ABSTRACT
Objective To reproduce an iron overload (IO) model of murine bone marrow derived mesenchymal stem cells (BM-MSCs), explore the effects of IO on murine BM-MSCs, and elucidate the involvement of reactive oxygen species (ROS) in this process. Methods Forty male mice (C57BL/6) were randomly divided into 4 groups (n=10): control group, IO group, Fe+iron-chelation (DFX, 125mg/kg) group and Fe+anti-oxidation (NAC, 40mmol/L) group. BM-MSCs were isolated from compact bone. The levels of iron particles, labile iron pool (LIP) and ROS in BM-MSCs were measured to confirm oxidative stress in the model. Cell proliferation was measured through population double time (DT) and by Cell Counting Kit-8(CCK-8) assay. The osteoblastic differentiation ability of BM-MSCs was assessed by alkaline phosphatase (ALP) activity, alizarin red staining and osteogenic differential genes assay. The adipogenic differentiation ability of BM-MSCs was detected by Oil-Red-O staining. Results Compared with control group, iron deposite increased significantly with higher levels of LIP and ROS in BM-MSCs of IO group (P<0.05). In IO group, the BM-MSCs showed a longer double time than that in control group (2.07 ± 0.14d vs 1.03 ± 0.07d), which can be reversed to 1.52 ± 0.07d by DFX or to 1.68 ± 0.03d by NAC (P<0.05). IO inhibited osteogenic differentiation and mineralization of BM-MSCs, which could be attributed to decreased expression of osteogenic gene alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2) and osteocalcin (OSN). The osteoblastic differentiation ability of BM-MSCs in IO group was suppressed by IO-induced ROS upregulation. NAC or DFX treatment could partially attenuate cell injury and inhibit the signaling pathway induced by excessive iron. Conclusion IO may impair the proliferation and differetiation ability of murine BM-MSCs by enhancing the generation of ROS.
ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the effect of tetra-arsenic tetra-sulfide (As4S4) therapy on the corrected QT interval (QTc) in the acute promyelocytic leukemia (APL) patients.</p><p><b>METHODS</b>Ninety cases of APL treated with As4S4 were divided into two groups--the remission induction group and maintenance therapy group. Blood arsenic concentration was measured and a 12-lead electrocardiogram (ECG) was simultaneously performed before treatment and after remission in the induction group, and before and 2, 4, 6, 8, 10 courses after the treatment in the maintenance therapy group. QT interval on each ECG was measured and corrected by the Bazett formula.</p><p><b>RESULTS</b>Oral administration of As4S4 could lead to the prolongation of QTc both in remission induction and maintenance therapy groups. QTc prolongation was related to the doses of As4S4 and blood arsenic levels. QTc prolongation and its variation range were increased with accumulative doses of As4S4 and the blood arsenic levels. In ten courses maintenance therapy patients, the average abnormal rate of QTc was 37.7%. Blood arsenic concentration was increased slowly with courses, but the variation had no statistical difference (P > 0.05). All the patients whose QTc was abnormal (> or = 440 ms) had neither symptoms nor serious cardiac events, such as ventricular tachycardia and Torsade de pointes and could complete the As4S4 therapy.</p><p><b>CONCLUSION</b>Although As4S4 therapy can lead to QTc prolongation in the treatment of APL patients, it does not preclude the completion of the therapy.</p>