Augmented <scp>NRF</scp>2 activation protects adult sickle mice from lethal acute chest syndrome

Ghosh, Samit; Hazra, Rimi; Ihunnah, Chibueze A.; Weidert, Frances; Flage, Bethany; Ofori-Acquah, Solomon Fiifi

doi:10.1111/bjh.15401

Cited by 15 publications

(17 citation statements)

References 15 publications

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“…Interestingly, our result also suggests a previously unreported impaired inducible reserve capacity of Hmox1 induction in the liver (Fig C). Our finding is consistent with the published effectiveness of augmented Hmox1 expression as a protective therapy through gene transfer (Belcher et al , ) or through Nrf2 activators (Ghosh et al , ; Ghosh et al , ) in sickle cell mice. In agreement with the current literature (Boyle et al , ; Loboda et al , ), our data offers novel insights regarding the organ‐specific Hmox1 expression in vivo .…”

Section: Discussionsupporting

confidence: 92%

“…All tissue processing was carried out at 4°C. Total haem in tissue lysates was quantified using a colourimetric assay kit (QuantiChrom haem assay kit; Bioassay Systems, Hayward, CA, USA) as described in previous studies (Ghosh et al , ). The bicinchoninic acid (BCA) assay kit (ThermoFisher Scientific, Catalogue number 23225) was used to quantify total protein in the lysates.…”

Section: Methodsmentioning

confidence: 99%

“…Hmox1 and Hrg1 expression is regulated by Nuclear factor (erythroid derived 2)‐like 2 (NFE2L2, also termed NRF2), a key cytoprotective transcription factor that also regulates the basal and inducible expression of multiple antioxidant proteins and detoxification enzymes (Alam et al , ; Motohashi & Yamamoto, ). Recent studies in mice have shown a protective effect of NRF2 in attenuating complications of SCD, such as inflammation, acute lung injury, anaemia (Ghosh et al , ; Ghosh et al , ) and spleen damage (Zhu et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac expression of HMOX1 and PGF in sickle cell mice and haem‐treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2)

et al. 2019

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Summary Haemolysis is a major feature of sickle cell disease (SCD) that contributes to organ damage. It is well established that haem, a product of haemolysis, induces expression of the enzyme that degrades it, haem oxygenase‐1 (HMOX1). We have also shown that haem induces expression of placental growth factor (PGF), but the organ specificity of these responses has not been well‐defined. As expected, we found high level expression of Hmox1 and Pgf transcripts in the reticuloendothelial system organs of transgenic sickle cell mice, but surprisingly strong expression in the heart (P < 0·0001). This pattern was largely replicated in wild type mice by intravenous injection of exogenous haem. In the heart, haem induced unexpectedly strong mRNA responses for Hmox1 (18‐fold), Pgf (4‐fold), and the haem transporter Slc48a1 (also termed Hrg1; 2·4‐fold). This was comparable to the liver, the principal known haem‐detoxifying organ. The NFE2L2 (also termed NRF2) transcription factor mediated much of the haem induction of Hmox1 and Hrg1 in all organs, but less so for Pgf. Our results indicate that the heart expresses haem response pathway genes at surprisingly high basal levels and shares with the liver a similar transcriptional response to circulating haem. The role of the heart in haem response should be investigated further.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac expression of HMOX1 and PGF in sickle cell mice and haem‐treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2)

et al. 2019

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“…A wide variety of small molecules are under development that target the downstream detrimental effects of sickle RBC formation including chronic hemolysis, NO depletion, and vasculopathy. 55,[57][58][59]65 For example, the Phase II SUSTAIN trial of crizanlizumab (SelG1) tested a humanized anti-P-selectin antibody that prolonged the time to first pain crisis in SCD patients 106 ; subsequently, SelG1 was shown to decrease the number of sickle cell pain crises over time. 107 Several other agents should emerge from these widespread clinical efforts establishing a repertoire of effective agents to develop combination therapy for SCD.…”

Section: Summary and Future Directionsmentioning

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)

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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.

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“…5A and C). To further evaluate whether IRG1 de ciencyinduced BDNF repression can be rescued by the induction of HO-1 expression, IRG1 −/− MCAO mice were administered with either vehicle or D3T, an Nrf2/HO-1 pathway inducer (16,(22)(23)(24), and the ischemic brains were then harvested to assess BDNF expression. D3T strongly upregulated BDNF expression in the ischemic brain of IRG1 −/− MCAO mice at both mRNA and protein levels ( Fig.…”

Section: Irg1 De Ciency Represses Bdnf Expression In the Ischemic Bramentioning

confidence: 99%

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

Kuo¹,

Weng²,

Scofield³

et al. 2020

Preprint

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Background Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of IRG1/itaconate axis has recently documented in LPS-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether IRG1/itaconate axis exerts an immunomodulatory effect in ischemic stroke is unknown. Thus, we investigated whether IRG1 plays a role in modulating brain injury in ischemic stroke. In addition, the molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke were elucidated. Methods Wild type (WT) C57BL/6 and IRG1−/− mice were subjected to 40 minutes middle cerebral artery occlusion (MCAO). Ischemic brain injury, microglia (MG) activation and peripheral immune cell infiltration of the ischemic brain were assessed. Furthermore, the expression of HO-1 and BDNF in the ischemic brain was measured. Finally, IRG1−/− MCAO mice were administered with D3T, an Nrf2/HO-1 pathway inducer, to determine its effects on cerebral BDNF expression and ischemic brain injury. Results We observed IRG1 was highly induced in the ischemic brain of WT but not IRG1−/− MCAO mice. Strikingly, IRG1−/− MCAO mice exhibited exacerbated brain injury with enlarged cerebral infarct, enhanced MG activation, and elevated immune cell infiltrates compared to WT MCAO controls. Further analysis of molecular mechanisms underlying the protective effects of IRG1 in ischemic stroke revealed that IRG1 promoted HO-1 and BDNF expression to restrain ischemic brain injury, as IRG1−/− MCAO mice exhibited reduced HO-1 and BDNF expression in the ischemic brain compared to WT MCAO controls. Notably, D3T, an Nrf2/HO-1 pathway inducer, promoted BDNF expression and lessened ischemic brain injury in IRG1−/− MCAO mice. Conclusions We demonstrate that the induction of IRG1 following ischemic stroke may serve as an endogenous protective mechanism to restrain ischemic brain injury, and that may be mediated through the protective effect of IRG1 on the induction of HO-1 and BDNF expression in the ischemic brain. Thus, our study suggests that targeting IRG1 may represent a novel approach for the treatment of ischemic stroke.

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Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome

Cited by 15 publications

References 15 publications

Cardiac expression of HMOX1 and PGF in sickle cell mice and haem‐treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2)

Cardiac expression of HMOX1 and PGF in sickle cell mice and haem‐treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2)

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

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

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