Extra- and intracellular free iron and the carotid body responses

The hypothesis that chelation of free iron, by decreasing reactive oxygen species (ROS), might mimic hypoxia and stimulate the carotid body was tested. We used the iron chelators, desferrioxamine (DFO, 200-400 microM) initially, and later ciclopirox olamine (CPX, 2.5-5.0 microM), on rat carotid body in vitro and measured chemosensory activity and [Ca2+]i in isolated cultured glomus cell clusters during normoxia and hypoxia. Although acute treatment of DFO might not penetrate the cell, and extracellular DFO would not influence these activities whereas CPX significantly increased chemosensory activities as well as increased [Ca2+]i in normoxia. We concluded that chelation of extracellular free iron did not alter ROS formation and oxygen sensing. Chelation of intracellular free iron and, therefore, a decrease in intracellular ROS appears to influence oxygen sensing in the carotid body.     

大豆异黄酮与锌离子的螯合作用研究

大豆异黄酮是近年来被广泛关注的保健产品,具有多种生物活性。实验采取大孔树脂法提纯,得到纯度为28.3%的大豆异黄酮产品,考察了大豆异黄酮与锌离子的螯合条件。实验结果表明:室温下pH值为5~6时螯合率较高,全螯合时大豆异黄酮与锌离子的质量比为4.27∶1。     

A natural antioxidant,tannic acid mitigates iron‐overload induced hepatotoxicity in Swiss albino mice through ROS regulation

Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron‐overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron‐overload triggered hepatotoxicity, followed by oral administration of TA for remediation. After treatment, liver, spleen, and blood samples were processed from sacrificed animals. The liver iron, serum ferritin, serum markers, ROS, liver antioxidant status, and liver damage parameters were assessed, followed by histopathology and protein expression studies. Our results show that TA is a prominent ROS and RNS scavenger as well as iron chelator in vitro. It also reversed the ROS levels in vivo and restricted the liver damage parameters as compared to the standard drug, desirox. Moreover, this natural polyphenol exclusively ameliorates the histopathological and fibrotic changes in liver sections reducing the iron‐overload, along with chelation of liver iron and normalization of serum ferritin. The protective role of TA against iron‐overload induced apoptosis in liver was further supported by changed levels of caspase 3, PARP as well as Bax/BCl‐2 ratio. Thus, TA can be envisaged as a better orally administrable iron chelator to reduce iron‐overload induced hepatotoxicity through ROS regulation.     

Transfusional iron overload in patients with myelodysplastic syndromes: A 10-year retrospective survey from a French general hospital

We retrospectively assessed the characteristics of 165 MDS patients from our institution having received at least 20 RBC units. In the vast majority of them various comorbidities (range: 1–6 per patient) were registered including mainly cardiovascular disorders. Serum ferritin was over 1000 μg/L in about half of tested individuals. A chelator agent was initiated in 43.6% of patients (mainly low-risk MDS). Transformation in AML occurred in 46 cases (27.8%). Overall, 112 patients died during follow up. The cause of death was documented in 65 cases and included mainly MDS or AML resistance to therapy. There was a context of bacterial or fungal-related sepsis in 35.3% of cases. We noticed a correlation between survival and number of RBC transfusions. Median OS from the 20th RBC unit was significantly prolonged among the chelated subgroup. Consequences of transfusional iron overload and chelation need to be clarified in MDS patients.     

Iron‐chelating therapy with deferasirox in transfusion‐dependent,higher risk myelodysplastic syndromes: a retrospective,multicentre study

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR‐MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion‐dependent, intermediate‐to‐very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty‐six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375–2500 mg) for a median of 11 months (range 0·4–75). Eight patients (16%) showed grade 2–3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR‐MDS are comparable, in terms of safety and efficacy, with those observed in lower‐risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR‐MDS patients.     

To chelate or not to chelate in MDS: That is the question!

Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopathies that exhibit physical manifestations with clinical consequences of bone marrow failure and inherent risk of progression to acute myeloid leukemia. Iron overload (IO) is common in MDS due to chronic transfusion support and disease-related alterations in iron metabolism. IO has been conclusively associated with inferior outcomes among MDS patients. Despite lack of randomized trials showing a survival impact of iron chelation therapy (ICT), ICT is recommended by experts and guidelines for select MDS patients with IO and is often used. The availability of effective oral ICT agents has reignited the controversy regarding ICT use in patients with MDS and IO. Here we summarize the studies evaluating the value of ICT in MDS and suggest a practical approach for use of these therapies. We also highlight controversies regarding use of ICT in MDS and discuss some ongoing efforts to answer these questions.