Excessive Reactive Iron Impairs Hematopoiesis by Affecting Both Immature Hematopoietic Cells and Stromal Cells

Tanaka, Hirokazu; Espinoza, J. Luis; Fujiwara, Ryosuke; Rai, Shinya; Morita, Yasuyoshi; Ashida, Takashi; Kanakura, Yuzuru; Matsumura, Itaru

doi:10.3390/cells8030226

Cited by 28 publications

(19 citation statements)

References 55 publications

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“…Oxidative stress is an important contributor to diabetic complications and exacerbates cellular damages. Excessive production of ROS contributes to the initiation of programmed cell death in diabetes, which increased neuronal apoptosis in diabetes [ 44 , 45 ]. In view of the important role of oxidative stress, strategies for intervention of ROS-induced cell apoptosis may be of particular relevance.…”

Section: Discussionmentioning

confidence: 99%

Oxymatrine Ameliorates Memory Impairment in Diabetic Rats by Regulating Oxidative Stress and Apoptosis: Involvement of NOX2/NOX4

Huang

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait and has been shown to exhibit a diverse range of pharmacological properties. The aim of the present study was to investigate the role of OMT in diabetic brain injury in vivo and in vitro. Diabetic rats were induced by intraperitoneal injection of a single dose of 65 mg/kg streptozotocin (STZ) and fed a high-fat and high-cholesterol diet. Memory function was assessed using a Morris water maze test. A SH-SY5Y cell injury model was induced by incubation with glucose (30 mM/l) to simulate damage in vitro. The serum fasting blood glucose, insulin, serum S100B, malondialdehyde (MDA), and superoxide dismutase (SOD) levels were analyzed using commercial kits. Morphological changes were observed using Nissl staining and electron microscopy. Cell apoptosis was assessed using Hoechst staining and TUNEL staining. NADPH oxidase (NOX) and caspase-3 activities were determined. The effects of NOX2 and NOX4 knockdown were assessed using small interfering RNA. The expression levels of NOX1, NOX2, and NOX4 were detected using reverse transcription-quantitative PCR and western blotting, and the levels of caspase-3 were detected using western blotting. The diabetic rats exhibited significantly increased plasma glucose, insulin, reactive oxygen species (ROS), S-100B, and MDA levels and decreased SOD levels. Memory function was determined by assessing the percentage of time spent in the target quadrant, the number of times the platform was crossed, escape latency, and mean path length and was found to be significantly reduced in the diabetic rats. Hyperglycemia resulted in notable brain injury, including histological changes and apoptosis in the cortex and hippocampus. The expression levels of NOX2 and NOX4 were significantly upregulated at the protein and mRNA levels, and NOX1 expression was not altered in the diabetic rats. NOX and caspase-3 activities were increased, and caspase-3 expression was upregulated in the brain tissue of diabetic rats. OMT treatment dose-dependently reversed behavioral, biochemical, and molecular changes in the diabetic rats. In vitro, high glucose resulted in increases in reactive oxygen species (ROS), MDA levels, apoptosis, and the expressions of NOX2, NOX4, and caspase-3. siRNA-mediated knockdown of NOX2 and NOX4 decreased NOX2 and NOX4 expression levels, respectively, and reduced ROS levels and apoptosis. The results of the present study suggest that OMT alleviates diabetes-associated cognitive decline, oxidative stress, and apoptosis via NOX2 and NOX4 inhibition.

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Section: Discussionmentioning

confidence: 99%

Oxymatrine Ameliorates Memory Impairment in Diabetic Rats by Regulating Oxidative Stress and Apoptosis: Involvement of NOX2/NOX4

Huang

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Excessive iron accumulation in the body can cause liver damage, cardiovascular damage, neurodegenerative diseases and many aging‐related diseases [21]. Iron overload has a profound effect on immature hematopoietic cells and stromal cells, and thereby destroys the hematopoietic process [22]. Previous studies have indicated that iron homeostasis is crucial for various kinds of stem cell.…”

Section: Discussionmentioning

confidence: 99%

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Han

Chen

et al. 2020

FEBS Open Bio

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Iron overload affects the cell cycle of various cell types, but the effect of iron overload on human pluripotent stem cells has not yet been reported. Here, we show that the proliferation capacities of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were significantly inhibited by ferric ammonium citrate (FAC) in a concentration‐dependent manner. In addition, deferoxamine protected hESCs/hiPSCs against FAC‐induced cell‐cycle arrest. However, iron overload did not affect pluripotency in hESCs/hiPSCs. Further, treatment of hiPSCs with FAC resulted in excess reactive oxygen species production and DNA damage. Collectively, our findings provide new insights into the role of iron homeostasis in the maintenance of self‐renewal in human pluripotent stem cells.

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“…An in vitro study examined the effects of iron load (that may simulate the process of iron infusion in patients with IDA) on the function of primary hematopoietic cells and stromal cell lines and found that iron overload impairs normal hematopoietic cells and modifies the function of stromal cells, indicating that iron overload impairs the whole hematopoietic system. The authors suggested that the deleterious effects of iron were mediated through its impact on hematopoietic stem/progenitor cells as well as in differentiated hematopoietic via reactive oxygen species (ROS) accumulation [24]. In addition, an in-vitro study showed that ferrous ammonium sulfate (FeAS) induced growth arrest and apoptosis in immature hematopoietic cells and led to insulin-like growth factor binding protein 2 (IGFBP2) and insulin-like growth factor 1 (IGF-1) down-regulation.…”

Section: Discussionmentioning

confidence: 99%

Iron-Induced Thrombocytopenia: A Mini-Review of the Literature and Suggested Mechanisms

Babikir¹,

Raza²,

Soliman³

et al. 2020

Cureus

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Anemia constitutes a major global health burden, and iron deficiency is the most common cause of it. Iron deficiency and replacement affect not only hemoglobin (Hb) levels but also other hematological parameters such as platelet count. In this mini-review, we explore thrombocytopenia as a side effect of iron replacement therapy. We searched for relevant articles published in English, and all case reports/series of iron-induced thrombocytopenia were collected and analyzed. A total of 11 case reports and one case series were found relating to very low Hb at a baseline level of 5.25 +/-2.2 g/dl and variable platelet count at baseline that dropped in 9 +/-3 days to an average of 121 +/-112 x 10 9 /L, which in most of the cases was self-corrected. The parenteral route was more commonly reported to be associated with thrombocytopenia, and discontinuation of therapy was needed in two patients. The mechanisms, prevalence, and clinical significance of thrombocytopenia associated with iron replacement are unknown; several effects of iron on the primary hematopoietic cells and stromal cell lines have been proposed, such as influence on common progenitors, effects on cytokines, and thrombopoietic effect of erythropoietin, which is directly affected by iron levels. Iron replacement can lead to significant thrombocytopenia. Further research is needed to describe the exact incidence, mechanism, and clinical significance of thrombocytopenia associated with iron supplementation.

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Excessive Reactive Iron Impairs Hematopoiesis by Affecting Both Immature Hematopoietic Cells and Stromal Cells

Cited by 28 publications

References 55 publications

Oxymatrine Ameliorates Memory Impairment in Diabetic Rats by Regulating Oxidative Stress and Apoptosis: Involvement of NOX2/NOX4

Oxymatrine Ameliorates Memory Impairment in Diabetic Rats by Regulating Oxidative Stress and Apoptosis: Involvement of NOX2/NOX4

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

Iron-Induced Thrombocytopenia: A Mini-Review of the Literature and Suggested Mechanisms

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