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Publication Metadata only Insertion of common mutations into the human β-globin locus using GET Recombination and an EcoRI endonuclease counterselection cassette(2003-02-27) Duangporn Jamsai; Mikhail Nefedov; Kumaran Narayanan; Michael Orford; Suthat Fucharoen; Robert Williamson; Panos A. Ioannou; Royal Children's Hospital, Melbourne; Mahidol University; Universiti Malaysia Sarawak; Cyprus Institute of Neurology and GeneticsA large number of mutations have been described in the human β-globin locus causing thalassemia or various hemoglobinopathies. However, only a very limited number of these mutations have been studied in animal model systems in the context... of the human β-globin locus. We report here the use of the GET Recombination system with an EcoRI/KanRcounterselection cassette to facilitate the introduction of the HbE (codon 26, GAG→AAG mutation and the codon 41-42 (-TTCT) deletion, two mutations foundPublication Metadata only A humanized mouse model for a common β0-thalassemia mutation(2005-01-01) Duangporn Jamsai; Faten Zaibak; Wantana Khongnium; Jim Vadolas; Lucille Voullaire; Kerry J. Fowler; Sophie Gazeas; Suthat Fucharoen; Robert Williamson; Panayiotis A. Ioannou; University of Melbourne; Mahidol University; Cyprus Institute of Neurology and GeneticsAccurate animal models that recapitulate the phenotype and genotype of patients with β-thalassemia would enable the development of a range of possible therapeutic approaches. Here we report the generation of a mouse model carrying the codons 41-42... (-TTCT) β-thalassemia mutation in the intact human β-globin locus. This mutation accounts for approximately 40% of β-thalassemia mutations in southern China and Thailand. We demonstrate a low level of production of γ-globins from the mutant locus in dayPublication Open Access Clinical severity of β-thalassaemia/Hb E disease is associated with differential activities of the calpain-calpastatin proteolytic system(2012-05) Suriyan Sukati; Saovaros Svasti; Stifanese, Roberto; Averna, Monica; Nantika Panutdaporn; Tipparat Penglong; Melloni, Edon; Suthat Fucharoen; Katzenmeier, Gerd; Mahidol University. Institute of Molecular Biosciences; Mahidol University. Faculty of Science. Department of BiochemistryEarlier observations in the literature suggest that proteolytic degradation of excess unmatched α-globin chains reduces their accumulation and precipitation in β-thalassaemia erythroid precursor cells and have linked this proteolytic degradation to the activity of calpain protease. The aim of this study was to correlate the activity of calpain and its inhibitor, calpastatin, with different degrees of disease severity in β-thalassaemia. CD34+ cells were enriched from peripheral blood of healthy individuals (control group) and patients with mild and severe clinical presentations of β0-thalassaemia/Hb E disease. By ex vivo cultivation promoting erythroid cell differentiation for 7 days, proerythroblasts, were employed for the functional characterization of the calpain-calpastatin proteolytic system. In comparison to the control group, enzymatic activity and protein amounts of μ-calpain were found to be more than 3-fold increased in proerythroblasts from patients with mild clinical symptoms, whereas no significant difference was observed in patients with severe clinical symptoms. Furthermore, a 1.6-fold decrease of calpastatin activity and 3.2-fold accumulation of a 34 kDa calpain-mediated degradation product of calpastatin were observed in patients with mild clinical symptoms. The increased activity of calpain may be involved in the removal of excess α-globin chains contributing to a lower degree of disease severity in patients with mild clinical symptoms.Publication Open Access Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice(2013) Somdet Srichairatanakool; Kanjana Pangjit; Chada Phisalaphong; Suthat Fucharoen; Mahidol University. Institute of Molecular Biosciences. Thalassemi a Research CentrerDesferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising effective iron chelators for the treatment of iron overload in (-thalassemia patients; nonetheless, their side effects have also been reported. 3-Hydroxypyridinone derivatives are being developed as a safer new chelator and in combined chelation therapy. We evaluated the iron-chelating activity of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in iron-loaded C57BL6 mice. The feeding of a ferrocene-supplemented diet (Fe diet) to mice resulted in iron overload, detectable plasma nontransferrin-bound iron (NTBI) and labile plasma iron (LPI), and increases of red cell membrane iron, plasma malondialdehyde (MDA) and excessive tissue iron deposits. Like DFP, the CM1 lowered the levels of the membrane non-heme iron, the NTBI and LPI (p < 0.05) and the MDA after 3 months of treatment. Administration of the Fe diet and the Fe diet along with the chelators did not change the morphology of the liver and heart. Numerous iron accumulations were observed in the liver and spleen tissues of the Fe dietfed mice, whereas the CM1 reduced such iron deposition. Thus, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) can be considered a candidate bidentate oral iron chelator and is effective in the removal of toxic irons in blood compartment and tissues. The effectiveness and toxicity of the CM1 need to be investigated extensively in thalassemia mice and patients with iron overload.