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Sources of reactive oxygen species (ROS) in the electron transport chain. During mitochondrial respiration partial reduction reactions occur, mainly from complexes I and III that cause the accumulation of superoxide and hydrogen peroxide mainly in the mitochondrial matrix.
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Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox enviro...
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... a recent review on the subject, see [18]. During mitochondrial respiration some "leakiness", or partial reduction reactions occur, mainly from complexes I and III even under physiologic conditions (Figure 2). This leakiness causes the release of superoxide and hydrogen peroxide mostly to the mitochondrial matrix [19,20]. ...
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... fact, it has been estimated that superoxide concentration is five-to ten-fold higher in the matrix than that in the cytosol [21]. Figure 2. Sources of reactive oxygen species (ROS) in the electron transport chain. ...
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... a recent review on the subject, see [18]. During mitochondrial respiration some "leakiness", or partial reduction reactions occur, mainly from complexes I and III even under physiologic conditions (Figure 2). This leakiness causes the release of superoxide and hydrogen peroxide mostly to the mitochondrial matrix [19,20]. ...
Citations
... One crucial mechanism by which mitochondria contribute to aging is through reactive oxygen species (ROS) production. When the balance between ROS production and neutralization is disrupted, oxidative stress occurs, leading to premature aging and tissue damage [62,63]. Mitochondrial dysfunction is involved in cellular aging and atherogenesis [64] and is associated with the development of numerous diseases, including CVDs [18,65,66]. ...
MicroRNAs (miRNAs) are small non-coding RNAs that play an important role by controlling gene expression in the cytoplasm in almost all biological pathways. Recently, scientists discovered that miRNAs are also found within mitochondria, the energy-producing organelles of cells. These mitochondrial miRNAs, known as mitomiRs, can originate from the nuclear or mitochondrial genome, and they are pivotal in controlling mitochondrial function and metabolism. New insights indicate that mitomiRs may influence key aspects of the onset and progression of cardiovascular disease, especially concerning mitochondrial function and metabolic regulation. While the importance of mitochondria in cardiovascular health and disease is well-established, our understanding of mitomiRs’ specific functions in crucial biological pathways, including energy metabolism, oxidative stress, inflammation, and cell death, is still in its early stages. Through this review, we aimed to delve into the mechanisms of mitomiR generation and their impacts on mitochondrial metabolic pathways within the context of vascular cell aging and atherosclerotic cardiovascular disease. The relatively unexplored field of mitomiR biology holds promise for future research investigations, with the potential to yield novel diagnostic tools and therapeutic interventions.
... S-Lactoylglutathione is a metabolite that is formed through the reaction between lactate and glutathione. Glutathione (gammaglutamyl-cysteinyl-glycine) is an antioxidative molecule that plays a key role in protecting against oxidative stress (Marí et al., 2020). This metabolite can be found in a wide variety of food sources, including fruits, vegetables, cereals, legumes, and nuts. ...
Diet plays an essential role in health and disease. Therefore, its determination is an important component of many investigations. The aim of the study was to evaluate the effect of a nutritional intervention on the urinary metabolome in children aged 6–12 years. Also, it was intended to identify biomarkers of diet quality and dietary intake. A 2‐month, randomized, controlled, parallel trial was conducted in Spanish children. The analyses focused on the ALINFA group, which followed a full‐fixed meal plan including healthy products, ready‐to‐eat meals, and healthy recipes. Diet quality was assessed by the KIDMED index and dietary intake by a food frequency questionnaire. Untargeted metabolomic analysis on urine samples was carried out, and multivariate analyses were performed for pattern recognition and characteristic metabolite identification. PLS‐DA and Volcano plot analyses were performed to identify the discriminating metabolites of this group. 12 putative metabolites were found to be the most relevant to this intervention. Most of them were products derived from protein and amino acid metabolism (N‐Ribosylhistidine, indolacrylic acid, and peptides) and lipid metabolism (3‐oxo‐2‐pentylcyclopentane‐1‐hexanoic acid methyl, Suberoyl‐L‐carnitine, and 7‐Dehydrodichapetalin E). All these metabolites decreased after the intervention, which was mainly associated with a decrease in the consumption of fatty meat and total fat, especially saturated fat. In turn, N‐Ribosylhistidine and Suberoyl‐L‐carnitine were negatively associated with diet quality, as well as able to predict the change in KIDMED index. In conclusion, the changes observed in urinary metabolome demonstrate the effectiveness of the ALINFA nutritional intervention.
... In addition, we observed a lower antioxidant capacity of the mitochondria, particularly in reduced glutathione, in AC iHLCs compared to H iHLCs. Recently mitochondrial glutathione was shown to have a major role in disease pathogenesis 47 . A dysfunctional downstream electron transport chain leads to increased production of superoxide 48 . ...
Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.
... Significant amounts of ROS can be generated by increased CYP activity; these ROS are typically neutralized or broken down by enzymatic and non-enzymatic antioxidant defense mechanisms (Altenburger et al., 2003;Santana et al., 2018). The most significant non-enzymatic defense against ROS is GSH (Marí et al., 2020). The GSH functions as a scavenger by forming glutathione disulfide (GSSG) through reactions with specific ROS and radicals (Santana et al., 2018). ...
... The production of reactive oxygen species (ROS) and the depletion of glutathion (GSH) are interconnected events that influence various signal transduction pathways reg ulating cell survival. Elevated ROS levels, coupled with decreased intracellular GSH con tent, contribute to mitochondrial dysfunction [50,51]. To elucidate the defense mechanism of the peptide against H2O2-induced cell injury in HepG2 cells, we assessed intracellula ROS and GSH levels using DCFH-DA and CMFDA, respectively. ...
... The production of reactive oxygen species (ROS) and the depletion of glutathione (GSH) are interconnected events that influence various signal transduction pathways regulating cell survival. Elevated ROS levels, coupled with decreased intracellular GSH content, contribute to mitochondrial dysfunction [50,51]. To elucidate the defense mechanism of the peptide against H 2 O 2 -induced cell injury in HepG2 cells, we assessed intracellular ROS and GSH levels using DCFH-DA and CMFDA, respectively. ...
Reactive oxygen species (ROS) are implicated in various pathological conditions due to their ability to induce oxidative damage to cellular components. In this study, we investigated the antioxidant properties of a peptide isolated from the hydrolysate of Manila clam (Ruditapes philippinarum) muscle. Purification steps yielded RPTE2-2-4, exhibiting potent scavenging activities against DPPH•, HO•, and O2•−, akin to Vitamin C. Structural analysis showed that the isolated peptide, LFKKNLLTL, exhibited characteristics associated with antioxidant activity, including a short peptide length and the presence of aromatic and hydrophobic amino acid residues. Moreover, our study demonstrated the cytoprotective effects of the peptide against H2O2-induced oxidative stress in HepG2 cells. Pretreatment with the peptide resulted in a dose-dependent reduction in intracellular ROS levels and elevation of glutathione (GSH) levels, indicating its ability to modulate cellular defense mechanisms against oxidative damage. Furthermore, the peptide stimulated the expression of the cytoprotective enzyme heme oxygenase-1 (HO-1), further reinforcing its antioxidant properties. Overall, our findings highlight the potential of the Manila clam-derived peptide as a natural antioxidant agent with therapeutic implications for oxidative stress-related diseases. Further investigation into its mechanisms of action and in vivo efficacy is warranted to validate its therapeutic potential.
... Glutathione (GSH) (γ-L-glutamyl-L-cysteinyl-glycine) is a tripeptide synthesized in the cytosol by two ATP-consuming enzymatic reactions 580 . GSH reaches millimolar levels (1-10 mM) within cells, micromolar levels (10-30 μM) in plasma, and its low redox potential (E ′ 0 = − 240 mV) makes GSH an ideal cellular redox buffer 581,582 . GSH is commonly found in reduced GSSG form in cytosol, nucleus, mitochondria, and endoplasmic reticulum 583 . ...
... Low GSH levels could also increase viral replication, pro-inflammatory cytokine release, endothelial damage, and immune-thrombosis, which is a hyper-coagulative clinical condition that could exacerbate morbidity and mortality in COVID-19 and PASC 598 . Since m-Dys and OxS jointly contribute to both COVID-19 and PASC pathology, nutritional to replenish optimal GSH levels could be a promising strategy to reset HMRD and support patient recovery 582 . ...
... Administration of antioxidant enzymes could be considered an effective nutritional strategy to resolve OxS and reset Fe-RH in COVID-19 and PASC. Since m-Dys and OxS jointly contribute to both COVID-19 and PASC pathology, nutritional reset of virus-induced HMRD with NAC, glutamine, GSH, and antioxidant enzymes (i.e., SOD, catalase) could potentially resolve OxS and persistent pulmonary fibrotic sequelae in PASC patients 582 . Bioactive nutrients such as flavan-3-ols that activate Nrf2 could also reduce chronic OxS, help restore activity of viral-hijacked serine proteases and reset HMRD in PASC patients. ...
SARS‐CoV‐2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is criticalfor the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. Thissingle-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates aplethora of virus–host protein–protein interactions in the human body. These extensive viral proteininteractions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well asaltered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectiousprocess, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases,TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL)for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectiousoutcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acuteCOVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii)hyperferritinemia (‘cytokine storm’), and (iii) thrombocytosis (coagulopathy). The mean incubation period forCOVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The meanviral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients,respectively. However, about 25–70% of virus-free COVID-19 survivors continue to sustain virus-inducedHMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new ‘onset’ clinicalincidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patientsexperience several debilitating clinical condition(s) with >200 different and overlapping symptoms that maylast for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-relatedpathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innatehost responses. Based on HMRD and virus-free clinical impairments of different human organs/systems,PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%)with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxietydisorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4(10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viralhijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage tomultiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. Wehave also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precisionnutrients to reset HMRD for health recovery of PASC patients.
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... Glutathione (GSH) is a tripeptide composed of cysteine, glutamic acid, and glycine [13]. It is a naturally occurring antioxidant found in various dietary sources, such as spinach, avocados, asparagus, and okra. ...
... Glutathione is an antioxidant peptide naturally formed in the liver [13]. It has important functions in the liver since this organ is particularly susceptible to ROS [23]. ...
Glutathione (GSH) has long been recognised for its antioxidant and detoxifying effects on the liver. The hepatoprotective effect of GSH involves the activation of antioxidative systems such as NRF2; however, details of the mechanisms remain limited. A comparative analysis of the biological events regulated by GSH under physiological and oxidative stress conditions has also not been reported. In this study, DNA microarray analysis was performed with four experiment arms including Control, GSH, hydrogen peroxide (HP), and GSH + HP treatment groups. The GSH-treated group exhibited a significant upregulation of genes clustered in cell proliferation, growth, and differentiation , particularly those related to MAPK, when compared with the Control group. Additionally, liver functions such as alcohol and cholesterol metabolic processes were significantly upregulated. On the other hand, in the HP-induced oxidative stress condition, GSH (GSH + HP group) demonstrated a significant activation of cell proliferation, cell cycle, and various signalling pathways (including TGFβ, MAPK, PI3K/AKT, and HIF-1) in comparison to the HP group. Furthermore, several disease-related pathways, such as chemical carcinogenesis-reactive oxygen species and fibrosis, were significantly downregulated in the GSH + HP group compared to the HP group. Collectively, our study provides a comprehensive analysis of the effects of GSH under both physiological and oxidative stress conditions. Our study provides essential insights to direct the utilisation of GSH as a supplement in the management of conditions associated with oxidative stress.
... However, when this balance is disturbed, and ROS production becomes excessive, it can overwhelm cellular antioxidant defenses. This imbalance leads to oxidative stress, which can precipitate premature aging and damage to tissues and organs (Chiang et al., 2020;Marí et al., 2020;Sreedhar et al., 2020;Zhou et al., 2021). Intriguing research by Zhu et al. (2022) has revealed that interleukin-13 (IL-13) treatment may prompt cellular aging in submandibular gland-C6 cells. ...
Aging is a natural aspect of mammalian life. Although cellular mortality is inevitable, various diseases can hasten the aging process, resulting in abnormal or premature senescence. As cells age, they experience distinctive morphological and biochemical shifts, compromising their functions. Research has illuminated that cellular senescence coincides with significant alterations in the microRNA (miRNA) expression profile. Notably, a subset of aging-associated miRNAs, originally encoded by nuclear DNA, relocate to mitochondria, manifesting a mitochondria-specific presence. Additionally, mitochondria themselves house miRNAs encoded by mitochondrial DNA (mtDNA). These mitochondria-residing miRNAs, collectively referred to as mitochondrial miRNAs (mitomiRs), have been shown to influence mtDNA transcription and protein synthesis, thereby impacting mitochondrial functionality and cellular behavior. Recent studies suggest that mitomiRs serve as critical sensors for cellular senescence, exerting control over mitochondrial homeostasis and influencing metabolic reprogramming, redox equilibrium, apoptosis, mitophagy, and calcium homeostasis-all processes intimately connected to senescence. This review synthesizes current findings on mitomiRs, their mitochondrial targets, and functions, while also exploring their involvement in cellular aging. Our goal is to shed light on the potential molecular mechanisms by which mitomiRs contribute to the aging process.
... Надмірне утворення АФК, як наслідок запальних процесів, призводить до окисного стресу, який є ключовим фактором у формуванні хронічних захворювань кишечника, підвищений рівень GSSG у тканинах корелює з важкістю запалення слизової оболонки. Водночас значне зниження GSH виявляють у пацієнтів з хворобою Крона, в слизовій оболонці товстої кишки за умов виразкового коліту, при інфаркті міокарда, ревматоїдному артриті, розсіяному склерозі та цукровому діабеті [2,41,64,67]. ...
... Глутатіон можна розглядати як потенційний засіб для профілактики й патогенетичного лікування діабетичної полінейропатії. З'явилися дані про участь GSSG у регуляції сну та виникненні нейро-та міопатій у людей із вродженими порушеннями синтезу глутатіону [4,40,41]. Дедалі ширше вивчають нейротропні ефекти трипептиду, активно досліджують та обговорюють гіпотезу щодо використання глутатіону як доповнення до антипухлинної терапії. У контексті лікування злоякісних новоутворень повноцінне функціонування системи глу-татіону є життєво необхідним для підтримання окисновідновного гомеостазу нормальних клітин організму, доведено [26,42,48] численні взаємозв'язки глутатіонової системи з розвитком і прогресуванням злоякісних новоутворень, але чимало ефектів глутатіону на метаболічні шляхи організму ще потребують детального вивчення. ...
... Щоб мінімізувати наслідки, система GSH виконує захисну функціюглутатіонування протеїнів. Це забезпечує "окисно-відновний буфер GSH", який регулює процеси транскрипції, трансляції, відповідає за стабільність хроматину, рівень протеїнів у ядрі, а отже, реплікацію та відновлення ДНК [35,37,41]. ...
Annotation. Under the conditions of entry of toxic substances into the body and activation of redox processes, compounds of natural origin with antioxidant properties are widely used to correct metabolic disorders. The purpose of the work is to conduct an analysis and systematization of basic and modern scientific sources of literature on the role of the glutathione system in the development of pathologies. For the scientific review, data from the scientometric databases PubMed, ScienceDirect, Web of Science, Google Scholar, etc. were used, and the analysis of scientific textbooks and monographs was carried out. Among water-soluble antioxidants, low- and high-molecular compounds containing SH-groups are popular in medicine, mono-, di- and tricarboxylic acids and other anions. Glutathione, a thiol-containing tripeptide, is the main endogenous non-enzymatic antioxidant that exerts cytoprotective and detoxifying properties. Various epithelial cells – enterocytes, endotheliocytes, alveolar cells of the lungs, epithelium of the proximal renal tubules, absorb and use glutathione most intensively, in particular, taken orally, so the idea of using glutathione in diseases of organs that actively participate in detoxification processes: kidneys, liver, lungs, as well as under the conditions of systemic diseases accompanied by endothelial dysfunction and oxidative stress – diabetes, atherosclerosis, nephropathy. Under physiological conditions, the body maintains a dynamic balance between the content of oxidants, which stimulate the processes of free radical oxidation of biomolecules, and the activity of antioxidant systems. But under the conditions of damage to any link of the living system, increased formation of reactive oxygen species (ROS) and inhibition of antioxidant systems contributes to the activation of free radical oxidation processes, the intensity of which depends on the concentration of oxygen in the tissues and on the enzymatic and non-enzymatic systems of antioxidant protection, which prevents the destruction of cells by active forms of oxygen.
... The evaluation of the effects of glyphosate-based herbicides (GBH) on organisms can be performed by quantifying antioxidant system enzymes, which are considered biomarkers of cellular defense (Demirci-Çekiç et al. 2022). Some of these enzymes rely on reduced glutathione (GSH), a molecule that acts, reducing other oxidizing molecules and playing a critical role in eliminating toxic substances for cells (Marí et al. 2020). Glutathione s-transferase (GST) utilizes GSH as a substrate to detoxify cells and assist in the reduction or elimination of xenobiotics. ...
Brazil is an important global agricultural producer and to increase production the country has extensively used glyphosate-based herbicides (GBH), surpassing consumption and sales records. Consequently, concerns have arisen regarding the potential impact of GBH on ecosystems and non-target organisms. Thus, the effects of GBH exposure were evaluated throughout the cricket Gryllus ( Gryllus ) assimilis ontogeny, with five developmental stages. Each period contained 3 control and 3 treated boxes, with 15 crickets each, resulting in 90 insects at a time. The control groups received water, while the treated ones were continuously exposed to GBH (0.864 mg.GBH.L-1), with the solutions changed every 48 hours. After each exposure time the crickets’ group were euthanized to assess the activity of antioxidant enzymes (GST, GR, GPx, and CAT), cholinergic enzymes (ChE), and lipid peroxidation (LPO). The results revealed changes in the systems throughout different developmental phases. Specifically, CAT activity exhibited a significant increase during the nymphal phase, associated with the dismutation of hydrogen peroxide. The GST increased GBH, indicating its role in cellular detoxification, particularly during adulthood. In the senescence stage there was a considerable rise in ChE enzymes, suggesting their involvement in both, choline esters breakdown and potential pesticide detoxification. The action of these enzymes to effectively control lipid peroxidation shows the adaptability of this species to environmental contamination. These findings underscore the long-term effects of agrochemical pollution and emphasize the importance of sustainable practices, effective regulations, and alternative weed control methods.
