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      Drug Design, Development and Therapy (submit here)

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      Comparison of the effects of deferasirox, deferoxamine, and combination of deferasirox and deferoxamine on an aplastic anemia mouse model complicated with iron overload


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          Background and aim

          Iron overload is commonly observed during the course of aplastic anemia (AA), which is believed to aggravate hematopoiesis, cause multiple organ dysfunction, lead to disease progression, and impair quality of life. Deferasirox (DFX) and deferoxamine (DFO) are among the most common iron chelation agents available in the clinical setting. The aim of this study was to investigate if the combination therapy with DFX and DFO is superior in hematopoietic recovery and iron chelation.


          Briefly, we developed a composite mouse model with AA and iron overload that was consequently treated with DFX, DFO, or with a combination of both agents. The changes in peripheral hemogram, marrow apoptosis, and its related protein expressions were compared during the process of iron chelation, while the iron depositions in liver and bone marrow and its regulator were also detected.


          The obtained results showed that compared to DFX, DFO has a better effect in protecting the bone marrow from apoptosis-induced failure. The combination of DFO and DFX accelerated the chelation of iron, while their efficiency on further hemogram improvement appeared limited.


          To sum up, our data suggest that single treatment with DFO may be a better choice for improving the hematopoiesis during the gradual chelation treatment irrespective of the convenience of oral DFX, while the combination treatment should be considered for urgent reduction of the iron burden.

          Most cited references28

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          Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis.

          Neogenin, a deleted in colorectal cancer (DCC) family member, has been identified as a receptor for the neuronal axon guidance cues netrins and repulsive guidance molecules repulsive guidance molecules (RGM). RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis. Here we provide evidence that neogenin plays a critical role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signaling. Livers of neogenin mutant mice exhibit iron overload, low levels of hepcidin, and reduced BMP signaling. Mutant hepatocytes in vitro show impaired BMP2 induction of Smad1/5/8 phosphorylation and hepcidin expression. Neogenin is expressed in liver cells in a reciprocal pattern to that of hepcidin, suggesting that neogenin functions in a cell nonautonomous manner. Further studies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein that interacts with neogenin and suppresses its secretion. Taken together, our results lead the hypothesis that neogenin regulates iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signaling and hepcidin expression. These results reveal a novel mechanism underlying neogenin regulation of HJV-BMP signaling.
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            The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice.

            Increasing numbers of reports have described hematopoietic improvement after iron chelation therapy in iron-overloaded patients. These observations indicate that excess iron could affect hematopoiesis unfavorably. To investigate how excess iron affects hematopoiesis in vivo, we generated iron-overloaded mice and examined hematopoietic parameters in these mice.
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              The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss

              Iron overload inhibits osteoblast function and promotes osteoclastogenesis. Hepcidin plays an important role in this process. The changes in iron content and the regulation of hepcidin under unloading-induced bone loss remain unknown. A hindlimb suspension model was adopted to simulate unloading-induced bone loss in mice. The results showed that iron deposition in both liver and bone was markedly increased in hindlimb unloaded mice, and was accompanied by the upregulation of osteoclast activity and downregulation of osteoblast activity. The iron chelator deferoxamine mesylate (DFO) reduced the iron content in bone and alleviated unloading-induced bone loss. The increased iron content in bone was mainly a result of the upregulation of transferrin receptor 1 (TfR1) and divalent metal transporter 1 with iron response element (DMT1+IRE), rather than changes in the iron transporter ferroportin 1 (FPN1). The hepcidin level in the liver was significantly higher, while the FPN1 level in the duodenum was substantially reduced. However, there were no changes in the FPN1 level in bone tissue. During hindlimb unloading, downregulation of hepcidin by siRNA increased iron uptake in bone and liver, which aggravated unloading-induced bone loss. In summary, these data show that unloading-induced bone loss was orchestrated by iron overload and coupled with the regulation of hepcidin by the liver.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                03 May 2018
                : 12
                : 1081-1091
                [1 ]Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
                [2 ]Department of Internal Medicine, Central Hospital of Jinhua Affiliated to Zhejiang University, Jinhua, Zhejiang, People’s Republic of China
                Author notes
                Correspondence: Dijiong Wu; Baodong Ye, Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, Zhejiang 310006, People’s Republic of China, Email wdj850@ 123456163.com ; 13588453501@ 123456163.com
                © 2018 Wu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                aplastic anemia,iron overload,mouse,animal model,deferasirox,deferoxamine


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