Article

L-Ergothioneine modulates oxidative damage in the kidney and liver of rats in vivo: Studies upon the profile of polyunsaturated fatty acids

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

L-ergothioneine is a fungal metabolite exhibiting antioxidant functions in cells. The aim of this study was to assess the effect of oral administration of L-ergothioneine on the oxidative damage in vivo caused by the Fenton reagent ferric-nitrilotriacetate. Rats were supplemented with L-ergo prior to the administration of acute dose of ferric-nitrilotriacetate. Kidney and liver levels of L-ergothioneine, glutathione, alpha-tocopherol, polyunsaturated fatty acids and conjugated dienes were assessed. Oral administration of 70 mg L-ergo/kg body weight of rats for 7 days prior to the injection of ferric-nitrilotriacetate protected the fatty acids against oxidation, with notable protections directed to: 20:5 (eicosapentaenoic acid) (23%), 22:6 (docosahexaenoinic acid) (30%), 20:3 n6 (eicosatrienoic acid) (22%), 20:4 (arachidonic acid) (25%), 18:2 linoleic acid (25%) and 18:1 oleic acid (14%) in the kidney. The protection of 20:5, 20:3 n6 and 18:1 in the liver by 32%, 20% and 11%, respectively, were statistically significant. L-ergothioneine significantly reduced kidney and liver levels of conjugated dienes and conserved the concentrations of alpha-tocopherol and glutathione in the kidney and liver in the ferric-nitrilotriacetate/L-ergothioneine treated rats. Supplementation with L-ergothioneine not only protects the organs against the lipid peroxidation but conserves the consumption of endogenous glutathione and alpha-tocopherol. However consumption of mushrooms may have better promise as dietary sources of L-ergothioneine to humans.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In addition, studies in various animal models have demonstrated antioxidant and cytoprotective actions of ET, including protection against ischemia-reperfusion injury (6,50), acute lung injury (48), damage caused by the pro-oxidants ferric-NTA (14) and b-amyloid (63), and d-galactose-induced exists as a thiol-thione; however, at physiological pH, the thione tautomeric form is favored, conferring greater stability. The structures for precursor and possible metabolic derivatives, hercynine (B), S-methylergothioneine (C), and ergothioneine sulfonate (D) are also shown. ...
... Indeed, studies have revealed that when animals are placed under oxidative stress, for example, administration of ferricnitrilotriacetate (14), ischemia-reperfusion injury (6,50), induced acute respiratory distress (48), or induced neurodegeneration (55,63), ET supplementation was able to decrease oxidative stress and inflammation, and to increase survival. In the absence of the ET transporter, OCTN1, the knockout animals devoid of tissue ET also appear normal until placed under stress (11,32,45). ...
... Other aspects of study compliance, including review of abstinence from ETrich foods, and administration of any medications were conducted during study visits. Blood and urine samples were collected on days 1, 3,5,8,14,21,28, and 35 (Fig. 2). Venous blood (8 ml) was collected in K 2 EDTA vacutainers (Becton Dickinson). ...
Article
Full-text available
Aim: We investigated the uptake and pharmacokinetics of ergothioneine (ET), a dietary thione with free radical scavenging and cytoprotective capabilities, after oral administration to humans, and its effect on biomarkers of oxidative damage and inflammation. Results: Following oral administration, ET is avidly absorbed and retained by the body with significant elevations in plasma and whole blood concentrations, and relatively low urinary excretion (less than 4% of administered ET). ET levels in whole blood were highly correlated to levels of hercynine and S-methyl-ergothioneine, suggesting that they may be metabolites. After ET administration, some decreasing trends were seen on biomarkers of oxidative damage and inflammation, including allantoin (urate oxidation), 8-hydroxy-2-deoxyguanosine (DNA damage), 8-iso-PGF2α (lipid peroxidation), protein carbonylation, and C-reactive protein. However, most of the changes were non-significant. Innovation: This is the first study investigating the administration of pure ET to healthy human volunteers, and monitoring its uptake and pharmacokinetics. This compound is rapidly gaining attention due to its unique properties, and this study lays the foundation for future studies. Conclusion: The uptake and retention of ET by the body suggests an important physiological function. The decreasing trend of oxidative damage biomarkers is consistent with animal studies suggesting that ET may function as a major antioxidant but perhaps only under conditions of oxidative stress.
... studies have highlighted the possible antioxidant and hepatoprotective capabilities of this compound [1,2,[34][35][36][37][38]. Many of these earlier studies supplemented animal models placed under stress (e.g. ...
... Numerous in vitro and a handful of in vivo studies have demonstrated the potentially beneficial properties of ET, in neurodegeneration [43,44] and cardiovascular disorders [45,46] and as an antioxidant [2,36,47], a metal chelator [4,5], and an anti-inflammatory agent [48,49]. ...
... that ET supplementation in rats protected the animal livers from lipid peroxidation following the administration of the Fenton catalyst ferric-nitrilotriacetate or ethionine, respectively [36,38]. ...
Article
L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe(2+), preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility.
... Conversely, silencing the gene encoding OCTN1 predisposes cells and animals to higher levels of oxidative damage [101][102][103]. This suggests that elevating tissue levels of ET in the body will be beneficial in protecting from oxidative damage [57,104]. Moreover, ET has a high bioavailability, being actively taken up into cells and tissues where it is needed. ...
... Indeed, ET would suit this therapeutic role. Studies in rodents have demonstrated that ET decreases oxidative damage in the kidneys and liver from the ROS-generating agent ferric-nitrilotriacetate [104]. By contrast, knocking out the ET transporter in murine models of chronic kidney disease increased kidney damage and fibrosis and elevated oxidative damage [105]. ...
... Like the kidney, ET may also be beneficial in the liver, where earlier studies have demonstrated that it is the first site of rapid ET accumulation following oral administration in mice [32]. Additionally, we have shown that the liver can upregulate the ET transporter in response to damage, further increasing tissue ET levels, where it may be protective against oxidative damage, inflammation, and fibrosis formation [56,104]. Similarly, studies by Tang et al. [55] identified that human hepatic stellate cells upregulated OCTN1 following administration of dimethylnitrosamine (DMN), a hepatotoxin that increased levels of both oxidative damage and α-smooth muscle actin, the latter being a marker for activated stellate cells and liver fibrosis. Supplementation with ET decreased oxidative damage and DMN-induced activation of liver fibrosis, while conversely, knocking out OCTN1 resulted in a significant elevation of liver fibrosis markers, oxidative damage, and inflammation in mice [55]. ...
Article
Full-text available
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.
... There is some in vivo evidence to suggest ERG acts as an anti-oxidant in animal models of lung injury [90], hepatorenal dysfunction [40], and ischaemia/reperfusion injury to the liver [37] and small intestine [50]. Studies using SLC22A4 -/mice show a deficiency of ERG in both serum and tissue. ...
... No difference was observed between lipid peroxidation biomarkers. Finally, Deiana et al. [40] detected ERG in the tissue of rats following oral supplementation (70 mg/kg/d). After one week of treatment the levels reported were 0.66 μg/mg tissue in the kidney and 1.33 μg/mg tissue in the liver. ...
Article
Full-text available
Ergothioneine (ERG), is a water-soluble amino acid that is derived entirely from dietary sources. It has received much attention as a therapeutic agent due to its anti-oxidant properties, and there are claims of preferential accumulation within high oxidative stress organs. Pre-eclampsia, a condition accompanied by increased oxidative stress, is one of the leading causes of maternal morbidity and mortality. Despite intense research efforts, its aetiologies remain somewhat unclear and there are still no effective treatment options. Clinical trials of the anti-oxidants vitamin C and vitamin E have proven largely ineffective with little improvement in clinical outcome or even a negative response. This could be explained in part by their inability to permeate the plasma and mitochondrial membranes and scavenge mitochondria-derived superoxide species, and for the former by the fact that it is actually a pro-oxidant in the presence of unliganded iron. ERG accumulates within tissues through the action of a specific organic cation transporter, SLC22A4 (previously referred to as OCTN1), which is possibly also expressed in mammalian mitochondria. Mitochondrial dysfunction has been implicated in a variety of vascular diseases including pre-eclampsia. This review discusses the use of ERG as a possibly mitochondrial-targeted anti-oxidant, focusing on its physical properties, potential mechanisms of action, safety profile and administration in relation to pregnancies complicated by pre-eclampsia.
... Generally, Fenton's reagent (FR) is used to treat a variety of industrial wastes. Recently, it has been utilized to cause oxidative stress-induced lipid peroxidation in animal experimental model in vivo [24]. The reaction generates highly reactive hydroxyl radicals (•OH) by utilizing hydrogen peroxide (H 2 O 2 ). ...
... This in vitro observation indicates a robust oxidative (free radical) mechanism as one of the significant avenues of LPO production. Our results are also consistent with the findings of Deiana et al. [24] and Traverso et al. [25]. The protective effect of Aloe vera gel against the in vitro oxidative stress led us to assess the possible dietary effects of gel on oxidative hepatic damage. ...
Article
Full-text available
Aloe vera is a semi-tropical plant of Liliaceae family which has a wide range of applications in traditional medicine. In the present study, we sought to investigate the heptaoprotective potential of Aloe vera gel as a diet supplement. To achieve this goal, we have designed in vitro and in vivo experimental models of chemical-induced liver damage using male Sprague-Dawley rat. In the in vitro model, its effect was evaluated on Fenton's reaction-induced liver lipid peroxidation. Co-incubation with gel significantly reduced the generation of liver lipid peroxide (LPO). Next, to see the similar effect in vivo, gel was orally administered to rats once daily for 21 successive days. Following 1 hour of the last administration of gel, rats were treated with intra-peritoneal injection of CCl4. Dietary gel showed significant hepatoprotection against CCl4-induced damage as evident by restoration of liver LPO, serum transaminases, alkaline phosphatase, and total bilirubin towards near normal. The beneficial effects were pronounced with the doses used (400 and 800 mg/kg body weight). Besides, we did not observe any significant drop in serum albumin, globulin as well as total protein levels of gel-administered rats. Histopathology of the liver tissue further supported the biochemical findings confirming the hepatoprotective potential of dietary gel.
... at ASPET Journals on July 9, 2020 jpet.aspetjournals.org production (Obayashi et al., 2005), lipid peroxidation (Deiana et al., 2004), and peroxynitrite oxidative damage (Aruoma et al., 1997). As opposed to other naturally occurring thiols (e.g., glutathione, N-acetylcysteine), ergothioneine is present in aqueous solutions predominantly as a thione rather than a tautomeric thiol structure. ...
... Although in vitro studies demonstrate that ergothioneine may act as a cytoprotectant (Aruoma et al., 1999;Rahman et al., 2003;Jang et al., 2004;Markova et al., 2009), few in vivo findings with ergothioneine are available. Oral administration of ergothioneine protects fatty acids against ferric-nitrilotriacetate-induced oxidation in rat kidney and liver (Deiana et al., 2004). In vivo treatment of rats with ergothioneine also protects intestinal and liver tissues from damage during ischemia/reperfusion injury (Bedirli et al., 2004;Sakrak et al., 2008). ...
Article
Full-text available
Ergothioneine is a thiourea derivative of histidine found in food, especially mushrooms. Experiments in cell-free systems and chemical assays identified this compound as a powerful antioxidant. Experiments were designed to test the ability of endothelial cells to take up ergothioneine and hence benefit from protection against oxidative stress. RT-PCR and Western blotting demonstrated transcription and translation of an ergothioneine transporter in human brain microvascular endothelial cells (HBMECs). Uptake of [3H]ergothioneine occurred by the organic cation transporter novel type-1 (OCTN-1), was sodium-dependent and was reduced when expression of OCTN-1 was silenced by siRNA. The effect of ergothioneine on the production of reactive oxygen species (ROS) in HBMECs was measured using dichlorodihydrofluorescin and lucigenin, and the effect on cell viability was studied using the 3-(4,5-Dimethylthgiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. ROS production and cell death induced by pyrogallol, xanthine oxidase plus xanthine and high glucose were suppressed by ergothioneine. The antioxidant and cytoprotective effects of ergothionine were abolished when OCTN-1 was silenced using siRNA. The expression of NADPH oxidase 1 was decreased, and those of glutathione reductase, catalase and superoxide dismutase enhanced by the compound. Ergothioneine attenuated the reduction in relaxation of isolated rat basilar arteries to the endothelium-dependent vasodilator acetylcholine caused by pyrogallol, xanthine oxidase plus xanthine or incubation in high glucose. Chronic treatment with the compound improved the response to acetylcholine in arteries of rats with streptozotocin-induced diabetes. In summary, ergothioneine is taken up by endothelial cells via OCTN-1, where the compound then protects against oxidative stress, curtailing endothelial dysfunction.
... Exposure of tissues to chronic inflammation and persistent oxidative stress due to environmental (chemical or radiation) insults, allergies, persistent infections, autoimmune reactions, and so on, can lead to damage and remodelling of tissue, eventually triggering fibrosis, which may ultimately lead to organ failure [74]. Multiple studies in cell cultures and animal models have demonstrated that ET not only modulates levels of inflammatory cytokines and mitigates oxidative or nitrosative damage [75][76][77], but may also slow or prevent fibrosis [26,78,79]. ...
... Moreover, OCTN1 expression in hepatocytes was elevated in wild-type mice following DMN treatment [78], which is consistent with an earlier study demonstrating an increase of liver OCTN1 expression and tissue ET in a guinea pig model of fatty liver disease [25]. Another study claimed that ET protected rat kidney and liver against oxidative damage caused by ferric-nitrilotriacetate [75]. Conversely, OCTN1-knockout in mice exacerbated indoxyl sulfate-induced kidney [26] and DMN-induced liver injury [78] and aggravated oxidative damage, inflammation and fibrosis in both models. ...
Article
Full-text available
There has been a recent surge of interest in the unique low molecular weight dietary thiol/thione, ergothioneine. This compound can accumulate at high levels in the body from diet and may play important physiological roles in human health and development, and possibly in prevention and treatment of disease. Blood levels of ergothioneine decline with age and onset of various diseases. Here we highlight recent advances in our knowledge of ergothioneine.
... For instance, endogenous GSH levels can be increased by dietary or pharmacological intake of GSH precursors or GSH mimics (Kosuge et al., 2003;Lee et al., 2007;Butterfield et al., 2002). Previously, Deiana et al. (2004) have reported that supplementation with EGT not only protects the organs against lipid peroxidation but conserves the consumption of endogenous GSH and alpha-tocopherol. ...
... From previous studies, it is apparent that mushrooms have great potential as a source of novel compounds (Deiana et al., 2004;Lee and Yun, 2006;Chen et al., 2012). For instance, ergothionine was isolated from Pleurotus citrinopileatus Singer, P. ostreatus (Jacq. ...
Article
Full-text available
A cupric reducing antioxidant capacity (CUPRAC)-guided purification approach was performed on a methanol extract of Lentinus squarrosulus (LsqMeOH) by using reversed phase-high performance liquid chromatography. Using reversed phase-high performance liquid chromatography, three fractions were separated arbitrarily named FR1, FR2 and FR3. Results showed that FR2 exhibited the highest antioxidant activity in CUPRAC assay (A450, 0.86) but not significantly different from LsqMeOH (A450, 0.84). FR1 and FR3 showed much lower absorbance, with values (A450, 0.21) and (A450, 0.36) respectively at 1 mg ml⁻¹. The most active fraction (F3) was further subjected to LC-MS/MS to obtain its detailed chemical profile. Uridine, ganoderic acid derivative, and flavonoids were the first time being found in L. squarrosulus antioxidative fractions. The present results indicate that the fraction extracts of L. squarrosulus possess antioxidant properties and can be used as free radical inhibitors. Therefore, this research suggested the potentials of L. squarrosulus as a source of antioxidant extract to be used in food industries (functional food).
... Actually, the i.p. injection of arzanol (DMSO, 4%) reduced the inflammatory reaction in an in vivo model of acute inflammation (Bauer et al., 2011). The Fe-NTA model is an excellent model of in vivo free radical induced damage associated with extensive peroxidation of membrane lipids (Ikeda et al., 1998;Deiana et al., 2001;Rosa et al., 2005a), and is widely used to evaluate the antioxidant properties of phenolic compounds (Deiana et al., 2004Rosa et al., 2005b). In particular, the Fe-NTA oxidative damage starts from the plasma compartment, where Fe-NTA finds the ideal environment to react with oxidizable lipids, and next continues with a similar pattern but a different speed and severity in the kidney and liver (Deiana et al., 2001Rosa et al., 2005a). ...
Article
The heterodimeric phloroglucinyl pyrone arzanol (Arz) has raised considerable interest because of its antiviral, anti-inflammatory, and antioxidant activity. We have investigated the effect of methylation of the pyrone moiety on the antioxidant activity and cytotoxicity of Arz. This manoeuvre, that left the polyphenolic moiety unscathed, was nevertheless detrimental for antioxidant activity in both the cholesterol thermal degradation- and the Cu²⁺-induced liposome oxidation assays, providing evidence of structure-activity relationships that go beyond the preservation of the polyphenolic pharmacophore. The antioxidant activity of Arz was retained also in the Fe-NTA model of in vivo oxidative stress, with protective effect on the oxidative degradation of plasmatic lipids, unsaturated fatty acids and cholesterol. Both Arz and methylarzanol (Me-Arz) were devoid of toxic effect on colonic differentiated Caco-2 cells up to 100 μM, but significantly reduced cancer Caco-2 cell viability at lower dosages. Arz could also selectively reduce viability of other cancer cell lines, [murine melanoma cells (B16F10 cells), human cervical carcinoma cells (HeLa cells)], suggesting that it can act as a selective modulator of cell processes typical of cancer cells. Taken together, our results qualify Arz as a lead structure for further in vivo investigation of its pharmacological potential.
... Similarly, age-related declines in glutathione (GSH) and glutathione peroxidase (GPx) have been observed [28,29]. Studies with ferric nitrotriacetate-induced oxidative stress in rats demonstrated that ET supplementation played a role in preserving GSH [24], while The total monthly mushroom consumption was tallied and correlated to blood ergothioneine levels of each individual. The self-reported consumption of mushrooms by the subject was found to significantly correlate (P < 0.001; r ¼ 0.491) to blood ergothioneine levels. ...
Article
Ergothioneine (ET), a naturally occurring thione, can accumulate in the human body at high concentrations from diet. Following absorption via a specific transporter, OCTN1, ET may accumulate preferentially in tissues predisposed to higher levels of oxidative stress and inflammation. Given its potential cytoprotective effects, we examined how ET levels change with age. We found that whole blood ET levels in elderly individuals decline significantly beyond 60 years of age. Additionally, a subset of these subjects with mild cognitive impairment had significantly lower plasma ET levels compared with age-matched subjects. This decline suggests that deficiency in ET may be a risk factor, predisposing individuals to neurodegenerative diseases.
... NTA toxicity increases when it is chelated to metal ions such as the interaction with [Fe +3 ] ions [38,39]. Ferric nitriloacetate chelate (Fe-NTA) has been reported to trigger hemochromatosis and insulin resistance via the oxidative damage of cellular lipids, proteins and DNA [39] thus it is an ideal model for assessing the anti-genotoxic effect of potential dietary antioxidants [40] prompting the work of Rimbach et al. [41]. FPP was demonstrated to effectively counteract Fe-NTA plus H 2 O 2 induced genotoxicity in human T-cell leukocytes [41]. ...
... Ergothioneine is a stable amino acid and can be produced by certain fungi and actinobacteria. Many studies have demonstrated that ergothioneine possessed multiple physiological activities, such as antioxidation (Deiana et al. 2004), anti-inflammatory (Rahman et al. 2003) and UV-irradiated skin cells repair (Markova et al. 2009); and the compound has been widely used in cosmetic products. In addition, phenolic compounds have been confirmed to exhibit multiple physiological benefits, such as anti-inflammation, antioxidant, antimicrobial and anti-cancer (Cheung et al. 2003;Rathee et al. 2009). ...
Article
Intense pulsed light irradiation is used in food decontamination and in production of mushrooms with high level of ergocalciferol. Lentinula edodes (Berk.) Pegler, shiitake, was freeze-dried and milled into powder and irradiated with 20, 40 and 60 pulses of pulsed light at a distance of 6 cm and the irradiation energy were 26.2, 52.4 and 78.5 kJ/m2, respectively. The contents of ergocalciferol and total phenols increased dose-dependently whereas ergothioneine contents were not affected. The most effective conversion of ergosterol to ergocalciferol was 20-pulse treatment. Further, irradiated and nonirradiated shiitake showed a moderate inhibition in decreasing nitric oxide and interleukin-6 productions but no effect on tumor necrosis factor-alpha production. In addition, pulse light treatment could improve antioxidant activities. Overall, using pulsed light irradiation could produce irradiated shiitake as an excellent vitamin D2 supplement with similar ergothioneine and higher total phenols contents as well as similar anti-inflammatory and better antioxidant activities. Using intense pulsed light irradiation, ergosterol could be efficiently transformed into ergocalciferol in freeze-dried shiitake powder at proper distance and treatment time. The content of ergocalciferol in freeze-dried shiitake powder could be increased from 5.91 to 37.17 μg/g after irradiating for 20 pulses (near 7 s), which is sufficient for the daily requirement of 15 μg for human body upon consumption of 0.4 g powder. In addition, the content of total phenol would be increased from 6.91 to 7.42 mg/g after 60 pulses of pulsed light irradiation, and the content of ergothioneine was similar during the different pulse treatments. Therefore, the irradiated shiitake powder could be a beneficial supplement which contains abundant vitamin D and exhibits good antioxidant activities.
... We identified ergothioneine to be most strongly associated with reported consumption of mushrooms-a novel finding. Ergothioneine is a thiol compound with demonstrated in vivo protection against lipid peroxidation [54] found in high concentrations in specialty mushrooms, in particular oyster and king bolete, and in lower amounts in oat bran and beans [55]. Recent data supports the notion that ergothioneine may prevent against vascular dysfunction [56]. ...
Article
Full-text available
Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P
... [37][38][39] Early in vivo studies in rats at 70 to 100 mg/kg confirm Lergothioneine's rapid urinary clearance (e.g., excretion into the urine by the kidneys) and its accumulation in the liver where, with the kidney, it is reported to modulate oxidative damage from polyunsaturated fatty acids. 40,41 Most recently, preclinical studies testing the genotoxicity of L-ergothioneine showed no mutagenic or clastogenic activity in in vitro Ames and chromosome aberration assays up to 5,000 mg/mL or in an in vivo mouse micronucleus test at concentrations of up to 150 mg/ mL or 1,500 mg/kg. 42,43 No adverse effects were reported during a 2,000 mg/kg oral acute limit test, a 14-day toxicity test, or reproductive fertility or developmental toxicity test in rats at concentrations of 0.1%, 0.3%, or 0.9% in the diet. ...
Article
l-(+) Ergothioneine is a naturally occurring thiol amino acid with antioxidant properties and potential benefits as a dietary supplement. Despite its century-old identification and wide distribution in human food, little is known of its mechanism of action and safety. The nature-identical biomimetic of l-(+) ergothioneine, produced by Mironova Labs and supplied as Mironova (EGT+), has been investigated in the present studies for its mutagenic and toxicologic potential. In a plate incorporation and preincubation assay with Salmonella typhimurium strains TA98, 100, 1,535, and 1,537 and Escherichia coli WP2uvrA strain, at dose concentrations of 1.58, 5, 15.8, 50, 158, 500, 1,580, and 5,000 μg/plate with and without metabolic activation, no cytotoxicity or mutagenicity was observed. Following a preliminary 28-day study, a repeated dose 90-day gavage study at dose levels of 0, 400, 800, and 1,600 mg/kg body weight (bw)/d in Sprague Dawley rats, in which dose-proportional systemic absorption was confirmed by plasma analysis, no adverse clinical, body weight/gain, food consumption and efficiency, clinical pathology, or histopathological changes associated with the administration of the nature-identical ergothioneine were observed. In conclusion, EGT+ administered over 90 days was well tolerated with a no adverse effect level at 1,600 mg/kg bw/d, the highest dose tested for male and female rats. In addition, the nature-identical test substance, EGT+ was not mutagenic in a bacterial reverse mutation assay at plate concentrations of up to 5,000 μg/mL in the presence or absence of metabolic activation.
... The discovery of OCTN1/ETT resulted in a renewed interest in L-ergothioneine as it also supports a beneficial role of this micronutrient in human metabolism. This is corroborated by the protective and antioxidant effects of L-ergothioneine that have been demonstrated in in vitro and in vivo studies (see Cheah and Halliwell 2012 for review; Akanmu et al. 1991;Aruoma et al. 1997Aruoma et al. , 1999Deiana et al. 2004;Hartman 1990). Moreover, recent studies have shown that L-ergothioneine is a safe compound (Schauss et al. 2010(Schauss et al. , 2011Forster et al. 2015). ...
Article
L-ergothioneine is an amino acid synthetized by fungi and mycobacteria that cannot be synthesized by other species. It has been detected in plants, animals, and the human body. In the last few years, it has been recognized as a good antioxidant and, recently, it has also been related to other properties besides antioxidant properties. Even though few studies on the toxicity of L-ergothioneine have been carried out, evidence suggests that L-ergothioneine is not harmful to health. Considering that L-ergothioneine has increasingly been linked to positive effects on human health, coupled with the fact that it seems to be safe for human consumption, this molecule may be suitable for use as an ingredient in foods. On the other hand, despite the positive effects reported for this molecule, no estimate of L-ergothioneine intake has been carried out until now. Thus, the aim of this work is to estimate the intake of L-ergothioneine through food consumption of several European countries and the United States. Values were estimated by using the deterministic and probabilistic approach. Results show that the populations with the highest intake of L-ergothioneine correspond to Italian population, both for children and adults.
... Ergothioneine (EGT) is a naturally occurring chiral amino acid that has been used as an antioxidant (1)(2)(3), radical scavenger, metal-ion chelator (4), ultraviolet ray filter (5) and regulator of oxidation-reduction reactions and cellular bioenergetics (6)(7)(8); it is a multifunctional physiological cytoprotector (9). EGT can be easily assimilated and exploited, and many research findings have revealed no harmful responses in humans or animals after EGT administration. ...
Article
A hydrophilic interaction liquid chromatography method has been established for the quantification of ergothioneine (EGT) in fermentation broth. Chromatographic separation was conducted on a Venusil hydrophilic interaction liquid chromatography (HILIC) column (250 × 4.6 mm, 5 µm) at an elution rate of 1.0 mL/min with an isocratic mobile phase consisting of acetonitrile/20 mmol/L ammonium acetate solution (85 : 15, v/v) adjusted to pH 6.0 with acetic acid. Analytes were detected at 254 nm using a UV–VIS detector. The injection volume was 10 µL, and the column temperature was 40°C. The limits of detection and limits of quantification were 63 and 21 µg/L, respectively. Excellent linearity [correlation coefficient (R2) = 0.9999] was achieved for EGT quantification in the range of 5–400 mg/L. The relative standard deviations of repeatability, intermediate precision and stability were 1.47, 1.03 and 1.66%, respectively, and EGT recoveries were within 99.2–100.8%. The chromatographic peak corresponding to EGT in the HILIC spectrum was confirmed using ESI–MS. In general, the method developed here is simple, reliable, accurate, and stable and may be useful for routine analyses in EGT biosynthesis research.
... This effect is believed to be due to the radical scavenging behavior of ESH (Franzoni et al., 2006). Furthermore, in the organism, ESH not only protects the organs against lipid peroxidation but also conserves endogenous glutathione and αtocopherol (Deiana et al., 2004). Discoloration of meats is known to result from interaction between Mb and lipid oxidation (Renerre, 1990); therefore, both glutathione and α-tocopherol have been used to stabilize meat color because of their antioxidant effects (Faustman et al., 1998;Corino et al., 1999;Casttellini et al., 2000;Phillips et al., 2001;Yang et al., 2002;Tang et al., 2003). ...
Article
A hydrophilic extract prepared from waste medium from mushroom (Flammulina velutipes) cultivation contained ergothioneine (ESH) at a concentration of 340 mg/L (= 48 mg/kg of solid medium). The content of ESH in the extract at which 50% of the DPPH radical was scavenged was 0.3 μg. Effects of the extract on color stability and lipid oxidation in dark muscle of yellowtail (Seriola quinqueradiata) during chilled storage for 4 days were evaluated by feeding the extract to the fish as a supplement. There was no mortality during the 4-week feeding period, and the fish grew normally. Browning development in dark muscle of yellowtail fed diets containing 1% and 10% of the extract was remarkably suppressed during 4 days of storage at 0–2 °C. These results clearly showed that the extract is a promising source of natural antioxidants that can be used in aquaculture to improve the quality of fish meat during post-harvest storage at lower temperatures.
... The antioxidant properties of ERG include the scavenging of free radicals and reactive oxygen species (Akanmu et al., 1991;Park et al., 2010;Ta et al., 2011) and the chelation of divalent metal ions (Hanlon, 1971). ERG has been shown to reduce oxidative damage in a variety of mammals (Deiana et al., 2004;Cheah and Halliwell, 2012). In humans, ERG is mainly accumulated in the liver, the kidneys, in erythrocytes, the eye lens, and in seminal fluid (Leone and Mann, 1951;Melville et al., 1954;Shires et al., 1997). ...
Article
Full-text available
L-(+)-Ergothioneine (ERG) is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise ERG, but acquire it from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is considered to be a nutraceutical and possible vitamin that is involved in the maintenance of health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is thus a potentially useful dietary supplement. Present methods of commercial production rely on extraction from natural sources or on chemical synthesis. Here we describe the engineering of the baker's yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined media. After integrating combinations of ERG biosynthetic pathways from different organisms, we screened yeast strains for their production of ERG. The highest-producing strain was also engineered with known ergothioneine transporters. The effect of amino acid supplementation of the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-out of TOR1 or YIH1. We also optimized the media composition using fractional factorial methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture in 1 L bioreactors. Because S. cerevisiae is a GRAS (“generally recognized as safe”) organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.
... scavenges peroxyl, hydroxyl, and peroxynitrite radicals more effectively than glutathione (5). In addition, several studies have determined that ergothioneine is a potent biological antioxidant, preventing many different types of oxidative damage, including lipid peroxidation oxidative DNA damage, and apoptosis, in cells or in animals (25)(26)(27)(28)(29)(30)(31). Metal coordination as an antioxidant mechanism has also been examined using density functional theory methods (32), and ergothioneine-copper coordination was found to prevent copper-mediated oxidative DNA and protein damage by inhibiting copper redox cycling (33). ...
Article
Thione- and selone-containing compounds and their transition metal complexes have been investigated for purposes ranging from antioxidant and anti-tumor activity to materials for optical electronics and light emitting diodes. With current investigations of sulfur-rich metalloenzyme active sites as well as the antioxidant activity of ergothioneine, selenoneine, and thione-containing anti-thyroid drugs, the coordination chemistry of thione and selone ligands with biologically common first-row transition metals has sparked considerable recent interest. This review focuses on the biological functions of thione- and selone-containing compounds, their coordination chemistry with iron, cobalt, nickel, copper, and zinc, and the biological implications of this chalcogenone-metal binding. While thione-metal coordination has been widely studied, only a few selone-metal complexes with first-row transition metals have been reported.
... Nonetheless, the ubiquitous presence of EGT, its ability to scavenge ROS in vitro, selective accumulation and tissue distribution, as well as uptake by a specifi c high affi nity transporter, collectively suggest that EGT may function as a physiological antioxidant. Under conditions of greater oxidative stress, such as ischaemia -reperfusion injury or administration of ferric nitrilotriacetate, the presence of EGT led to lower oxidative burden and greater survivability in mice and rats, respectively [20,21]. Under normal unchallenged conditions, octn1 -/mice, as well as rats fed on an EGTdepleted diet appear phenotypically normal despite them being defi cient in EGT, however closer examination reveals a greater predisposition to intestinal infl ammation [20,22]. ...
Article
Abstract In addition to excretion of metabolic waste products, organic ionic transporters facilitate uptake of specific compounds of physiological importance. In humans, the organic cation transporter, OCTN1 was found to enable the specific uptake of the unique amino acid, ergothioneine (EGT). EGT can accumulate in the body at up to millimolar concentrations and is believed to function as a physiological antioxidant. However the main function of EGT and the reason for its active accumulation in the body remain obscure. Through bioinformatic approaches, we identified an analogous EGT transporter in the nematode, Caenorhabditis elegans. The present study investigated and characterized deletion mutants of this gene, OCT-1 in the nematodes. Gene deletion mutations of the OCT-1 transporter were shown to decrease overall lifespan of the worms and increase oxidative damage. However the absence of impaired EGT uptake and the inability of excess EGT to rescue the debilitating phenotype indicate that EGT transport does not explain the deleterious effects of the gene deletion.
... Research on the role of EGT in the liver is limited. It has been shown that the liver is the main site to accumulate EGT, and a previous animal study found that supplementation of EGT [70 mg/kg body weight (bw)] in rats for 7 days before injection of ferric-nitrilotriacetate could protect the liver from the injury of lipid peroxidation (Deiana et al., 2004). The indexes detection of the NAFLD animal model established by cholesterol showed that under stress, the liver could up-regulate the expression of OCTN1 to increase the uptake and accumulation of EGT, and there was a significant correlation between the liver level of EGT and cholesterol and iron, although there was no difference in the diet content of EGT (Cheah et al., 2016b). ...
Article
Full-text available
L-Ergothioneine (EGT) is a natural antioxidant derived from microorganisms, especially in edible mushrooms. EGT is found to be highly accumulated in tissues that are susceptible to oxidative damage, and it has attracted extensive attention due to its powerful antioxidant activity and the tight relationships of this natural product with various oxidative stress-related diseases. Herein, we 1) introduce the biological source and in vivo distribution of EGT; 2) review the currently available evidence concerning the relationships of EGT with diabetes, ischemia-reperfusion injury-related diseases like cardiovascular diseases and liver diseases, neurodegenerative diseases, and other diseases pathogenically associated with oxidative stress; 3) summarize the potential action mechanisms of EGT against these diseases; 4) discuss the advantages of EGT over other antioxidants; and 5) also propose several future research perspectives for EGT. These may help to promote the future application of this attractive natural antioxidant.
... The alleviation of the organic cation transporter N1 (OCTN1) which is the particular ergothioneine transporter was also confirmed the cytoprotective effects of ergothioneine in hepatic tissues (Cheah et al. 2016). Ergothioneine for instance, was reported to inhibit the formation of hydroxyl radicals and lipid peroxidation (Deiana et al. 2004;Li et al. 2014). The ion chelating activity posses by ergothioneine allays the involvement of divalent cation in oxidation cycle. ...
Article
Pleurotus pulmonarius crude aqueous (CA) extract was previously reported to have therapeutic potential, thus its ability to alleviate serum total cholesterol, vasodilation, and improve the aortic tissue structure in hypercholesterolemia rat model was studied. Eight groups of Wistar-Kyoto rats were involved including normal (G1), hypercholesterolemia (G2), treatment (G3 to G5) and prevention (G6 to G8). Two doses of CA; 0.5 g/kg body weight (BW), 2.0 g/kg BW, and simvastatin 10 mg/kg BW were orally fed to the rats (G3 to G8). Treatment groups were induced with hypercholesterolemia and later treated with CA/simvastatin, while prevention groups were given both hypercholesterolemia-diet and CA/simvastatin simultaneously. The thoracic aortic rings (TAR) were subjected to contractility study and histopathology examination. In organ bath analysis, pre-contracted TAR of G1 with phenylephrine (PE) achieved 60% vasodilation response towards acetylcholine (ACh) whereas TAR of G2 unable to respond to ACh. G3 to G5 groups failed to dilate when induced with ACh whereas G6 to G8 groups showed a slight improvement. The repeated precontracted TAR of G1 and G2 significantly dilated with the presence of CA and simvastatin. TAR of G1 achieved 100% vasodilation at 3.0 mg/mL CA and 2.4 mg/mL simvastatin. TAR of G2 achieved 73% vasodilation at 6.0 mg/mL CA whereas 76.8% dilation recorded for simvastatin at 4.8 mg/mL. Histopathological examination found that CA was able to improve the structure of the aortic cells. These observations suggest that CA helps to improve tissue condition and vasodilation of the hypercholesterolemic aorta.
... Ergothioneine (ERG) is a water-soluble amino acid derived from dietary sources usually synthesized by fungi and bacteria [85]. The antioxidant potential of ERG has been evaluated in several disease models [86,87]. The ability of ERG to localize and accumulate within mitochondria has been previously shown [88]. ...
Article
Full-text available
Despite considerable research efforts over the past few decades, the pathology of preeclampsia (PE) remains poorly understood with no new FDA-approved treatments. There is a substantial amount of work being conducted by investigators around the world to identify targets to develop therapies for PE. Oxidative stress has been identified as one of the crucial players in pathogenesis of PE and has garnered a great deal of attention by several research groups including ours. While antioxidants have shown therapeutic benefit in preclinical models of PE, the clinical trials evaluating antioxidants (vitamin E and vitamin C) were found to be disappointing. Although the idea behind contribution of mitochondrial oxidative stress in PE is not new, recent years have seen an enormous interest in exploring mitochondrial oxidative stress as an important pathological mediator in PE. We and others using animals, cell models, and preeclamptic patient samples have shown the evidence for placental, renal, and endothelial cell mitochondrial oxidative stress, and its significance in PE. These studies offer promising results; however, the important and relevant question is can we translate these results into clinical efficacy in treating PE. Hence, the purpose of this review is to review the existing literature and offer our insights on the potential of mitochondrial antioxidants in treating PE.
... The dose for ERG (25 mg/kg per day) was selected based on previously published rodent studies using this antioxidant. 22,23 ERG was provided by Tetrahedron (Paris, France; www.tetrahedron.fr). ...
Article
Full-text available
Preeclampsia is a multifactorial hypertensive disorder of pregnancy founded on abnormal placentation, and the resultant placental ischemic microenvironment is thought to play a crucial role in its pathophysiology. Placental ischemia because of fluctuations in the delivery of oxygen results in oxidative stress, and recent evidence suggests that mitochondrial dysfunction may be a prime mediator. However, large clinical trials of therapeutic antioxidants such as vitamins C and E for the treatment of preeclampsia have been disappointing. L-(+)-ergothioneine (ERG)-an unusual amino acid betaine derived from histidine-has important cytoprotective and antioxidant properties under conditions of high oxidative stress. In this study, we investigated the potential therapeutic effects of administration of ERG in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. ERG (25 mg/kg per day) was administered to rats on gestational day 11. On gestational day 14, RUPP surgery was performed, and on gestational day 19, blood pressure (mean arterial pressure) and fetal growth were measured. Production of mitochondria-specific H2O2 was analyzed in vivo in kidney samples. ERG ameliorated the hypertension (129±3 versus 115±4 mm Hg; P=0.01; n=8) and significantly increased pup weight in RUPP rats. ERG also significantly decreased circulating levels of antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) in RUPP rats (1367±245 pg/mL; P=0.04). Mitochondria-specific H2O2 (0.022±0.003 versus 0.029±0.001; MitoP/B ratio, n=3; P=0.05) was also significantly decreased in kidney tissue in RUPP rats treated with ERG. These data support the potential use of ERG for the treatment of preeclampsia.
... L-egt (as shown in Fig. 1) possesses antioxidant and anti-inflammatory properties, while its accumulation at the sites of tissue injury has been hypothesized as an adaptive mechanism of protecting tissues at risk of damage and regenerating injured tissues [21,42]. Also, L-egt has been reported to activate the Nrf2 (nuclear factor erythroid-2 related factor-2) antioxidant signaling pathway to protect against cellular injury, enhance glutathione level and reduce oxidative damage in the kidney as well as activates sirt1 and 6 to protect against high glucose-induced cell senescence [12,13,22]. Furthermore, coadministration of L-egt with existing therapy (such as melatonin and hispidin) significantly increases treatment benefits both in-vitro and in-vivo [52,53], suggesting that L-egt may improve the efficacy of available treatment options. ...
Article
Full-text available
L-ergothioneine (L-egt) is a bioactive compound recently approved by the food and drug administration as a supplement. L-egt exerts potent cyto-protective, antioxidant and anti-inflammatory properties in tissues exposed to injury, while metformin is a first-line prescription in type-2 diabetes. Therefore, the present study investigated the protective effect of L-egt alone, or combined with metformin, on renal damage in a type-2 diabetic (T2D) rat model. T2D was induced in male Sprague-Dawley rats using the fructose-streptozotocin rat model. L-egt administration, alone or combined with metformin, began after confirming diabetes and was administered orally for seven weeks. After the experiment, all animals were euthanized by decapitation, blood samples were collected, and both kidneys were excised. Biochemical analysis, Enzyme-link Immunoassay (ELISA), Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), western blotting, and histological analyses were done to evaluate various biomarkers and structural changes associated with renal damage. Untreated diabetic rats showed loss of kidney functions characterized by increased serum creatinine, blood urea nitrogen, proteinuria, triglycerides, lipid peroxidation, inflammation, and decreased antioxidant enzymes. Histological evaluation showed evidence of fibrosis, mesangial expansion, and damaged basement membrane in the nephrons. However, L-egt alleviates these functional and structural derangements in the kidney, while co-administration with metformin reduced hyperglycemia and improves therapeutic outcomes. Furthermore, L-egt treatment significantly increased the expression of major antioxidant transcription factors, cytoprotective genes and decreased the expression of inflammatory genes in the kidney. Thus, combining L-egt and metformin may improve therapeutic efficacy and be used as an adjuvant therapy to alleviate renal damage in type-2 diabetes.
... The used ergothioneine dose is consistent with a previously published work. [27] The Fe group was treated with ip injection of 30 mg/kg iron-dextransaline every other day over the 10-day experimental period (150 mg/kg total injected iron). [8,28] The Fe + Erg group received both iron (30 mg/kg) and ergothioneine (70 mg/kg) the same way as the Fe and Erg groups. ...
Article
The liver is highly susceptible to iron overload-evoked oxidative injury. Ergothioneine is a thio-histidine amino acid that has exhibited strong antioxidant and metal chelating activities. This study aimed at exploring the potential modulating effects of ergothioneine on iron-triggered liver injury. The results showed that ergothioneine inhibited iron-evoked inflammation and apoptosis as demonstrated by a significant reduction in tumor necrosis factor-α and interleukin-6 levels and in caspase-3 activity. Ergothioneine significantly improved liver cell survival as indicated by modulating phosphatidylinositol 3-kinase/protein kinase B signaling. Consistent with reduced necrotic cell death, ergothioneine diminished the iron-evoked histopathological changes and decreased serum activity of the liver enzymes. Mechanistically, ergothioneine reduced nuclear translocation of nuclear factor kappa B p65 and modulated p38 mitogen-activated protein kinase/c-Fos signaling. In addition, it enhanced the liver tissue antioxidant potential and curbed hepatic iron load. Together, these results point out the modulatory effects of ergothioneine on iron-evoked liver cell injury that are possibly mediated via anti-inflammatory, antioxidant, and possible iron chelation capabilities.
... In addition to its anti-oxidative actions, ergothioneine also exerts several cytoprotective functions such as lipid peroxidation inhibition 46,47 and DNA/protein damage control 23,48 . A study using control mice reported the antidepressant-like effects of ergothioneine in forced swim and tail suspension tests 30 ; however, to our knowledge, no study has examined the effect of ergothioneine in stressed animal models. ...
Article
Full-text available
The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least 1 month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression.
... The effect of the ET treatment was explored using four experimental groups (Table 1): Sham control (SC, n = 5), RUPP control (RC, n = 5), Sham + ET (ST, n = 5), RUPP + ET (RT, n = 5). From GD11-GD19, ET was added to the drinking water at 25mg/kg/day, as reported in previous animal studies [25,26]. Blood was collected on GD19 into EDTA vacutainers, these were ...
Article
Full-text available
Introduction Pre-eclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. Its pathophysiology remains unclear, but mitochondrial dysfunction and oxidative stress have been implicated. L-Ergothioneine is a naturally occurring, water-soluble betaine, that has demonstrated antioxidant properties. Using the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia, this study aimed to define the plasma metabolic profile following treatment with L-Ergothioneine. Methods The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n = 5), RUPP control (RC, n = 5), Sham +ET (ST, n = 5), RUPP +ET (RT, n = 5). Differential expression of plasma metabolites were obtained using untargeted liquid chromatography coupled to mass spectrometry. Statistical analysis was performed on normalised data comparing RC to SC, RT to RC, and RT to ST. Metabolites significantly altered (FDR < 0.05) were identified through database search. Results We report significantly lower levels of L-palmitoylcarnitine in RC compared to SC, a fatty acyl substrate involved in beta-oxidation in the mitochondria. We report that a metabolite that has been associated with oxidative stress (Glutamylcysteine) was detected at significantly higher levels in RT vs RC and RT vs ST. Five metabolites associated with inflammation were significantly lower in RT vs RC and three metabolites in RT vs ST, demonstrating the anti-inflammatory effects of ET in the RUPP rat model of pre-eclampsia. Conclusions L-Ergothioneine may help preserve mitochondrial function by increasing antioxidant levels, and reducing inflammatory responses associated with pre-eclampsia. This study shows the potential of L-Ergothioneine as a treatment for pre-eclampsia.
... In conclusion, it was determined that T. virgatum mushroom is a suitable source of some phenolic compounds including chlorogenic acid, catechin, and gallic acid. The presence of considerable antioxidant contents in mushrooms may confer protection against many chronic diseases such as cardiovascular disease (CVD), neurodegenerative disease, and other oxidative stress related diseases [26][27][28]. Their health promotion effects on oxidative stress-related diseases such as CVD are often attributed to their antioxidant capabilities, in particular their free radical scavenging ability plus metal ion homoeostasis via chelating activities. [29][30][31] 3.2. ...
Article
Full-text available
Tricholoma is one of the famous genera of Basidiomycota division. Although some species of this genus have been used as culinary mushrooms, very negligible investigations have been conducted on Tricholoma genus phenolic contents and their biological activities. In the present study, the antioxidant, antimicrobial, and DNA protection properties of total phenolic contents of Tricholoma virgatum (Fr.) P. Kumm. (54% methanolic extract) were assessed. T. virgatum phenolic content was determined by an analytic high-performance liquid chromatography (HPLC) method based on compression with standard phenolic compounds including gallic acid, catechin, chlorogenic acid, epicatechin, and coumaric acid. Total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) values were determined using Rel Assay kits. For DNA protective potential assay, pBR322 supercoiled DNA method was used. The antimicrobial activity assay was done based on the agar dilution method on six different microorganisms include Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Candida tropicalis. The total phenolic contents of this mushroom lied within range of 2.02-56.85 ppm based on coumaric acid and chlorogenic acid as standards. TAS, TOS, and OSI values were determined as 3.754±0.088 mmol/L, 8.362 ±0.085 μmol/L, and 0.223 ±0.007, respectively. T. virgatum methanol extract could exhibit a protective effect on DNA against the hydroxyl radical at 100 μg/mL concentration. Although T. virgatum is not recommended as an edible mushroom, according to our results, this mushroom could be considered as valuable source for phenolic compounds with significant antioxidant/antimicrobial effects.
... Oxidative stress can be defined and measured in many ways (461)(462)(463)(464)(465)(466)(467)(468) , but is broadly taken to involve a dysregulation in the various redox systems of the organism of interest, coupled to the production of various 'reactive oxygen species', principally peroxide, superoxide, hydroxyl radical, and singlet oxygen. ERG has been shown to decrease oxidative stress in the liver and kidney of rats (469) , rescued cells from β-amyloid-induced apoptotic death (231) , protected against palmitic acid-induced cell death (470) , mercuric chloride-induced cellular dysfunction (471) , and prevented Cu-induced oxidative damage to DNA (472,473) . It is protective against the oxidation of various kinds of molecule (251,474) , including astaxanthin (475) , and accumulates in a guinea-pig model of non-alcoholic fatty liver disease (476) , massively so in mouse models of myocardial infarction and heart failure (477) , and in a rat model of optic nerve crush (478) . ...
Article
Full-text available
Ergothioneine (ERG) is an unusual thio-histidine betaine amino acid that has potent antioxidant activities. It is synthesised by a variety of microbes, especially fungi (including in mushroom fruiting bodies) and actinobacteria, but is not synthesised by plants and animals who acquire it via the soil and their diet, respectively. Animals have evolved a highly selective transporter for it, known as solute carrier family 22, member 4 (SLC22A4) in humans, signifying its importance, and ERG may even have the status of a vitamin. ERG accumulates differentially in various tissues, according to their expression of SLC22A4, favouring those such as erythrocytes that may be subject to oxidative stress. Mushroom or ERG consumption seems to provide significant prevention against oxidative stress in a large variety of systems. ERG seems to have strong cytoprotective status, and its concentration is lowered in a number of chronic inflammatory diseases. It has been passed as safe by regulatory agencies, and may have value as a nutraceutical and antioxidant more generally.
... The discovery of OCTN1/ETT resulted in a renewed interest in L-ergothioneine as it also supports a beneficial role of this micronutrient in human metabolism. This is corroborated by the protective and antioxidant effects of L-ergothioneine that have been demonstrated in in vitro and in vivo studies (see Cheah and Halliwell 2012 for review; Akanmu et al. 1991;Aruoma et al. 1997Aruoma et al. , 1999Deiana et al. 2004;Hartman 1990). Moreover, recent studies have shown that L-ergothioneine is a safe compound (Schauss et al. 2010(Schauss et al. , 2011Forster et al. 2015). ...
Article
L-ergothioneine is an amino acid synthetized by fungi and mycobacteria which cannot be synthesized by other species. It has been detected in plants, animals and the human body. In the last past years, it has been recognized as a good antioxidant and recently, it has also been related to other properties besides antioxidant properties. Even though few studies on the toxicity of L-ergothioneine have been carried out, evidence suggests that L-ergothioneine is not harmful to health. Considering that L-ergothioneine is increasingly been linked to positive effects on human health coupled with the fact that it seems to be safe for human consumption, this molecule may be suitable for use as an ingredient in foods. On the other hand, despite the positive effects reported for this molecule, no estimate of L-ergothioneine intake has been carried out until now. Thus, the aim of this work is to estimate the intake of L-ergothioneine through food consumption of several European Countries and the United States. Values were estimated by using the deterministic and probabilistic approach. Results shown that the populations with the highest intake of L-ergothioneine correspond to Italian population, both for children and adults.
Chapter
Full-text available
Antioxidants and Functional Components in Aquatic Foods compiles for the first time the past and present research done on pro and antioxidants in aquatic animals. The book addresses an area of extreme importance for aquatic foods, since lipid oxidation leads to such a large number of quality problems. Many of these problems are also seen in other muscle based foods, but are exaggerated in aquatic foods, so the book’s contents will be of great use and interest to other fields. Written by top researchers in the field, the book offers not only general overviews of lipid oxidation in aquatic foods and aquatic food pro and antioxidant systems, but also covers specifics and gives the latest information on the key pro and anti-oxidants derived from aquatic foods as well as some of the most recent and innovative means to control lipid oxidations in aquatic foods and food systems with fish oils. Coverage includes the latest research on the effects aquatic foods have on oxidative stress in the human body, an area of great interest recently. Additionally, a chapter is devoted to the latest techniques to measure antioxidative potential of aquatic foods, an area still in development and one very important to the antioxidant research community.
Article
It has been reported that the phenolic fraction (PF) of extra virgin olive oil contains compounds that are important inhibitors of lipid peroxidation in vitro and are believed to be effective through their free radical scavenging and metal chelating properties. An excellent model of in vivo free radical induced damage, associated with extensive lipid peroxidation, is the ferricnitrilotriacetate (Fe-NTA) model. Intraperitoneal injection (i.p.) of Fe-NTA leads in rats to increasing oxidative stress, that starts from the plasma compartment, where Fe-NTA finds the ideal environment to react with oxidizable lipids, as unsaturated fatty acids (UFA) and cholesterol in lipoproteins particles. To investigate the action of the PF as inhibitor of the lipid peroxidation process in the plasma compartment, we treated Wistar rats with the PF (25 mg-50 mg/Kg bw) prior to the administration of a sub-lethal dose (15 mg Fe/Kg bw) of Fe-NTA. Fe-NTA treatment induced a significant decrease of UFA and cholesterol, together with an increase of fatty acids hydroperoxides (HP) and 7-ketocholesterol (7-keto). I.p. administration of PF significantly inhibited fatty acids and cholesterol oxidation, and reduced the levels of HP and 7-keto. Phenolic compounds may associate with lipoproteins particles, increasing their resistance against oxidation or may directly trap radicals generated in the plasma aqueous compartment.
Article
We measured the anti-oxidative and anti-inflammatory activities of hot water extracts prepared from 11 species of mushrooms. Anti-oxidative activity was evaluated using the oxygen radical absorbance capacity method, and anti-inflammatory activity was examined by measuring the inhibition of lysine chloramine formation by hypochlorous acid. Hot water extracts of Grifola gargal (G. gargal) showed the strongest anti-oxidative activity and inhibitory effects on lysine chloramines. Hot water extracts of G. gargal were evaluated by HPLC and divided into 8 fractions. The most active fraction among these 8 fractions was further purified by preparative HPLC. The active component isolated by HPLC was identified as ergothioneine (EGT) using spectral analysis. On HPLC analysis, the EGT content in G. gargal was the highest among the 11 species of mushrooms. We also examined the protective role of EGT by examining the inflammatory response of adipocyte cells induced by tumor necrosis factor-α.
Article
The present study was undertaken to evaluate the possible ameliorating effect of butylated hydroxyl toluene (BHT), associated with ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress and liver injury in mice. The treatment of mice with Fe-NTA alone enhances ornithine decarboxylase activity to 4.6 folds, protein carbonyl formation increased up to 2.9 folds and DNA synthesis expressed in terms of [(3)H] thymidine incorporation increased to 3.2 folds, and antioxidants and antioxidant enzymes decreased to 1.8-2.5 folds, compared with the corresponding saline-treated controls. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of BHT. Our data show that BHT can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent.
Article
Ergothioneine (ET) is a natural compound that humans and other vertebrates must absorb from dietary sources. In general, ET is considered an intracellular antioxidant. However, the precise physiological purpose of ET and the consequences of ET deficiency are still unclear. The ergothioneine transporter ETT (human gene symbol SLC22A4) is a highly specific transporter for the uptake of ET. Here, we sought to identify and knockout ETT from zebrafish (Danio rerio) to determine the function of ET. We cloned and assayed three related proteins from zebrafish, only one of which catalyzed the uptake of ET. RT-PCR analysis revealed that the protein is strongly expressed in the skin, brain, kidney, intestine, and eye. In ETT-knockout animals generated by retroviral insertion into exon 1, ET content was reduced by more than 1000-fold compared to the wild type. Thus, ETT is the sole transporter responsible for uptake of ET into zebrafish. ETT-knockout fish did not exhibit obvious differences in morphology or behaviour. In whole-fish homogenates, an increase in 4-hydroxy-2,3-trans-nonenal and malondialdehyde was observed, but only following stress caused by incubation with Pb(2+) or Cu(2+). Comparison of unstressed fish at the level of small molecules by LC-MS difference shading revealed a 3.8-fold increase in 8-oxoguanine (8-oxo-7,8-dihydroguanine) in the skin of ETT-knockout animals. Our knockout represents a new model for examining the consequences of complete absence of ET. Based on the phenotype observed here, we hypothesize that the specific purpose of ET could be to eliminate singlet oxygen. Copyright © 2015. Published by Elsevier Inc.
Article
Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [11C]PIB, [11C]ERGO, and [18F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.
Article
Edible mushrooms contain considerable amounts of the potent natural antioxidant 2-thiol-l-histidine-betaine (l-ergothioneine, ESH). The objective of this study was to evaluate the effects of extraction solvents, common cooking methods and storage conditions on the ESH content, total phenols (TPs) and antioxidant capacity of the edible mushroom Flammulina velutipes fruiting body and its hot water extract that had been stored at different temperatures. Regarding cooking procedures, boiling in water resulted in the highest losses of antioxidant activity of both ESH and TPs. Most of the losses of ESH and TPs were detected in the cooking water. The ESH contents in the raw mushroom fruiting bodies significantly decreased after 8 days of refrigerated storage under both dark and fluorescent lighting conditions. However, the TP content in the raw mushroom stored under fluorescent lighting significantly increased during 10 days of refrigeration. In contrast, the ESH and TP contents as well as DPPH radical scavenging ability of the fruiting bodies remained unchanged for up to 15 days of frozen storage at -18 degrees C. The same behaviour was obtained with the mushroom extract packed in plastic tubes. The correlation between DPPH radical scavenging activity and ESH contents was higher than that for TP compounds.
Article
An efficient and sensitive method was established for quantitative analysis of L-Ergothioneine during fermentation analyze by reversed-phase-high performance liquid chromatography (RP-HPLC). The method was carried out on two C18 columns (4.6 × 250 mm, 5 um), and the isocratic mobile phase was 1 % methanol containing boric acid adjusted to a pH of 5.0 with a flow rate of 0.7 mL/min. An UV-VIS detector equipped with a wavelength of 257 nm was employed. The injection volume was 5 μL, with the columns temperature being 25 °C. The linearity, recovery, limit of detection (LOD) and quantification (LOQ), precision, repeatability, stability, and recovery were all tested and good results were obtained. The method was simple, rapid, accurate, and high sensitivity and could be utilized for the research and development of L-Ergothioneine in industry.
Article
Previous studies have demonstrated a number of physiological functions for shiitake mushroom (Lentinula edodes), among which the antioxidant activity has been evaluated primarily using conventional chemical techniques. To date, there have been no reports on the anti-oxidative stress effect or on the antioxidant enzyme induction activity of shiitake/shiitake artifact. Therefore, in this study, we evaluated the anti-oxidative stress effect of shiitake grown in Miyazaki Prefecture and shiitake artifact from luminescence values obtained using a HepG2-ARE luciferase reporter assay system. The results showed that shiitake exhibited an anti-oxidative stress effect and, based on western blot analysis, was able to induce the expression of the antioxidant enzyme HO-1. Moreover, the anti-oxidative stress effect was found to be retained in dried shiitake. It is possible that the anti-oxidative stress effect of shiitake might be increased via heat processing or lactic acid fermentation.
Article
The effects of supplementing ergothioneine-rich mushroom extracts (ME) on discoloration and lipid oxidation in astaxanthin-pigmented salmon muscles were evaluated. ME (Flammulina velutipes) were added (in vitro) to minced Oncorhynchus mykiss muscles and stored at -10°C. During several weeks of storage, the ME-treated group showed lower lipid hydroperoxide (HPO) accumulation and higher retained astaxanthin levels than in the control group. The effects of adding concentrated ME (Pleurotus cornucopiae) to Oncorhynchus kisutch diets were also tested over a 2-month feeding trial. No adverse effects on fish growth or pigmentation were observed. Muscle samples were collected, stored (-2 or -18°C), and evaluated. At the end of the storage period, the ME-treated group had lower HPO and higher retained astaxanthin levels in the muscle samples than the levels in the control group. Thus, the addition of ergothioneine from MEs successfully controlled lipid oxidation and stabilized astaxanthin during post-harvest storage at low temperatures
Preprint
Full-text available
L-(+)-Ergothioneine is an unusual, naturally occurring antioxidant nutraceutical that has been shown to help reduce cellular oxidative damage. Humans do not biosynthesise it, so can acquire it only from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is considered to be a nutraceutical and possible vitamin that is involved in the maintenance of health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is thus a potentially useful dietary supplement. Present methods of commercial production rely on extraction from natural sources or on chemical synthesis. Here we describe the engineering of the baker's yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined media. After integrating combinations of ERG biosynthetic pathways from different organisms, we screened yeast strains for their production of ERG. The highest-producing strain was also engineered with known ergothioneine transporters. The effect of amino acid supplementation of the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-out of TOR1 or YIH1. We also optimized the media composition using fractional factorial methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture in bioreactors. Because S. cerevisiae is a GRAS ('generally recognised as safe') organism that is widely used for nutraceutical production, this work provides a promising process for the biosynthetic production of ERG.
Article
Aim Cisplatin is a potent chemotherapeutic agent whose therapeutic application is hindered by the associated nephrotoxicity. Cisplatin-evoked nephrotoxicity has been largely attributed to the induction of oxidative stress and inflammatory responses. The current study aimed at investigating the ability of ergothioneine to mitigate cisplatin-evoked nephrotoxicity and to elucidate the underlining molecular mechanisms. Main methods Wistar rats were treated with a daily dose of ergothioneine (70 mg/kg, po) for fourteen days and a single dose of cisplatin (5 mg/kg, ip) on day ten. On day fifteen, kidneys and blood specimens were collected and subjected to Western blotting, ELISA, histopathological, and spectrophotometric analysis. Key findings Ergothioneine significantly enhanced renal function in cisplatin-treated rats as manifested by increased GFR and decreased serum creatinine and blood urea nitrogen. Ergothioneine effectively reduced the cisplatin-induced oxidative stress and mitigated apoptosis and the histopathological changes. Mechanistically, ergothioneine induced the expression of the antioxidant transcription factor Nrf2 and up-regulated its downstream targets NQO1 and HO-1. Equally important, ergothioneine inhibited γ-glutamyl transpeptidase that plays crucial roles in biotransformation of cisplatin into a toxic metabolite. Additionally, it reduced the pro-apoptotic protein p53 and the inflammatory transcription factor NF-κB along with its downstream pro-inflammatory cytokines TNF-α and IL-1β. Significance The results of the current work shed the light on the ameliorating effect of ergothioneine on cisplatin-evoked nephrotoxicity that is potentially mediated through modulation of Nrf2, p53, and NF-κB signaling and inhibition of γ-glutamyl transpeptidase. This findings support the potential application of ergothioneine in controlling cisplatin-associated nephrotoxicity although clinical investigations are warranted.
Article
Full-text available
Ergothioneine (ERGO) is a rare amino acid mostly found in fungi, including mushrooms, with recognized antioxidant activity to protect tissues from damage by reactive oxygen species (ROS) components. Prior to this publication, the biodistribution of ERGO has been performed solely in vitro using extracted tissues. The aim of this study was to develop a feasible chemistry for the synthesis of an ERGO PET radioligand, [11C]ERGO, to facilitate in vivo study. The radioligand probe was synthesized with identical structure to ERGO by employing an orthogonal protection/deprotection approach. [11C]methylation of the precursor was performed via [11C]CH3OTf to provide [11C]ERGO radioligand. The [11C]ERGO was isolated by RP-HPLC with a molar activity of 690 TBq/mmol. To demonstrate the biodistribution of the radioligand, we administered approximately 37 MBq/0.1 mL in 5XFAD mice, a mouse model of Alzheimer’s disease via the tail vein. The distribution of ERGO in the brain was monitored using 90-min dynamic PET scans. The delivery and specific retention of [11C]ERGO in an LPS-mediated neuroinflammation mouse model was also demonstrated. For the pharmacokinetic study, the concentration of the compound in the serum started to decrease 10 min after injection while starting to distribute in other peripheral tissues. In particular, a significant amount of the compound was found in the eyes and small intestine. The radioligand was also distributed in several regions of the brain of 5XFAD mice, and the signal remained strong 30 min post-injection. This is the first time the biodistribution of this antioxidant and rare amino acid has been demonstrated in a preclinical mouse model in a highly sensitive and non-invasive manner.
Article
This study aimed to evaluate the impact of ergothioniene (ESH) concentrated extract (CE) to lipid anti‐oxidation and γ‐aminobutyric acid (GABA), γ‐oryzanol (GORZ) biosynthesis during germinated brown rice (GBR) processing. To do that 0, 2, 4 and 6% ESH CE was supplemented to soaking stage of brown rice for 6 hr and determined changes about the quality of GBR during processing. The results showed when added 4% of ESH CE to soaking stage, total lipid was stable during four stages of GBR processing as 1.96, 1.87, 1.77, and 1.67 g/100 g corresponding to less increasing peroxide and thiobarbituric acid–reactive substances (TBARs) as 0.53, 0.54, 0.55, and 0.55 meq/kg lipid and 0.21, 0.23, 0.25, and 0.26 µmol TBARs/g while GABA and GORZ increased considerably to 2378.63 mg/kg and 222 mg/kg, respectively. The results indicated that ESH CE helps to increase GABA, GORZ and prevent lipid oxidation that contributes to improving the quality of GBR. GBR contains various bioactive compounds such as GABA, GORZ, which have positive effects for human health. So, it becomes one of the value‐added products from rice. However, in GBR processing, there are still some problems that impact negatively on the quality of GBR such as low levels of GABA, GORZ and high levels of peroxide and TBAR values that may occur during processing. To address these problems, this study used ESH, a powerful antioxidant compound, which was biosynthesized from Aspergillus oryzae applying to GBR processing. The results show that ESH CE not only inhibits fat oxidation during GBR processing but also increases significantly GABA, GORZ level. So, this study contributed one of great solutions for improving the quality of GBR products.
Article
Full-text available
Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a trimethylated and sulphurised histidine derivative which exhibits antioxidant properties. Here we report that deletion of Aspergillus fumigatus egtA (AFUA_2G15650), which encodes a trimodular enzyme, abrogated EGT biosynthesis in this opportunistic pathogen. EGT biosynthetic deficiency in A. fumigatus significantly reduced resistance to elevated H2O2 and menadione, respectively, impaired gliotoxin production and resulted in attenuated conidiation. Quantitative proteomic analysis revealed substantial proteomic remodelling in ΔegtA compared to wild-type under both basal and ROS conditions, whereby the abundance of 290 proteins was altered. Specifically, the reciprocal differential abundance of cystathionine γ-synthase and β-lyase, respectively, influenced cystathionine availability to effect EGT biosynthesis. A combined deficiency in EGT biosynthesis and the oxidative stress response regulator Yap1, which led to extreme oxidative stress susceptibility, decreased resistance to heavy metals and production of the extracellular siderophore triacetylfusarinine C and increased accumulation of the intracellular siderophore ferricrocin. EGT dissipated H2O2in vitro, and elevated intracellular GSH levels accompanied abrogation of EGT biosynthesis. EGT deficiency only decreased resistance to high H2O2 levels which suggests functionality as an auxiliary antioxidant, required for growth at elevated oxidative stress conditions. Combined, these data reveal new interactions between cellular redox homeostasis, secondary metabolism and metal ion homeostasis.
Article
Full-text available
Ergothioneine is widely distributed in biological systems, particularly in red blood cells of animals. However, it's functional role in human body is not well understood. In order to investigate the biochemical effect of L-ergothioneine, its concentration changes in human blood with respect to ages in healthy individuals was first investigated. L-ergothioneine concentrations in the blood of Saudi males from western province at different stages of life were measured by the procedure of Carlsson et al., 1974. At early stages of life (1-10 years), the concentrations of LER is 1.5-2.0 mg/100 ml. It increases gradually at the age of 11-18 years where it reaches the maximum value of 3.7 mg/100 ml. Then, it declines gradually to 3.0-2.3 mg/ 100 ml during the period of 19-50 years. An increase in the level of LER (2.8 mg/100 ml) was seen at the age of 51+.
Article
Full-text available
Ergothioneine (ESH) is a low-molecular-mass thiol present in millimolar concentrations in a limited number of tissues, including erythrocytes, kidney, seminal fluid and liver; however, its biological function is still unclear. In the present study we investigated the role of ESH in the catabolism of S-nitrosoglutathione (GSNO). The results show that: (1) GSNO decomposition is strongly influenced by ESH (k"=0.178+/-0.032 M(-1) x s(-1)); (2) ammonia is the main nitrogen-containing compound generated by the reaction; and (3) nitrite is practically absent under both aerobic and anaerobic conditions. These findings are markedly different from those reported for the GSH-induced decomposition of GSNO, in which the nitrogen-containing end products are nitrite, ammonia and nitrous oxide (N(2)O) under aerobic conditions but nitrite, ammonia, nitric oxide (NO) and small quantities of hydroxylamine under anaerobic conditions. Considering the high concentration of ESH in specific cells, the reaction with GSNO should be considered as an important molecular event occurring in the cell.
Article
Intraperitoneal injection of the iron-complex, ferric-nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage associated with oxidative damage in vivo. Fe-NTA induced a time-dependent decrease of several polyunsaturated fatty acids (PUFA), together with increased conjugated diene values and decreased cellular levels of α-tocopherol and glutathione. At the time of maximum detectable oxidation (3 h), after the injection of a sublethal dose of Fe-NTA there were clear reductions in the peak values over the controls for several fatty acids notably, 20:5 (eicosapentaenoic acid) (36%), 22:6 (docosahexanoic acid) (30%), 20:3 n6 (eicosatrienoic acid) (30%) and 20:4 (arachidonic acid) (28%) in the kidney. Fewer fatty acids showed a reduction in their residual values in the liver. 20:5 was reduced by 45% and for the 18:3 n3 and 18:3 n6, reductions of 35%, respectively. The profile of PUFAs is sensitive to the oxidative damage due to Fe-NTA and this may find applications as oxidative biomarker model.
Article
Weaning mice were fed a diet supplemented with beef tallow (BT) or BT plus docosahexaenoic acid (DHA) containing 100 mg α-tocopherol/kg (α-Toc100) or 500 mg α-tocopherol/kg (α-Toc500) for 4 wk to modify membrane fatty acid unsaturation, and then were administered ferric nitrilotriacetate (Fe-NTA). The mortality caused by Fe-NTA was higher in the group fed the DHA (α-Toc100) diet than in the BT diet groups but the DHA (α-Toc500) diet suppressed this increase. Serum and kidney α-tocopherol contents were slightly influenced by the dietary fatty acids but not significantly. These results indicate that the increased unsaturation of tissue lipids enhances oxidative damage induced by Fe-NTA in mice fed DHA (α-Toc100) but not when additional α-tocopherol is supplemented. The apparent discrepancy between the observed enhancement by dietary DHA of oxidative damage and the beneficial effects of dietary DHA on the so-called free radical diseases is discussed in terms of strong bolus oxidative stress and moderate chronic oxidative stress.
Article
Conjugated diene isomers of linoleic acid (CLA), possess anticarcinogenic and antiatherogenic properties, but little is known about their metabolism. We have recently obtained evidence that CLA present in partially hydrogenated oil can be metabolized to conjugated linolenic and eicosatrienoic acids in rat liver. In the present study, we have investigated whether CLA are metabolized in the liver of lambs, which normally consume high levels of CLA produced in the rumen and present in their diet, consisting exclusively of milk. Conjugated linolenic, eicosatrienoic, and arachidonic acids were detected in lamb liver phospholipids showing that elongation and desaturation of CLA occur also in lamb tissues, and that all metabolites maintain the conjugated diene structure.
Article
A commercially available partially hydrogenated fat was analyzed for fatty acids containing conjugated dienes. The fatty acids were isolated by high-performance liquid chromatography (HPLC), and analyzed with a photodiode array detector and an atmospheric-pressure ionization mass spectrometer. Conventional and second-derivative ultraviolet (UV) spectra of the peaks eluting from the HPLC were recorded with the photodiode array detector, and peaks displaying second-derivative UV spectra characteristic of the conjugated diene chromophore were analyzed by mass spectrometry. The UV and mass spectra of the fatty acids with conjugated dienes, present in the partially hydrogenated fat, were identical to those of reference preparations of linoleic acid isomers with conjugated dienes. The results obtained emphasize that care must be exercised in the interpretation of clinical and experimental data concerning the detection of conjugated dienes in tissues or body fluids of humans and experimental animals. The conjugated dienes may not reflect an ongoing process of lipid peroxidation, but may be of dietary origin.
Article
Free radicals and other reactive oxygen species (ROS) are constantly formed in the human body. Free-radical mechanisms have been implicated in the pathology of several human diseases, including cancer, atherosclerosis, malaria, and rheumatoid arthritis and neurodegenerative diseases. For example, the superoxide radical (O 2 ·− ) and hydrogen peroxide (H2O2) are known to be generated in the brain and nervous system in vivo, and several areas of the human brain are rich in iron, which appears to be easily mobilizable in a form that can stimulate free-radical reactions. Antioxidant defenses to remove O 2 ·− and H2O2 exist. Superoxide dismutases (SOD) remove O 2 ·− by greatly accelerating its conversion to H2O2. Catalases in peroxisomes convert H2O2 into water and O2 and help to dispose of H2O2 generated by the action of the oxidase enzymes that are located in these organelles. Other important H2O2-removing enzymes in human cells are the glutathione peroxidases. When produced in excess, ROS can cause tissue injury. However, tissue injury can itself cause ROS generation (e.g., by causing activation of phagocytes or releasing transition metal ions from damaged cells), which may (or may not, depending on the situation) contribute to a worsening of the injury. Assessment of oxidative damage to biomolecules by means of emerging technologies based on products of oxidative damage to DNA (e.g., 8-hydroxydeoxyguanosine), lipids (e.g., isoprostanes), and proteins (altered amino acids) would not only advance our understanding of the underlying mechanisms but also facilitate supplementation and intervention studies designed and conducted to test antioxidant efficacy in human health and disease.
Article
Oxidative damage by free radicals, which is the basis for the free radical theory of aging, has been well investigated within the context of oxidant/antioxidant balance. Age-associated disorders are believed to be associated with the time-dependent shift in the antioxidant/prooxidant balance in favor of oxidative stress. In this brief review, the importance of dietary antioxidant intervention on longevity and age-associated changes in bodily functions and diseases are discussed. Evidence has indicated that increasing the endogenous antioxidants defense system and modulation of free radical production by dietary restrictions contribute to increased longevity in animal models. Thus, increasing dietary intake of antioxidants is believed to increase longevity. Earlier studies have shown some increase in median life span in animal models. It was found that supplementing middle-aged (18 months) C57/BL mice with various antioxidants (vitamin E, glutathione, melatonin, and strawberry extract) had no effect on longevity as measured by the average age of death. Therefore, dietary antioxidant supplementation seems unlikely to increase longevity when begun in middle age; supplementation started in early life might be more effective. However, in middle-aged mice, vitamin E was effective in reducing lung viral titer when animals were exposed to influenza virus. Vitamin E supplementation improves cell-mediated immunity in mice and in humans. In addition to modulating the oxidation of low-density lipoproteins, vitamin E can modulate immune/endothelial cells interactions, thus reducing the risk of cardiovascular disease (CVD), a major cause of morbidity and mortality in elderly. Thus, antioxidants such as vitamin E from food sources or supplements appear to be promising for successful aging by improving immune function, and reducing the risk of several age-associated chronic diseases, such as CVD.
Article
Both aging and age-associated neurodegenerative diseases are associated with various degrees of behavioral impairments, and among the prime candidates responsible for producing the neuronal changes mediating these behavioral deficits appear to be free radicals and the oxidative stress they generate. Therefore, there have been a number of studies which have examined the putative positive benefits of antioxidants in altering, reversing, or forestalling these neuronal/behavioral decrements, with varying degrees of success. Additional experiments have examined the effects of diets rich in fruits and vegetables or herbal extracts in reducing certain types of cancer and cardiovascular diseases, and evidence emerging from such experiments suggests that these kinds of dietary modifications may be beneficial in altering neuronal/behavioral deficits in aging, as well. These kinds of diets are particularly rich in antioxidants such as vitamins A, C, E, and bioflavonoids (such as flavones, tannins, and anthocyanins), and thus, there may be synergistic effects among them. The present paper will review studies concerning the influence of dietary and synthetic antioxidants on normal, pathological age-related, and reactive oxygen species-induced behavioral changes in human and animal subjects. The antioxidants reviewed are vitamin E, α-lipoic acid, and the phytochemicals contained in herbals, fruits and vegetables.
Article
Laboratory studies with classical renal carcinogens in the rat and mouse, as well as research investigation with some of the chemicals proving positive for the kidney in National Toxicology Program carcinogenicity bioassays, have demonstrated the existence of a range of diverse mechanisms underlying rodent kidney carcinogenesis. The classical carcinogens used as experimental models for studying renal tumor pathogenesis, such as the nitrosamines, are genotoxic and interact directly with DNA, forming DNA adducts with mutagenic potential. In contrast, potassium bromate and ferric nitrilotriacetate (Fe-NTA), also effective renal carcinogens, appear to cause indirect damage to DNA mediated by oxidative stress. A number of nongenotoxic chemicals are associated with epigenetic renal tumor induction in rodents, and the activity of these tends to involve prolonged stimulation of cell proliferation throughout the duration of exposure. This mode of action reflects a sustained regenerative response, either due to direct chemical toxicity to the tubule cells, as with chloroform, or to indirect cytotoxicity associated with lysosomal overload, as in alpha2u-globulin accumulation in male rats resulting from the administration of such chemicals as d-limonene and tetrachloroethylene. The histopathologic nature of hydroquinone renal carcinogenesis suggests that an additional epigenetic pathway to renal tubule tumor formation in rats may be through chemical-mediated exacerbation of, and interaction with, the age-related spontaneous renal disease, chronic progressive nephropathy. These various mechanistic pathways have implications for the nature of the induced cancer process with respect to tumor incidence, latency, malignancy, and sex predisposition.
Article
Rats and rabbits parenterally treated with a large daily dose of ferric nitrilotriacetate manifested diabetic symptoms such as hypergycemia, glycosuria, ketonemia, and ketonuria after approximately 60 days fo treatment. The blood insulin response to oral glucose loading was poor. Heavy iron deposits were found in liver parenchymal cells and in pancreatic exocrine cells, although some iron was deposited in the macrophages and reticuloendothelial cells of the organs. Faint iron staining was found in some pancreatic islet cells, with a reduction in beta granules and weak zinc staining. Cirrhotic liver changes and skin pigment deposition were not observed. Repeated blood withdrawals from ferric-nitrilotriacetate-treated animals resulted in disappearance of hypergycmia, glycosuria, ketonemia, and ketonuria; disappearance of iron from the liver and pancreas; and restoration of islet beta granules to the control level.
Article
The high performance liquid chromatographic procedure was established for the determination of ergothioneine in biological materials. The procedure is also applicable to the purification of 3H-ergothioneine. The metabolism of ergothioneine given to rats was very slow ; the ergothioneine was not disappear even after 1 week fasting. The ergothioneine administrated was mostly concentrated in the liver and the level was 10 times as high as that in blood. All ergothioneine in the blood was found in blood corpuscles 24 hr after the administration.
Article
A sensitive, highly reproducible method for tissue tocopherol analysis that combines saponification in the presence of large nmount of ascorbic acid to remove interfering substances, extraction fo the nonsponifiable lipids with hexane, and fluorometric measurement of the tocopherol is presented. The nonsaponifiable lipids phase contained only one fluorochrome in the 290 am excitation and 330 nm emission range, and it was identified as tocopherol by thin layer and column chromatography. Column chromatography of the hexane extract of a saponified, 14C-tocopherolspiked microsomal fraction showed that no measurable oxidation to tocopherylquinone had occurred. The flurometric method for tocopherol analysis was applied to homogenates and subcellular fractions from rat liver, kidney, lung, and heart and red blood cells. The heavy mitochondrial and microsomal fractions had the highest subcellular concentrations of tocopherol.
Article
Ergothioneine is a product of plant origin that accumulates in animal tissues. Its suggested ability to act as an antioxidant has been evaluated. Ergothioneine is a powerful scavenger of hydroxyl radicals (.OH) and an inhibitor of iron or copper ion-dependent generation of .OH from hydrogen peroxide (H2O2). It is also an inhibitor of copper ion-dependent oxidation of oxyhaemoglobin, and of arachidonic acid peroxidation promoted by mixtures of myoglobin (or haemoglobin) and H2O2. Ergothioneine is a powerful scavenger of hypochlorous acid, being able to protect alpha 1-antiproteinase against inactivation by this molecule. By contrast, it does not react rapidly with superoxide (O2-) or hydrogen peroxide (H2O2) and it does not inhibit microsomal lipid peroxidation in the presence of iron ions. Overall, our results show that ergothioneine at the concentrations present in vivo could act as an antioxidant.
Article
The effects of thiols and thiocarbamides on hydroxyl radical (.OH) formation by the hypoxanthine(HYP)-xanthine oxidase(XOD)-Fe3+ .EDTA system were investigated in the range of 0.5-5 mM by colorimetrically measuring salicylate hydroxylation. Thiocarbamides powerfully inhibited the hydroxylation while thiols showed a paradoxical effect, enhancing it at low concentrations, but inhibiting it at high ones. Thiols in the presence of Fe3+ .EDTA generated superoxide anions (O2-.) and .OH during the oxidation, but thiocarbamides did not. A study of the effect of ergothioneine, a thiocarbamide present in mammals, on the .OH spin adduct of 5,5-dimethyl-1-pyrroline-N-oxide(DMPO) by EPR spectrometry showed that it effectively decreased the .OH spin adduct without causing the appearance of other signals. Reaction mechanisms are proposed for the O2-. evolution and .OH formation by the thiols themselves in the presence of Fe3+ .EDTA and .OH with thiols and thiocarbamides.
Article
Wistar male rats were tested for nephrotoxicity and carcinogenicity after administration of ferric nitrilotriacetate [(NTA) CAS: 139-13-9] (Fe-NTA) [No. of rats (n) = 24] and Al-NTA (n = 24). The control rats were given AlCl3 (n = 10), NTA (n = 10), and saline (n = 10). Sublethal doses of Fe-NTA [5-7 mg Fe/kg (body wt)] and Al-NTA [1.5-2.0 mg Al/kg (body wt)] were chosen and injected ip for 3 months. AlCl3 and NTA were given in equivalent doses and saline was given in equivalent volumes. All the rats given Fe-NTA or Al-NTA had a depressed weight gain, polyuria, and glucosuria from the 1st week. Histologically, acute tubular necrosis and regenerating epithelial cells were observed. Regenerative atypical epithelial cells in the renal cortex were seen at the termination of Fe-NTA or Al-NTA administration. Control rats had no remarkable changes. After 1 year, primary renal cell carcinoma and metastases to liver, lung, and peritoneum were observed only in Fe-NTA-treated rats (14 of 18 surviving rats). On the contrary, there were no tumors in Al-NTA-treated rats (none of 12 surviving rats). The results suggest that nephrotoxicity and renal cell carcinoma are two independent phenomena from Al-NTA treatment and that a long-term sublethal dose of Al-NTA is not related to renal carcinogenicity.
Article
This laboratory has previously postulated that bromobenzene-induced hepatic necrosis results from the formation of a reactive metabolite that arylates vital cellular macromolecules. Accordingly, the severity of liver necrosis has been compared with the formation of metabolites of bromobenzene and with covalent binding of metabolites in vivo and in vitro after various pretreatment regimens that alter hepatotoxicity. These data provide direct kinetic evidence that 3,4-bromobenzene oxide is the reactive hepatotoxic metabolite. The studies also demonstrate that the hepatotoxic metabolite is preferentially conjugated (detoxified) with glutathione, thereby depleting glutathione from the liver. Liver necrosis and arylation of cellular macromolecules occur only when glutathione is no longer available. Thus, a dose threshold exists for bromobenzene-induced hepatic necrosis.
Article
The interaction of ergothioneine (I) with a number of divalent metal ions was determined using a pH titration method. Formation constants for complexes containing 2 moles of ligand and 1 mole of metal ion were found to be 1018.2 (Cu2+) 1011.6 (Zn2+), 108.2 (Ni2+), and 108.2 (Co2+). A study of the inhibitory power of I on selected Zn and Cu metalloenzymes was made. None of the 4 Zn-containing enzymes, including 3 dehydrogenases and alkaline phosphatase, were inhibited even if preincubated for 6 hr with 10-2 M I. Four different Cu enzyme systems were investigated, including uricase, ascorbate oxidase, MAO, and a number of polyphenol oxidases. Of these, only the polyphenol oxidases were inhibited by I. Kinetic measurements using Psalliota campestris (mushroom) polyphenol oxidase showed that inhibition by I does not involve removal of Cu from the enzyme, but is reversible and displays characteristics of both competitive and noncompetitive inhibition. This type of inhibition may result from the presence of Cu at noncatalytic as well as catalytic sites of mushroom polyphenol oxidase.
Article
When ergothioneine was administered to rats for 7 d, the pentobarbital sleeping time was reduced significantly. This action was specific to ergothioneine and was not shown by various ergothioneine-related compounds (cysteine, glutathione, carnitine and histidine). This action of ergothioneine did not appear to be caused by induction of the drug-metabolizing enzyme system. The level of ergothioneine in the liver decreased markedly when phenobarbital or ethionine was administered to rats. Ergothioneine inhibited hepatic injury and significantly decreased the level of lipid peroxide induced by ethionine administration.
Article
(1) Ergothioneine is contained as a component of the organella membranes in the rat liver, and is liberated by heat treatment or dithiothreitol treatment. The amount of bound form increases with aging up to 11 weeks of age, and then decreases. All of the ergothioneine measured by the normal determination procedures can be considered to be free form. (2) Ergothioneine is bound to proteins in the blood plasma, but is present in free form in erythrocytes. (3) Biosynthesis of ergothioneine from amino acids in rats was not detectable. Ergothioneine is ingested from the diet and accumulated in the body. (4) When dietary ergothioneine is restricted for 18 weeks, the amount in the liver falls to a threshold value but apparently does not fall further, and no deficiency symptoms are observed. (5) Experimental ergothioneine-free rats were successfully produced in the second generation (born to parent rats fed on ergothioneine-free diet).
Article
This chapter discusses the detection of conjugated dienes by second derivative ultraviolet spectrophotometry. Conjugated dienes (CD) refers to two double bonds separated by a single bond. This structure is unusual in polyunsaturated fatty acids (PUFA). It is generally accepted that the occurrence of conjugated dienes in lipids means autoxidation of lipids. In fact, because of the divinylmethane structure, PUFA are particularly susceptible to hydrogen abstraction by free radical attack, becoming themselves free radical intermediates. This results in the rearrangement of the double bond to conjugated dienes and, in the presence of O2, the formation of fatty acid hydroperoxides. The conjugated diene moiety is a strong chromophore that can be detected spectrophotometrically. When present in fatty acids they show a characteristic absorption in the UV region at around 234 nm. However, detection and quantitation of conjugated dienes in mixtures of peroxidized and nonperoxidized lipids, by means of simple UV spectrophotometry, is complicated by the end absorption exhibited by naturally occurring and nonperoxidized lipids.
Article
An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and free 4-hydroxy-2-nonenal (HNE) was observed in the kidney homogenates of rats treated with Fe-NTA. Based on the fact that HNE is capable of reacting with cellular proteins, we attempted to detect the localization of HNE-modified proteins in rat kidney tissues with an immunohistochemical procedure. By means of an immunohistochemical technique using polyclonal antibody against the HNE-modified proteins, it was shown that HNE-modified proteins are formed in the target cells of this carcinogenesis model. HNE-modified proteins were detected in the renal proximal tubules 1 hr after i.p. administration of Fe-NTA (15 mg of iron per kg). Intense positivity was found in the cells with degeneration. After 6 hr, the level of HNE-protein conjugates decreased due to the subsequent necrosis. The intensity of the immunochemical reaction with HNE-modified proteins increased in parallel with an increase in the amounts of thiobartituric acid-reactive substances and free HNE that were found. Furthermore, histochemical detection of aldehydes by cold Schiff's reagent demonstrated that location of aldehydes was identical to that of the HNE-modified proteins determined by immunohistochemical procedures. It would thus appear that the production of HNE, a genotoxic and mutagenic aldehyde, and its reaction with proteins may play a role in Fe-NTA-induced renal carcinogenesis.
Article
The following thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetylcysteine, and penicillamine. As a measure for protection, the inhibition of in vitro irreversible photobinding of the labeled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to protein and DNA was used. Besides photobinding to biomacromolecules, the photodegradation of CPZ and the formation of promazine (PZH) and hydroxypromazine (PZOH) were measured as well. Because of the H-atom and electron donating capacity of the thiols, the ratio [PZOH]/[PZH] was expected to be decreased and the photodegradation of CPZ was expected to be higher in the presence of thiols. Maximum inhibition of CPZ photobinding ranged for the different thiols between 21-100% (DNA) and 17-87% (human serum albumin). All thiols enhanced the photodegradation of CPZ (19-84%) and inhibited the ratio [PZOH]/[PZH] (90-97%). 8-MOP photobinding to human serum albumin was also clearly inhibited (75-96%), but remarkably less to DNA (2-41%). This study indicates that thiols are able to cope with a variety of reactive species. Scavenging of radicals, quenching of singlet molecular oxygen species and reaction with excited states seem to be essential mechanisms involved with this process.
Article
Redox reactions of endogenous and exogenous sulphur-containing compounds are involved in protection against oxidative damage arising from the incidence and/or treatment of many diseases, including cancer. We have investigated, via pulse radiolysis, the one-electron oxidation of ergothioneine, a molecule with antioxidant properties which is detected at millimolar concentrations in certain tissues and fluids subject to oxidative stress, including erythrocytes and plasma. The spectrum of the transient species, assigned to the product of one-electron oxidation, observed after reaction of ergothioneine with the oxidizing radicals OH., N3. and CCl3O2. has a maximum absorption at 520 nm and is very similar to that obtained by oxidation of analogous molecules such as 2-mercaptoimidazole, 1-methyl-2-mercaptoimidazole, S-methyl- and S,N-dimethyl-ergothioneine. In the presence of vitamin C, the oxidized form of ergothioneine is repaired by a rapid reduction (k = 6.3 x 10(8) M(-1).s(-1)) producing ascorbyl radicals. This co-operative interaction between ergothionine and ascorbate, similar to that previously observed between vitamin E and ascorbate, may contribute to essential biological redox protection.
Article
Systemic administration of copper, an essential trace metal in the human body, has never been reported to be carcinogenic in animals. We investigated the induction of tumors by the cupric complex of nitrilotriacetic acid (Cu-NTA) in male Wistar rats. Thirty-two animals received ip injections of Cu-NTA, 3 to 5 mg of copper/kg body weight 5 days a week for 12 weeks, and were kept under close observation. For comparison, 31 animals received ip injections of ferric nitrilotriacetate (Fe-NTA), 5 to 10 mg of iron/kg body weight, and 16 animals received nitrilotriacetic acid (NTA) alone at the molar dose equivalent to Cu-NTA for the same period of time. Sixteen animals were left untreated as controls. Fourteen animals in the Cu-NTA group died of hepatic failure during the treatment period, and renal cell carcinoma (RCC) was induced in eight animals (25%). Of these, four animals died of either pulmonary metastasis or intraperitoneal hemorrhage. A total of 12 RCC were obtained, of which six tumors were > or = 5 mm. The Cu-NTA group yielded fewer RCC and required a longer latent period for their incubation than the Fe-NTA group. Furthermore, the Cu-NTA group showed one hepatocellular carcinoma and one high-grade sarcoma of hepatic origin. No renal or hepatic tumor was observed in the NTA or control groups. The nontumorous part of the kidney treated with Cu-NTA presented hemosiderosis caused by copper-induced hemolytic anemia. This is the first report that systemic administration of copper compounds can induce malignant tumors in animals. Not only copper but also iron may play a role in the Cu-NTA-induced renal carcinogenesis model.
Article
Free radicals and antioxidants are widely discussed in the clinical and nutritional literature. Antioxidants are needed to prevent the formation and oppose the actions of reactive oxygen and nitrogen species, which are generated in vivo and cause damage to DNA, lipids, proteins, and other biomolecules. Endogenous antioxidant defenses (superoxide dismutases, H2O2-removing enzymes, metal binding proteins) are inadequate to prevent damage completely, so diet-derived antioxidants are important in maintaining health. Many dietary compounds have been suggested to be important antioxidants: The evidence for a key role of vitamins E and C is strong, but that for carotenoids and related plant pigments is weaker. Interest is also growing in the role of plant phenolics, especially flavonoids. Some antioxidants can exert prooxidant effects in vitro, but their physiological relevance is uncertain. Experimental approaches to the optimization of antioxidant nutrient intake are proposed.
Article
The superoxide radical (O.2-) and nitric oxide (NO.) combine very rapidly to form peroxynitrite (ONOO-), a reactive tissue damaging nitrogen species thought to be involved in the pathology of several chronic diseases. The natural product ergothioneine protects against the nitration of tyrosine and the inactivation of alpha 1-antiproteinase by ONOO-. Ergothioneine merits further investigation as a biological and therapeutic antioxidant agent.
Ergothioneine (ERT), is a low molecular weight, sulfur-containing antioxidant occurring in up to millimolar amounts in mammalian tissues. Using an improved HPLC assay, ERT levels have been measured and compared in bovine and porcine eyes and erythrocytes. The rank order of ERT levels in bovine ocular tissue was lens > retina = cornea > pigmented retinal epithelium (RPE) > aqueous humor (AQ) > vitreous humor (VIT) > sclera. In porcine ocular tissue, the rank order was retina > AQ > VIT > RPE > cornea > lens > sclera. ERT levels in bovine lens were about 250 x > that in porcine lens. Porcine erythrocyte levels were 5.5 x > bovine levels. Species differences were also observed in the retina, VIT and AQ where porcine levels were 2 to 10-fold greater than bovine levels. ERT in bovine lens and cornea was 35 and 14 times greater than the corresponding level of reduced glutathione (GSH). Porcine lens had 45 times more GSH than ERT. Values for ERT and GSH in other tissues from both species were of the same order of magnitude. These results are consistent with a role for ERT in prevention of oxidative damage to the eye.