RESUMO
Mitochondrial dysfunction is implicated in a wide range of human disorders including many neurodegenerative and cardiovascular diseases, metabolic diseases, cancers, and respiratory disorders. Studies have suggested the potential of l-ergothioneine (ET), a unique dietary thione, to prevent mitochondrial damage and improve disease outcome. Despite this, no studies have definitively demonstrated uptake of ET into mitochondria. Moreover, the expression of the known ET transporter, OCTN1, on the mitochondria remains controversial. In this study, we utilise mass spectrometry to demonstrate direct ET uptake in isolated mitochondria as well as its presence in mitochondria isolated from ET-treated cells and animals. Mitochondria isolated from OCTN1 knockout mice tissues, have impaired but still detectable ET uptake, raising the possibility of alternative transporter(s) which may facilitate ET uptake into the mitochondria. Our data confirm that ET can enter mitochondria, providing a basis for further work on ET in the prevention of mitochondrial dysfunction in human disease.
Assuntos
Ergotioneína , Camundongos Knockout , Mitocôndrias , Ergotioneína/metabolismo , Ergotioneína/farmacologia , Animais , Mitocôndrias/metabolismo , Humanos , Camundongos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Simportadores/metabolismo , Simportadores/genéticaRESUMO
Natural products from mushrooms, plants, microalgae, and cyanobacteria have been intensively explored and studied for their preventive or therapeutic potential. Among age-related pathologies, neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) represent a worldwide health and social problem. Since several pathological mechanisms are associated with neurodegeneration, promising strategies against neurodegenerative diseases are aimed to target multiple processes. These approaches usually avoid premature cell death and the loss of function of damaged neurons. This review focuses attention on the preventive and therapeutic potential of several compounds derived from natural sources, which could be exploited for their neuroprotective effect. Curcumin, resveratrol, ergothioneine, and phycocyanin are presented as examples of successful approaches, with a special focus on possible strategies to improve their delivery to the brain.
Assuntos
Curcumina , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Resveratrol , Fármacos Neuroprotetores/farmacologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Curcumina/farmacologia , Resveratrol/farmacologia , Ergotioneína/farmacologia , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Ficocianina/farmacologia , Animais , Cianobactérias , Agaricales/química , MicroalgasRESUMO
Radiotherapy commonly causes damage to healthy tissues, particularly radiation-induced skin injury (RISI) that affects a significant majority of patients undergoing radiotherapy. Effective treatments for RISI are lacking. This study focuses on the pathogenesis of RISI, which primarily involves oxidative stress. Excessive reactive oxygen species (ROS) generation during radiation induces damage to biological macromolecules, triggering oxidative stress and inflammation. To address this, ergothioneine (EGT), a natural and biocompatibile thiol compound with excellent antioxidant activity, is explored as a potential radiation-protective agent. By utilizing its specific transport and absorption in the skin tissue, as well as its efficient and stable clearance of radiation-induced "ROS storm", EGT is combined with sodium hyaluronate (NaHA) to develop a novel radiation protective dressing suitable for the skin. This EGT-NaHA dressing demonstrates an effective ability to scavenge free radicals and reduce oxidative stress in vitro and in vivo, reducing cellular apoptosis and inflammation. These results demonstrate the protective properties of EGT against RISI, with far-reaching implications for research and development in the field of radioprotection.
Assuntos
Bandagens , Ergotioneína , Ácido Hialurônico , Estresse Oxidativo , Protetores contra Radiação , Pele , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Ergotioneína/farmacologia , Ergotioneína/química , Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Pele/patologia , Camundongos , Humanos , Protetores contra Radiação/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/prevenção & controleRESUMO
The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.
Assuntos
Envelhecimento , Antioxidantes , Cóclea , Modelos Animais de Doenças , Progressão da Doença , Ergotioneína , Potenciais Evocados Auditivos do Tronco Encefálico , Camundongos Endogâmicos CBA , Estresse Oxidativo , Presbiacusia , Animais , Ergotioneína/farmacologia , Feminino , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Masculino , Presbiacusia/fisiopatologia , Presbiacusia/patologia , Presbiacusia/tratamento farmacológico , Presbiacusia/metabolismo , Presbiacusia/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Antioxidantes/farmacologia , Fatores Sexuais , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Cóclea/fisiopatologia , Cóclea/patologia , Fatores Etários , Apoptose/efeitos dos fármacos , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Limiar Auditivo/efeitos dos fármacos , Audição/efeitos dos fármacos , Camundongos , Anti-Inflamatórios/farmacologiaRESUMO
The continual exposure of retinal tissues to oxidative stress leads to discernible anatomical and physiological alterations. Specifically, the onslaught of oxidative damage escalates the irreversible death of retinal pigmented epithelium (RPE) cells, pinpointed as the fundamental pathological event in dry age-related macular degeneration (AMD). There is a conspicuous lack of effective therapeutic strategies to counteract this degenerative process. This study screened a library of antioxidants for their ability to protect RPE cells against oxidative stress and identified L-ergothioneine (EGT) as a potent cytoprotective agent. L-ergothioneine provided efficient protection against oxidative stress-damaged RPE and maintained cell redox homeostasis and normal physiological functions. It maintained the normal structure of the retina in mice under oxidative stress conditions. Transcriptomic analysis revealed that EGT counteracted major gene expression changes induced by oxidative stress. It upregulated antioxidant gene expression and inhibited NRF2 translocation. The inhibition of NRF2 abolished EGT's protective effects, suggesting that NRF2 activation contributes to its mechanism of action. In conclusion, we identified EGT as a safe and effective small-molecule compound that is expected to be a novel antioxidative agent for treating AMD.
Assuntos
Antioxidantes , Ergotioneína , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Epitélio Pigmentado da Retina , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Animais , Ergotioneína/farmacologia , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Células Cultivadas , Humanos , Western Blotting , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Healthy aging has emerged as a crucial issue with the increase in the geriatric population worldwide. Food-derived sulfur-containing amino acid ergothioneine (ERGO) is a potential dietary supplement, which exhibits various beneficial effects in experimental animals although the preventive effects of ERGO on aging and/or age-related impairments such as frailty and cognitive impairment are unclear. We investigated the effects of daily oral supplementation of ERGO dissolved in drinking water on lifespan, frailty, and cognitive impairment in male mice from 7 weeks of age to the end of their lives. Ingestion of 4 ~ 5 mg/kg/day of ERGO remarkably extended the lifespan of male mice. The longevity effect of ERGO was further supported by increase in life and non-frailty spans of Caenorhabditis elegans in the presence of ERGO. Compared with the control group, the ERGO group showed significantly lower age-related declines in weight, fat mass, and average and maximum movement velocities at 88 weeks of age. This was compatible with dramatical suppression by ERGO of the age-related increments in plasma biomarkers (BMs) such as the chemokine ligand 9, creatinine, symmetric dimethylarginine, urea, asymmetric dimethylarginine, quinolinic acid, and kynurenine. The oral intake of ERGO also rescued age-related impairments in learning and memory ability, which might be associated with suppression of the age-related decline in hippocampal neurogenesis and TDP43 protein aggregation and promotion of microglial shift to the M2 phenotype by ERGO ingestion. Ingestion of ERGO may promote longevity and healthy aging in male mice, possibly through multiple biological mechanisms.
Assuntos
Caenorhabditis elegans , Ergotioneína , Envelhecimento Saudável , Longevidade , Animais , Ergotioneína/farmacologia , Masculino , Longevidade/efeitos dos fármacos , Envelhecimento Saudável/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Camundongos , Suplementos Nutricionais , Camundongos Endogâmicos C57BL , FragilidadeRESUMO
Neuronal cell death is a key mechanism involved in the development and exacerbation of Parkinson's disease (PD). The excessive production of reactive oxygen species (ROS) is a major cause leading to neuronal death; therefore, compounds that prevent oxidative stress-dependent neuronal death may be promising as a preventive method for PD. Ergothioneine is a natural amino acid with antioxidant properties, and its protective functions in the body are attracting attention. However, there has been no investigation into the protective functions of ergothioneine using in vivo and in vitro PD models. Thus, in this study, we analyzed the efficacy of ergothioneine against 6-hydroxydopamine (6-OHDA)-dependent neuronal cell death using immortalized hypothalamic neurons (GT1-7 cells). First, we found that ergothioneine prevents 6-OHDA-dependent neuronal cell death by suppressing ROS overproduction in GT1-7 cells. The cytoprotective effect of ergothioneine was partially abolished by verapamil, an inhibitor of OCTN1, which is involved in ergothioneine uptake. Furthermore, ergothioneine-rich Rice-koji (Ergo-koji) showed cytoprotective and antioxidant effects similar to those of ergothioneine. Taken together, these results suggest that ergothioneine or foods containing ergothioneine may be an effective method for preventing the development and progression of PD.
Assuntos
Ergotioneína , Ergotioneína/farmacologia , Ergotioneína/metabolismo , Oxidopamina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neurotoxinas/farmacologia , Morte Celular , Antioxidantes/farmacologia , Antioxidantes/metabolismoRESUMO
This study examined the effects of ergothioneine (EGT) supplementation as an antioxidant on the quality of boar spermatozoa when using liquid and frozen preservation methods. In the first experiment, boar semen was preserved in an extender supplemented with 0, 50, 100 and 200 µM EGT, at 15 °C, part of the samples for one and another part for three weeks. In comparison with the control (without EGT), EGT supplementation at 100 µM significantly increased the percentage of total motility of spermatozoa that were preserved as a liquid both for one and three weeks (P < 0.05). EGT supplementation did not affect the quality of preserved spermatozoa, irrespective of the EGT concentration. In the second experiment, semen was frozen and thawed in the freezing extender supplemented with 0, 50, 100 and 200 µM EGT. In comparison with the control, the 100 µM EGT supplementation significantly increased the percentages of total and progressive motility of frozen-thawed spermatozoa (P < 0.05). EGT (100 µM) supplementation did not affect the viability, the plasma membrane integrity, or the acrosomal integrity of frozen-thawed spermatozoa. These findings indicate that supplementing extenders with 100 µM EGT may improve the motility of boar sperm in both liquid and freezing preservation methods.
Assuntos
Ergotioneína , Masculino , Suínos , Animais , Ergotioneína/farmacologia , Sêmen , Suplementos Nutricionais , Antioxidantes/farmacologia , EspermatozoidesRESUMO
Semen cryopreservation causes extensive chemical and physical damage to sperm structure, which generates premature aging and reduces viability and fertility of spermatozoa. The addition of antioxidants to freezing extenders can reduce the oxidative damage caused by excessive generation of reactive oxygen species (ROS), and the premature aging could be reduced by adding an enzyme inhibitor that prevents an anticipated capacitation. The aim of this study was to evaluate the in vitro effect of quercetin (Q), L-ergothioneine (E) and H89 addition to cryopreserved equine spermatozoa. Six experimental groups were stablished: control, Q, E, H89, H89Q and H89E. The analyzed parameters were sperm motility and kinematic using computer assisted sperm analysis (CASA), plasma membrane functionality with the hypoosmotic swelling test (HOST) and fertilizing capability with in vitro heterologous fertilization. Quercetin reduced curvilinear velocity (VCL) and increased beat-cross frequency (BCF), while its combination with H89 (H89Q) reduced total motility, progressive motility, VCL and hyperactive sperm (HA). Likewise, H89 and its combination with E (H89E) decreased VCL and amplitude of lateral head displacement (ALH). No significant differences were observed among treatments for membrane functionality and fertilizing capacity of sperm. In conclusion H89 in combination with Q and E reduced sperm motility or some kinematic parameters. However, they did not influence plasma membrane functionality and in vitro fertilizing capacity of frozen-thawed equine semen.
Assuntos
Senilidade Prematura , Ergotioneína , Isoquinolinas , Sulfonamidas , Masculino , Animais , Cavalos , Sêmen , Ergotioneína/farmacologia , Motilidade dos Espermatozoides , Quercetina/farmacologia , Fenômenos Biomecânicos , Senilidade Prematura/veterinária , Fertilização , Criopreservação/veterinária , Membrana CelularRESUMO
Oxidative stress can upset the antioxidant balance and cause accelerated aging including neurodegenerative diseases and decline in physiological function. Therefore, an antioxidant-rich diet plays a crucial role in healthy aging. This study aimed to identify and quantify mushrooms with the highest ergothioneine content through HPLC analysis and evaluate their anti-aging potential as a natural antioxidant and antisenescence in HT22 cells. Among the 14 evaluated mushroom species, Lentinula edodes (LE), shiitake mushroom contains the highest ergothioneine content and hence was used for the in-vitro studies. The cells were preincubated with ethanolic extract of ergothioneine-rich mushroom and the equimolar concentration of EGT on t-BHP-induced senescence HT22 cells. The extract was analyzed for its free radical scavenging properties using DPPH and ABTS methods. Then, the neuroprotective effect was conducted by measuring the cell viability using MTT. Senescence-associated markers and ROS staining were also analyzed. Our results revealed that a low dose of t-BHP reduces cell viability and induces senescence in HT22 cells as determined through ß-galactosidase staining and expressions of P16INK4a, P21CIPL which are the markers of cellular senescence. However, the pretreatment with ethanolic extract of LE for 8 h significantly improved the cell viability, reversed the t-BHP-induced cellular senescence in the neuronal cells, and reduced the reactive oxygen species visualized through DCFH-DA staining. These results suggest that ergothioneine-rich mushroom is a potential candidate for anti-aging exploration through the elimination of senescent cells.
Assuntos
Agaricales , Ergotioneína , Ergotioneína/farmacologia , Ergotioneína/química , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Agaricales/química , Agaricales/metabolismo , Senescência CelularRESUMO
Ergothioneine (EGT) is a bioactive compound derived from certain edible mushrooms. The activation of hepatic stellate cells (HSCs) is critically involved in the etiology of liver fibrosis (LF). Here, we report that in LX-2 HSCs, EGT upregulates the expression of Hint1 and Smad7 and suppresses their activation provoked by TGFß1. The EGT-triggered inhibition of HSC activation is abolished by knocking down the expression of Hint1. Overexpression of Hint1 increases Smad7 and represses TGFß1-provoked activation of LX-2 HSCs. In silico predictions unveiled that in the promoter region of the human Hint1 gene, there are two conserved cis-acting elements that have the potential to interact with the transcription factor Foxa3 termed hFBS1 and hFBS2, respectively. The knockdown of Foxa3 obviously declined Hint1 expression at both mRNA and protein levels. Transfection of Foxa3 or EGT treatment increased the activity of the luciferase reporter driven by the Hint1 promoter in an hFBS2-dependent manner. The knockdown of Foxa3 eliminated EGT-mediated upregulation of Hint1 promoter activity. Additionally, EGT triggered the nuclear translocation of Foxa3 without obviously affecting its expression level. Molecular docking analysis showed that EGT has the potential to directly interact with the Foxa3 protein. Moreover, Foxa3 played a critical role in EGT-mediated hepatoprotection. EGT modulated the Foxa3/Hint1/Smad7 signaling in mouse primary HSCs and inhibited their activation. The gavage of EGT considerably relieved CCl4-induced LF in mice. Our data provide new insights into the anti-LF activity of EGT. Mechanistically, EGT triggers the nuclear translocation of Foxa3 in HSCs, which promotes Hint1 transcription and subsequently elevates Smad7.
Assuntos
Ergotioneína , Camundongos , Humanos , Animais , Ergotioneína/farmacologia , Células Estreladas do Fígado/metabolismo , Simulação de Acoplamento Molecular , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/metabolismo , Fator 3-gama Nuclear de Hepatócito/genética , Fator 3-gama Nuclear de Hepatócito/metabolismoRESUMO
The high recurrence rate of cystine lithiasis observed in cystinuria patients highlights the need for new therapeutic options to address this chronic disease. There is growing evidence of an antioxidant defect in cystinuria, which has led to test antioxidant molecules as new therapeutic approaches. In this study, the antioxidant l-Ergothioneine was evaluated, at two different doses, as a preventive and long-term treatment for cystinuria in the Slc7a9-/- mouse model. l-Ergothioneine treatments decreased the rate of stone formation by more than 60% and delayed its onset in those mice that still developed calculi. Although there were no differences in metabolic parameters or urinary cystine concentration between control and treated mice, cystine solubility was increased by 50% in the urines of treated mice. We also demonstrate that l-Ergothioneine needs to be internalized by its transporter OCTN1 (Slc22a4) to be effective, as when administrated to the double mutant Slc7a9-/-Slc22a4-/- mouse model, no effect on the lithiasis phenotype was observed. In kidneys, we detected a decrease in GSH levels and an impairment of maximal mitochondrial respiratory capacity in cystinuric mice that l-Ergothioneine treatment was able to restore. Thus, l-Ergothioneine administration prevented cystine lithiasis in the Slc7a9-/- mouse model by increasing urinary cystine solubility and recovered renal GSH metabolism and mitochondrial function. These results support the need for clinical trials to test l-Ergothioneine as a new treatment for cystinuria.
Assuntos
Cistinúria , Ergotioneína , Litíase , Animais , Camundongos , Ergotioneína/farmacologia , Litíase/prevenção & controle , Cistinúria/tratamento farmacológico , Cistina , Antioxidantes/farmacologia , Camundongos Knockout , Masculino , Feminino , Camundongos Endogâmicos C57BL , Glutationa/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse OxidativoRESUMO
Paraquat (PQ) is exceptionally toxic to the human body. PQ ingestion can cause severe organ damage with a mortality rate of 50-80%, resulting from the absence of effective antidotes and detoxification solutions. Herein, a host-guest formulation is proposed, in which ergothioneine (EGT), an antioxidant drug, was encapsulated by carboxylatopillar[6]arene (CP6A) to achieve a combinational therapy for PQ poisoning. Nuclear magnetic resonance (NMR) and fluorescence titration were employed to confirm the complexation between CP6A and EGT as well as PQ with robust affinities. In vitro studies proved that EGT/CP6A significantly reduced PQ toxicity. Treatment with EGT/CP6A could effectively relieve organ damage caused by PQ ingestion and enhance the normalization of hematological and biochemical parameters. The host-guest formulation EGT/CP6A also improved the survival ratio in PQ-poisoned mice. These favorable outcomes originated from synergistic effects that PQ triggered the release of EGT to combat peroxidation damage and excess PQ was engulfed within the cavity of CP6A.
Assuntos
Anti-Infecciosos , Ergotioneína , Surfactantes Pulmonares , Camundongos , Humanos , Animais , Paraquat/química , Antídotos , Ergotioneína/farmacologia , Antioxidantes , PenicilinasRESUMO
Acute lung injury (ALI) is a heterogeneous pulmonary illness that is fast developing and has a high fatality rate. The current investigation set out to interpret the convergence of oxidative stress, inflammatory cytokines, TNF-α, snail, vimentin, e-cadherin, and NF-kB activation in ALI pathology. The outcome of assays of oxidative stress, ELISA, and western blot showed the declined of CAT, SOD, GPx, IL-1ß, TNF-α, and upregulation of TGF-ß, smad2/3, smad4, NF-kB, snail, and vimentin, concurrently with downregulation of e-cadherin expression in lung tissues as well as BALF in LPS-injected rats. The photomicrographs of the lungs marked severe congestion, infiltration of cytokines, and thickening of the alveolar walls. Pretreatments of ergothioneine after LPS-induced ALI, inhibited EMT-induction by blocking TGF-ß, smad2/3, smad4, snail, vimentin, NF-kB, and inflammatory cytokines, and increased the expression of E-cadherin and antioxidant levels in a dose-dependent manner. These events helped to restore lung histoarchitecture and reduce acute lung injury. The present findings suggest that ergothioneine at 100 mg/kg is as effective as febuxostat (reference drug). The study concluded that ergothioneine may be replaced with febuxostat as a treatment option for ALI owing to its side effects after clinical trials for pharmaceutical purposes.
Assuntos
Lesão Pulmonar Aguda , Ergotioneína , Animais , Ratos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Caderinas/metabolismo , Citocinas/metabolismo , Ergotioneína/farmacologia , Febuxostat/farmacologia , Lipopolissacarídeos/toxicidade , Pulmão/patologia , NF-kappa B/metabolismo , Estresse Oxidativo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vimentina/metabolismoRESUMO
Myocardial infarction (MI) remains the leading cause of cardiovascular death worldwide. Studies have shown that soluble fms-like tyrosine kinase-1 (sFlt-1) has a harmful effect on the heart after MI. However, ergothioneine (ERG) has been shown to have protective effects in rats with preeclampsia by reducing circulating levels of sFlt-1. In this study, we aimed to investigate the mechanism by which ERG protects the heart after MI in rats. Our results indicate that treatment with 10 mg/kg ERG for 7 days can improve cardiac function as determined by echocardiography. Additionally, ERG can reduce the size of the damaged area, prevent heart remodeling, fibrosis, and reduce cardiomyocyte death after MI. To explain the mechanism behind the cardioprotective effects of ERG, we conducted several experiments. We observed a significant reduction in the expression of monocyte chemoattractant protein-1 (MCP-1), p65, and p-p65 proteins in heart tissues of ERG-treated rats compared to the control group. ELISA results also showed that ERG significantly reduced plasma levels of sFlt-1. Using Glutaredoxin-1 (GLRX) and CD31 immunofluorescence, we found that GLRX was expressed in clusters in the myocardial tissue surrounding the coronary artery, and ERG can reduce the expression of GLRX caused by MI. In vitro experiments using a human coronary artery endothelial cell (HCAEC) hypoxia model confirmed that ERG can reduce the expression of sFlt-1, GLRX, and Wnt5a. These findings suggest that ERG protects the heart from MI damage by reducing s-glutathionylation through the NF-ĸB-dependent Wnt5a-sFlt-1 pathway.
Assuntos
Ergotioneína , Infarto do Miocárdio , Gravidez , Feminino , Ratos , Humanos , Animais , NF-kappa B/metabolismo , Ergotioneína/farmacologia , Ergotioneína/uso terapêutico , Infarto do Miocárdio/metabolismo , Coração , Miocárdio/metabolismo , Receptores Proteína Tirosina Quinases , Fator A de Crescimento do Endotélio Vascular , Proteína Wnt-5aRESUMO
Radiation gastroenteritis represents one of the most prevalent and hazardous complications of abdominopelvic radiotherapy, which not only severely reduces patients' life quality but also restricts radiotherapy efficacy. However, there is currently no clinically available oral radioprotector for this threatening disease due to its complex pathogenesis and the harsh gastrointestinal environment. To this end, this study developed a facile but effective oral radioprotector, ergothioneine hyaluronate (EGT@HA) gel, protecting against radiation gastroenteritis by synergistically regulating oxidative stress, inflammation, and gut microbiota. In vitro and cellular experiments verified the chemical stability and free radical scavenging ability of EGT and its favorable cellular radioprotective efficacy by inhibiting intracellular reactive oxidative species (ROS) generation, DNA damage, mitochondrial damage, and apoptosis. At the in vivo level, EGT@HA with prolonged gastrointestinal residence mitigated radiation-induced gastrointestinal tissue injury, apoptosis, neutrophil infiltration, and gut flora dysbiosis. For the first time, this work investigated the protective effects of EGT@HA gel on radiation gastroenteritis, which not only hastens the advancement of the novel gastrointestinal radioprotector but also provides a valuable gastrointestinal radioprotection paradigm by synergistically modulating oxidative stress, inflammation, and gut microbiota disturbance.
Assuntos
Ergotioneína , Gastroenterite , Microbioma Gastrointestinal , Lesões por Radiação , Humanos , Ergotioneína/genética , Ergotioneína/farmacologia , Antioxidantes/farmacologia , Disbiose/tratamento farmacológico , Disbiose/prevenção & controle , Apoptose , Inflamação/tratamento farmacológico , Inflamação/prevenção & controleRESUMO
BACKGROUND: Ergothioneine (EGT) is a natural amino acid derivative in various animal organs and is a bioactive compound recognized as a food and medicine. OBJECTIVES: This study examined the effects of EGT supplementation during the in vitro maturation (IVM) period on porcine oocyte maturation and subsequent embryonic development competence after in vitro fertilization (IVF). METHODS: Each EGT concentration (0, 10, 50, and 100 µM) was supplemented in the maturation medium during IVM. After IVM, nuclear maturation, intracellular glutathione (GSH), and reactive oxygen species (ROS) levels of oocytes were investigated. In addition, the genes related to cumulus function and antioxidant pathways in oocytes or cumulus cells were investigated. Finally, this study examined whether EGT could affect embryonic development after IVF. RESULTS: After IVM, the EGT supplementation group showed significantly higher intracellular GSH levels and significantly lower intracellular ROS levels than the control group. Moreover, the expression levels of hyaluronan synthase 2 and Connexin 43 were significantly higher in the 10 µM EGT group than in the control group. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H quinone dehydrogenase 1 (NQO1) were significantly higher in the oocytes of the 10 µM EGT group than in the control group. In the assessment of subsequent embryonic development after IVF, the 10 µM EGT treatment group improved the cleavage and blastocyst rate significantly than the control group. CONCLUSIONS: Supplementation of EGT improved oocyte maturation and embryonic development by reducing oxidative stress in IVM oocytes.
Assuntos
Antioxidantes , Ergotioneína , Gravidez , Feminino , Suínos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Ergotioneína/farmacologia , Ergotioneína/análise , Ergotioneína/metabolismo , Técnicas de Maturação in Vitro de Oócitos/veterinária , Espécies Reativas de Oxigênio/metabolismo , Oócitos , Desenvolvimento Embrionário , Glutationa/análise , Glutationa/metabolismo , Glutationa/farmacologia , Fertilização in vitro/veterinária , Blastocisto/metabolismoRESUMO
Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage. Exposure of human brain endothelial cells to 7KC led to a loss of cell viability, together with an increase in intracellular free calcium levels, increased cellular and mitochondrial reactive oxygen species, a decrease in mitochondrial membrane potential, reductions in ATP levels, and increases in mRNA expression of TFAM, Nrf2, IL-1ß, IL-6 and IL-8. These effects were significantly decreased by ET. Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC. OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells.
Assuntos
Ergotioneína , Humanos , Ergotioneína/farmacologia , Células Endoteliais/metabolismo , Cetocolesteróis/farmacologia , Encéfalo/metabolismo , RNA MensageiroRESUMO
Ergothioneine, a sulfur-containing micromolecular histidine derivative, has attracted increasing attention from scholars since it was confirmed in the human body. In the human body, ergothioneine is transported and accumulated specifically through OCTN-1, especially in the mitochondria and nucleus, suggesting that it can target damaged cells and tissues as an antioxidant. It shows excellent antioxidant, anti-inflammatory effects, and anti-aging properties, and inhibits melanin production. It is a mega antioxidant that may participate in the antioxidant network system and promote the reducing glutathione regeneration cycle. This review summarizes studies on the antioxidant effects of ergothioneine on various free radicals in vitro to date and systematically introduces its biological activities and potential mechanisms, mostly in dermatology. Additionally, the application of ergothioneine in cosmetics is briefly summarized. Lastly, we propose some problems that require solutions to understand the mechanism of action of ergothioneine. We believe that ergothioneine has good prospects in the food and cosmetics industries, and can thus meet some needs of the health and beauty industry.
Assuntos
Antioxidantes , Ergotioneína , Humanos , Antioxidantes/farmacologia , Ergotioneína/farmacologia , Glutationa/metabolismo , Estresse Oxidativo , Histidina/metabolismoRESUMO
BACKGROUND: Exercise-induced oxidative stress is a challenge in equine sports. This study aims at determining the effects of ergothioneine on heat shock protein-70 (HSP-70) following the stress of an endurance exercise of 30 km by Arabian stallions. Molecular docking was also done to investigate the interaction between the ligand ergothioneine and heat shock protein-70 using sulfogalactosylceramide and sulfogalactoglycerolipid as standards. The study involved a total of 18 clinically healthy stallions, with an average age of 6.7 ± 2.4 years and an average weight of 411.54 ± 12.46 kg. Only clinically healthy stallions were selected as subjects. The stallions were divided into two groups of nine stallions each. Group I (ERGX) was administered ergothioneine at a dose of 0.02 mg/kg once daily orally for four weeks while group II (ERGN) was not administered ergothioneine. The activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were determined in the two groups before and post-exercise. The concentrations of malondialdehyde and HSP-70 were also determined. RESULTS: The results obtained showed that the activities of the antioxidant enzymes and concentration of HSP-70 were higher (P < 0.05) in the ERGX group compared to the ERGN group. The concentration of malondialdehyde was however lower in the ERGX group. Following molecular docking, ergothioneine and the selected standards have common amino acids at the site of interaction with the target protein (HSP-70) suggesting that ergothioneine may have a modulatory effect on the synthesis of HSP-70. CONCLUSION: The results obtained indicated that ergothioneine modulated the synthesis of HSP-70 and the biomarkers of oxidative stress. It was therefore concluded that ergothioneine may be beneficial to horses subjected to endurance exercise.