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The Pleurotus oyster is a common edible mushroom rich in ergothioneine, a bioactive that has shown benefits to cognition in animals when administered in extract form. The OYSACO study investigated the acute effects of oyster mushroom (OM) on cognition, mood, inflammation and metabolism in healthy older adults. In a cross-over study, 33 participants consumed a noodle soup containing 0.5 (OM0.5), 1 (OM1) and 2 (OM2) servings of OM, and a calorie-matched control soup (OM0), on four separate occasions, each separated by one week. Cognitive function, mood and subjective appetite were assessed at baseline (BL, prior to intervention) and then at 2-, 4- and 6-hours post-consumption. Intervention palatability was recorded after consumption, and a serum sample was taken at 6-hours. Linear Mixed Modelling, with BL as covariate, revealed a significant decline in Positive Affect and concomitant increase in Mental Fatigue over the test day after consuming OM0, while no significant variation in mood was seen throughout the day following OM interventions. Cognitive findings were mixed with no consistent pattern of effects seen following OM interventions compared to OM0. Postprandial inflammatory markers (nitrite, NADPH oxidase 2 and inducible nitric oxide synthase) were significantly lower following OM interventions compared to OM0. Unexpectedly, brain derived neurotrophic factor was found to be dose-dependently lower after consuming OM compared to OM0. Overall, OM interventions helped maintain mood and lower inflammatory markers in healthy older adults, following acute supplementation. Further studies are required to unravel the underlying mechanisms involved.

BACKGROUND: Dementia, particularly Alzheimer's disease, is a major healthcare challenge in ageing societies. OBJECTIVE: This study aimed to investigate the efficacy and safety of a dietary compound, ergothioneine, in delaying cognitive decline in older individuals. METHODS: Nineteen subjects aged 60 or above with mild cognitive impairment were recruited for this double-blinded, randomized, and placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404, registration date: 19/08/2018). Subjects received either ergothioneine (25 mg per capsule) or a placebo, taken 3 times a week for one year. The whole blood profile, markers of renal and liver functions, neurocognitive performance, plasma levels of ergothioneine and its metabolites, and plasma biomarkers related to neurodegeneration were measured across the study. RESULTS: Ergothioneine intake did not alter clinical safety markers (blood counts, kidney and liver function) throughout the study, further validating its safety for human consumption. Subjects receiving ergothioneine demonstrated improved performance in assessment of learning ability and stabilized plasma levels of neurofilament light chain, compared with the placebo group, which saw no improvement in cognitive assessments and a significant increase in neurofilament light chain levels. CONCLUSIONS: Prolonged intake of ergothioneine showed no toxicity in elderly people. Enhanced Rey Auditory Verbal Learning Test performance and stabilized neurofilament light chain levels suggest improvements in memory and learning abilities and a deceleration of neuronal damage, respectively. Our results add to existing data that ergothioneine is safe for extended consumption and may hold the potential to delay cognitive decline in elderly adults.

Transporters of the SLC22 family, such as organic cation transporter 1 (OCT1), possess very broad substrate specificity. It is unclear to what extent the inhibitory potencies of OCT1 depend on the substrate used. Here, we describe a multisubstrate drug cocktail that allows for the simultaneous testing of drug-drug interactions using 8 different victim drugs: fenoterol, salbutamol, sumatriptan, zolmitriptan, ipratropium, trospium, methylnaltrexone, and metformin. There were no significant differences in Michaelis constant (KM) and vmax of the OCT1-mediated uptake of the substrates alone or in the cocktail. Depending on the victim drug analyzed, we observed 6.7-fold differences in the inhibitory potency of fenoterol (IC50 of 0.75 μM for metformin and 5.1 μM for sumatriptan). Similarly, the inhibitory potency of verapamil varied 6.7-fold (IC50 of 1.3 μM for zolmitriptan and 8.7 μM for ipratropium). Two groups of inhibitors showed strong correlations in their victim-dependent inhibitory potencies. Group 1 comprised verapamil, quinidine, fenoterol, and ipratropium, and group 2 comprised metformin, sumatriptan, and trimethoprim. By comparing OCT1 paralogs and orthologs, the broadest substrate spectra were observed for OCT1 and multidrug and toxin extrusion 1, followed by OCT2, multidrug and toxin extrusion 2-K, and OCT3. In contrast, organic cation transporters novel 1 and organic cation transporters novel 2 exhibited very narrow substrate specificity, transporting only L-carnitine and L-ergothioneine, respectively. In conclusion, OCT1 demonstrates substantial differences in inhibitory potencies, depending on the victim drug used. We developed a cocktail approach that enables rapid screening for such differences, facilitating the identification of drug-drug interactions at the early stages of drug development. This approach can be extended to other transporters with broad substrate specificity. SIGNIFICANCE STATEMENT: Polyspecific transporters have a broad substrate-binding cavity with no defined single binding position. Consequently, inhibitors may exhibit different inhibitory potencies depending on the victim drug used for testing. Here, we demonstrate this for orga

4. J Agric Food Chem. 2025 Apr 30;73(17):10186-10200. doi: 10.1021/acs.jafc.4c10263. Epub 2025 Apr 17. Synergistic Neuroprotective Effects of Ergothioneine and Lactoferrin in APP/PS1 Transgenic Mice and Mouse N2a Cells. Li H(1), Wang X(2), Li R(3), Chen L(1), Cheng G(2)(4)(5)(6), Xiong J(4)(7).

The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.

AIMS: This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the concentrations of ergothioneine in plasma at baseline and following mushroom consumption. METHODS: Ten healthy male subjects were recruited and received a diet containing no mushrooms (treatment A) or a high mushroom diet (treatment B; after at least a 7 day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg. RESULTS: Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine concentrations that were sustained for more than 48 h. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1 ± 25.1 vs. 76.9 ± 20.6 ml min(-1) , P = 0.031). No significant changes in AUC(0,tlast ) of gabapentin were observed (P = 0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin. CONCLUSIONS: These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUC(0,tlast ) of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies. © 2013 The British Pharmacological Society.

The antiarthritis drug D-penicillamine (D-PEN) catalyzes zinc(II) transfer from carboxypeptidase A to chelators such as thionein and EDTA at a rate constant up to 400-fold faster than the uncatalyzed release. Once D-PEN releases zinc(II) from enzyme stronger chelators can tightly bind zinc(II) leading to complete and essentially irreversible inhibition. D-PEN is the first drug to inhibit a zinc protease by catalyzing metal removal, and the name "catalytic chelation" is proposed for this mechanism. The interaction of selected natural products with human recombinant glutathione transferases. Hayeshi R(1), Mukanganyama S, Hazra B, Abegaz B, Hasler J. Author information: (1)Department of Biochemistry, University of Zimbabwe, Harare, Zimbabwe. The interaction of geshoidin, diospyrin and ergothioneine, with heterologously expressed human glutathione transferases (GSTs) was investigated in vitro. Diospyrin and geshoidin inhibited the three GST isoforms tested, with IC50 values in the range 0.1-0.5 microm, whereas ergothioneine had no effect on the GSTs. The predominant mode of inhibition was noncompetitive with respect to both glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). Diospyrin, however, competitively inhibited A1-1 and M1-1 with respect to GSH and geshoidin displayed mixed inhibition toward A1-1 with respect to GSH. The Ki values for diospyrin with respect to both GSH and CDNB were in the range 0.08-0.6 microM and those for geshoidin were in the range 16-173 microM. These results indicate that diospyrin is a potent inhibitor of heterologously expressed human GSTs A1-1, M1-1 and P1-1. Diospyrin and geshoidin were also found to inactivate P1-1 with diospyrin being a potent inactivator. Given these inhibitory properties, diospyrin may be a potential GST chemomodulator. Ergothioneine inactivated P1-1 only after preincubation and it enhanced ethacrynic acid inactivation of P1-1. Inactivation of P1-1 by ergothioneine may have implications for the antioxidant roles of P1-1 and ergothioneine in vivo. Copyright 2004 John Wiley & Sons, Ltd.

8. Phytother Res. 2004 Nov;18(11):877-83. doi: 10.1002/ptr.1481. The interaction of selected natural products with human recombinant glutathione transferases. Hayeshi R(1), Mukanganyama S, Hazra B, Abegaz B, Hasler J. Author information: (1)Department of Biochemistry, University of Zimbabwe, Har

Hyperpigmentation constitutes a significant dermatological challenge, exacerbated by oxidative stress and glycation. This study aims to develop and evaluate a novel dual-effect composition (DEC) that integrates antioxidant agents (ergothioneine and tocopheryl glucoside) and antiglycation agents (decarboxy carnosine and naringin) for the management of hyperpigmentation. A multi-model approach was employed to comprehensively assess DEC efficacy. In vitro studies on A875 melanoma cells showed DEC lowered reactive oxygen species (ROS) level, enhanced Nrf2 and superoxide dismutase (SOD) expression, suppressed advanced glycation end-product (AGE)-RAGE signaling, and reduced tyrosinase (TYR) levels and melanin production. Using the MelaFulKutis™ 3D pigmented skin model under UV and methylglyoxal exposure, the DEC-containing serum also reduced melanin deposition and downregulated microphthalmia-associated transcription factor (MITF) and TYR expression by 63.37% and 80.39%, respectively. In a clinical trial involving 34 Asian participants, DEC-containing serum significantly improved skin lightness (ΔL*: +0.98%, P = 0.003), reduced facial sallowness (Δb*: -5.92%, P < 0.001), decreased skin autofluorescence (SAF: -14.23, P < 0.001), and received 97% participant satisfaction after 56 days. In conclusion, DEC effectively targets both oxidative stress and glycation pathways to inhibit melanogenesis, highlighting the potential of dual-targeting approaches in hyperpigmentation treatment. © 2025. The Author(s).

Ergothioneine (ET) is an under recognised diet-derived compound which has the potential to be a "longevity vitamin". It was found to be beneficial for cognitive function and age-related neurodegenerative disorder (ARND). Thus, this study was conducted to synthesise the existing evidence of ET's effects on cognition and ARND, emphasizing its potential as a micronutrient for healthy aging. This study also highlights the future prospects of the research regarding ET's effects on cognition and ARND that are suggested in existing literature. Three databases (Pubmed, Scopus, and Web of Science) were used to search for the studies that meet the inclusion and exclusion criteria. A total of 19 studies were included after screening in this review. The risk of bias of each study was assessed using the Office of Health Assessment and Translation (OHAT) risk of bias rating tool. All studies' characteristics and main findings were tabulated according to their type of study. Mechanisms of ET in improving cognitive function and preventing ARND were found to be through its antioxidative, anti-inflammatory and antisenescence properties. Its role in neurotransmission and neuroprotection also contributed to improving cognition and preventing ARND. In conclusion, ET is a potential compound to be explored as its role in cognition and ARND have been discovered through several studies. © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.