Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review

Owusu-Ansah, Amma; Choi, Sung Hee; Petrosiute, Agne; Letterio, John J.; Huang, Alex Y.

doi:10.1007/s11684-015-0375-1

Cited by 15 publications

(11 citation statements)

References 69 publications

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“…Oxidative stress and inflammation play a major role in the pathophysiology of SCD, so drugs that induce HbF and reduce oxidative stress have greater clinical efficacy [29,50,51,52]. There is mounting evidence that treatment with NRF2 activators in SCD mice reduces oxidative stress while inducing HbF [23,24,29,30,40].…”

Section: Discussionmentioning

confidence: 99%

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease

Zhu

Ward

et al. 2019

Experimental Hematology

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Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis to identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. Using samples from patients with contrasting HbF levels, we observed an eightfold upregulation of miR-144–3p (miR-144) and miR-144–5p in the low-HbF group compared with those with high HbF. Additional analysis by reverse transcription quantitative polymerase chain reaction confirmed individual miR-144 expression levels of subjects in the two groups. Subsequent functional studies in normal and sickle erythroid progenitors showed NRF2 gene silencing by miR-144 and concomitant repression of γ-globin transcription; by contrast, treatment with miR-144 antagomir reversed its silencing effects in a dose-dependent manner. Because NRF2 regulates reactive oxygen species levels, additional studies investigated mechanisms of HbF regulation using a hemin-induced oxidative stress model. Treatment of KU812 cells with hemin produced an increase in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. Chromatin immunoprecipitation assay confirmed NRF2 binding to the γ-globin antioxidant response element, which was inhibited by miR-144 mimic treatment. The genome-wide miRNA microarray and primary erythroid progenitor data support a miR-144/NRF2-mediated mechanism of γ-globin gene regulation in SCD.

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Section: Discussionmentioning

confidence: 99%

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease

Zhu

Ward

et al. 2019

Experimental Hematology

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“…It has been shown that naturally occurring triterpenoids affect Nrf2/ARE pathway and its downstream targets by triterpenoids were shown to be protective in different diseases [ 173 , 174 , 175 ]. Furthermore, Nrf2 activation and subsequent regulation of the transcription of the plethora of protective genes may be increased due to the chemical modifications of the triterpenoid structure [ 173 ].…”

Section: Oxidative Stress and Transcription Factorsmentioning

confidence: 99%

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

2015

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Silymarin (SM), an extract from the Silybum marianum (milk thistle) plant containing various flavonolignans (with silybin being the major one), has received a tremendous amount of attention over the last decade as a herbal remedy for liver treatment. In many cases, the antioxidant properties of SM are considered to be responsible for its protective actions. Possible antioxidant mechanisms of SM are evaluated in this review. (1) Direct scavenging free radicals and chelating free Fe and Cu are mainly effective in the gut. (2) Preventing free radical formation by inhibiting specific ROS-producing enzymes, or improving an integrity of mitochondria in stress conditions, are of great importance. (3) Maintaining an optimal redox balance in the cell by activating a range of antioxidant enzymes and non-enzymatic antioxidants, mainly via Nrf2 activation is probably the main driving force of antioxidant (AO) action of SM. (4) Decreasing inflammatory responses by inhibiting NF-κB pathways is an emerging mechanism of SM protective effects in liver toxicity and various liver diseases. (5) Activating vitagenes, responsible for synthesis of protective molecules, including heat shock proteins (HSPs), thioredoxin and sirtuins and providing additional protection in stress conditions deserves more attention. (6) Affecting the microenvironment of the gut, including SM-bacteria interactions, awaits future investigations. (7) In animal nutrition and disease prevention strategy, SM alone, or in combination with other hepatho-active compounds (carnitine, betaine, vitamin B12, etc.), might have similar hepatoprotective effects as described in human nutrition.

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“…Activation of Nrf2 with dimethylfumarate (DMF), enhances antioxidant defenses, and inhibits inflammation and vaso-occlusion in SCD mice, also in an HO-1-dependent manner [312]. Triterpenoids have been suggested as a potential approach for SCD and synthetic oleanane (derived from oleanolic acid) triterpenoids (SOTs) are known to exert anti-inflammatory effects through Nrf2 activation, leading to transcription of enzymes, including HO-1 [430].…”

Section: Anti-inflammatory Therapeutic Approaches For Scdmentioning

confidence: 99%

Inflammation in sickle cell disease

Conran

Belcher

2018

178

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The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.

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Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review

Cited by 15 publications

References 69 publications

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease

MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell disease

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

Inflammation in sickle cell disease

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