Longevity Wiki

Oxidative Stress

oxidative stress.png

Oxidative stress is a critical factor in the aging process and is believed to contribute significantly to the deterioration of physiological functions over time. This concept has been supported by extensive research and studies over the years.

Reactive Oxygen Species (ROS)

Oxidative stress is characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify these reactive intermediates or to repair the resulting damage.[1] ROS are highly reactive molecules, including free radicals like superoxide radicals (O2-), hydroxyl radicals (OH.), and non-radical species such as hydrogen peroxides (H2O2).[2]

Reactive oxygen species (ROS) are primarily produced by the mitochondria during normal metabolic processes, with the electron transport chain being a significant source.[3] The production of ROS is a complex process involving the reduction of oxygen molecules, leading to a cascade of other ROS.

Additionally, ROS are produced through various physiological and pathological processes, including cellular respiration and inflammatory responses.[4] Their generation and subsequent conversion involve enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, which play crucial roles in controlling oxidative stress.

The Oxidative Stress Theory of Aging

The oxidative stress theory of aging posits that the gradual accumulation of oxidative damage to biomolecules is a primary driver of the aging process. This damage increases with age and correlates with a decline in life expectancy in various organisms.[10.1016/S1566-2772(03)00007-0] Oxidative damage affects multiple aspects of aging and is a key factor in many age-related diseases. Particularly, telomeres are highly susceptible to oxidative damage, which can lead to accelerated aging and increased risk of age-related diseases.[5][6][7]

Controversy and Complexity in Oxidative Stress Research

While there is substantial evidence linking oxidative damage to aging, the direct relationship between oxidative stress and aging is not conclusively established.[8] ROS have complex roles in the body, contributing to cellular homeostasis at physiological levels but causing damage when in excess.[1] This dual role is embodied in the concept of mitohormesis, where low levels of ROS can be beneficial.

Impact of Oxidative Stress on Biomolecules

Oxidative stress can lead to damage in various biomolecules:

  • Lipids: Polyunsaturated fatty acids (PUFAs) are particularly vulnerable to lipid peroxidation, affecting membrane fluidity and leading to cell apoptosis.[9][10]
  • Proteins: Oxidation of proteins can alter their structure and function, affecting enzyme activity and signal transduction.[11][12][13][14][15]
  • Nucleic Acids: ROS, especially hydroxyl radicals, can cause oxidative damage to DNA, leading to mutations, strand breaks, and DNA-protein cross-linking, contributing to genome instability and cell death.[3][16][17][18][19][20]

Antioxidants

Main article: Antioxidants

Antioxidants are compounds that can prevent or slow down the oxidation of other molecules. Oxidation is a chemical reaction that can produce free radicals, leading to chain reactions that may damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates and inhibiting other oxidation reactions. They do this by being oxidized themselves, making them crucial in the body's defense against oxidative stress.

Antioxidative Stress

Antioxidative stress is the fundamental opposite is oxidative stress. It is an overabundance of bioavailable antioxidant compounds that interfere with the immune system's ability to neutralize pathogenic threats.

Antioxidant compounds reduce reactive oxygen species (ROS), which reduces emitted free-radicals. When ROS function is impaired, there is more susceptibility to atopic disorders or diseases due to impairment of the attack-kill-present-respond behavior of the Th-1 immune response chain. Over-consumption of antioxidants could thus lead to antioxidative stress, where antioxidants might weaken or block the adaptive stress responses and cause dangerous health conditions and cause harm.[21]

The concept of antioxidative stress may best be described by excessive or detrimental nutritional consumption of a diet rich in antioxidants,[22] unbalancing the immune systems' pathogenic response processes. Serious health conditions can result if these processes are chronically unbalanced, ranging from acute to chronic. Immunological stress by over-supplementation of antioxidants facilitates adverse health effects specifically including allergies, asthma, and physiological alterations (especially of the skin).

Many foods contain antioxidant content, while numerous dietary supplements are exceptionally rich in antioxidants.[23] Products marketed with health benefits routinely tout antioxidant content as a beneficial product aspect without consideration of overall dietary oxidative balances.[24] This is generally due to the biological effects of antioxidants being misunderstood in popular culture, focusing only on their beneficial qualities to reduce ROS to prevent excessive free-radicals which may otherwise lead to well-known disease conditions.

Conclusion

In summary, oxidative stress is a multifaceted factor in aging, with a significant impact on various biomolecules, leading to physiological decline and increased risk of age-related diseases. Understanding and mitigating oxidative stress remains a key area in longevity research.

Further Reading

  • 2018, Oxidative stress, aging, and diseases [25]
  • 2022, Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives [26]

See Also

Todo

Todo

References

  1. ↑ 1.0 1.1 Sies H et al.: Oxidative Stress. Annu Rev Biochem 2017. (PMID 28441057) [PubMed] [DOI] Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level of oxidant challenge, termed oxidative eustress, is essential for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which redox signaling integrates these converse properties. Redox balance is maintained by prevention, interception, and repair, and concomitantly the regulatory potential of molecular thiol-driven master switches such as Nrf2/Keap1 or NF-κB/IκB is used for system-wide oxidative stress response. Nonradical species such as hydrogen peroxide (H2O2) or singlet molecular oxygen, rather than free-radical species, perform major second messenger functions. Chemokine-controlled NADPH oxidases and metabolically controlled mitochondrial sources of H2O2 as well as glutathione- and thioredoxin-related pathways, with powerful enzymatic back-up systems, are responsible for fine-tuning physiological redox signaling. This makes for a rich research field spanning from biochemistry and cell biology into nutritional sciences, environmental medicine, and molecular knowledge-based redox medicine.
  2. ↑ Liochev SI: Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 2013. (PMID 23434764) [PubMed] [DOI] The traditional view in the field of free radical biology is that free radicals and reactive oxygen species (ROS) are toxic, mostly owing to direct damage of sensitive and biologically significant targets, and are thus a major cause of oxidative stress; that complex enzymatic and nonenzymatic systems act in concert to counteract this toxicity; and that a major protective role is played by the phenomenon of adaptation. Another part of the traditional view is that the process of aging is at least partly due to accumulated damage done by these harmful species. However, recent workers in this and in related fields are exploring the view that superoxide radical and reactive oxygen species exert beneficial effects. Thus, such ROS are viewed as involved in cellular regulation by acting as (redox) signals, and their harmful effects are seen mostly as a result of compromised signaling, rather than due to direct damage to sensitive targets. According to some followers of this view, ROS such as hydrogen peroxide and superoxide are not just causative agents of aging but may also be agents that increase the life span by acting, for example, as prosurvival signals. The goal of this review is to recall that many of the effects of ROS that are interpreted as beneficial may actually represent adaptations to toxicity and that some of the most extravagant recent claims may be due to misinterpretation, oversimplification, and ignoring the wealth of knowledge supporting the traditional view. Whether it is time to abandon the free radical (oxidative stress) theory of aging is considered.
  3. ↑ 3.0 3.1 Luo J et al.: Ageing, age-related diseases and oxidative stress: What to do next?. Ageing Res Rev 2020. (PMID 31733333) [PubMed] [DOI] Among other mechanisms, oxidative stress has been postulated to play an important role in the rate of ageing. Oxidative damage contributes to the hallmarks of ageing and essential components in pathological pathways which are thought to drive multiple age-related diseases. Nonetheless, results from studies testing the hypothesis of oxidative stress in ageing and diseases showed controversial results. While observational studies mainly found detrimental effects of high oxidative stress levels on disease status, randomized clinical trials examining the effect of antioxidant supplementation on disease status generally showed null effects. However, re-evaluations of these counterinitiative observations are required considering the lack of reliability and specificity of traditionally used biomarkers for measuring oxidative stress. To facilitate these re-evaluations, this review summarizes the basic knowledge of oxidative stress and the present findings regarding the role of oxidative damage in ageing and age-related diseases. Meanwhile, two approaches are highlighted, namely proper participants selection, together with the development of reliable biomarkers. We propose that oxidized vitamin E metabolites may be used to accurately monitor individual functional antioxidant level, which might serve as promising key solutions for future elucidating the impact of oxidative stress on ageing and age-related diseases.
  4. ↑ Al-Gubory KH et al.: Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress. Reprod Biomed Online 2012. (PMID 23063822) [PubMed] [DOI] Progesterone produced by the corpus luteum (CL) regulates the synthesis of various endometrial proteins required for embryonic implantation and development. Compromised CL progesterone production is a potential risk factor for prenatal development. Reactive oxygen species (ROS) play diverse roles in mammalian reproductive biology. ROS-induced oxidative damage and subsequent adverse developmental outcomes constitute important issues in reproductive medicine. The CL is considered to be highly exposed to locally produced ROS due to its high blood vasculature and steroidogenic activity. ROS-induced apoptotic cell death is involved in the mechanisms of CL regression that occurs at the end of the non-fertile cycle. Luteal ROS production and propagation depend upon several regulating factors, including luteal antioxidants, steroid hormones and cytokines, and their crosstalk. However, it is unknown which of these factors have the greatest contribution to the maintenance of CL integrity and function during the oestrous/menstrual cycle. There is evidence to suggest that antioxidants play important roles in CL rescue from luteolysis when pregnancy ensues. As luteal phase defect impacts fertility by preventing implantation and early conceptus development in livestock and humans, this review attempts to address the importance of ROS-scavenging antioxidant enzymes in the control of mammalian CL function and integrity. The corpus luteum (CL) is a transient endocrine organ that develops after ovulation from the ovulated follicle during each reproductive cycle. The main function of the CL is the production and secretion of progesterone which is necessary for embryonic implantation and development. Compromised CL progesterone production is a potential risk factor for prenatal development and pregnancy outcomes. Reactive oxygen species (ROS), which are natural by-products of cellular respiration and metabolism, play diverse roles in mammalian reproductive biology. ROS-induced oxidative damage and subsequent development of adverse pregnancy outcomes constitute important issues in reproductive medicine. Before the end of the first trimester, a high rate of human and animal conceptions end in spontaneous abortion and most of these losses occur at the time of implantation in association with ROS-induced oxidative damage. Every cell in the body is normally able to defend itself against the oxidative damage caused by the ROS. The cellular antioxidant enzymes constitute the first line of defence against the toxic effects of ROS. The CL is considered to be highly exposed to locally produced ROS due to its high blood vasculature and metabolic activity. There is now evidence to suggest that cellular antioxidants play important roles in CL rescue from regression when pregnancy ensues. As defective CL function impacts fertility by preventing implantation and early conceptus development in livestock and humans, this review attempts to address the importance of antioxidant enzymes in the control of mammalian CL function and integrity.
  5. ↑ von Zglinicki T: Role of oxidative stress in telomere length regulation and replicative senescence. Ann N Y Acad Sci 2000. (PMID 10911951) [PubMed] [DOI] Replicative senescence is tied into organismal aging processes in more than one respect, and telomeres appear to be the major trigger of replicative senescence under many conditions in vitro and in vivo. However, the structure-function relationships in telomeres, the mechanisms of telomere shortening with advancing replicative age, and the regulation of senescence by telomeres are far from understood. Combining recent data on telomere structure, function of telomere-binding proteins, and sensitivity of telomeres to oxidative damage, an integrative model of telomere shortening and signaling is developed. The model suggests that t-loop formation hinders access of repair proteins to telomeres, leading to accumulation of a basic sites and single-strand breaks. These might contribute to accelerated telomere shortening by transient stalling of replication as well as, if present in high concentrations, to a relief of torsional tension which might destabilize the telomeric loop structure. As a result, the single-stranded G-rich overhang, which is present at the very ends of telomeres but is normally protected at the base of the telomeric loop, will be exposed to the nucleoplasm. Free G-rich telomeric single strands are a strong inductor of the p53 pathway, and exposure of the overhangs seems to be the first step in the signal transduction cascade to replicative senescence.
  6. ↑ von Zglinicki T: Oxidative stress shortens telomeres. Trends Biochem Sci 2002. (PMID 12114022) [PubMed] [DOI] Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
  7. ↑ Blackburn EH et al.: Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015. (PMID 26785477) [PubMed] [DOI] Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.
  8. ↑ Sohal RS et al.: Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 2002. (PMID 12208343) [PubMed] [DOI] The main purpose of this article is to provide a critical overview of the currently available evidence bearing on the validity of the oxidative stress hypothesis of aging, which postulates that senescence-associated attenuations in physiological functions are caused by molecular oxidative damage. Several lines of correlative evidence support the predictions of the hypothesis, e.g., macromolecular oxidative damage increases with age and tends to be associated with life expectancy of organisms. Nevertheless, a direct link between oxidative stress and aging has not as yet been established. Single gene mutations have been reported to extend the life spans of lower organisms, such as nematodes and insects; however, such prolongations of chronological clock time survival are usually associated with decreases in the rate of metabolism and reproductive output without affecting the metabolic potential, i.e., the total amount of energy consumed during life. Studies on genetic manipulations of the aging process have often been conducted on relatively short-lived strains that are physiologically weak, whereby life-span extensions can not be unambiguously assigned to a slowing effect on the rate of aging. It is concluded that although there is considerable evidence implicating oxidative stress in the aging process, additional evidence is needed to clearly define the nature of the involvement.
  9. ↑ Yin H et al.: Free radical lipid peroxidation: mechanisms and analysis. Chem Rev 2011. (PMID 21861450) [PubMed] [DOI]
  10. ↑ Sousa BC et al.: Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds. Free Radic Biol Med 2017. (PMID 28192230) [PubMed] [DOI] The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually α,β-unsaturated), γ-substituted alkenals and bis-aldehydes. Isolevuglandins are non-fragmented di-carbonyl compounds derived from H2-isoprostanes, and oxidation of the ω-3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate α-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the α,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule. However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research.
  11. ↑ Berlett BS & Stadtman ER: Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 1997. (PMID 9252331) [PubMed] [DOI]
  12. ↑ Davies MJ: Protein oxidation and peroxidation. Biochem J 2016. (PMID 27026395) [PubMed] [DOI] [Full text] Proteins are major targets for radicals and two-electron oxidants in biological systems due to their abundance and high rate constants for reaction. With highly reactive radicals damage occurs at multiple side-chain and backbone sites. Less reactive species show greater selectivity with regard to the residues targeted and their spatial location. Modification can result in increased side-chain hydrophilicity, side-chain and backbone fragmentation, aggregation via covalent cross-linking or hydrophobic interactions, protein unfolding and altered conformation, altered interactions with biological partners and modified turnover. In the presence of O2, high yields of peroxyl radicals and peroxides (protein peroxidation) are formed; the latter account for up to 70% of the initial oxidant flux. Protein peroxides can oxidize both proteins and other targets. One-electron reduction results in additional radicals and chain reactions with alcohols and carbonyls as major products; the latter are commonly used markers of protein damage. Direct oxidation of cysteine (and less commonly) methionine residues is a major reaction; this is typically faster than with H2O2, and results in altered protein activity and function. Unlike H2O2, which is rapidly removed by protective enzymes, protein peroxides are only slowly removed, and catabolism is a major fate. Although turnover of modified proteins by proteasomal and lysosomal enzymes, and other proteases (e.g. mitochondrial Lon), can be efficient, protein hydroperoxides inhibit these pathways and this may contribute to the accumulation of modified proteins in cells. Available evidence supports an association between protein oxidation and multiple human pathologies, but whether this link is causal remains to be established.
  13. ↑ Stadtman ER: Protein oxidation and aging. Free Radic Res 2006. (PMID 17090414) [PubMed] [DOI] Organisms are constantly exposed to various forms of reactive oxygen species (ROS) that lead to oxidation of proteins, nucleic acids, and lipids. Protein oxidation can involve cleavage of the polypeptide chain, modification of amino acid side chains, and conversion of the protein to derivatives that are highly sensitive to proteolytic degradation. Unlike other types of modification (except cysteine oxidation), oxidation of methionine residues to methionine sulfoxide is reversible; thus, cyclic oxidation and reduction of methionine residues leads to consumption of ROS and thereby increases the resistance of proteins to oxidation. The importance of protein oxidation in aging is supported by the observation that levels of oxidized proteins increase with animal age. The age-related accumulation of oxidized proteins may reflect age-related increases in rates of ROS generation, decreases in antioxidant activities, or losses in the capacity to degrade oxidized proteins.
  14. ↑ Davies KJ: Protein oxidation and proteolytic degradation. General aspects and relationship to cataract formation. Adv Exp Med Biol 1990. (PMID 2244532) [PubMed] [DOI] 1) Intracellular proteins are subject to oxidative and photooxidative denaturation. 2) Proteolytic systems recognize and selectively degrade oxidatively denatured, and photooxidatively denatured proteins. By degrading mildly denatured proteins these proteolytic systems prevent further oxidative/photooxidative damage which could otherwise result in the formation of cross-linked (undigestible) proteins, or protein fragments with toxic biological activities. Proteolytic systems also provide amino acids for the synthesis of new (replacement) proteins. 3) A 700,000 dalton neutral endoproteinase, which we have called macroxyproteinase or M.O.P., appears to be mostly responsible for the degradation of oxidatively denatured proteins. M.O.P. has been shown to function in red blood cells and in the eye lens, and appears to also exist in many other mammalian cell types. 4) Cataract is a disease associated with aging, and with photooxidative denaturation (and cross-linking) of lens crystallins and other proteins. 5) Both cataract and aging of lens cells are associated with declining proteolytic capacity and diminished antioxidant protection. 6) Lens aging and in vivo photooxidative stress can cause opacity ("cataract"), cross-linking of crystallins, and diminished proteolytic capacity. 7) High levels of dietary ascorbate increase ascorbate concentrations in lens tissue, and are associated with greater resistance of lens proteins and lens proteolytic enzymes to oxidative/photooxidative stress in vitro.
  15. ↑ Höhn A et al.: Pathophysiological importance of aggregated damaged proteins. Free Radic Biol Med 2014. (PMID 24632383) [PubMed] [DOI] Reactive oxygen species (ROS) are formed continuously in the organism even under physiological conditions. If the level of ROS in cells exceeds the cellular defense capacity, components such as RNA/DNA, lipids, and proteins are damaged and modified, thus affecting the functionality of organelles as well. Proteins are especially prominent targets of various modifications such as oxidation, glycation, or conjugation with products of lipid peroxidation, leading to the alteration of their biological function, nonspecific interactions, and the production of high-molecular-weight protein aggregates. To ensure the maintenance of cellular functions, two proteolytic systems are responsible for the removal of oxidized and modified proteins, especially the proteasome and organelles, mainly the autophagy-lysosomal systems. Furthermore, increased protein oxidation and oxidation-dependent impairment of proteolytic systems lead to an accumulation of oxidized proteins and finally to the formation of nondegradable protein aggregates. Accordingly, the cellular homeostasis cannot be maintained and the cellular metabolism is negatively affected. Here we address the current knowledge of protein aggregation during oxidative stress, aging, and disease.
  16. ↑ Grollman AP & Moriya M: Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet 1993. (PMID 8379000) [PubMed] [DOI] The presence of reactive oxygen species in cells ensures that the oxidatively damaged base 8-oxoguanine will be generated at high frequency in the DNA of all living organisms. DNA damage threatens genomic integrity: enzymes have evolved that protect prokaryotes and eukaryotes from the mutagenic effect of this ubiquitous lesion.
  17. ↑ Dehennaut V et al.: DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair. J Biol Chem 2013. (PMID 23417673) [PubMed] [DOI] [Full text] HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene frequently epigenetically silenced in human cancers. HIC1 encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that HIC1 can be either acetylated or SUMOylated on lysine 314. This deacetylation/SUMOylation switch is governed by an unusual complex made up of SIRT1 and HDAC4 which deacetylates and thereby favors SUMOylation of HIC1 by a mechanism not yet fully deciphered. This switch regulates the interaction of HIC1 with MTA1, a component of the NuRD complex and potentiates the repressor activity of HIC1. Here, we show that HIC1 silencing in human fibroblasts impacts the repair of DNA double-strand breaks whereas ectopic expression of wild-type HIC1, but not of nonsumoylatable mutants, leads to a reduced number of γH2AX foci induced by etoposide treatment. In this way, we demonstrate that DNA damage leads to (i) an enhanced HDAC4/Ubc9 interaction, (ii) the activation of SIRT1 by SUMOylation (Lys-734), and (iii) the SUMO-dependent recruitment of HDAC4 by SIRT1 which permits the deacetylation/SUMOylation switch of HIC1. Finally, we show that this increase of HIC1 SUMOylation favors the HIC1/MTA1 interaction, thus demonstrating that HIC1 regulates DNA repair in a SUMO-dependent way. Therefore, epigenetic HIC1 inactivation, which is an early step in tumorigenesis, could contribute to the accumulation of DNA mutations through impaired DNA repair and thus favor tumorigenesis.
  18. ↑ Johnson PA et al.: The mitotic spindle and DNA damage-induced apoptosis. Toxicol Lett 2000. (PMID 10720713) [PubMed] [DOI] EM9 Chinese hamster ovary cells cannot rejoin DNA strand breaks induced by alkylating agents. Ethyl methanesulphonate (EMS)-treated EM9cells underwent G2 arrest for a prolonged period followed by entry into mitosis and apoptosis. EM9 cells treated with EMS in G1 entered mitosis 24-36 h after release from synchrony, approximately 12 h after untreated control cells, but the mitoses were morphologically abnormal. The spindle-poison nocodazole reduced apoptosis by greater than 60%, and allowed some cells to complete a second round of DNA replication. We conclude that the assembly of a mitotic spindle, or progression beyond the mitotic checkpoint, is important for apoptosis following DNA strand breakage.
  19. ↑ Yan T et al.: DNA mismatch repair (MMR) mediates 6-thioguanine genotoxicity by introducing single-strand breaks to signal a G2-M arrest in MMR-proficient RKO cells. Clin Cancer Res 2003. (PMID 12796402) [PubMed] PURPOSE: The DNA mismatch repair (MMR) system plays an important role in mediating cell death after treatment with various types of chemotherapeutic agents, although the molecular mechanisms are not well understood. In this study, we sought to determine what signal is introduced by MMR after 6-thioguanine (6-TG) treatment to signal a G(2)-M arrest leading to cell death. EXPERIMENTAL DESIGN: A comparison study was carried out using an isogenic MMR(+) and MMR(-) human colorectal cancer RKO cell system, which we established for this study. Cells were exposed to 6-TG (3 micro M x 24 h) and then harvested daily for the next 3-6 days for growth inhibition assays. Cell cycle effects were determined by flow cytometry, and DNA strand breaks were measured using pulsed-field gel electrophoresis and alkaline Comet assays. RESULTS: We first established MMR(+) RKO cell lines by transfection of human MutL homologue 1 (hMLH1) cDNA into the hMLH1-deficient (MMR(-)) RKO cell line. The ectopically expressed hMLH1 protein restored a MMR-proficient phenotype in the hMLH1(+) transfectants, showing a significantly increased and prolonged G(2)-M arrest followed by cell death after 6-TG exposure, compared with the vector controls. The MMR-mediated, 6-TG-induced G(2)-M arrest started on day 1, peaked on day 3, and persisted to day 6 after 6-TG removal. We found that DNA double-strand breaks were comparably produced in both our MMR(+) and MMR(-) cells, peaking within 1 day of 6-TG treatment. In contrast, single-strand breaks (SSBs) were more frequent and longer lived in MMR(+) cells, and the duration of SSB formation was temporally correlated with the time course of 6-TG-induced G(2)-M arrest. CONCLUSIONS: Our data suggest that MMR mediates 6-TG-induced G(2)-M arrest by introducing SSBs to signal a persistent G(2)-M arrest leading to enhanced cell death.
  20. ↑ Dizdaroglu M et al.: Structure of a hydroxyl radical induced DNA-protein cross-link involving thymine and tyrosine in nucleohistone. Biochemistry 1989. (PMID 2545260) [PubMed] [DOI] Hydroxyl radical induced formation of a DNA-protein cross-link involving thymine and tyrosine in nucleohistone is described. Hydroxyl radicals were generated in N2O-saturated aqueous solution by ionizing radiation. Samples of nucleohistone were hydrolyzed with HCl and trimethylsilylated. Analysis of irradiated samples by gas chromatography-mass spectrometry with selected-ion monitoring showed the presence of a thymine-tyrosine cross-link on the basis of typical fragment ions from the previously known mass spectrum of its trimethylsilyl derivative. The yield of this DNA-protein cross-link in nucleohistone was measured at incrementing doses of radiation and found to be a linear function of radiation dose between 14 and 300 Gy (J.kg-1). This yield amounted to 0.003 mumol.J-1. The mechanism of formation of this DNA-protein cross-link is thought to result from H atom abstraction by hydroxyl radicals from the methyl group of thymine followed by the addition of the resultant thymine radical to the carbon 3 position of the tyrosine ring and subsequent oxidation of the adduct radical.
  21. ↑ Poljsak et al.; "The Neglected Significance of "Antioxidative Stress"" , https://doi.org/10.1155/2012/480895
  22. ↑ Katharina Schroecksnadel et al.; "Antioxidants Suppress Th1-Type Immune Response In Vitro" , https://www.researchgate.net/publication/24266258 , https://doi.org/10.2174/187231207781369816
  23. ↑ Carlsen et al.; "The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide" , https://doi.org/10.1186/1475-2891-9-3
  24. ↑ Template:Cite news
  25. ↑ Liguori I et al.: Oxidative stress, aging, and diseases. Clin Interv Aging 2018. (PMID 29731617) [PubMed] [DOI] [Full text] Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.
  26. ↑ Hajam YA et al.: Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives. Cells 2022. (PMID 35159361) [PubMed] [DOI] [Full text] Reactive oxygen and nitrogen species (RONS) are generated through various endogenous and exogenous processes; however, they are neutralized by enzymatic and non-enzymatic antioxidants. An imbalance between the generation and neutralization of oxidants results in the progression to oxidative stress (OS), which in turn gives rise to various diseases, disorders and aging. The characteristics of aging include the progressive loss of function in tissues and organs. The theory of aging explains that age-related functional losses are due to accumulation of reactive oxygen species (ROS), their subsequent damages and tissue deformities. Moreover, the diseases and disorders caused by OS include cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases and cancer. OS, induced by ROS, is neutralized by different enzymatic and non-enzymatic antioxidants and prevents cells, tissues and organs from damage. However, prolonged OS decreases the content of antioxidant status of cells by reducing the activities of reductants and antioxidative enzymes and gives rise to different pathological conditions. Therefore, the aim of the present review is to discuss the mechanism of ROS-induced OS signaling and their age-associated complications mediated through their toxic manifestations in order to devise effective preventive and curative natural therapeutic remedies.
Retrieved from "https://www.longewiki.com/w139/index.php?title=Oxidative_Stress&oldid=2975"