ERGOTHIONEINE PRESERVES SPLENIC ARCHITECTURE AND ATTENUATES HEPATIC HISTOPATHOLOGICAL ALTERATIONS IN A HUMANIZED MOUSE MODEL OF SICKLE CELL ANEMIA
- 1Universidade Estadual Paulista (UNESP), São José do Rio Preto, SP, Brazil
- 2Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil
- 3Universidade Federal de Mato Grosso do Sul (UFMS), Três Lagoas, MS, Brazil
Abstract
Introduction: Sickle cell anemia (SCA) is characterized by chronic hemolysis, oxidative stress, inflammation, and recurrent vaso-occlusive events that promote progressive damage in multiple organs. Ergothioneine (ERT) is a naturally occurring thiol antioxidant that accumulates in erythrocytes through the OCTN1 transporter and has cytoprotective properties that may attenuate oxidative tissue injury. However, its effects on chronic histopathological alterations associated with SCA remain poorly understood. This study evaluated the effects of prolonged ERT supplementation on histopathological alterations in the spleen, liver, and kidney of humanized SCA mice. Methods: Humanized mice were generated by transplantation of bone marrow mononuclear cells from Berkeley SS or SA donors into lethally irradiated recipients (CEUA/UNICAMP; protocol 5955-1/2022). Experimental groups comprised SA controls, untreated SS mice, and SS mice treated with ERT (35 mg/kg/day, orally, for 60-days; n=5/group). Histopathological evaluation of spleen, liver, and kidney sections was performed using hematoxylin-eosin and Masson's trichrome staining. Tissue organization, perivascular erythrocyte accumulation, fibrosis, megakaryocyte infiltration, hemosiderin deposition, necrosis, and, in the liver, hyperplasia were assessed using a blinded three-point semiquantitative scoring system. Group comparisons were performed using the Kruskal-Wallis test followed by Dunn's multiple-comparison test with Holm correction. Results: ERT selectively modulated histopathological alterations in humanized SCA mice. In the spleen, ERT significantly improved tissue organization (p=0.025 vs. SS) and reduced megakaryocyte infiltration (p=0.011 vs. SS), whereas no significant effects were observed on fibrosis, hemosiderin deposition, or perivascular erythrocyte accumulation. In the liver, ERT significantly reduced perivascular erythrocyte accumulation (p=0.025 vs. SS) and hyperplasia (p=0.003 vs. SS), while hemosiderin deposition remained unchanged. Renal architecture remained preserved across all experimental groups, and ERT did not significantly modify renal perivascular erythrocyte accumulation. Conclusion: Collectively, these findings demonstrate that prolonged ERT supplementation selectively attenuated histopathological alterations associated with SCA, predominantly affecting splenic tissue organization and megakaryocyte infiltration, as well as hepatic vascular congestion and hyperplasia. These results support further investigation of ERT as an adjunctive strategy to mitigate chronic organ injury associated with SCA.
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BibTeX
@article{bernardo2026ergothioneine,
title = {{ERGOTHIONEINE PRESERVES SPLENIC ARCHITECTURE AND ATTENUATES HEPATIC HISTOPATHOLOGICAL ALTERATIONS IN A HUMANIZED MOUSE MODEL OF SICKLE CELL ANEMIA}},
author = {Victoria Simões BERNARDO and Flaviene Felix TORRES and Bárbara Braga Vieira MARQUES and Lucas Nathan De Souza NUNES and Daniela Cagnoto NORONHA and Mayara Cristina Moreira SILVA and Fernando Ferreira COSTA and Marcus Alexandre Finzi CORAT and Edis BELINI-JÚNIOR and Danilo Grunig Humberto DA SILVA},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.106651},
url = {https://doi.org/10.1016/j.htct.2026.106651},
note = {CC BY},
}
RIS
TY - JOUR
TI - ERGOTHIONEINE PRESERVES SPLENIC ARCHITECTURE AND ATTENUATES HEPATIC HISTOPATHOLOGICAL ALTERATIONS IN A HUMANIZED MOUSE MODEL OF SICKLE CELL ANEMIA
AU - Victoria Simões BERNARDO
AU - Flaviene Felix TORRES
AU - Bárbara Braga Vieira MARQUES
AU - Lucas Nathan De Souza NUNES
AU - Daniela Cagnoto NORONHA
AU - Mayara Cristina Moreira SILVA
AU - Fernando Ferreira COSTA
AU - Marcus Alexandre Finzi CORAT
AU - Edis BELINI-JÚNIOR
AU - Danilo Grunig Humberto DA SILVA
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.106651
UR - https://doi.org/10.1016/j.htct.2026.106651
AB - Introduction: Sickle cell anemia (SCA) is characterized by chronic hemolysis, oxidative stress, inflammation, and recurrent vaso-occlusive events that promote progressive damage in multiple organs. Ergothioneine (ERT) is a naturally occurring thiol antioxidant that accumulates in erythrocytes through the OCTN1 transporter and has cytoprotective properties that may attenuate oxidative tissue injury. However, its effects on chronic histopathological alterations associated with SCA remain poorly understood. This study evaluated the effects of prolonged ERT supplementation on histopathological alterations in the spleen, liver, and kidney of humanized SCA mice. Methods: Humanized mice were generated by transplantation of bone marrow mononuclear cells from Berkeley SS or SA donors into lethally irradiated recipients (CEUA/UNICAMP; protocol 5955-1/2022). Experimental groups comprised SA controls, untreated SS mice, and SS mice treated with ERT (35 mg/kg/day, orally, for 60-days; n=5/group). Histopathological evaluation of spleen, liver, and kidney sections was performed using hematoxylin-eosin and Masson's trichrome staining. Tissue organization, perivascular erythrocyte accumulation, fibrosis, megakaryocyte infiltration, hemosiderin deposition, necrosis, and, in the liver, hyperplasia were assessed using a blinded three-point semiquantitative scoring system. Group comparisons were performed using the Kruskal-Wallis test followed by Dunn's multiple-comparison test with Holm correction. Results: ERT selectively modulated histopathological alterations in humanized SCA mice. In the spleen, ERT significantly improved tissue organization (p=0.025 vs. SS) and reduced megakaryocyte infiltration (p=0.011 vs. SS), whereas no significant effects were observed on fibrosis, hemosiderin deposition, or perivascular erythrocyte accumulation. In the liver, ERT significantly reduced perivascular erythrocyte accumulation (p=0.025 vs. SS) and hyperplasia (p=0.003 vs. SS), while hemosiderin deposition remained unchanged. Renal architecture remained preserved across all experimental groups, and ERT did not significantly modify renal perivascular erythrocyte accumulation. Conclusion: Collectively, these findings demonstrate that prolonged ERT supplementation selectively attenuated histopathological alterations associated with SCA, predominantly affecting splenic tissue organization and megakaryocyte infiltration, as well as hepatic vascular congestion and hyperplasia. These results support further investigation of ERT as an adjunctive strategy to mitigate chronic organ injury associated with SCA.
SN - 2531-1379
SN - 2531-1387
ER -