Comment on "The influence of hydroxyurea on oxidative stress in sickle cell anemia"

Beers, Eduard J. van; Kato, Gregory J.

doi:10.5581/1516-8484.20120099

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…HU is an FDA‐approved drug for the treatment of SCD through reduction in HbS polymerization and vaso‐occlusive crises by fetal hemoglobin augmentation . HU is suggested to produce direct oxidant and indirect antioxidant effects; however, there have been contradictory reports regarding the protective role of HU therapy in SCD patients . To examine the possible proactive role of HU treatment on oxidative imbalance in β‐thalassemia, we studied oxidative stress biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy inβ-Thalassemia Patients

Zohaib

Ansari

Hashim

et al. 2015

The Journal of Clinical Pharmacology

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β-Thalassemia is the most common hereditary disorder characterized by reduced production of β-globin chains of hemoglobin A (HbA). In recent years, hydroxyurea (HU) has shown promising therapeutic benefits in patients with β-thalassemia by fetal hemoglobin augmentation. We have analyzed effects of hydroxyurea treatment on oxidative stress in β-thalassemia patients by assessing activities of paraoxonase (PON) and arylesterase along with malondialdehyde (MDA) and total reactive oxygen species (ROS) concentrations. Blood samples from 159 individuals including 56 HU-treated and 58 untreated β-thalassemia patients and 45 healthy controls were analyzed. PON activity was found to be highest in healthy individuals (177.76 ± 4.44 U/mL) as compared to treated (52.67 ± 3.65 U/mL) and untreated (55.11 ± 3.26 U/mL) patients. A similar trend was observed in the case of arylesterase activity in normal, β-thalassemia-treated, and untreated (210.0 ± 11.25 U/mL, 163.03 ± 9.04 U/mL, 139.77 ± 10.10 U/mL) subjects. Serum MDA concentrations (2.59 ± 0.09 nmol/mL, 2.45 ± 0.08 nmol/mL, and 1.15 ± 0.05 nmol/mL) and total ROS concentrations (3.73 ± 0.20 nmol/mL, 3.54 ± 0.23 nmol/mL, and 2.45 ± 0.14 nmol/mL) were significantly elevated in both groups (untreated and treated) as compared to healthy individuals (P < .01). Oxidative stress was found to be markedly elevated in β-thalassemia patients as compared to healthy controls. Insignificant differences were, however, observed in mean concentrations of PON1 paraoxonase and arylesterase activities, serum MDA concentration and total ROS concentrations between HU-treated and untreated patients. We propose that HU therapy alone seems to be ineffective in managing oxidative stress and is likely to offer a better clinical outcome when supplemented with efficient iron chelation therapy and antioxidants.

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Section: Discussionmentioning

confidence: 99%

Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy inβ-Thalassemia Patients

Zohaib

Ansari

Hashim

et al. 2015

The Journal of Clinical Pharmacology

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Sickle cell disease patient plasma sensitizes iPSC-derived sensory neurons from sickle cell disease patients

Allison

Burand

Torres

et al. 2023

Preprint

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Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. In order to develop novel therapies, it is necessary to better understand the neurobiological mechanisms underlying SCD pain. There are many barriers to gaining mechanistic insight into pathogenic SCD pain processes, such as differential gene expression and function of sensory neurons between humans and mice with SCD, as well as the limited availability of patient samples. These can be overcome by utilizing SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs). Here, we characterize the key gene expression and function of SCD iSNs to establish a model for higher-throughput investigation of intrinsic and extrinsic factors that may contribute to increased SCD patient pain. Importantly, identified roles for C-C Motif Chemokine Ligand 2 (CCL2) and endothelin 1 (ET1) in SCD pain can be recapitulated in SCD iSNs. Further, we find that plasma taken from SCD patients during acute pain increases SCD iSN calcium response to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at baseline or healthy control plasma samples. Together, these data provide the framework necessary to utilize iSNs as a powerful tool to investigate the neurobiology of SCD and identify potential intrinsic mechanisms of SCD pain which may extend beyond a blood-based pathology.

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Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma

Allison,

Welby,

Ehlers

et al. 2024

Blood

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Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from SCD patients. Here we used SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Further, we find that plasma taken from SCD patients during acute pain associated with a vaso-occlusive event increases the calcium responses in SCD iSNs to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of SCD patient plasma, which sensitizes SCD iSNs to sub-threshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.

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Comment on "The influence of hydroxyurea on oxidative stress in sickle cell anemia"

Cited by 4 publications

References 21 publications

Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy inβ-Thalassemia Patients

Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy inβ-Thalassemia Patients

Sickle cell disease patient plasma sensitizes iPSC-derived sensory neurons from sickle cell disease patients

Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma

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