Iron chelation effect of curcumin and baicalein on aplastic anemia mouse model with iron overload

Document Type : Original Article

Authors

1 Department of Hematology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

2 Department of Internal Medicine, Central Hospital of Jinhua Affiliated to Zhejiang University, Jinhua, Zhejiang, China

3 Department of Hematology, Taizhou Central Hospital, Taizhou, Zhejiang, China

Abstract

Objective(s): The current work aimed to assess whether curcumin and baicalein can chelate iron in aplastic anemia (AA) complicated with iron overload, exploring the potential mechanisms.
Materials and Methods: A mouse model of AA with iron overload complication was firstly established. Low and high-dose curcumin or baicalein treatment groups were set up, as well as the deferoxamine positive control, normal and model groups (n=8). Hemogram and bone marrow mononuclear cell detection were performed, and TUNEL and immunohistochemical staining were used to evaluate hematopoiesis and apoptosis in the marrow. ELISA, Western blot, and qRT-PCR were employed to assess serum iron (SI), serum ferritin (SF), bone morphogenetic protein 6 (BMP-6), SMAD family member4 (SMAD4) and transferrin receptor 2 (TfR2) amounts.
Results: Both curcumin and baicalein improved white blood cell (increase of 0.28-0.64×109/l in high-dose groups) and hemoglobin (increase of around 10 g/l) amounts significantly, which may related to decreased apoptosis (nearly 30%-50% of that in the model group) in the bone marrow, while their effects on platelet recovery were limited and inferior to that of deferoxamine (DFO). Both test compounds up-regulated hepcidin and its regulators (BMP-6, SMAD, and TfR2) at the protein and mRNA levels; high dosage treatment may be beneficial, being better than DFO administration in lessening iron deposition in the bone marrow.
Conclusion: Curcumin and baicalein protect hematopoiesis from immune and iron overload-induced apoptosis, exerting iron chelation effects in vivo.

Keywords

Main Subjects

References

1. Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program 2013; 2013: 76-81.
2. Wu YH, Shao ZH, Liu H, Cui ZZ, Qin TJ, Fu R, et al. The clinical features of severe aplastic anemia patients with complication of infection. Zhonghua Xue Ye Xue Za Zhi 2003; 24: 530-533.
3. Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Society for Standards in H. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol 2016; 172: 187-207.
4. Pawelec K, Salamonowicz M, Panasiuk A, Leszczynska E, Krawczuk-Rybak M, Demkow U et al. Influence of iron overload on immunosuppressive therapy in children with severe aplastic anemia. Adv Exp Med Biol 2015; 866: 83-89.
5. Gao C, Li L, Chen B, Song H, Cheng J, Zhang X et al. Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia. Patient Prefer Adherence 2014; 8: 513-517.
6. Chai X, Li D, Cao X, Zhang Y, Mu J, Lu W, et al. Corrigendum: ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice. Sci Rep 2017; 7: 41900.
7. Shaw J, Chakraborty A, Nag A, Chattopadyay A, Dasgupta AK, Bhattacharyya M. Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients. Eur J Haematol 2017; 99: 399-408.
8. Kohgo Y, Urabe A, Kilinc Y, Agaoglu L, Warzocha K, Miyamura K, et al. Deferasirox decreases liver iron concentration in iron-overloaded patients with myelodysplastic syndromes, aplastic anemia and other rare anemias. Acta Haematol 2015; 134: 233-242.
9. Ansari S, Azarkeivan A, Miri-Aliabad G, Yousefian S, Rostami T. Comparison of iron chelation effects of deferoxamine, deferasirox, and combination of deferoxamine and deferiprone on liver and cardiac T2* MRI in thalassemia maior. Caspian J Intern Med 2017; 8: 159-164.
10. Kim IH, Moon JH, Lim SN, Sohn SK, Kim HG, Lee GW, et al. Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload. Transfusion 2015; 55: 1613-1620.
11. Karnon J, Tolley K, Oyee J, Jewitt K, Ossa D, Akehurst R. Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom. Curr Med Res Opin 2008; 24: 1609-1621.
12. Kim KH, Park YD, Park H, Moon KO, Ha KT, Baek NI, et al. Synthesis and biological evaluation of a novel baicalein glycoside as an anti-inflammatory agent. Eur J Pharmacol 2014; 744: 147-156.
13. Zhao S, Ma L, Cao C, Yu Q, Chen L, Liu J. Curcumin-loaded redox response of self-assembled micelles for enhanced antitumor and anti-inflammation efficacy. Int J Nanomedicine 2017; 12: 2489-2504.
14. Adiwidjaja J, McLachlan AJ, Boddy AV. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions. Expert Opin Drug Metab Toxicol 2017; 13: 953-972.
15. Bie B, Sun J, Guo Y, Li J, Jiang W, Yang J, Huang C, Li Z. Baicalein: A review of its anti-cancer effects and mechanisms in hepatocellular carcinoma. Biomed Pharmacother 2017; 93: 1285-1291.
16. Li M, Shi A, Pang H, Xue W, Li Y, Cao G, et al. Safety, tolerability, and pharmacokinetics of a single ascending dose of baicalein chewable tablets in healthy subjects. J Ethnopharmacol 2014; 156: 210-215.
17. Wu S, Xiao D. Effect of curcumin on nasal symptoms and airflow in patients with perennial allergic rhinitis. Ann Allergy Asthma Immunol 2016; 117: 697-702 e691.
18. Badria FA, Ibrahim AS, Badria AF, Elmarakby AA. Curcumin attenuates iron accumulation and oxidative stress in the liver and spleen of chronic iron-overloaded rats. PLoS One 2015; 10: e0134156.
19. Chin D, Huebbe P, Frank J, Rimbach G, Pallauf K. Curcumin may impair iron status when fed to mice for six months. Redox Biol 2014; 2: 563-569.
20. Perez CA, Wei Y, Guo M. Iron-binding and anti-Fenton properties of baicalein and baicalin. J Inorg Biochem 2009; 103: 326-332.
21. Gao D, Sakurai K, Katoh M, Chen J, Ogiso T. Inhibition of microsomal lipid peroxidation by baicalein: a possible formation of an iron-baicalein complex. Biochem Mol Biol Int 1996; 39: 215-225.
22. Wu D, Wen X, Liu W, Xu L, Ye B, Zhou Y. A composite mouse model of aplastic anemia complicated with iron overload. Exp Ther Med 2018; 15: 1449-1455.
23. Swolin B, Simonsson P, Backman S, Lofqvist I, Bredin I, Johnsson M. Differential counting of blood leukocytes using automated microscopy and a decision support system based on artificial neural networks--evaluation of DiffMaster Octavia. Clin Lab Haematol 2003; 25: 139-147.
24. Wu DJ, Ye BD, Hu ZP, Shen YP, Shen JP, Lin SY, et al. Bone marrow angiogenesis in patients presenting with differential Chinese medicine syndrome: correlation with the clinico-pathological features of aplastic anemia. Chin J Integr Med 2013; 19: 905-912.
25. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408.
26. Viale M, Merli A, Bacigalupo A. Analysis at the clonal level of T-cell phenotype and functions in severe aplastic anemia patients. Blood 1991; 78: 1268-1274.
27. Rascon J, Rageliene L, Stankeviciene S, Palionis D, Tamosiunas AE, Valeviciene N et al. An assessment of iron overload in children treated for cancer and nonmalignant hematologic disorders. Eur J Pediatr 2014; 173: 1137-1146.
28. Wu D, Ye B, Luo Y, Zeng Y, Wen X, Shen Y, et al. Effects of deferoxamine on 42 patients with blood diseases and blood transfusion related iron overload. J Pra Med 2013; 29: 4097-4099.
29. Xu Z, Sun W, Li Y, Ling S, Zhao C, Zhong G, et al. The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss. Bone 2017; 94: 152-161.
30. Detivaud L, Island ML, Jouanolle AM, Ropert M, Bardou-Jacquet E, Le Lan C, et al. Ferroportin diseases: functional studies, a link between genetic and clinical phenotype. Hum Mutat 2013; 34: 1529-1536.
31. Lee DH, Zhou LJ, Zhou Z, Xie JX, Jung JU, Liu Y, et al. Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood 2010; 115: 3136-3145.
32. Wu XG, Wang Y, Wu Q, Cheng WH, Liu W, Zhao Y, et al. HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression. Blood 2014; 124: 1335-1343.
33. Chen J, Enns CA. CD81 promotes both the degradation of transferrin receptor 2 (TfR2) and the Tfr2-mediated maintenance of hepcidin expression. J Biol Chem 2015; 290: 7841-7850.
Iranian Journal of Basic Medical Sciences
Volume 22, Issue 6
June 2019
Pages 660-668

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