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Arugula is susceptible to postharvest deterioration. We tested the impact of exogenous antioxidant (i.e., ergothioneine and glutathione) dip solutions on arugula quality during storage at 4 °C or 10 °C for up to 17 days relative to a non-antioxidant treatment. Leaves from each dip treatment and storage temperature were assessed for visual quality and endogenous antioxidant metabolite profiles. Overall, leaf discolouration, wilting, and decay were more rapid at 10 °C than at 4 °C. Both antioxidant treatments limited leaf discolouration at 4 °C. Exogenous ergothioneine reduced wilting at 4 °C, whereas exogenous glutathione limited the incidence of leaf decay. At 10 °C, glutathione reduced the incidence of discolouration and decay, whereas both antioxidant dip treatments limited the decline in leaf yellowing. Ergothioneine was solely detected in ergothioneine-treated leaves; a decrease occurred within the first two days of storage but was unchanged thereafter. Although both antioxidant treatments did not affect endogenous glutathione concentrations at either storage temperature, glutathione disulfide was stable within the glutathione-treated leaves, whereas it increased in the other treatments. Ascorbate degradation was delayed in ergothioneine-treated leaves at 4 °C relative to all other treatments, whereas both antioxidant treatments little affected ascorbate metabolism in leaves stored at 10 °C. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) induce oxidative stress in cells and are associated with various diseases, including autoimmune diseases. Ergothioneine (EGT) is a natural amino acid derivative derived from the ergot fungus and has been reported to exhibit an effective antioxidant function in many models of oxidative stress-related diseases. Recently, mutations in OCTN1, a membrane transporter of EGT, have been reported to be associated with rheumatoid arthritis. Therefore, we investigated the chondrocyte-protective function of EGT using a model of oxidative stress-induced injury of chondrocytes by hydrogen peroxide (H2O2). Human chondrocytes were subjected to oxidative stress induced by H2O2 treatment, and cell viability, the activity of lactate dehydrogenase (LDH) released into the medium, dead cell ratio, intracellular ROS production, and mitochondrial morphology were assessed. EGT improved chondrocyte viability and LDH activity in the medium and strongly suppressed the dead cell ratio. EGT also exerted protective effects on intracellular ROS production and mitochondrial morphology. These results provide evidence to support the protective effects of EGT on chondrocytes induced by oxidative stress. [ABSTRACT FROM AUTHOR]

Oxidative stress can damage tissues and cells, and their resilience or susceptibility depends on the robustness of their antioxidant mechanisms. The latter include small molecules, proteins, and enzymes, which are linked together in metabolic pathways. Red blood cells are particularly susceptible to oxidative stress due to their large number of hemoglobin molecules, which can undergo auto-oxidation. This yields reactive oxygen species that participate in Fenton chemistry, ultimately damaging their membranes and cytosolic constituents. Fortunately, red blood cells contain robust antioxidant systems to enable them to circulate and perform their physiological functions, particularly delivering oxygen and removing carbon dioxide. Nonetheless, if red blood cells have insufficient antioxidant reserves (e.g., due to genetics, diet, disease, or toxin exposure), this can induce hemolysis in vivo or enhance susceptibility to a "storage lesion" in vitro, when blood donations are refrigerator-stored for transfusion purposes. Ergothioneine, a small molecule not synthesized by mammals, is obtained only through the diet. It is absorbed from the gut and enters cells using a highly specific transporter (i.e., SLC22A4). Certain cells and tissues, particularly red blood cells, contain high ergothioneine levels. Although no deficiency-related disease has been identified, evidence suggests ergothioneine may be a beneficial "nutraceutical." Given the requirements of red blood cells to resist oxidative stress and their high ergothioneine content, this review discusses ergothioneine's potential importance in protecting these cells and identifies knowledge gaps regarding its relevance in enhancing red blood cell circulatory, storage, and transfusion quality. [ABSTRACT FROM AUTHOR]

Cell death involving oxidative stress and mitochondrial dysfunction is a major cause of dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's disease patients. Ergothioneine (ET), a natural dietary compound, has been shown to have cytoprotective functions, but neuroprotective actions against PD have not been well established. 6-Hydroxydopamine (6-OHDA) is a widely used neurotoxin to simulate the degeneration of dopaminergic (DA) neurons in Parkinson's disease. In this study, we investigated the protective effect of ET on 6-OHDA treated iPSC-derived dopaminergic neurons (iDAs) and further confirmed the protective effects in 6-OHDA-treated human neuroblastoma SH-SY5Y cells. In 6-OHDA-treated cells, decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mROS), reduced cellular ATP levels, and increased total protein carbonylation levels were observed. 6-OHDA treatment also significantly decreased tyrosine hydroxylase levels. These effects were significantly decreased when ET was present. Verapamil hydrochloride (VHCL), a non-specific inhibitor of the ET transporter OCTN1 abrogated ET's cytoprotective effects, indicative of an intracellular action. These results suggest that ET could be a potential therapeutic for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Arugula is susceptible to postharvest deterioration. We tested the impact of exogenous antioxidant (i.e., ergothioneine and glutathione) dip solutions on arugula quality during storage at 4 °C or 10 °C for up to 17 days relative to a non-antioxidant treatment. Leaves from each dip treatment and storage temperature were assessed for visual quality and endogenous antioxidant metabolite profiles. Overall, leaf discolouration, wilting, and decay were more rapid at 10 °C than at 4 °C. Both antioxidant treatments limited leaf discolouration at 4 °C. Exogenous ergothioneine reduced wilting at 4 °C, whereas exogenous glutathione limited the incidence of leaf decay. At 10 °C, glutathione reduced the incidence of discolouration and decay, whereas both antioxidant dip treatments limited the decline in leaf yellowing. Ergothioneine was solely detected in ergothioneine-treated leaves; a decrease occurred within the first two days of storage but was unchanged thereafter. Although both antioxidant treatments did not affect endogenous glutathione concentrations at either storage temperature, glutathione disulfide was stable within the glutathione-treated leaves, whereas it increased in the other treatments. Ascorbate degradation was delayed in ergothioneine-treated leaves at 4 °C relative to all other treatments, whereas both antioxidant treatments little affected ascorbate metabolism in leaves stored at 10 °C.

Reactive oxygen species (ROS) induce oxidative stress in cells and are associated with various diseases, including autoimmune diseases. Ergothioneine (EGT) is a natural amino acid derivative derived from the ergot fungus and has been reported to exhibit an effective antioxidant function in many models of oxidative stress-related diseases. Recently, mutations in OCTN1, a membrane transporter of EGT, have been reported to be associated with rheumatoid arthritis. Therefore, we investigated the chondrocyte-protective function of EGT using a model of oxidative stress-induced injury of chondrocytes by hydrogen peroxide (H2O2). Human chondrocytes were subjected to oxidative stress induced by H2O2 treatment, and cell viability, the activity of lactate dehydrogenase (LDH) released into the medium, dead cell ratio, intracellular ROS production, and mitochondrial morphology were assessed. EGT improved chondrocyte viability and LDH activity in the medium and strongly suppressed the dead cell ratio. EGT also exerted protective effects on intracellular ROS production and mitochondrial morphology. These results provide evidence to support the protective effects of EGT on chondrocytes induced by oxidative stress.

Cell death involving oxidative stress and mitochondrial dysfunction is a major cause of dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson’s disease patients. Ergothioneine (ET), a natural dietary compound, has been shown to have cytoprotective functions, but neuroprotective actions against PD have not been well established. 6-Hydroxydopamine (6-OHDA) is a widely used neurotoxin to simulate the degeneration of dopaminergic (DA) neurons in Parkinson’s disease. In this study, we investigated the protective effect of ET on 6-OHDA treated iPSC-derived dopaminergic neurons (iDAs) and further confirmed the protective effects in 6-OHDA-treated human neuroblastoma SH-SY5Y cells. In 6-OHDA-treated cells, decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial reactive oxygen species (mROS), reduced cellular ATP levels, and increased total protein carbonylation levels were observed. 6-OHDA treatment also significantly decreased tyrosine hydroxylase levels. These effects were significantly decreased when ET was present. Verapamil hydrochloride (VHCL), a non-specific inhibitor of the ET transporter OCTN1 abrogated ET’s cytoprotective effects, indicative of an intracellular action. These results suggest that ET could be a potential therapeutic for Parkinson’s disease.

Oxidative stress can damage tissues and cells, and their resilience or susceptibility depends on the robustness of their antioxidant mechanisms. The latter include small molecules, proteins, and enzymes, which are linked together in metabolic pathways. Red blood cells are particularly susceptible to oxidative stress due to their large number of hemoglobin molecules, which can undergo auto-oxidation. This yields reactive oxygen species that participate in Fenton chemistry, ultimately damaging their membranes and cytosolic constituents. Fortunately, red blood cells contain robust antioxidant systems to enable them to circulate and perform their physiological functions, particularly delivering oxygen and removing carbon dioxide. Nonetheless, if red blood cells have insufficient antioxidant reserves (e.g., due to genetics, diet, disease, or toxin exposure), this can induce hemolysis in vivo or enhance susceptibility to a “storage lesion” in vitro, when blood donations are refrigerator-stored for transfusion purposes. Ergothioneine, a small molecule not synthesized by mammals, is obtained only through the diet. It is absorbed from the gut and enters cells using a highly specific transporter (i.e., SLC22A4). Certain cells and tissues, particularly red blood cells, contain high ergothioneine levels. Although no deficiency-related disease has been identified, evidence suggests ergothioneine may be a beneficial “nutraceutical.” Given the requirements of red blood cells to resist oxidative stress and their high ergothioneine content, this review discusses ergothioneine’s potential importance in protecting these cells and identifies knowledge gaps regarding its relevance in enhancing red blood cell circulatory, storage, and transfusion quality.

From bacteria to plants and humans, the glutathione system plays a pleiotropic role in cell defense against metabolic, oxidative and metal stresses. Glutathione (GSH), the γ-L-glutamyl-L-cysteinyl-glycine nucleophile tri-peptide, is the central player of this system that acts in redox homeostasis, detoxification and iron metabolism in most living organisms. GSH directly scavenges diverse reactive oxygen species (ROS), such as singlet oxygen, superoxide anion, hydrogen peroxide, hydroxyl radical, nitric oxide and carbon radicals. It also serves as a cofactor for various enzymes, such as glutaredoxins (Grxs), glutathione peroxidases (Gpxs), glutathione reductase (GR) and glutathione-S-transferases (GSTs), which play crucial roles in cell detoxication. This review summarizes what is known concerning the GSH-system (GSH, GSH-derived metabolites and GSH-dependent enzymes) in selected model organisms (Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana and human), emphasizing cyanobacteria for the following reasons. Cyanobacteria are environmentally crucial and biotechnologically important organisms that are regarded as having evolved photosynthesis and the GSH system to protect themselves against the ROS produced by their active photoautotrophic metabolism. Furthermore, cyanobacteria synthesize the GSH-derived metabolites, ergothioneine and phytochelatin, that play crucial roles in cell detoxication in humans and plants, respectively. Cyanobacteria also synthesize the thiol-less GSH homologs ophthalmate and norophthalmate that serve as biomarkers of various diseases in humans. Hence, cyanobacteria are well-suited to thoroughly analyze the role/specificity/redundancy of the players of the GSH-system using a genetic approach (deletion/overproduction) that is hardly feasible with other model organisms (E. coli and S. cerevisiae do not synthesize ergothioneine, while plants and humans acquire it from their soil and their diet, respectively). [ABSTRACT FROM AUTHOR]

Background: Anthracyclines such as doxorubicin remain a primary treatment for hematological malignancies and breast cancers. However, cardiotoxicity induced by anthracyclines, possibly leading to heart failure, severely limits their application. The pathological mechanisms of anthracycline-induced cardiac injury are believed to involve iron-overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. The dietary thione, ergothioneine (ET), is avidly absorbed and accumulated in tissues, including the heart. Amongst other cytoprotective properties, ET was shown to scavenge ROS, decrease proinflammatory mediators, and chelate metal cations, including Fe2+, preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Plasma ET levels are also strongly correlated to a decreased risk of cardiovascular events in humans, suggesting a cardioprotective role. This evidence highlights ET's potential to counteract anthracycline cardiotoxicity. Methods and Findings: We investigated whether ET supplementation can protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and revealed that it had significant protective effects. Moreover, ET administration in a mouse breast cancer model did not exacerbate the growth of the tumor or interfere with the chemotherapeutic efficacy of doxorubicin. Conclusion: These results suggest that ET could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers. [ABSTRACT FROM AUTHOR]

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19. [ABSTRACT FROM AUTHOR]

Background: Anthracyclines such as doxorubicin remain a primary treatment for hematological malignancies and breast cancers. However, cardiotoxicity induced by anthracyclines, possibly leading to heart failure, severely limits their application. The pathological mechanisms of anthracycline-induced cardiac injury are believed to involve iron-overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. The dietary thione, ergothioneine (ET), is avidly absorbed and accumulated in tissues, including the heart. Amongst other cytoprotective properties, ET was shown to scavenge ROS, decrease proinflammatory mediators, and chelate metal cations, including Fe2+, preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Plasma ET levels are also strongly correlated to a decreased risk of cardiovascular events in humans, suggesting a cardioprotective role. This evidence highlights ET’s potential to counteract anthracycline cardiotoxicity. Methods and Findings: We investigated whether ET supplementation can protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and revealed that it had significant protective effects. Moreover, ET administration in a mouse breast cancer model did not exacerbate the growth of the tumor or interfere with the chemotherapeutic efficacy of doxorubicin. Conclusion: These results suggest that ET could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers.

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures.

Ergothioneine (EGT) is a sulfur-containing amino acid analog that is biosynthesized in fungi and bacteria, accumulated in plants, and ingested by humans where it is concentrated in tissues under oxidative stress. While the physiological function of EGT is not yet fully understood, EGT is a potent antioxidant in vitro. Here we report that oxidized forms of EGT, EGT-disulfide (ESSE) and 5-oxo-EGT, can be reduced by the selenoenzyme mammalian thioredoxin reductase (Sec-TrxR). ESSE and 5-oxo-EGT are formed upon reaction with biologically relevant reactive oxygen species. We found that glutathione reductase (GR) can reduce ESSE, but only with the aid of glutathione (GSH). The reduction of ESSE by TrxR was found to be selenium dependent, with non-selenium-containing TrxR enzymes having little or no ability to reduce ESSE. In comparing the reduction of ESSE by Sec-TrxR in the presence of thioredoxin to that of GR/GSH, we find that the glutathione system is 10-fold more efficient, but Sec-TrxR has the advantage of being able to reduce both ESSE and 5-oxo-EGT directly. This represents the first discovered direct enzymatic recycling system for oxidized forms of EGT. Based on our in vitro results, the thioredoxin system may be important for EGT redox biology and requires further in vivo investigation.

Infection with SARS-CoV-2 causes the coronavirus infectious disease 2019 (COVID-19), a pandemic that has, at present, infected more than 11 million people globally. Some COVID-19 patients develop a severe and critical illness, spurred on by excessive inflammation that can lead to respiratory or multiorgan failure. Numerous studies have established the unique array of cytoprotective properties of the dietary amino acid ergothioneine. Based on studies in a range of in vitro and in vivo models, ergothioneine has exhibited the ability to modulate inflammation, scavenge free radicals, protect against acute respiratory distress syndrome, prevent endothelial dysfunction, protect against ischemia and reperfusion injury, protect against neuronal damage, counteract iron dysregulation, hinder lung and liver fibrosis, and mitigate damage to the lungs, kidneys, liver, gastrointestinal tract, and testis, amongst many others. When compiled, this evidence suggests that ergothioneine has a potential application in the treatment of the underlying pathology of COVID-19. We propose that ergothioneine could be used as a therapeutic to reduce the severity and mortality of COVID-19, especially in the elderly and those with underlying health conditions. This review presents evidence to support that proposal.

Ergothioneine (EGT) is a sulfur-containing amino acid analog that is biosynthesized in fungi and bacteria, accumulated in plants, and ingested by humans where it is concentrated in tissues under oxidative stress. While the physiological function of EGT is not yet fully understood, EGT is a potent antioxidant in vitro. Here we report that oxidized forms of EGT, EGT-disulfide (ESSE) and 5-oxo-EGT, can be reduced by the selenoenzyme mammalian thioredoxin reductase (Sec-TrxR). ESSE and 5-oxo-EGT are formed upon reaction with biologically relevant reactive oxygen species. We found that glutathione reductase (GR) can reduce ESSE, but only with the aid of glutathione (GSH). The reduction of ESSE by TrxR was found to be selenium dependent, with non-selenium-containing TrxR enzymes having little or no ability to reduce ESSE. In comparing the reduction of ESSE by Sec-TrxR in the presence of thioredoxin to that of GR/GSH, we find that the glutathione system is 10-fold more efficient, but Sec-TrxR has the advantage of being able to reduce both ESSE and 5-oxo-EGT directly. This represents the first discovered direct enzymatic recycling system for oxidized forms of EGT. Based on our in vitro results, the thioredoxin system may be important for EGT redox biology and requires further in vivo investigation. [ABSTRACT FROM AUTHOR]

H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and it functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics. [ABSTRACT FROM AUTHOR]

Infection with SARS-CoV-2 causes the coronavirus infectious disease 2019 (COVID-19), a pandemic that has, at present, infected more than 11 million people globally. Some COVID-19 patients develop a severe and critical illness, spurred on by excessive inflammation that can lead to respiratory or multiorgan failure. Numerous studies have established the unique array of cytoprotective properties of the dietary amino acid ergothioneine. Based on studies in a range of in vitro and in vivo models, ergothioneine has exhibited the ability to modulate inflammation, scavenge free radicals, protect against acute respiratory distress syndrome, prevent endothelial dysfunction, protect against ischemia and reperfusion injury, protect against neuronal damage, counteract iron dysregulation, hinder lung and liver fibrosis, and mitigate damage to the lungs, kidneys, liver, gastrointestinal tract, and testis, amongst many others. When compiled, this evidence suggests that ergothioneine has a potential application in the treatment of the underlying pathology of COVID-19. We propose that ergothioneine could be used as a therapeutic to reduce the severity and mortality of COVID-19, especially in the elderly and those with underlying health conditions. This review presents evidence to support that proposal. [ABSTRACT FROM AUTHOR]