Iron is critical for almost all living organisms because it serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism. Disruption of iron homeostasis is associated with a wide range of diseases. Thus mammals have developed sophisticated mechanisms to maintain optimal range of iron concentration. Iron regulation involves processes at the systemic and cellular levels. These processes are regulated by hepcidin and iron regulatory proteins. Hepcidin modulates systemic iron homeostasis with ability to impede cellular iron export via interaction with the iron export protein, ferroportin. Whereas, iron regulatory proteins control cellular iron homeostasis by translational regulation of proteins which involve iron metabolism. Recent advances in the study of iron metabolism have shown promising results that hepcidin-targeted strategies may help to improve the diagnosis and treatment of iron related diseases. Although these strategies are now under development, ongoing studies can help to elucidate its application possibilities.
Diagnosis ; Energy Metabolism ; Hepcidins ; Homeostasis ; Iron Metabolism Disorders ; Iron* ; Iron-Regulatory Proteins ; Mammals ; Metabolism* ; Oxygen

Iron accumulation in the brain is associated with the pathogenesis of Parkinson's disease (PD). Misexpression of some iron transport and storage proteins is related to iron dyshomeostasis. Iron regulatory proteins (IRPs) including IRP1 and IRP2 are cytosolic proteins that play important roles in maintaining cellular iron homeostasis. F-box and leucine-rich repeat protein 5 (FBXL5) is involved in the regulation of iron metabolism by degrading IRP2 through the ubiquitin-proteasome system. Nitric oxide (NO) enhances the binding activity of IRP1, but its effect on IRP2 is ambiguous. Therefore, in the present study, we aim to determine whether sodium nitroprusside (SNP), a NO donor, regulates FBXL5 and IRP2 expression in cultured SH-SY5Y cells. MTT assay revealed that treatment of SNP attenuated the cell viability in a dose-dependent manner. Flow cytometry test showed that 100 and 300 μmol/L SNP administration significantly reduced the mitochondrial membrane potential by 45% and 60%, respectively. Moreover, Western blotting analysis demonstrated that 300 μmol/L SNP significantly increased FBXL5 expression by about 39%, whereas the expression of IRP2 was decreased by 46%, correspondingly. These findings provide evidence that SNP could induce mitochondrial dysfunction, enhance FBXL5 expression and decrease IRP2 expression in SH-SY5Y cells.
Cell Line ; Cell Survival ; F-Box Proteins ; metabolism ; Homeostasis ; Humans ; Iron Regulatory Protein 2 ; metabolism ; Nitric Oxide ; metabolism ; Nitroprusside ; pharmacology ; Proteasome Endopeptidase Complex ; Ubiquitin ; metabolism ; Ubiquitin-Protein Ligase Complexes ; metabolism

Animals ; Antimicrobial Cationic Peptides ; physiology ; Carrier Proteins ; physiology ; Cation Transport Proteins ; physiology ; Ceruloplasmin ; physiology ; Female ; Ferritins ; physiology ; Hemochromatosis Protein ; Hepcidins ; Histocompatibility Antigens Class I ; physiology ; Humans ; Iron ; metabolism ; Iron-Regulatory Proteins ; physiology ; Membrane Proteins ; physiology ; Placenta ; metabolism ; Pregnancy ; Transferrin ; physiology

OBJECTIVETo study the mechanism of how iron-regulatory protein (hepcidin) affect iron overload in alcoholic liver disease (ALD).

METHODSThirty male wistar rats were randomly divided into 3 groups: Lieber-Decarli liquid without alcohol group (control group), Lieber-Decarli liquid with alcohol (alcohol group) and hepcidin intraperitoneally injected group (hepcidin group), each rat was fed for 6 weeks. The Serum concentration of Alanine Aminotransferase (ALT), Aspartate Amino Transferase (AST), Iron, Total Iron Binding capacity (TIBC), Ferritin, Malonyl Dialdehyde (MDA) and Hepcidin were determined. Hepatic tissue was examined by hematoxylin and eosin staining, prussian blue iron staining and immunohistochemistry staining.

RESULTS(1) Serum concentration of ALT in control group, alcohol group and hepcidin group were (25.2 ± 4.6) U/L, (37.9 ± 14.3) U/L and (40.9 ± 14.1) U/L (F = 4.907, P < 0.05), respectively. Serum AST among three groups were (32.3 ± 13.4) U/L, (55.0 ± 18.6) U/L and (48.3 ± 26.0) U/L (F = 3.742, P < 0.05), respectively. The secretions of ferritin were (224.72 ± 85.49) ng/ml, (345.59 ± 124.75) ng/ml and (339.47 ± 138.47) ng/ml (F = 3.539, P < 0.05). The serum concentrations of TIBC were (147.30 ± 31.98) μmol/L, (148.04 ± 58.74) μmol/L and (143.28 ± 37.38) μmol/L (F = 1.209, P > 0.05), respectively. The serum concentrations of iron were (55.64 ± 13.32) μmol/L, (60.37 ± 25.89) μmol/L and (49.77 ± 17.64) μmol/L (F = 0.651, P > 0.05), respectively. The serum concentration of MDA were (5.84 ± 2.17) nmol/ml, (6.51 ± 2.23) nmol/ml and (4.27 ± 2.68) nmol/ml (F = 2.782, P > 0.05), respectively. The serum concentration of Hepcidin were (155.96 ± 44.91)ng/ml, (124.11 ± 31.98) ng/ml and (114.96 ± 25.81) ng/ml (F = 3.839, P < 0.05), respectively. (2) Significant fat change observed in the liver of alcohol group. The positive granulations of iron staining were (0.8 ± 1.0), (1.2 ± 1.6) and (1.1 ± 1.1) (F = 0.254, P > 0.05), respectively. No differences found of liver iron express among the three groups. Intraperitoneal injection of hepcidin increased hepcidin expression in liver which was inhibited by alcohol (F = 4.139, P < 0.05).

CONCLUSIONSALD rats with lower hepcidin expression in liver can result in iron metabolism disorder. Ectogenic hepcidin can protect liver against alcohol damage by inhibiting lipid peroxidation.

Alanine Transaminase ; blood ; Animals ; Antimicrobial Cationic Peptides ; metabolism ; Hepcidins ; Iron-Regulatory Proteins ; metabolism ; Liver ; metabolism ; pathology ; Liver Diseases, Alcoholic ; metabolism ; pathology ; Male ; Rats ; Rats, Wistar

To explore a rapid and easy method to detect labile iron of pool (LIP) in cells, HL-60 and K562 cells were cultured at a concentration 1 x 10(6)/ml in RPMI 1640 containing 10% heat-inactivated fetal bovine serum. The iron deprivation was induced by adding desferrioxamine (DFO) 10 - 100 micromol/L for 0 - 48 hours. The intracellular LIP was measured by probe calcein-AM. Calcein fluorescence was monitored in 1420 multilabel counter. The results indicated that when HL-60 and K562 cells were incubated with different concentrations of DFO, the calcein fluorescence intensity was higher than that of control group at 12, 24 and 48 hours (P < 0.05). Fluorescence value of representing LIP in DFO groups was lower than that in the control group. In conclusion, DFO can decrease LIP in leukemia cells. The approach used in this study may provide a simple and reliable method for detection of intracellular iron homeostasis.
Cation Transport Proteins ; antagonists & inhibitors ; biosynthesis ; metabolism ; Deferoxamine ; pharmacology ; Fluoresceins ; Fluorescent Dyes ; HL-60 Cells ; Humans ; Iron ; metabolism ; Iron Chelating Agents ; analysis ; metabolism ; Iron-Regulatory Proteins ; metabolism ; K562 Cells

Mitochondrial ferritin (MtF), a new player in iron metabolism, first identified in 2001, is highly homologous to ferritin both structurally and functionally. Preliminary studies have suggested that MtF might play very important roles in the regulation of mitochondrial iron homeostasis. Leukemic cells, just like other malignant cells, demand more iron for their greater proliferation potential. However, little is known about what roles MtF might play in leukemic cell iron metabolism and cell proliferation. The aim of this study was to investigate the expression of MtF, transferrin receptor 1 (TfR1) and ferritin (Fn) mRNAs in K562 leukemic cells during TPA-induced cell differentiation and to explore the interrelationship between the expression levels of these iron metabolism-related molecules. K562 cells cultured with or without TPA (16 nmol/L) were collected at 24, 72 and 120 hours respectively. Cell differentiation toward monocyte lineage was confirmed by microscopic study (Wright's staining) and flow cytometry. Semiquantitative RT-PCR was performed to determine mRNA expression, with house-keeping gene beta-actin as control reference. This study revealed that over 95% of K562 cells showed morphological features of monocyte/macrophage, and the expression of CD64 on cell surface increased significantly at day 5 with TPA treatment. K562 cells could express a certain level of MtF before TPA-induced differentiation. With increase of TPA-induced cell differentiation, MtF mRNA expressions were downregulated progressively. After 5 days of induced cell differentiation, expression levels of MtF and TfR1 mRNA were just 50.3% and 68.2% of that before TPA treatment. While Fn mRNA expression increased to 1.97 folds of that before TPA treatment. It is concluded that MtF expression is downregulated during TPA-induced K562 cell differentiation, with concomitant downregulation of TfR1 and upregulation of Fn. The coordinated expression regulation of these key iron metabolism-related molecules during cell differentiation may in turn inhibit TfR1-mediated iron uptake via endocytosis and thus adversely affect cell proliferation potential.
Antigens, CD ; metabolism ; Cell Proliferation ; Cell Transformation, Neoplastic ; drug effects ; Ferritins ; biosynthesis ; genetics ; Humans ; Iron-Regulatory Proteins ; metabolism ; K562 Cells ; Mitochondria ; metabolism ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Transferrin ; metabolism ; Tetradecanoylphorbol Acetate ; pharmacology

BACKGROUND/AIMS: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. METHODS: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. RESULTS: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) and beta-catenin. CONCLUSIONS: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-kappaB and beta-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.
Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Benzoates/*pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/*drug effects ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Imatinib Mesylate/*pharmacology ; Iron Chelating Agents/*pharmacology ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction/drug effects ; Triazoles/*pharmacology

OBJECTIVETo investigate the mRNA expression of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) in the full-term placenta from different maternal iron status, and explore the mechanism of placental iron transport and regulation.

METHODSThe mRNA level of TfR1 and IRP1 in full-term placentae was detected by reverse transcription polymerase chain reaction (RT-PCR) in normal group (N), iron deficiency group (ID) and iron deficiency anemia group (IDA).

RESULTS(1) The expression of TfR1 mRNA in N group was 0.4813 +/- 0.1891, in ID group was 0. 6647 +/- 0.2788, and in IDA group was 0.9767 +/- 0.2858. There was significant difference between IDA group and N group or ID group (t = 0.002, P < 0.01 or t = 0.028, P < 0.05), and was no difference between ID group and N group (t = 0.117, P > 0.05). (2) The expression of IRP1 mRNA in N group was 0.2616 +/- 0.0785, in ID group was 0.3696 +/- 0.1801, and in IDA group was 0.3971 +/- 0.0902 and was no difference among the three groups (F = 1.845, P = 0.179).

CONCLUSIONSThe expression of TfR1 mRNA is increased when maternal iron deficiency progressed while there is no change in the expression of IRP1 mRNA in the placentae of TfR1 mRNA indicated that IRP1 takes part in the regulation of placenta iron transport.

Anemia, Iron-Deficiency ; genetics ; Antigens, CD ; metabolism ; Female ; Humans ; Iron Regulatory Protein 1 ; metabolism ; Placenta ; metabolism ; Pregnancy ; RNA, Messenger ; metabolism ; Receptors, Transferrin ; metabolism

No abstract available.
Cardio-Renal Syndrome ; Hepcidins

No abstract available.
Anemia* ; Arthritis, Rheumatoid* ; Hepcidins* ; Humans