

    “The level of oxidative stress, quantified by the oxidative stress markers, has been found elevated in aging individuals or people with bad lifestyles, taking unhealthy food, smoking, drinking alcohol, lack of physical exercise, and genetic predisposition.”

  • The paper relies on this without support.

    Superoxide does not react with DNA directly.

    “Since superoxide does not react with DNA directly, in the context of DNA damage is of important dismutation reaction of superoxide radical2”

  • The paper relies on this without support.

    Hydrogen peroxide plays an important role in growth factor-induced signal transduction, maintenance of thiol redox homeostasis, and mitochondrial functioning.

    “Hydrogen peroxide plays an important role in growth factor-induced signal transduction, maintenance of thiol redox homeostasis, and mitochondrial functioning.”

  • The paper relies on this without support.

    Peroxynitrite is a very powerful oxidant capable of causing damage to biomolecules including proteins and DNA.

    “Peroxynitrite is a very powerful oxidant capable of causing damage to biomolecules including proteins and DNA.”

  • The paper relies on this without support.

    Several chronic diseases and aging are characterized by oxidative stress as a common denominator.

    “In the next sections, we will discuss several chronic diseases and aging characterized by oxidative stress as a common denominator.”

  • The paper relies on this without support.

    Oxidative stress, cellular senescence, and SASP are involved in the incidence of chronic diseases involving cardiovascular diseases, cancer, metabolic, renal, lung, and neurological disorders, and other diseases.

    “Oxidative stress, cellular senescence, and SASP are involved in the incidence of chronic diseases involving cardiovascular diseases, cancer, metabolic, renal, lung, and neurological disorders (Alzheimer’s and Parkinson’s disease), and other diseases.”

  • The paper relies on this without support.

    ROS are known to interfere with various components of SASP.

    “ROS are known to interfere with various components of SASP.”

  • The paper relies on this without support.

    Hyperhomocysteinemia occurs approximately in about 5% of the population, and among patients with cardiovascular diseases this condition occurs in up to 45% of patients.

    “This condition occurs approximately in about 5% of the population, however, among patients with cardiovascular diseases this condition occurs in up to 45% of patients and represents a serious risk of heart attack, endothelial dysfunction, arterial diseases, extracranial carotid artery disease, a common cause of the transient ischemic attack, termed also “mini-stroke”.”

  • The paper relies on this without support.

    Hyperactivation of ERK plays an important role in cancer progression.

    “Hyperactivation of ERK plays an important role in cancer progression.”

  • The paper relies on this without support.

    Cancer cells produce significantly higher amounts of ROS than normal cells.

    “Cancer cells produce significantly higher amounts of ROS than normal cells”

  • The paper relies on this without support.

    The onset of PD is associated with severely decreased levels of reduced glutathione (GSH) in the substantia nigra.

    “The onset of PD is associated with severely decreased levels of reduced glutathione (GSH) in the substantia nigra.”

  • The paper relies on this without support.

    GSH depletion precedes the dysfunction of mitochondrial complex I and lowered dopamine levels.

    “GSH depletion has been confirmed to precede the dysfunction of mitochondrial complex I and lowered dopamine levels.”

  • The paper relies on this without support.

    Dopamine transport, utilization, and storage may be involved in increased ROS formation followed by cellular dysfunction.

    “Dopamine transport, utilization, and storage may be involved in increased ROS formation followed by cellular dysfunction.”

  • The paper relies on this without support.

    Calcium is an essential metal involved in the pathogenesis of PD.

    “Calcium is another essential metal involved in the pathogenesis of PD.”

  • The paper relies on this without support.

    The most important genes associated with familial PD involve α-synuclein, DJ-1, Parkin, PINK-1, and others.

    “The most important genes associated with familial PD involve α-synuclein (discussed above), DJ-1, Parkin, PINK-1, and others.”

  • The paper relies on this without support.

    Vitamin D supplementation did not improve symptoms in bipolar disorder patients with low levels of vitamin D.

    “Surprisingly, supplementation of patients with vitamin D did not improve the symptoms of bipolar disorder patients with low levels of vitamin D.”

  • The paper relies on this without support.

    Oxidative stress is a common denominator of kidney diseases and associated complications such as cardiovascular diseases and inflammation.

    “In fact, oxidative stress is a common denominator of kidney diseases and associated complications such as cardiovascular diseases and inflammation.”

  • The paper relies on this without support.

    About 85% of lung cancers are associated with smoking.

    “About 85% of lung cancers are associated with smoking, however, lung cancer occurs also among non-smokers and represents the seventh most common cause of cancer mortality which indicates that other factors such as genetic predisposition, diet, silica, asbestos, high energy radiation, concentration of radon and other factors play a role.”
21 of 21

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Chalcones and quinones are known for their redox properties, which neutralize free radicals and reduce oxidative stress.

    “These compounds are known for their redox properties, which neutralize free radicals and reduce oxidative stress [48,49,50].”

    From Comparative Analysis of Infusions and Ethanolic Extracts of Annona muricata Leaves from Colima, Mexico: Phytochemical Profile and Antioxidant Activity (2024) · cites this paper as [49]

    The Lung cancer section identifies chalcones as compounds tested for Nrf2 activation, a pathway that enhances antioxidant synthesis. It does not say chalcones directly neutralize free radicals through redox properties, and searches for quinones found no passage supporting that part of the claim. The Chemistry of low molecular weight antioxidants section describes radical scavenging by flavonoids generally, not by both named compound classes. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Singlet species is called a radical despite having no unpaired electrons

    Minor

    The paper defines a free radical as having at least one unpaired electron, but later calls a species with no unpaired electrons a "Singlet radical."

  • Ex-527 is described as both inhibiting and increasing SIRT1 activity

    Minor

    The paper calls Ex-527 a potent SIRT1 inhibitor, but also attributes its protective effect to an increase in SIRT1 activity without explaining how the two claims fit together.

  • 3-NT is given two different meanings

    Minor

    The paper first identifies 3-NT as 3-nitrotyrosine, then calls it "3 neurotrophic factor" in the bipolar-disorder section.

3 of 3

Cites

1 retracted

Flagged first, then by citations

3 of the 675 references couldn’t be matched to a known paper.

Research works printed but not linked: 11

  1. Aiken CA (2018) Common antioxidant shows promise in bipolar depression. Psychiatr times 35:20
  2. Bandyopadhyay U, Das D, Banerjee RK (1999) Reactive oxygen species: oxidative damage and pathogenesis. Curr Sci 77(5):658–666
  3. Bernardo VS (2021) Ergotionein as a therapeutic alternative: antioxidant and/or modulating effects on K562 erythroleukemic cells [Master thesis, Universidade Estadual Paulista]. UNESP Institutional Repository, M.Sc. Thesis. https://hdl.handle.net/11449/204323. Accessed 7 Aug 2023
  4. Kouser S, Kausar S, Khan S, Ghani M, Yousef N (2021) Role of antioxidants in the management of Schizophrenia: a randomized control trail. J Appl Mech Eng 10(3):1–4
  5. Krishnamurthy P, Wadhwani A (2012) Antioxidant enzymes and human health. Antioxidant enzyme. InTech
  6. Mandal A, Hossain U, Sil PC (2022) Antioxidants and cardiovascular diseases. In: Nabavi SM, Silva A (eds) Antioxidants in health, the bright and dark side, 1st edn. Elsevier, pp 613–640
  7. O-Uchi J, Jhun BS, Mishra J, Sheu SS (2018) Organellar ion channels and transporters in cardiac electrophysiology: from cell to bedside, 7th edn. Elsevier, pp 66–69
  8. Rahman I, Biswas SK (2006). In: Laurent GJ, Shapiro SD (eds) Oxidants and antioxidants, encyclopedia of respiratory medicine, 2006 258–266. Elsevier
  9. Sies H (1985) Oxidative stress: introductory remarks. In: Sies H (ed) Oxidative stress. Academic Press, London, pp 1–8
  10. Wang L, Azad N, Kongkaneramit L, Chen F, Lu Y, Jiang BH, Rojanasakul Y (2012) The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation. J Immunol 180(5):3072–3080. https://doi.org/10.4049/jimmunol.180.5.3072 · DOI · Paper page
  11. WHO (2001) Biomarkers in risk assessment: validity and validation. WHO, Geneva

Cited by

Sorted by citations

Related

Authors
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M.
Affiliations
King Saud University (SA)
ORCID
Venue
Archives of Toxicology
Publisher
Springer Science and Business Media LLC
Published
2023-08-19
Volume
97
Issue
10
Pages
2499-2574
ISSN
  • 0340-5761 (ISSN-L)
  • 1432-0738
DOI
10.1007/s00204-023-03562-9
PMC
PMC10475008
OpenAlex
W4385999933
Semantic Scholar
abdd2f05f5822aeb73759a0339f5fc5d803f1f57
Cited by
2,638
References
675
Citations by year
2026: 852 · 2025: 1193 · 2024: 559 · 2023: 33
FWCI
52.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Archives of Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • DSFP contract
  • Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR (1/0482/20)
  • Czech Ministry of Health (NV19-09-00578)
  • Slovak Technical University
Topics
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
Keywords
reactive oxygen species, reactive nitrogen species, oxidative stress, antioxidants, chronic disease, aging, oxidative damage, oxidative stress biomarkers, superoxide, hydrogen peroxide, hydroxyl radicals, peroxynitrite, nitric oxide, lipid peroxidation, DNA damage, protein oxidation, antioxidant enzymes, superoxide dismutase, catalase, glutathione peroxidase, vitamin E, flavonoids, melatonin, ergothioneine, sirtuins
MeSH terms
Antioxidants, Chronic Disease, Humans, Reactive Oxygen Species, Oxidative Stress

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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