Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model.

Abstract

Sickle cell disease (SCD) is a recessively inherited blood disorder caused by abnormal β-globin production. The β-globin mutation changes erythrocyte morphology into a sickle shape and increases erythrocyte vulnerability to hemolysis. Oxidative stress and concomitant inflammation eventually result in damage to multiple organs. Nrf2 is a master regulator of the oxidative stress response, homeostasis, and metabolism. Keap1 modulates Nrf2 protein levels; Nrf2 inducers alter nuclear Nrf2 levels by interacting with Keap1. Genetic modification of Keap1 helps to reduce inflammation and tissue damage in SCD model mice through Nrf2 induction. Here, we investigated the benefits of a mild and safe Nrf2 agonist, sulforaphane (SFN), in ameliorating SCD pathology in a murine model. SFN is a phytochemical and is found in cruciferous vegetables as its inert precursor, glucoraphanin. We found that dietary SFN administration for 14 days or 2 months increased the expression of Nrf2-dependent cytoprotective genes, but SFN uptake did not have deleterious effects on the food consumption and growth of SCD model mice. SFN ameliorated the liver damage of SCD mice, which could be validated by the rescue of liver function and the significantly reduced liver necrotic area. SFN administration also helped to eliminate heme released from lysed sickle cells. These results indicate that dietary supplementation with SFN relieves SCD symptoms by inducing Nrf2 and support our contention that SFN is a potential drug for the long-term treatment of children with SCD.

• Authors: Harit Panda, Nadine Keleku-Lukwete, Ayumi Kuga, Nobuo Fuke, Hiroyuki Suganuma, Mikiko Suzuki, Masayuki Yamamoto
• Journal: Experimental hematology (Exp Hematol) Vol. 77 Pg. 51-60.e1 (09 2019) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 31404577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Isothiocyanates
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Sulfoxides
• Heme
• sulforaphane

Topics

• Anemia, Sickle Cell (drug therapy, genetics, metabolism, pathology)
• Animals
• Dietary Supplements
• Disease Models, Animal
• Female
• Heme (genetics, metabolism)
• Humans
• Isothiocyanates (pharmacology)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Liver (metabolism, pathology)
• Liver Diseases (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Transgenic
• NF-E2-Related Factor 2 (genetics, metabolism)
• Sulfoxides