Red Blood Cell-Derived Iron Alters Macrophage Function in COPD

Lung macrophage iron levels are increased in COPD patients. Lung macrophage iron levels are thought to be increased by cigarette smoke, but the role of red blood cells (RBCs) as a source of iron has not been investigated. We investigate RBCs as a potential source of alveolar iron in COPD, and determine the effect of RBC-derived iron on macrophage function. We used lung tissue sections to assess RBC coverage of the alveolar space, iron and ferritin levels in 11 non-smokers (NS), 15 smokers (S) and 32 COPD patients. Lung macrophages were isolated from lung resections (n = 68) and treated with hemin or ferric ammonium citrate (50, 100 or 200 μM). Lung macrophage phenotype marker gene expression was measured by qPCR. The phagocytosis of Non-typeable Haemophilus influenzae (NTHi) was measured by flow cytometry. Cytokine production in response to NTHi in iron-treated macrophages was measured by ELISA. Lung macrophage iron levels were significantly correlated with RBC coverage of the alveolar space (r = 0.31, p = 0.02). Furthermore, RBC coverage and lung macrophage iron were significantly increased in COPD patients and correlated with airflow obstruction. Hemin treatment downregulated CD36, CD163, HLA-DR, CD38, TLR4, CD14 and MARCO gene expression. Hemin-treated macrophages also impaired production of pro-inflammatory cytokines in response to NTHi exposure, and decreased phagocytosis of NTHi (200 μM: 35% decrease; p = 0.03). RBCs are a plausible source of pulmonary iron overload in COPD. RBC-derived iron dysregulates macrophage phenotype and function.

Deferasirox combination with eltrombopag shows anti-myelodysplastic syndrome effects by enhancing iron deprivation–related apoptosis

Iron overload (IO) affected the survival of patients with myelodysplastic syndrome (MDS). Deferasirox (DFX) is widely used in patients with MDS for iron chelation therapy, but is not suitable for MDS patients with severe thrombocytopenia. Eltrombopag (ELT) is a type of thrombopoietin receptor (TPOR) analog used in the treatment of thrombocytopenia. Therefore, we sought to explore the synergistic effects and possible mechanisms of DFX combination with ELT in MDS cells. In our study, the combination of DFX with ELT synergistically inhibited proliferation, induced apoptosis and arrested cell cycle of MDS cells. Through the RNA-sequence and gene set enrichment analysis (GSEA), iron metabolism–related pathway played important roles in apoptosis of SKM-1 cells treated with DFX plus ELT. Transferrin receptor (TFRC) was significantly highly expressed in combination group than that in single agent groups, without affecting TPOR. Furthermore, the apoptosis of the combination group MDS cells could be partially reversed by ferric ammonium citrate (FAC), accompanied with decreased expression of TFRC. These results suggested that the combination of DFX and ELT synergistically induced apoptosis of MDS cells by enhancing iron deprivation–related pathway.

Lactate production can function to increase human epithelial cell iron concentration

Iron is an essential micronutrient required by every cell, inclusive of both prokaryotes and eukaryotes. Under conditions of limited iron availability, plants and microbes evolved mechanisms to acquire iron which include carbon metabolism reprogramming, with the activity of several enzymes involved in the Krebs cycle and the glycolytic pathway being stimulated by metal deficiency. Following release, resultant carboxylates/hydroxycarboxylates can function as ligands to complex iron and facilitate its solubilization and uptake, reversing the deficiency. Human epithelial tissue may produce lactate, a hydroxycarboxylate, during absolute and functional iron deficiency in an attempt to import metal to reverse limited availability. Here we investigate 1) if lactate can increase cell metal import, 2) if lactic dehydrogenase (LDH) activity in and lactate production by cells correspond to metal availability, and 3) if blood concentrations of LDH in a human cohort correlate with indices of iron homeostasis. Exposures of Caco-2 cells to both Na lactate and ferric ammonium citrate (FAC) increased metal import relative to FAC alone. Fumaric, isocitric, malic, and succinic acid exposure revealed that FAC co-incubation similarly increased iron import relative to FAC alone. Increased iron import following exposures to Na lactate and FAC elevated both ferritin and metal associated with mitochondria. LDH in Caco-2 cell scrapings did not change after exposure to deferoxamine but decreased with 24 hr exposure to FAC. Lactate levels in both the supernatants and cell scrapings revealed decreased levels at 4, 8, and 24 hr with FAC. In the National Health and Nutrition Examination Survey (NHANES 2005-2010), Spearman correlations demonstrated significant negative relationships between LDH concentrations and serum iron. We conclude that iron import in human cells can involve lactate, LDH activity can reflect the availability of this metal, and blood LDH concentrations can correlate with indices of iron homeostasis.

Acclimation and Characterization of Marine Cyanobacterial Strains Euryhalinema and Desertifilum for C-Phycocyanin Production

This study involves evaluation of two native cyanobacterial strains Euryhalinema and Desertifilum isolated from a mangrove pond in Haikou (China) for their possible phycocyanin (C-PC) production. Maximal growth rate with highest chlorophyll and C-PC accumulation were observed at 28°C and 60 μmol photons m−2 s−1 photon flux density for Euryhalinema sp., while for Desertifilum sp. at 32°C and 80 μmol photons m−2 s−1. Nitrogen and iron concentration trails revealed that double strength concentration of sodium nitrate and ferric ammonium citrate in original BG11 media increased growth rate and accumulation of C-PC for both strains. Three different C-PC extraction methods were tested. The combined extraction protocol of freeze–thaw and ultrasonication markedly increased the C-PC extraction efficiency and attained the food grade purity (A620/A280 ratio >0.7), whereas a higher C-PC yield was found with Na-phosphate buffer. Furthermore, the clarified crude extract was used to purify C-PC by fractional ammonium sulfate [(NH₄)₂SO₄] precipitation, Sephadex G-25 gel filtration chromatography, and DEAE-sephadex ion exchange chromatography and attained analytical grade purity (A620/A280 ratio >3.9). Taken together, both strains showed their potential to be domesticated for valuable phycocyanin production.

Effects of Local Administration of Iron Oxide Nanoparticles in the Prefrontal Cortex, Striatum, and Hippocampus of Rats

Iron oxide nanoparticles (IONPs) are used for diverse medical approaches, although the potential health risks, for example adverse effects on brain functions, are not fully clarified. Several in vitro studies demonstrated that the different types of brain cells are able to accumulate IONPs and reported a toxic potential for IONPs, at least for microglia. However, little information is available for the in vivo effects of direct application of IONPs into the brain over time. Therefore, we examined the cellular responses and the distribution of iron in the rat brain at different time points after local infusion of IONPs into selected brain areas. Dispersed IONPs or an equivalent amount of low molecular weight iron complex ferric ammonium citrate or vehicle were infused into the medial prefrontal cortex (mPFC), the caudate putamen (CPu), or the dorsal hippocampus (dHip). Rats were sacrificed 1 day, 1 week, or 4 weeks post-infusion and brain sections were histologically examined for treatment effects on astrocytes, microglia, and neurons. Glial scar formation was observed in the mPFC and CPu 1 week post-infusion independent of the substance and probably resulted from the infusion procedure. Compared to vehicle, IONPs did not cause any obvious additional adverse effects and no additional tissue damage, while the infusion of ferric ammonium citrate enhanced neurodegeneration in the mPFC. Results of iron staining indicate that IONPs were mainly accumulated in microglia. Our results demonstrate that local infusions of IONPs in selected brain areas do not cause any additional adverse effects or neurodegeneration compared to vehicle.

Iron accumulation deteriorated bone loss in estrogen-deficient rats

Background Postmenopausal osteoporosis is characterized by an imbalance of bone resorption exceeding bone formation, resulting in a net loss of bone mass. Whether a menopause-related excess of iron contributes to the development of postmenopausal osteoporosis has remained unresolved due to a lack of an appropriate animal model. This study aimed to explore the effects of iron accumulation in bone mass in estrogen-deficient rats. Methods In the present study, ovariectomy (OVX) was performed in female rats and the changes of iron metabolism and some related modulated genes were detected. Ferric ammonium citrate (FAC) was used as a donor of iron for OVX rats. Moreover, micro-CT was performed to assess the bone microarchitecture in sham group, OVX, and FAC groups. Histological detection of iron in liver was assessed by Perl’s staining. The expressions of β-CTX and osteocalcin were assessed by ELISA. Results It was found that serum iron decreased after OVX. It was found that the expressions of Hepcidin in liver and Fpn, DMT-1 in duodenum significantly decreased at transcriptional level in OVX group than sham group. However, no difference existed in the expression of DMT-1. Then, ferric ammonium citrate (FAC) was used as a donor of iron for OVX rats. The FAC group manifested significant iron accumulation by increased serum iron and hepatic iron content. In addition, FAC treatment accelerated bone loss and decreased BMD and biomechanics in OVX rats. Moreover, bone biomarker β-CTX rather than osteocalcin increased significantly in FAC groups than OVX group. Conclusions In conclusion, no iron accumulation occurred in OVX rats. Furthermore, iron accumulation could further deteriorate osteopenia through enhanced bone resorption.