Reduced Ferritin Levels Research Articles

Zinc inhibits oxidative stress-induced iron signaling and apoptosis in Caco-2 cells

Studies in humans and animals have suggested negative interactions of iron and zinc during their intestinal absorption. Further, zinc seems to prevent iron-induced oxidative damage in rats, which was hypothesized to be through the modulation of the intracellular iron signaling pathway. The aim of this study was, therefore, to understand the effects of zinc on oxidant-induced iron signaling and cell death in human enterocyte-like Caco-2 cells. We demonstrate that zinc decreases glucose/glucose oxidase (H 2O 2-generating system)-induced iron uptake and inhibits iron-regulatory protein 1 activation and divalent metal ion transporter 1 expression. There was also a concomitant decrease in oxidant-induced intracellular labile iron and restoration of ferritin and metallothionein expression. Further, zinc enhanced the Bcl-2/Bax ratio and reduced caspase-3 activity, leading to inhibition of apoptosis. Interestingly, bathophenanthroline disulfonic acid, an extracellular iron chelator, emulated the effects of zinc except for the reduced ferritin levels. These results suggest that zinc inhibits apoptosis by reducing oxidant-induced iron signaling in Caco-2 cells.

Survey on prenatal intakeof various nutrients and pregnancy outcomes

：Objective To investigatethe maternal nutritional status and its influences on pregnancy outcomes in order toprovide evidence for possible prenatal interventions.Methods A survey was conducted in 800pregnant women,who presented at Xiamen Maternal and Child Healthcare Hospital betweenJanuary 2006 to April 2008.The information of knowledge,attitude and behavior towardsmaternal nutrition were collected in 734 women and 571 women were followed up before 20weeks of gestation,at 26-27 weeks,and 35-36 weeks to analyze the relationship betweendifferent nutrients and the pregnant outcomes.Results The questionnaire survey showed thatwomen who had received higher education presented with better knowledge,attitude andbehavior on maternal nutrition (P<0.05).Among the 734 women,39.2%(288) had poorknowledge,44.5%(326) were lack of knowledge,and 44.8%(358) with poor behavior.Prenataldiet analysis found that the percentage of these women with milk,fish and beans intakedaily was 52.2%,34.3%,and 29.5%,respectively.Before 20 weeks of gestation,significantdifference was identified only in the level of triglyceride among different BMI groups,andthe higher the BMI,the higher the level of triglyeeride (P<0.01).With the progress ofpregnancy,the level of serum ferritin and folic acid was decreasing (P<0.05),while thelevel of triglyceride and cholesterol was increasing (P<0.01).The newborn's birthweight was positively correlated to maternal BMI before 20 weeks (r=0.23,P<0.05),andhigher BMI was a risk factor for abnormal birth weight (OR=4.051,95%CI:1.085～15.117,P<0.05) and alsocomplicated with higher cesarean section rate than those women with lower or normal BMI(60.3%vs 29.4%and 34.7%,P<0.05).The rate of postpartum hemorrhage was increased withthe reduced ferritin level (P<0.05).Conclusions The pregnancy outcomes can be improvedthrough the following measures:appropriate control of the maternal weight before andduring the pregnancy,increased intake of milk,fish,beans and so on,reduced intake of foodcontaining abundant fat and sugar,more intake of red animal foodstuff,supplementation offolie acid,iron and calcium throughout the pregnancy,and prevention against high level oftriglyceride and cholesterol. Key words: Prenatal nutrition physiology; Nutritionsurveys; Food; Pregnancy outcome

Inhibition of HIV-1 by Ferroprotin Expression.

HIV-1 transcription is induced by viral Tat protein, which recruits transcriptional co-activators to the HIV-1 promoter. We recently showed that Tat is phosphorylated in the Ser16 and Ser 46 residues by protein kinase CDK2 and that mutations in these residues prevent HIV-1 transcription and viral replication [1]. We also found that iron depletion by iron chelators inhibits cellular activity of CDK2, prevents Tat phosphorylation and inhibits HIV-1 transcription [2]. Thus our previous studies suggest that a decrease in cellular iron might have a protective effect against HIV-1 through inhibition of CDK2 and Tat phosphorylation. Here, we analyzed the effect of the iron exporter, ferroportin, on HIV-1 transcription and viral replication. Increased expression of ferroportin by transfection in iron-treated 293T cells significantly reduced ferritin protein levels compared to increased expression of CD4 or EGFP in iron-treated cells as controls. Treatment with hepcidin increased ferritin levels in 293T cells that expressed wild type ferroportin but not the C326Y mutant of ferroprotin which is not sensitive to hepcidin. Expression of both wild type ferroportin and the C326Y mutant in 293T cells significantly inhibited HIV-1 transcription. Treatment with hepcidin partially restored HIV-1 transcription in the cells expressing wild type ferroportin and not in those expressing the C326Y mutant of ferroportin. Treatment of promonocytic THP-1 cells with iron increased cellular ferritin level. Subsequent treatment with phorbol myristate acetate (PMA) led to increased expression of ferroportin and reduced ferritin level, and this reduction in ferritin was partially alleviated by exposing the cells to hepcidin. Thus, PMA appeared to reduce intracellular iron through increased iron export by ferroportin. HIV-1 replication in iron-supplemented THP-1 cells or primary human monocytes was significantly reduced by treatment with PMA. Subsequent exposure of the PMA-treated monocytes to hepcidin partially restored HIV-1 replication, suggesting that HIV-1 was inhibited in part by the expression of ferroportin and its associated iron-exporting activity. Taken together, our results indicate that expression of ferroportin leads to reduction of cellular iron and also reduced HIV-1 transcription and replication, and that exposure to hepcidin may lead to increased cellular iron content and enhancement of HIV-1 replication. Thus our results suggest that iron depletion of cells that harbor HIV might serve as a strategy to combat this infection, and they point to the need to develop iron chelators specifically designed for HIV-1 therapy.

Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B.

To study the sequential changes of serum ferritin levels in lamivudine-treated patients with chronic viral hepatitis B and the clinical implications. Thirty-eight patients with chronic viral hepatitis B were prospectively studied during their treatment with lamivudine. Each patient received 100 mg oral lamivudine daily for 12 mo, and was observed and tested for blood biochemistry and hepatitis B virus (HBV) DNA levels and serum ferritin levels at baseline and at 3, 6 and 12 mo during the treatment. Serum HBV DNA levels were quantitatively determined using fluorescent quantitative polymerase chain reaction (FQ-PCR), and serum ferritin levels were measured by radioimmunoassay. The sequential changes of serum ferritin levels and their relationships with virological, serological and biochemical responses in the patients were analyzed. All the patients had a baseline HBV DNA level higher than 1 x 10(7) copies/L as determined by FQ-PCR and positive HBsAg and HBeAg and abnormal ALT levels. At the end of the 12-mo treatment, 19 of the 38(50.00%) patients had undetectable serum HBV DNA levels by FQ-PCR, and 12(31.58%) became negative for serum HBeAg and 10(26.32%) had seroconversion from HBeAg to HBeAb. Nineteen out of the 38(50.00%) patients had biochemically normal ALT levels after 12-mo lamivudine treatment. Sequential determination showed that lamivudine treatment significantly reduced ferritin levels in chronic hepatitis B patients. When the patients were divided into different groups according to their post-treatment virological, serological and biochemical responses for analysis of the sequential changes of ferritin levels, it was found that the decrease of ferritin levels in HBV DNA-negative group was significantly more obvious than that in HBV DNA-positive group at 6 mo during the treatment (P=0.013). Consecutive comparisons showed that ferritin levels at 3 mo of treatment were obviously decreased as compared with the baseline levels (P<0.05) in HBeAg-negative group, and the decrease of serum ferritin levels in patients with normalized ALT was more significant than that in patients with abnormal ALT at the end of the 12-mo treatment (P=0.048). Lamivudine treatment can reduce the serum ferritin levels in chronic viral hepatitis B patients and decreases of ferritin levels can be more significant in patients exhibiting virological, serological and biochemical responses, indicating that dynamic observation of serum ferritin levels in patients with chronic viral hepatitis B during lamivudine treatment might be helpful for monitoring and predicting patients' responses to the therapy.

Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells.

Iron regulatory proteins (IRPs), the cytosolic proteins involved in the maintenance of cellular iron homeostasis, bind to stem loop structures found in the mRNA of key proteins involved iron uptake, storage, and metabolism and regulate the expression of these proteins in response to changes in cellular iron needs. We have shown previously that HFE-expressing fWTHFE/tTA HeLa cells have slightly increased transferrin receptor levels and dramatically reduced ferritin levels when compared to the same clonal cell line without HFE (Gross et al., 1998, J Biol Chem 273:22068-22074). While HFE does not alter transferrin receptor trafficking or non-transferrin mediated iron uptake, it does specifically reduce (55)Fe uptake from transferrin (Roy et al., 1999, J Biol Chem 274:9022-9028). In this report, we show that IRP RNA binding activity is increased by up to 5-fold in HFE-expressing cells through the activation of both IRP isoforms. Calcein measurements show a 45% decrease in the intracellular labile iron pool in HFE-expressing cells, which is in keeping with the IRP activation. These results all point to the direct effect of the interaction of HFE with transferrin receptor in lowering the intracellular labile iron pool and establishing a new set point for iron regulation within the cell.

Induction of ferritin synthesis in ischemic-reperfused rat liver: Analysis of the molecular mechanisms

BACKGROUND & AIMS: Iron may catalyze the production of reactive oxygen species (ROS) during postischemic reoxygenation. Ferritin, a cellular iron storage protein, can either represent a source of iron or perform a cytoprotective action against ROS. The aim of this study was to address the role of ferritin in postischemic reperfusion. METHODS: Transcriptional and posttranscriptional mechanisms controlling ferritin gene expression were studied in reperfused rat livers. RESULTS: Proteolysis reduced ferritin levels 2 hours after reperfusion, but a concomitant increase of synthesis, accompanied by enhanced transcription and accumulation of H and L ferritin subunit messenger RNAs (mRNAs), almost re-established normal ferritin content at 4 hours. Pretreatment with interleukin 1 receptor antagonist (IL-1RA) did not prevent the rise of ferritin mRNAs. RNA bandshift assays showed that the activity of the iron regulatory proteins (IRPs), which control ferritin mRNA translation, declined early after reperfusion and recovered progressively thereafter. Pretreatment with either the antioxidant N-acetyl cysteine or IL-1RA was sufficient to prevent almost completely down-regulation of IRP activity. CONCLUSIONS: Postischemic reperfusion causes degradation of ferritin, possibly increasing iron levels. However, induction of ferritin gene transcription, possibly mediated by ferritin-derived iron and ROS- mediated inactivation of IRP, which allows translation of ferritin mRNAs, counteracts this effect and concurs to reestablish the amount of ferritin, which may thus act to limit reperfusion damage. (Gastroenterology 1997 Sep;113(3):946-53)

Effect of iron and retinoic acid on the control of transferrin receptor and ferritin in the human promonocytic cell line U937

The effect of changes in iron availability and induction of differentiation on transferrin receptor expression and ferritin levels has been examined in the promonocytic cell line U937. Addition of iron (as 200 μg/ml saturated transferrin) or retinoic acid (1 μM) both caused approx. 70% reduction in the average number of surface transferrin receptors, while the iron chelator desferrioxamine caused an 84% increase. Comparable changes also occurred in the levels of transferrin receptor mRNA. Neither iron nor retinoic acid significantly altered the half-life of transferrin receptor mRNA in the presence of actinomycin D (approx. 75 min) but a 10-fold increase in stability occurred in the presence of desferrioxamine. Iron and retinoic acid both caused an increase in intracellular ferritin levels (approx. 4-and 3-fold, respectively), while desferrioxamine reduced ferritin levels by approx. two-thirds. The effect of iron and retinoic acid added together did not differ greatly from that of each agent alone. None of the treatments greatly affected levels of L-ferritin mRNA. Virtually no H-ferritin mRNA was detected in U937 cells. These results show that changes in ferritin and transferrin receptor caused by treatment with retinoic acid are similar to those induced by excess iron, and suggest that changes in these proteins during cell differentiation are due to redistribution of intracellular iron into the regulatory pool(s), rather than to iron-independent mechanisms.

Iron deficiency in ethnic minorities: associations with dietary fibre and phytate

Routine full blood counts and serum ferritin determinations were carried out after admission to hospital in 112 children which included a white caucasian group ( n = 65) and two ethnic minority groups of West Indians ( n = 24) and Asians ( n = 23). In these 3 groups those children between the ages of 1 week and 6 months were found to have similar haemoglobin, mean corpuscular volume, and ferritin levels. In the remaining children (aged from 7 months to 14 years 5 months) serum ferritin levels were lower in the ethnic minority groups than in white caucasians, but the haemoglobin and mean corpuscular volume were not significantly different. Children with lower height centiles had reduced ferritin levels, irrespective of their ethnic origins. A nutritional survey between the ages of 7 months and 14 years 5 months showed that mean daily dietary intakes of energy, protein, and iron in white caucasions were similar to those in West Indian and Asian children. The differences noted were in larger phytate and fibre intakes in the ethnic minority groups. Asian diets appeared to differ in containing meat less often as a source of iron, while pulses and chapattis provided more phytate and fibre. It is suggested that dietary intakes of phytate and fibre are important in causing lower ferritin levels by reducing iron absorption.