Spinal cord injury (SCI) usually introduces permanent or long-lasting neurological impairments. Maintaining the integrity of the limited number of white matter bundles (5–10%) preserves wholly or ...partially locomotor following SCI. Considering that the basic structure of white matter bundles is axon wrapped by oligodendrocytes, promoting oligodendrocytes survival might be a feasible strategy for reducing white matter injury (WMI) after SCI. Oligodendrocytes are rich in unsaturated fatty acid and susceptible to ferroptosis-induced damage. Hence, exploring method to reduce ferroptosis is supposed to expedite oligodendrocytes survival, thereafter mitigating WMI to facilitate functional recovery post-SCI. Here, the results indicated the administration of hepcidin reduced iron accumulation to promote oligodendrocytes survival and to decrease spinal cord atrophy, therefore facilitating functional recovery. Then, the WMI was evidently decreased owing to attenuating ferroptosis. Subsequently, the results revealed that the expression of divalent metal transporter 1 (DMT1) and transferrin receptor (TfR) was expressed in CC1
+
cells. The expression level of DMT1 and TfR was significantly increased, while this phenomenon was obviously neutralized with the administration of hepcidin in the epicenter of spinal cord after SCI. Afterward, the application of hepcidin downregulated reactive oxygen species (ROS) overload, which was evidently increased with the treatment of 20 μM FeCl
3
, therefore increasing cell viability and reducing lactate dehydrogenase (LDH) activity through downregulating the expression of DMT1 and TfR to inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs). The present study provides evidence that the application of hepcidin facilitates oligodendrocytes survival to alleviate WMI via reducing the expression of DMT1 and TfR.
Iron deficiency anemia remains a significant public health issue in developing countries. The regulation of iron metabolism is primarily controlled by hepcidin, a key regulatory protein. During ...erythropoiesis, erythroferrone (ERFE), a hormone produced by erythroblasts in response to erythropoietin (EPO) synthesis, mediates the suppression of hepcidin. In this study, it was aimed to determine the correlation between erythroferrone (ERFE) and hepcidin levels in children with iron deficiency anemia.
This is a case-control study conducted at Kırşehir Ahi Evran University Training and Research Hospital Pediatrics Clinic between 1 and 31 September 2020. The study included 26 healthy children and 26 children with iron deficiency anemia. In order to evaluate iron status,whole blood count, serum iron, total iron binding capacity (TIBC), and ferritin levels were analyzed. The study measured the levels of hepcidin and erythroferrone in the serum of children diagnosed with iron deficiency before and after one month of iron treatment, as well as in a control group, using the ELISA method. Correlation between whole blood count, initial ferritin, hepcidin, ERFE and ferritin in the iron deficiency group was evaluated.
Compared with healthy controls, the iron-deficient group had significantly lower haemoglobin (p < 0.001), MCV (p = 0.001), MCH (p < 0.001), MCHC (p < 0.001), iron (p < 0.001), ferritin (p < 0.001) and hepcidin (p = 0.001). Ferritin and hepcidin levels increased while erythroferrone levels remained unchanged after iron deficiency treatment. There was no correlation between hepcidin and ferritin levels in treatment group.
The study found a strong and positive correlation between ferritin and hepcidin levels in iron-deficient children, but not between ERFE levels, suggesting that hepcidin is largely regulated by iron deposition levels. In addition, there was an increase in ferritin and hepcidin levels after iron treatment. The study found no significant difference in erythroferrone levels between the iron-deficient group and the control group. It is thought that this may be due to the short duration of iron treatment given to the patients with iron deficiency anemia included in the study.
Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ...ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (
= 39) were randomly assigned to 20 IU·kg body wt
rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (
≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (
< 0.05) and hepcidin levels (
< 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (
< 0.05) and ERFE (
≤ 0.001) parallel with increases in hematocrit (
< 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (
= 0.13,
< 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.
Virtually all living organisms, including microbes and humans, depend on iron to survive and grow. During an infection, the plasma level of iron and several iron-related proteins change ...substantially. We hypothesized that iron and iron-related proteins could predict short- and long-term outcomes in community-acquired pneumonia.
Blood samples from a prospective cohort of 267 in-patients with community-acquired pneumonia were analysed for hepcidin, ferritin, iron, transferrin, transferrin saturation, and soluble transferrin receptor at admission and 6-weeks post-discharge. Adverse short-term outcome was defined as admission to intensive care unit or death within 30 days, and long-term outcome was assessed as 5-year overall mortality. Logistic regression, Kaplan Meier survival curves, and Cox regression models with cut-offs at median for the potential biomarkers were used for statistical evaluation.
Low admission levels of hepcidin predicted 5-year overall mortality, independently of age, sex, comorbid conditions, and anaemia. Low levels of ferritin at admission as well as low levels of iron and transferrin saturation and high levels of soluble transferrin receptor at the 6-week follow-up were predictors of 5-year overall mortality in univariable, but not in multivariable analyses. Neither of these potential biomarkers predicted adverse short-term outcomes.
In hospitalized patients with community-acquired pneumonia, low levels of hepcidin at admission predicted 5-year overall mortality, but not short-term adverse outcome.
Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage ...subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron export protein ferroportin is targeted for degradation on a limited number of cell types, including monocytes and macrophages. Such changes in monocyte iron metabolism raise the possibility of non-invasively tracking the activity of these immune cells using magnetic resonance imaging (MRI). We hypothesized that hepcidin-mediated changes in monocyte iron regulation influence both cellular iron content and MRI relaxation rates. In response to varying conditions of extracellular iron supplementation, ferroportin protein levels in human THP-1 monocytes decreased two- to eightfold, consistent with paracrine/autocrine regulation of iron export. Following hepcidin treatment, ferroportin protein levels further decreased two- to fourfold. This was accompanied by an approximately twofold increase in total transverse relaxation rate, R
*, compared to non-supplemented cells. A positive correlation between total cellular iron content and R
* improved from moderate to strong in the presence of hepcidin. These findings suggest that hepcidin-mediated changes detected in monocytes using MRI could be valuable for in vivo cell tracking of inflammatory responses.
Hepcidin, a peptide hormone produced in the liver, decreases intestinal iron absorption and macrophage iron release via effects on ferroportin. Bone morphogenic protein and Stat3 signaling regulate ...Hepcidin's transcription. Hepcidin is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. To generate a tool for identifying small molecules that modulate Hepcidin expression, we stably transfected human hepatocytes (HepG2) cells with a reporter construct containing 2.7kb of the human Hepcidin promoter upstream of a firefly reporter gene. We used high throughput methods to screen 10,169 chemicals in duplicate for their effect on Hepcidin expression and cell viability. Regulators were identified as chemicals that caused a change >3 standard deviations above or >1 standard deviation below the mean of the other chemicals (z-score >3 or <1), while not adversely affecting cell viability, quantified by fluorescence assay. Following validation assays, we identified 16 chemicals in a broad range of functional classes that promote Hepcidin expression. All of the chemicals identified increased expression of bone morphogenic protein-dependent and/or Stat3-dependent genes, however none of them strongly increased phosphorylation of Smad1,5,8 or Stat3.
Transmembrane serine protease 6 (Tmprss6) has been correlated with the occurrence and progression of tumors, but any specific molecular mechanism linking the enzyme to oncogenesis has remained ...elusive thus far. In the present study, we found that Tmprss6 markedly inhibited mouse neuroblastoma N2a (neuro-2a) cell proliferation and tumor growth in nude mice. Tmprss6 inhibits Smad1/5/8 phosphorylation by cleaving the bone morphogenetic protein (BMP) co-receptor, hemojuvelin (HJV). Ordinarily, phosphorylated Smad1/5/8 binds to Smad4 for nuclear translocation, which stimulates the expression of hepcidin, ultimately decreasing the export of iron through ferroportin 1 (FPN1). The decrease in cellular iron levels in neuro-2a cells with elevated Tmprss6 expression limited the availability of the metal forribo nucleotide reductase activity, thereby arresting the cell cycle prior to S phase. Interestingly, Smad4 promoted nuclear translocation of activating transcription factor 3 (ATF3) to activate the p38 mitogen-activated protein kinases signaling pathway by binding to ATF3, inducing apoptosis of neuro-2a cells and inhibiting tumor growth. Disruption of ATF3 expression significantly decreased apoptosis in Tmprss6 overexpressed neuro-2a cells. Our study describes a mechanism whereby Tmprss6 regulates the cell cycle and apoptosis. Thus, we propose Tmprss6 as a candidate target for inhibiting neuronal tumor growth.
Iron homeostasis in the Metabolic Syndrome Datz, Christian; Felder, Thomas K.; Niederseer, David ...
European journal of clinical investigation,
February 2013, Letnik:
43, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The metabolic syndrome (MetS) affects iron homeostasis in a many‐faceted fashion. On the one side, hyperferritinaemia with normal or mildly elevated transferrin saturation is observed in ...approximately one‐third of patients with non‐alcoholic fatty liver disease (NAFLD) or the MetS. This constellation has been named the ‘dysmetabolic iron overload syndrome (DIOS)’. Current evidence suggests that elevated body iron stores exert a detrimental effect on the clinical course of obesity‐related conditions and that iron removal improves insulin sensitivity and delays the onset of T2DM. On the other side, iron deficiency is a frequent finding in more progressed stages of obesity. The mechanisms underlying the DIOS and obesity‐related iron deficiency appear strikingly similar as elevated hepcidin concentrations, low expression of duodenal ferroportin (FPN) and impaired iron absorption are found in both conditions. This review summarizes the current knowledge about the dysregulation of iron homeostasis in the MetS and particularly in its hepatic manifestation NAFLD.
Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid‐β (Aβ) induces inflammation and oxidative ...stress, which have pivotal roles in the pathogenesis of AD. Hepcidin is a key regulator of systemic iron homeostasis. Recently, an anti‐inflammatory response to hepcidin was reported in macrophages. Under the hypothesis that hepcidin mediates anti‐inflammatory response in the brain, in this study, we evaluated the putative anti‐inflammatory role of hepcidin on Aβ‐activated astrocytes and microglia. Primary culture of astrocytes and microglia were treated with Aβ, with or without hepcidin, and cytokine levels were then evaluated. In addition, the toxicity of Aβ‐treated astrocyte‐ or microglia‐conditioned media was tested on neurons, evaluating cellular death and oxidative stress generation. Finally, mice were injected in the right lateral ventricle with Aβ, with or without hepcidin, and hippocampus glial activation and oxidative stress were evaluated. Pre‐treatment with hepcidin reduced the expression and secretion of TNF‐α and IL‐6 in astrocytes and microglia treated with Aβ. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with Aβ. Stereotaxic intracerebral injection of hepcidin reduced glial activation and oxidative damage triggered by Aβ injection in mice. Overall, these results are consistent with the hypothesis that in astrocytes and microglia hepcidin down‐regulates the inflammatory and pro‐oxidant processes induced by Aβ, thus protecting neighboring neurons. This is a newly described property of hepcidin in the central nervous system, which may be relevant for the development of strategies to prevent the neurodegenerative process associated with AD.
Aggregated amyloid‐β peptide induces inflammation and oxidative stress, which have pivotal roles in the pathogenesis of Alzheimer's disease. Here, we show that the iron homeostasis regulator hepcidin reduces the expression of TNF‐α and IL‐6 in both astrocytes and microglia treated with Aβ. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with Aβ. We propose that hepcidin is a neuroprotective agent, under inflammatory conditions triggered by the Aβ peptide.
Emerging evidence suggests that pulmonary iron accumulation is implicated in a spectrum of chronic lung diseases. However, the mechanism(s) involved in pulmonary iron deposition and its role in the ...in vivo pathogenesis of lung diseases remains unknown. Here we show that a point mutation in the murine ferroportin gene, which causes hereditary hemochromatosis type 4 (Slc40a1C326S), increases iron levels in alveolar macrophages, epithelial cells lining the conducting airways and lung parenchyma, and in vascular smooth muscle cells. Pulmonary iron overload is associated with oxidative stress, restrictive lung disease with decreased total lung capacity and reduced blood oxygen saturation in homozygous Slc40a1C326S/C326S mice compared to wild-type controls. These findings implicate iron in lung pathology, which is so far not considered a classical iron-related disorder.
•Ferroportin resistance to hepcidin binding leads to pulmonary iron overload.•Lung iron accumulation is restricted to specific cell types.•Iron overload causes restrictive lung disease and decreased blood oxygen saturation.
Pulmonary iron accumulation is associated with a wide spectrum of lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. Impaired lung function was further reported in patients with thalassemia major, a disease hallmarked by transfusional iron overload. So far, the mechanism(s) leading to pulmonary iron deposition and its role in disease onset and progression are still unknown. Our study shows that in a murine disease model, in which the control of systemic iron homeostasis is disrupted, iron accumulates in the lung and correlates with oxidative stress, restrictive lung disease and decreased blood oxygen saturation. These findings implicate iron overload in lung pathology, which is not considered a classical iron-related disorder.
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