Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

Doss, Jennifer F.; Jonassaint, Jude; Garrett, Melanie E.; Ashley-Koch, Allison E.; Telen, Marilyn J.; Chi, Jen‐Tsan

doi:10.1371/journal.pone.0152895

Cited by 51 publications

(52 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is intriguing because of an assumed link between mitochondrial dysfunction and ROS production and the necessity of squelching mitochondria-derived free radicals through the activation of Nrf2. This additional functional impact of SFN is of potential importance given the more than 30 clinical trials currently underway testing SFN for the treatment of a variety of diseases including prostate cancer, obstructive pulmonary disease, and sickle cell disease [7], [10], [47].…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

2017

View full text Add to dashboard Cite

The KEAP1-Nrf2-ARE antioxidant system is a principal means by which cells respond to oxidative and xenobiotic stresses. Sulforaphane (SFN), an electrophilic isothiocyanate derived from cruciferous vegetables, activates the KEAP1-Nrf2-ARE pathway and has become a molecule-of-interest in the treatment of diseases in which chronic oxidative stress plays a major etiological role. We demonstrate here that the mitochondria of cultured, human retinal pigment epithelial (RPE-1) cells treated with SFN undergo hyperfusion that is independent of both Nrf2 and its cytoplasmic inhibitor KEAP1. Mitochondrial fusion has been reported to be cytoprotective by inhibiting pore formation in mitochondria during apoptosis, and consistent with this, we show Nrf2-independent, cytoprotection of SFN-treated cells exposed to the apoptosis-inducer, staurosporine. Mechanistically, SFN mitigates the recruitment and/or retention of the soluble fission factor Drp1 to mitochondria and to peroxisomes but does not affect overall Drp1 abundance. These data demonstrate that the beneficial properties of SFN extend beyond activation of the KEAP1-Nrf2-ARE system and warrant further interrogation given the current use of this agent in multiple clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

2017

View full text Add to dashboard Cite

show abstract

“…In a Phase I clinical trial, treatment with broccoli sprout homogenate containing the NRF2 activator, sulforaphane, increased the peripheral blood mRNA levels for HMOX1 in SCD patients. 65 There are other proteins regulated by NRF2 involved in heme biosynthesis such as the ATP binding cassette Figure 3. Predicted NRF2 binding sites across the human b-like globin (HBB) locus.…”

Section: Nrf2 Regulation Of Multiple Cellular Protein Targets Influenmentioning

confidence: 99%

Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease

Zhu

Oseghale

Nicole

et al. 2019

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Individuals with sickle cell disease have severe anemia due to the production of abnormal hemoglobin S, chronic red blood cell hemolysis, and increased oxidative stress leading to endothelial cell dysfunction, vasculopathy, and progressive organ damage. The transcription factor NRF2 (erythroid-derived 2)-like 2) is a master regulator of antioxidant proteins; under low oxidative stress, NRF2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, β-transducin repeat-containing protein or HRD1, and directed to the proteasome for degradation. When cells are exposed to oxidative stress, NRF2 is released from these repressor proteins, translocates to the nucleus, and activates antioxidant genes to suppress cellular reactive oxidant species and inflammation. In erythroid progenitors, NRF2 also modulates fetal hemoglobin expression through direct binding in the γ-globin promoter and modification of chromatin structure in the β-globin locus. In sickle erythroid cells, NRF2 provides unique benefits through fetal hemoglobin induction to inhibit hemoglobin S polymerization and protection against oxidative stress due to chronic hemolysis. Thus, development of small chemical molecules that activate NRF2 has the potential to ameliorate the clinical severity of sickle cell disease. In this review, we discuss progress towards understanding NRF2 regulation and strategies to develop agents for the treatment of sickle cell disease. Impact statement Sickle cell disease (SCD) is a group of inherited blood disorders caused by mutations in the human β-globin gene, leading to the synthesis of abnormal hemoglobin S, chronic hemolysis, and oxidative stress. Inhibition of hemoglobin S polymerization by fetal hemoglobin holds the greatest promise for treating SCD. The transcription factor NRF2, is the master regulator of the cellular oxidative stress response and activator of fetal hemoglobin expression. In animal models, various small chemical molecules activate NRF2 and ameliorate the pathophysiology of SCD. This review discusses the mechanisms of NRF2 regulation and therapeutic strategies of NRF2 activation to design the treatment options for individuals with SCD.

show abstract

“…S6A), and oral administration is sufficient to increase levels of glutathione 45 , allowing for long-term dietary supplementation. Dietary SFN supplementation has therapeutic relevance as it is safely tolerated in humans and under investigation for the treatment of a variety of disorders in humans [46][47][48][49] . We therefore developed a therapeutic strategy to deliver SFN to ALDH7A1 cKO Astro mice from 3 weeks of age until adulthood.…”

Section: Sfn Ameliorates Astrocyte Aldh7a1-induced Excitatory-inhibitmentioning

confidence: 99%

Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

Faust

Xin

Lee

et al. 2019

Preprint

View full text Add to dashboard Cite

Mutations in the astrocyte-enriched enzyme aldehyde dehydrogenase 7a1 (ALDH7A1) cause a neonatal epilepsy accompanied by treatment-resistant, inter-ictal neuropsychiatric symptoms.Nevertheless, the mechanistic impact of ALDH7A1 dysfunction in the brain remains elusive. We generated ALDH7A1 knockout mice and report that constitutive global ALDH7A1 depletion increases chemoconvulsant sensitivity and altered mood-associated behaviors. However, contrary to our expectation, astrocyte-specific ALDH7A1 depletion only affects mood-associated behaviors.Accordingly, in astrocyte-specific ALDH7A1 knockout mice, we show enhanced redox-sensitive microdomain Ca 2+ signaling in astrocytes and both elevated synaptic inhibitory tone and increased dendritic spine density in prelimbic pyramidal neurons. Sulforaphane (SFN), an indirect antioxidant and dietary supplement, has been explored as a possible treatment to ameliorate neuropsychiatric manifestations in autism and schizophrenia, at least at the clinical levels, but its mechanism in the brain is unclear. Here we show that SFN rescues both the physiological and behavioral changes by targeting astrocytic redox imbalance in ALDH7A1 knockout mice, implicating astrocyte redox changes in creating cortical excitatory-inhibitory imbalance and mood alteration.

show abstract

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

Cited by 51 publications

References 40 publications

Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission

Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease

Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

Contact Info

Product

Resources

About