L-ergothioneine and its combination with metformin attenuates renal dysfunction in type-2 diabetic rat model by activating Nrf2 antioxidant pathway

Dare, Ayobami; Channa, Mahendra L.; Nadar, Anand

doi:10.1016/j.biopha.2021.111921

Cited by 23 publications

(17 citation statements)

References 64 publications

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“…According to Dare et al (2021), ERT can be intimately related to the activation of the Nrf2-ARE pathway. The authors showed, in silico, that ERT could directly bind to Nrf2 by substituting the IVV-ligand with ERT in the Nrf2-IVV crystal complex, leading to Nrf2-Keap1 complex dissociation, nuclear accumulation of the freed Nrf2, thus the activation of antioxidant genes [ 79 ]. Moreover, indirectly, ERT could activate the Nrf2 pathway through the oxidized intermediates of the ERT (i.e., sulfonated [ESO 3 H] and desulfurized [EH] forms, also known as hercinin and disulfide [ESSE]) generated from the direct detoxification of H 2 O 2 [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells

Bernardo

Torres

Paula

et al. 2022

Genes

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This study aimed to establish the importance of ergothioneine (ERT) in the erythroid adaptation mechanisms by appraising the expression levels of redox-related genes associated with the PI3K/AKT/FoxO3 and Nrf2-ARE pathways using K562 cells induced to erythroid differentiation and H2O2-oxidative stress. Cell viability and gene expression were evaluated. Two concentrations of ERT were assessed, 1 nM (C1) and 100 µM (C2), with and without stress induction (100 µM H2O2). Assessments were made in three periods of the cellular differentiation process (D0, D2, and D4). The C1 treatment promoted the induction of FOXO3 (D0 and 2), PSMB5, and 6 expressions (D4); C1 + H2O2 treatment showed the highest levels of NRF2 transcripts, KEAP1 (D0), YWHAQ (D2 and 4), PSMB5 (D2) and PSMB6 (D4); and C2 + H2O2 (D2) an increase in FOXO3 and MST1 expression, with a decrease of YWHAQ and NRF2 was observed. in C2 + H2O2 (D2) an increase in FOXO3 and MST1, with a decrease in YWHAQ and NRF2 was observed All ERT treatments increased gamma-globin expression. Statistical multivariate analyzes highlighted that the Nrf2-ARE pathway presented a greater contribution in the production of PRDX1, SOD1, CAT, and PSBM5 mRNAs, whereas the PI3K/AKT/FoxO3 pathway was associated with the PRDX2 and TRX transcripts. In conclusion, ERT presented a cytoprotective action through Nrf2 and FoxO3, with the latter seeming to contribute to erythroid proliferation/differentiation.

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Section: Discussionmentioning

confidence: 99%

Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells

Bernardo

Torres

Paula

et al. 2022

Genes

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“…Along with RUNX1, transcription of the SLC22A4 gene has also been shown to be regulated by the NF-κB transcription factor, and the inflammatory cytokines IL-1 β and TNF-α (63) , data suggestive of ergothioneine accumulation being part of an orchestrated cellular immune defence. Moreover, multiple in vitro (64,65) and in vivo (66,67) studies suggest that ergothioneine activates the transcription factor nuclear factor erythroid 2related factor 2 (Nrf2), which triggers the cellular antioxidant defence system. Recent molecular docking and dynamic simulation data predict ergothioneine binds Nrf2 directly, preventing Nrf2 degradation (67) .…”

Section: Biological Rolesmentioning

confidence: 99%

“…Moreover, multiple in vitro (64,65) and in vivo (66,67) studies suggest that ergothioneine activates the transcription factor nuclear factor erythroid 2related factor 2 (Nrf2), which triggers the cellular antioxidant defence system. Recent molecular docking and dynamic simulation data predict ergothioneine binds Nrf2 directly, preventing Nrf2 degradation (67) . These data underscore the pleiotropic cytoprotective effects of ergothioneine beyond its redox activity.…”

Section: Biological Rolesmentioning

confidence: 99%

“…Ergothioneine supplementation attenuated diabetes-related alterations in sirtuin-1 and NF-κB mRNA expression in the liver, as well as the sterol regulatory element-binding transcription factor 1 and fatty acid synthase, the rate-limiting enzyme in fatty acid synthesis (91) . Separate work from the same investigators showed benefit from ergothioneine taken alone or in combination with metformin for improving markers of kidney injury (hypertrophy, serum creatinine, blood urea nitrogen and urine albumin and protein) (67) . Notably, the reduction of lipid peroxidation with ergothioneine supplementation has been reported in multiple injury models (67,84,85,91) and is of relevance to non-alcoholic fatty liver disease (NAFLD) pathogenesis.…”

Section: Healthy Ageing and The Prevention Of Cardiometabolic Diseasementioning

confidence: 99%

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Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?

2023

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Ergothioneine is a naturally occurring amino acid and thiol antioxidant found in high amounts in mushrooms and fermented foods. Humans and animals acquire ergothioneine from the diet through the pH-dependent activity of a membrane transporter, the large solute carrier 22A member 4 (SLC22A4), expressed on the apical membrane of the small intestine. The SLC22A4 transporter also functions in the renal reabsorption of ergothioneine in the kidney, with avid absorption and retention of ergothioneine from the diet observed in both animals and humans. Ergothioneine is capable of scavenging a diverse range of reactive oxygen and nitrogen species, has metal chelation properties, and is predicted to directly regulate nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Although not lethal, the genetic knockout of the SLC22A4 gene in multiple organisms increases susceptibility to oxidative stress, damage and inflammation; in agreement with a large body of preclinical data suggesting the physiological function of ergothioneine is as a cellular antioxidant and cytoprotectant agent. In humans, blood levels of ergothioneine decline after the age of 60 years, and lower levels of ergothioneine are associated with more rapid cognitive decline. Conversely, high plasma ergothioneine levels have been associated with significantly reduced cardiovascular mortality and overall mortality risks. In this horizon’s manuscript, we review evidence suggesting critical roles for dietary ergothioneine in healthy ageing and the prevention of cardiometabolic disease. We comment on some of the outstanding research questions in the field and consider the question of whether or not ergothioneine should be considered a conditionally essential micronutrient.

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“…Very recently, in an in silico study, Dare et al. [73] showed that, by substitution of the IVV‐ligand by EGT in the corresponding Nrf2‐IVV crystal complex, EGT could bind Nrf2 with internal energy of 11.4 kcal. Such a direct binding of EGT on Nrf2 needs to be demonstrated by an in vitro crystallization study of Nrf2 in the presence of EGT .…”

Section: Molecular Biological Activities Of Egtmentioning

confidence: 99%

Matching chemical properties to molecular biological activities opens a new perspective on l‐ergothioneine

Yadan¹

2022

FEBS Letters

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Edited by Barry HalliwellL-ergothioneine is a low-molecular weight natural product, the chemical structure of which comprises oxygen-, nitrogen-and sulfur-containing functional groups. This gives L-ergothioneine specific physicochemical properties and allows a better understanding of its chemical reactivity, which is primarily due to the 2-thio-imidazole group. Here, a review is provided of how different modes of chemical reactivity account for the reported molecular biological activities of L-ergothioneine. By matching the physicochemical properties to the biological properties of L-ergothioneine, a new perspective of the function and the mode of action of this enigmatic molecule emerges.

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L-ergothioneine and its combination with metformin attenuates renal dysfunction in type-2 diabetic rat model by activating Nrf2 antioxidant pathway

Cited by 23 publications

References 64 publications

Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells

Potential Cytoprotective and Regulatory Effects of Ergothioneine on Gene Expression of Proteins Involved in Erythroid Adaptation Mechanisms and Redox Pathways in K562 Cells

Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing?

Matching chemical properties to molecular biological activities opens a new perspective on l‐ergothioneine

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