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

Panda, Harit; Keleku-Lukwete, Nadine; Kuga, Ayumi; Fuke, Nobuo; Suganuma, Hiroyuki; Suzuki, Mikiko; Yamamoto, Masayuki

doi:10.1016/j.exphem.2019.08.001

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…For example, two weeks of oral dietary supplementation with SFN was enough to attenuate liver damage and decrease the free heme levels in the plasma of four-week-old young SCD mice. Importantly, even long-term (two-month) treatment did not cause saturation of this protective effect, nor did it result in any associated adverse events [23].…”

Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 92%

“…SFN, a phytochemical found abundantly in cruciferous vegetables, is a mild NRF2 inducer that is suitable for use in long-term treatment. SFN administration can reverse SCD-related pathology [23]. For example, two weeks of oral dietary supplementation with SFN was enough to attenuate liver damage and decrease the free heme levels in the plasma of four-week-old young SCD mice.…”

Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 99%

“…SFN is an interesting NRF2 activator, especially in the case of a malady, such as SCD (Figure 9). Since SFN is a phytonutrient available as a food supplement that induces mild NRF2 activation and because SCD is evident at a young age, SFN is well suited to be a long-term treatment regimen for children [23]. In fact, a phase 1 study of an SFN-containing broccoli sprout homogenate (BSH) was tested in patients with SCD, and the results showed that BSH was tolerated in the adults and did not cause deleterious side effects [106].…”

Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 99%

“…Hence, the KEAP1-NRF2 system is an attractive target for therapeutic interventions in various oxidative stress-linked maladies. In fact, we have shown through animal studies that genetic and pharmacological activation of NRF2 ameliorates many pathological conditions, such as multiple sclerosis [18], chronic obstructive pulmonary disease (COPD) [19], Alzheimer's diseases [20], diabetes mellitus [21], and sickle cell disease (SCD) [22,23]. The NRF2 inducer dimethyl fumarate (DMF, Tecfidera ® ) has been approved by the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis.…”

Section: Introduction-the Physiological Roles Of the Keap1-nrf2 Axismentioning

confidence: 99%

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Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

et al. 2022

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In a multicellular environment, many different types of cells interact with each other. The KEAP1–NRF2 system defends against electrophilic and oxidative stresses in various types of cells. However, the KEAP1–NRF2 system also regulates the expression of genes involved in cell proliferation and inflammation, indicating that the system plays cell type-specific roles. In this review, we introduce the multifarious roles of the KEAP1–NRF2 system in various types of cells, especially focusing on cancer and inflammatory diseases. Cancer cells frequently hijack the KEAP1–NRF2 system, and NRF2 activation confers cancer cells with a proliferative advantage and therapeutic resistance. In contrast, the activation of NRF2 in immune cells, especially in myeloid cells, suppresses tumor development. In chronic inflammatory diseases, such as sickle cell disease, NRF2 activation in myeloid and endothelial cells represses the expression of proinflammatory cytokine and adherent molecule genes, mitigating inflammation and organ damage. Based on these cell-specific roles played by the KEAP1–NRF2 system, NRF2 inducers have been utilized for the treatment of inflammatory diseases. In addition, the use of NRF2 inducers and/or inhibitors with canonical antineoplastic drugs is an emerging approach to cancer treatment.

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Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 92%

Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 99%

Section: Nrf2 Inducers Ameliorate Scd Pathologymentioning

confidence: 99%

Section: Introduction-the Physiological Roles Of the Keap1-nrf2 Axismentioning

confidence: 99%

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Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

et al. 2022

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“…These cytotoxic molecules can accumulate in various tissues, including the liver [3][4][5][6][7]. Thus, hepatic injury has been described in 10-40% of patients with SCD and in animal models of hemolytic pathologies [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

Rayego‐Mateos

Morgado‐Pascual

García‐Caballero

et al. 2023

The Journal of Pathology

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Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme‐mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD‐promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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The Cytoprotective Activity of Nrf2 Is Regulated by Phytochemicals (Sulforaphane, Curcumin, and Silymarin)

Vargas-Mendoza

Sandoval-Gallegos

Madrigal-Santillán

et al. 2021

Plant Antioxidants and Health

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The evolution of species has encouraged organisms to adapt to their environment; in this process, an aerobic metabolism was the product of exposure to certain atmospheric conditions. Oxygen consumption in most cellular systems results in the production of reactive oxygen species (ROS) that may be capable of causing cellular damage at a certain level; however, these molecules are crucial to trigger cell signaling pathways for the maintenance of homeostasis. The high production of ROS increases oxidative stress (OS) which may affect some cellular structures. Thus, cells have to develop effective cytoprotective systems to defend themselves against damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of protection; its activation induces the Nrf2/Keap1/ARE pathway for the expression of a wide range of genes involved in detoxification and the antioxidant response. Researchers have paid special attention to the mechanism that favors this pathway and have found that some phytochemicals are potent Nrf2 activators. Therefore, in this work, we provide an overview of three of the most efficient bioactivators and the evidence supporting them as potential therapeutic elements under different medical conditions.

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

Cited by 7 publications

References 34 publications

Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

Multifaceted Roles of the KEAP1–NRF2 System in Cancer and Inflammatory Disease Milieu

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade

The Cytoprotective Activity of Nrf2 Is Regulated by Phytochemicals (Sulforaphane, Curcumin, and Silymarin)

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