Our findings indicated that iron uptake mechanisms in cultured thalassemic cardiomyocytes are mainly mediated by TTCC, suggesting that TTCC is the important pathway for iron uptake in this cultured thalassemic cardiomyocyte model.

Summary. Previous studies have suggested that nontransferrin-bound plasma iron (NTBI) is present in patients undergoing cytotoxic chemotherapy, and that this may exacerbate untoward organ damage and increase the risk of bacterial infections following chemotherapy. However, the source of NTBI during myelosuppressive chemotherapy is controversial. In this study we have examined the kinetics of the appearance and disappearance of NTBI with chemotherapy. NTBI was present in only two out of 24 patients prior to chemotherapy but, following chemotherapy, was present in 19 patients, with peak NTBI levels at 5 d after onset of chemotherapy (mean 3 . 06 mM). Thereafter levels fell, but were still detectable in seven patients 14 d after the end of chemotherapy. The appearance of NTBI was associated with a sudden rise in transferrin saturation, but NTBI was detected on four occasions in the absence of full transferrin saturation. We have also established that daunorubicin cannot itself liberate NTBI from serum. There was no relationship between induced NTBI levels and serum iron or ferritin levels, previous or current blood transfusions, disease stage, or the type of chemotherapy given. The appearance of NTBI following chemotherapy was inverserely related to the fall in reticulocytes and serum transferrin receptor (TfR) levels, suggesting that NTBI formation is a consequence of suspension of erythropoietic activity.

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Ethanolic extracts of 30 Thai medicinal plants, traditionally used as alternative treatments in diabetes, were evaluated for antioxidative activity by the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) method. They were evaluated in vitro for oxidative stress by thiobarbituric acid-reactive substance (TBARS) assay in pooled plasma of diabetic patients compared to without treatment of the extracts (control). The extracts were also assayed for protein glycation. The results showed that five plants had strong antioxidant activity: Phyllanthus emblica Linn. (PE), Terminalia chebula Retz. (TC), Morinda citrifolia Linn. (MC), Kaempferia parviflora Wall. (KP) and Houttuynia cordata Thunb.(HC), respectively. Thirty plant extracts were good correlation between total antioxidant activity and antiradical activity by TBARS as well as by glycation (r = 0.856, p<0.01 and r = 0.810, p<0.01). PE had stronger antioxidative activity as well as inhibition of TBARS and glycation than the other plants. The investigation showed that total polyphenol and tannin content of PE and the flavonoid content of HC were the highest. The results imply that these plants are potential sources of natural antioxidants which have free radical scavenging activity and might be used for reducing oxidative stress in diabetes.

Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred-fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4-8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non-transferrin-bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high-dose DFO are less desirable than continuous infusions at low doses, particularly in high-risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*-visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes.

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BackgroundIron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated.Methods and FindingsMale Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.ConclusionsThe combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats.