High Dietary Iron Research Articles

Deferiprone has less benefits on gut microbiota and metabolites in high iron-diet induced iron overload thalassemic mice than in iron overload wild-type mice: A preclinical study

AimsThis study aimed to investigate the changes in gut microbiota in iron-overload thalassemia and the roles of an iron chelator on gut dysbiosis/inflammation, and metabolites, including short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO). Main methodsAdult male C57BL/6 mice both wild-type (WT: n = 15) and heterozygous β-thalassemia (BKO: n = 15) were fed on either a normal (ND: n = 5/group) or a high‑iron diet for four months (HFe: n = 10/group). HFe-treated WT and HFe-treated BKO groups were further subdivided into two subgroups and each subgroup given either vehicle (n = 5/subgroup) or deferiprone (n = 5/subgroup) during the last month. Gut microbiota profiles, gut barrier characteristics, levels of proinflammatory cytokines, and plasma SCFAs and TMAO were determined at the end of the study. Key findingsHFe-fed WT mice showed distinct gut microbiota profiles from those of ND-fed WT mice, whereas HFe-fed BKO mice showed slightly different gut microbiota profiles from ND-fed BKO. Gut inflammation and barrier disruption were found only in HFe-fed BKO mice, however, an increase in plasma TMAO levels and decreased levels of SCFAs were observed in both WT and BKO mice with HFe-feeding. Treatment with deferiprone, gut dysbiosis and disturbance of metabolites were attenuated in HFe-fed WT mice, but not in HFe-fed BKO mice. Increased Verrucomicrobia and Ruminococcaceae were associated with the beneficial effects of deferiprone. SignificanceIron-overload leads to gut dysbiosis/inflammation and disturbance of metabolites, and deferiprone alleviates those conditions more effectively in WT than in those that are thalassemic.

Hydrogen Sulfide Inhibits Ferroptosis in Cardiomyocytes to Protect Cardiac Function in Aging Rats.

Aging contributes significantly to cardiovascular diseases and cardiac dysfunction. To explore the reasons for the decline in cardiac function in the elderly, we collected clinical data and blood samples from 231 individuals. Our results indicated that aging was accompanied by a decline in cardiac function and remodeling of the left ventricle, and cardiac function was negatively correlated with age. Serum hydrogen sulfide (H2S) decreased, while serum malondialdehyde (MDA) and iron increased with aging in healthy individuals. A rat model of aging and iron overload was constructed for in vivo research. In the animal model, we found that the expression of endogenous H2S-producing enzymes decreased, and endogenous H2S levels decreased, while oxidative stress levels rose. The regulation of iron metabolism and the maintenance of iron homeostasis declined. The accumulation of MDA and iron led to ferroptotic cell death and subsequent myocardial injury and deterioration. A high-iron diet accelerated the aging process and death in rats. The decline of cardiac function in aging rats and iron-overload rats may be caused by cardiomyocyte ferroptosis. Exogenous H2S enhanced the expression of endogenous H2S synthase, promoted endogenous H2S production, regulated iron metabolism, and reduced oxidative stress levels. The protective effects of H2S on cardiac function in aging rats and iron-overload rats may be partly due to the inhibition of cardiomyocyte ferroptosis. We demonstrated that cardiac dysfunction associated with aging was closely related to decreased endogenous H2S levels and cardiomyocyte ferroptosis. H2S-regulated iron metabolism reduced oxidative stress levels in cardiomyocytes, inhibited cardiomyocyte ferroptosis, and protected cardiac function in aging rats.

Dietary iron modulates hepatic glucose homeostasis via regulating gluconeogenesis

Iron exerts significant influences on glucose metabolism. However, the regulatory mechanisms underlying disordered glucose response remains largely unclear. The aim of this study was to examine the impact of dietary iron on hepatic gluconeogenesis in mice and in rat liver-derived cells. High iron models of C57BL/6J mice were fed with 1.25 g Fe/kg diets for 9 weeks, and high-iron BRL-3A cell models were treated with 250 μmol/L FeSO4 for 12 h and 24 h. Our data showed that higher iron intake resulted in higher hepatic iron without iron toxicity, and reduced body weight gain with no difference of food intakes. High dietary iron significantly increased 61% of hepatic glycogen deposition, but exhibited impairment in glucose responses in mice. Moreover, high dietary iron suppressed hepatic gluconeogenesis by repressing the expression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Meanwhile, mice fed with higher iron diets exhibited both decreased AMP-activated protein kinase (AMPK) activity and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protein levels. Furthermore, in BRL-3A cells, iron treatment increased cellular glucose uptake, and altered gluconeogenesis rhythmically by regulating the activation of AMPK and expression of PGC-1α successively. This study demonstrated that dietary high iron was able to increase hepatic glycogen deposition by enhancement of glucose uptake, and suppress hepatic gluconeogenesis by regulation of AMPK and PGC-1α.

Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway.

Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters (zip14 and fpn1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.

High Dietary Organic Iron Supplementation Decreases Growth Performance and Induces Oxidative Stress in Broilers.

Simple SummaryIron (Fe) is an essential trace element nutrient that plays a vital role in metabolic processes, such as oxygen transportation and electron transfer during respiration. However, exposure to high levels of dietary Fe can have negative effects on growth performance and antioxidant function in broilers. Organic Fe has a considerably higher bioavailability than inorganic Fe. To evaluate the safety of Fe chelates with lysine and glutamic acid (Fe–LG) in broilers, we investigated the effects of high concentrations of dietary Fe–LG on serum biochemical parameters, antioxidant status, and duodenal Fe transporter mRNA expression in broilers. A supplementation of 800 mg/kg Fe induced kidney function injury and liver oxidative stress in broilers, and decreased duodenal Fe transporter mRNA expression. Hence, this study demonstrated that high levels of Fe–LG negatively affect broiler health, and proposed a maximum supplemental dose of Fe–LG in broiler diet as a nutritional feed additive.Although Iron (Fe) is an essential nutrient that plays a vital role in respiratory processes, excessive Fe in the diet can affect the health of broilers. We investigated the effects of diet supplemented with high levels of iron chelates with lysine and glutamic acid (Fe–LG) on the growth performance, serum biochemical parameters, antioxidant status, and duodenal mRNA expression of Fe transporters in broilers. A total of 800 1-day-old male Arbor Acres broilers were assigned to 5 groups, with 8 replicates each. Broilers were fed a corn–soybean meal basal diet or basal diets supplemented with 40, 80, 400, or 800 mg Fe/kg as Fe–LG for 6 weeks. The body weight (BW) was increased in the 80 mg Fe/kg treatment group, but decreased in the 800 mg Fe/kg treatment group on day 21. During days 1–21, compared with the control group, the supplementation of the 80 mg Fe/kg increased the average daily gain (ADG) and average daily feed intake (ADFI); however, the supplementation of the 800 mg Fe/kg group decreased the ADG and increased the FCR in broilers (p < 0.05). The heart, liver, spleen, and kidney indices were reduced in the 800 mg Fe/kg treatment group (p < 0.05). The supplementation of the 800 mg Fe/kg group increased the serum aspartate aminotransferase activity and the levels of creatinine and urea nitrogen on day 42 (p < 0.05). The broilers had considerably low liver total superoxide dismutase activity and total antioxidant capacity in the 800 mg Fe/kg treatment group (p < 0.05). Serum and liver Fe concentrations were elevated in the 400 and 800 mg Fe/kg treatment groups, but were not affected in the 40 and 80 mg Fe/kg treatment groups. The duodenal Fe transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) were downregulated in the Fe–LG treatment groups (p < 0.05). We conclude that a high dietary supplement of 800 mg Fe/kg in broilers leads to detrimental health effects, causing kidney function injury and liver oxidative stress.

Dietary High Dose of Iron Aggravates the Intestinal Injury but Promotes Intestinal Regeneration by Regulating Intestinal Stem Cells Activity in Adult Mice With Dextran Sodium Sulfate-Induced Colitis.

The effects of excessive dietary iron intake on the body have been an important topic. The purpose of this study was to investigate the effects of high-dose iron on intestinal damage and regeneration in dextran sodium sulfate (DSS)-induced colitis model mice. A total of 72 8-week-old adult C57BL/6 mice were randomly divided into two dietary treatment groups: the basal diet supplemented with 45 (control) and 450 mg/kg iron (high-iron) from ferrous sulfate. The mice were fed different diets for 2 weeks, and then 2.5% DSS was orally administered to all mice for 7 days. Samples of different tissues were collected on days 0, 3, and 7 post administration (DPA). High-iron treatment significantly decreased the relative weight of the large intestine at 7 DPA but not at 0 DPA or 3 DPA. High dietary iron increased the jejunal villus width at 0 DPA, decreased the villus width and the crypt depth of the jejunum at 3 DPA, and decreased the number of colonic crypts at 7 DPA. Meanwhile, high dietary iron decreased the number of goblet cells in the jejunal villi and the Paneth cells in the jejunal crypts at 0 DPA, increased the number of goblet cells per crypt of the colon at 3 DPA, and the number of Paneth cells in the jejunal crypts, the goblet cells in the colon, the Ki67-positive proliferating cells in the colon, and the Sex-determining region Y-box transcription factor 9+ (SOX9) cells in the jejunum crypts and colon at 7 DPA. The organoid formation rate was increased by high-iron treatments at 3 DPA and 7 DPA. High dietary iron treatment decreased the mRNA level of jejunal jagged canonical Notch ligand 2 (Jag-2) at 0 DPA and bone morphogenetic protein 4 (Bmp4) and neural precursor cell-expressed developmentally downregulated 8 (Nedd8) in the jejunum and colon at 7 DPA, whereas it increased the mRNA expression of the serum/glucocorticoid-regulated kinase 1 (Sgk1) in the colon at 3 DPA. The results suggested that a high dose of iron aggravated intestinal injury but promoted intestinal repair by regulating intestinal epithelial cell renewal and intestinal stem cell activity in adult mice with colitis.

High Iron Exposure from the Fetal Stage to Adulthood in Mice Alters Lipid Metabolism.

Iron supplementation is recommended during pregnancy and fetal growth. However, excess iron exposure may increase the risk of abnormal fetal development. We investigated the potential side effects of high iron levels in fetuses and through their adult life. C57BL/6J pregnant mice from 2 weeks of gestation and their offspring until 30 weeks were fed a control (CTRL, FeSO4 0 g/1 kg) or high iron (HFe, FeSO4 9.9 g/1 kg) diets. HFe group showed higher iron accumulation in the liver with increased hepcidin, reduced TfR1/2 mRNAs, and lowered ferritin heavy chain (FTH) proteins in both liver and adipose tissues despite iron loading. HFe decreased body weight, fat weight, adipocyte size, and triglyceride levels in the blood and fat, along with downregulation of lipogenesis genes, including PPARγ, C/EBPα, SREBP1c, FASN, and SCD1, and fatty acid uptake and oxidation genes, such as CD36 and PPARα. UCP2, adiponectin, and mRNA levels of antioxidant genes such as GPX4, HO-1, and NQO1 were increased in the HFe group, while total glutathione was reduced. We conclude that prolonged exposure to high iron from the fetal stage to adulthood may decrease fat accumulation by altering ferritin expression, adipocyte differentiation, and triglyceride metabolism, resulting in an alteration in normal growth.

Identification of Novel Disease-Relevant Genes and Pathways in the Pathogenesis of Type 1 Diabetes: A Potential Defect in Pancreatic Iron Homeostasis.

Multiple pathways contribute to the pathophysiological development of type 1 diabetes (T1D); however, the exact mechanisms involved are unclear. We performed differential gene expression analysis in pancreatic islets of NOD mice versus age-matched congenic NOD.B10 controls to identify genes that may contribute to disease pathogenesis. Novel genes related to extracellular matrix development and glucagon and insulin signaling/secretion were changed in NOD mice during early inflammation. During "respective" insulitis, the expression of genes encoding multiple chemosensory olfactory receptors were upregulated, and during "destructive" insulitis, the expression of genes involved in antimicrobial defense and iron homeostasis were downregulated. Islet inflammation reduced the expression of Hamp that encodes hepcidin. Hepcidin is expressed in β-cells and serves as the key regulator of iron homeostasis. We showed that Hamp and hepcidin levels were lower, while iron levels were higher in the pancreas of 12-week-old NOD versus NOD.B10 mice, suggesting that a loss of iron homeostasis may occur in the islets during the onset of "destructive" insulitis. Interestingly, we showed that the severity of NOD disease correlates with dietary iron intake. NOD mice maintained on low-iron diets had a lower incidence of hyperglycemia, while those maintained on high-iron diets had an earlier onset and higher incidence of disease, suggesting that high iron exposure combined with a loss of pancreatic iron homeostasis may exacerbate NOD disease. This mechanism may explain the link seen between high iron exposure and the increased risk for T1D in humans.

Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus.

The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.

X-ray absorption spectroscopy of copper and iron in sheep digesta

BackgroundThe bioavailable supply of copper to ruminants has long been problematic. Complexities in supply exist due to interactions with other dietary elements in the rumen, most notably with iron or molybdenum in combination with sulphur, which can result in copper binding preventing its absorption. The molybdenum-sulphur-copper interaction has been extensively studied over the years. However, very little is known about the iron-sulphur-copper interaction, especially its mode of action in the gastrointestinal tract. MethodsIn the present work digesta from the rumen and jejunum of sheep fed a high copper, sulphur and iron diet was analysed using X-ray absorption spectroscopy (XAS). ResultsX-ray absorption fine structure (XAFS) and X-ray absorption near edge structure (XANES) indicated that all of the copper and iron had changed in bonding in the rumen and that the oxidation state of the elements had been reduced into a mix of Fe2+ & Fe3+ and Cu+ with some Cu0. ConclusionThe copper compounds were most likely to be thiol co-ordinated in line with Cu+ chemistry. Changes to the copper compounds took place in the jejunum, although thiols were still highly favoured the possible existence of a copper-iron-sulphur complex which also included oxygen and chloride was also observed. This possibly has some resemblance to the crystal structure of bornite.

Iron accumulation with age alters metabolic pattern and circadian clock gene expression through the reduction of AMP-modulated histone methylation

Iron accumulates with age in mammals, and its possible implications in altering metabolic responses are not fully understood. Here, we report that both high-iron diet and advanced age in mice consistently altered gene expression of many pathways, including those governing the oxidative stress response and the circadian clock. We used a metabolomic approach to reveal similarities between metabolic profiles and the daily oscillation of clock genes in old and iron-overloaded mouse livers. In addition, we show that phlebotomy decreased iron accumulation in old mice, partially restoring the metabolic patterns and amplitudes of the oscillatory expression of clock genes Per1 and Per2. We further identified that the transcriptional regulation of iron occurred through a reduction in AMP-modulated methylation of histone H3K9 in the Per1 and H3K4 in the Per2 promoters, respectively. Taken together, our results indicate that iron accumulation with age can affect metabolic patterns and the circadian clock.

Ferrostatin-1 Ameliorates Liver Dysfunction via Reducing Iron in Thioacetamide-induced Acute Liver Injury in Mice.

Background and Aims: Hepatic iron overload always leads to oxidative stress, which has been found to be involved in the progression of liver disease. However, whether iron disorder is involved in acute liver disease and the further molecular mechanisms remain unclear. Methods: A mice model of acute liver injury (ALI) was established via intraperitoneal injection of thioacetamide (TAA) (250 mg/kg/day) for 3 consecutive days. Ferrostatin-1 (Fer-1) was administered intraperitoneally (2.5 μM/kg/day) starting 3 days before TAA treatment. Deferoxamine (DFO) was intraperitoneally injected (200 mg/kg/day) with TAA treatment for 3 days. We further observed the effect of Fer-1 on TAA model with high-iron diet feeding. ALI was confirmed using histological examination and liver function activity. Moreover, expressions of iron metabolism and ferroptosis proteins were measured by Western blot analysis. Results: The study revealed that the iron accumulation and ferroptosis contributed to TAA-induced ALI pathogenesis. TAA induced prominent inflammation and vacuolar degeneration in the liver as well as liver dysfunction. In addition, protein expression of the cystine/glutamate antiporter SLC7A11 (xCT) and glutathione peroxidase 4 (GPX4) was significantly decreased in the liver, while transferrin receptor 1 (TfR1), ferroportin (Fpn) and light chain of ferritin (Ft-L) expression levels were increased after TAA exposure. As the same efficiency as DFO, pre-administration of Fer-1 significantly decreased TAA-induced alterations in the plasma ALT, AST and LDH levels compared with the TAA group. Moreover, both Fer-1 and DFO suppressed TfR1, Fpn and Ft-L protein expression and decreased iron accumulation, but did not affect xCT or GPX4 expression in the liver. Both Fer-1and DFO prevented hepatic ferroptosis by reducing the iron content in the liver. Furthermore, Fer-1 also reduced iron and reversed liver dysfunction under iron overload conditions. Conclusion: These findings indicate a role of TAA-induced iron accumulation and ferroptosis in the pathogenesis of ALI model. The effect of Fer-1 was consistent with that of DFO, which prevented hepatic ferroptosis by reducing the iron content in the liver. Thus, Fer-1 might be a useful reagent to reverse liver dysfunction and decreasing the iron content of the liver may be a potential therapeutic strategy for ALI.

Dietary Iron Restriction Improves Muscle Function, Dyslipidemia, and Decreased Muscle Oxidative Stress in Streptozotocin-Induced Diabetic Rats.

Diabetes mellitus is a chronic degenerative disease characterized by hyperglycemia and oxidative stress. Iron catalyzes free radical overproduction. High iron concentrations have previously been reported to promote an increase in oxidative stress; however, the effect of iron restriction in diabetes has not yet been explored, so we tested to see if iron restriction in diabetic rats reduces oxidative damage and improved muscle function. Wistar rats were assigned to 4 groups: Control; Diabetic; Diabetic rats with a high iron diet, and Diabetic with dietary iron restriction. After 8 weeks the rats were sacrificed, the muscles were extracted to prepare homogenates, and serum was obtained for biochemical measurements. Low iron diabetic rats showed an increase in the development of muscle strength in both muscles. Dietary iron restriction decreased triglyceride concentrations compared to the untreated diabetic rats and the levels of extremely low-density lipoproteins. Aggravation of lipid peroxidation was observed in the diabetic group with a high iron diet, while these levels remained low with iron restriction. Iron restriction improved muscle strength development and reduced fatigue times; this was related to better lipid profile control and decreased oxidant stress markers.

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding.

Vampire bats are the only mammals that feed exclusively on blood. To uncover genomic changes associated with this dietary adaptation, we generated a haplotype-resolved genome of the common vampire bat and screened 27 bat species for genes that were specifically lost in the vampire bat lineage. We found previously unknown gene losses that relate to reduced insulin secretion (FFAR1 and SLC30A8), limited glycogen stores (PPP1R3E), and a unique gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2 and CTRL) and distinct pathogen diversity of blood (RNASE7) and predict the complete lack of cone-based vision in these strictly nocturnal bats (PDE6H and PDE6C). Notably, REP15 loss likely helped vampire bats adapt to high dietary iron levels by enhancing iron excretion, and the loss of CYP39A1 could have contributed to their exceptional cognitive abilities. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to blood feeding.

Berberine Is a Promising Alkaloid to Attenuate Iron Toxicity Efficiently in Iron-Overloaded Mice

Iron toxicity in iron-overloaded conditions, including high iron diet and blood transfusion, causes deleterious effects on vital organs. There currently are a number of chemical chelators in clinics to reduce iron concentration, for example , deferoxamine and deferiprone, but these produce diverse side effects. Hence, the need for a safe and effective iron chelator is demanded. To evaluate rigorously the potential of berberine on iron chelation and its anti-oxidant effect, 30 mice were divided into 5 groups of 6. Except for the control group, other groups received iron sucrose 5 times a week for 4 successive weeks as an i.p injection. Afterward, either berberine or deferoxamine was injected for 1 month. The mice were then euthanized and liver, kidney and lungs were carefully removed for biochemical and pathological analysis. In comparison with the iron group with an extraordinary amount of iron deposits, berberine (20 mg/kg/day) dramatically reduced iron sedimentation in all tissues ( P &lt; 0.01). Moreover, berberine lowered clinical symptoms of iron overdose, including inflammation, fibrosis and tissue degeneration. In terms of the activity of antioxidant enzymes, catalase and superoxide dismutase, iron overdose greatly reduced their activity compared to the control group. Berberine progressively increased their activity in comparison with the controls by lowering oxidative conditions ( P &lt; 0.05). Iron overdose similarly increased lipid peroxidation by increasing the level of malondialdehyde. Berberine promptly suppressed lipid peroxidation in an efficient manner and reduced the level of malondialdehyde, a marker of lipid peroxidation in the tissues. Accordingly, berberine, as a natural antioxidant compound, could adequately serve as a substitute for chemical chelators with fewer side effects and comparable effectiveness.

Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway

Ferroptosis is a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. At present, the underlying molecular mechanisms remain elusive. Herein, we hypothesized that mitochondria and the NRF2 (transcription factor nuclear factor E2-related factor 2) are potential mediators of ferroptosis, considering their well-established involvement in the oxidative stress pathway. We found that a high iron diet increased hepatic iron content and promoted glutathione (GSH) depletion, lipid peroxidation and oxidative stress. Dietary iron overload also decreased mRNA and protein expression levels of glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11), and increased mRNA and protein expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which are all markers of ferroptosis. Consistent with ferroptosis, iron overload promoted lipid peroxidation and the generation of mitochondrial reactive oxygen species (ROS), and decreased the mitochondrial membrane potential (MMP). Pre-treatment with deferoxamine mesylate (DFO, an iron chelator) alleviated ROS generation and lipid peroxidation, indicating a causative link between iron overload and lipid peroxidation. Suppression of mitochondrial oxidative stress attenuated ferroptosis. Experiments with HEK293T cells revealed that Fe-induced ferroptosis involved direct inhibition of NRF2 binding to antioxidant response elements (AREs) within the promoters of the gpx4 and slc7a11 genes, which in turn induced transcriptional silencing. In conclusion, our study provided a direct link between mitochondrial oxidative stress and ferroptosis via the NRF2-ARE pathway.

Dietary Trace Element Intake and Risk of Breast Cancer: A Mini Review.

Trace elements are essentially required for various physiological and metabolic functions, and any disturbance in the trace elements homeostasis may result in the development of chronic diseases including breast cancer. Breast cancer is the most prevalent cancer type reported in women equally affecting both the high-income and low-income countries. This review therefore aimed to evaluate the impact of dietary trace element intake in relation to the incidence of breast cancer. We focused on five trace elements, thus emphasizing dietary selenium, zinc, iron, copper, and cadmium intake and risk of breast cancer. A systematic approach was applied to perform this review through entering a search term in PubMed and Scopus databases. A total of 24 articles were included after meeting the inclusion and exclusion criteria. Most of the studies regarding dietary iron intake showed a detrimental effect of increased dietary heme iron on breast cancer incidence risk. In addition, there is a limited evidence of high dietary intake of selenium and zinc to reduce the risk of breast cancer. Also, a few studies showed a relationship between high cadmium consumption and risk of breast cancer. More studies related to cadmium and copper exposure are needed to confirm this relationship. As a result, the findings of this review suggested that high dietary heme iron is a potential risk factor for breast cancer.

Iron excess affects release of neutrophil extracellular traps and reactive oxygen species but does not influence other functions of neutrophils.

Neutrophils apply several antimicrobial strategies including degranulation, phagocytosis, the generation of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs) to fight pathogens. Iron is considered to be an invaluable constituent of host immune defense and plays a dual role in immunity. It is a well-known component of antimicrobial proteins and is a necessary microelement for pathogen survival. The aim of this study was to broaden the knowledge regarding the impact of iron on the function of neutrophils. Neutrophils from healthy blood donors and patients with mild iron-deficiency anemia and HL-60 cells differentiated toward granulocyte-like cells were incubated with Fe2+ , Fe3+ or holo-transferrin (holo-Tf). Moreover, we isolated murine neutrophils of HFE gene knockout (KO) mice and mice fed iron-deficient, iron-equivalent and high-iron diets. We analyzed the release of NETs, phagocytosis, degranulation of azurophilic granules, ROS release, bactericidal activity of granulocytes against Escherichia coli and neutrophil elastase (NE) activity. We show that holo-Tf inhibits the release of NETs stimulated by phorbol 12-myristate 13-acetate by inhibiting NE activity. Studies performed in mice models reveal that iron overload inhibits the release of NETs and ROS production in neutrophils isolated from HFE KO mice and mice fed a high-iron diet. No impact of a low-iron diet on neutrophil phagocytosis, ROS production or release of NETs was observed. Our study underscores the physiological significance of iron in neutrophil function, specifically in the release of NETs.

Dietary Iron Overload and Hfe-/- Related Hemochromatosis Alter Hepatic Mitochondrial Function.

Iron is an essential co-factor for many cellular metabolic processes, and mitochondria are main sites of utilization. Iron accumulation promotes production of reactive oxygen species (ROS) via the catalytic activity of iron species. Herein, we investigated the consequences of dietary and genetic iron overload on mitochondrial function. C57BL/6N wildtype and Hfe−/− mice, the latter a genetic hemochromatosis model, received either normal diet (ND) or high iron diet (HI) for two weeks. Liver mitochondrial respiration was measured using high-resolution respirometry along with analysis of expression of specific proteins and ROS production. HI promoted tissue iron accumulation and slightly affected mitochondrial function in wildtype mice. Hepatic mitochondrial function was impaired in Hfe−/− mice on ND and HI. Compared to wildtype mice, Hfe−/− mice on ND showed increased mitochondrial respiratory capacity. Hfe−/− mice on HI showed very high liver iron levels, decreased mitochondrial respiratory capacity and increased ROS production associated with reduced mitochondrial aconitase activity. Although Hfe−/− resulted in increased mitochondrial iron loading, the concentration of metabolically reactive cytoplasmic iron and mitochondrial density remained unchanged. Our data show multiple effects of dietary and genetic iron loading on mitochondrial function and linked metabolic pathways, providing an explanation for fatigue in iron-overloaded hemochromatosis patients, and suggests iron reduction therapy for improvement of mitochondrial function.

Effects of high dietary iron on the lipid metabolism in the liver and adipose tissue of male broiler chickens

Iron overload is associated with the obesity and type 2 diabetes in humans. To investigate its effects on lipid metabolism in the liver and adipose tissue of broiler chickens, a total of 320 1-day-old male broiler chickens were assigned to 2 groups with 8 replicate pens (20 birds per pen). The broiler chickens were fed diets containing either 139 mg Fe/kg (adequate dietary iron; control) or 609 mg Fe/kg (high dietary iron; high-iron) by FeSO4 supplement (dry matter basis). After 21 days, the samples of blood, liver, and abdominal adipose tissue were collected. High dietary iron decreased body weight (BW), abdominal adipose tissue weight, and the percentage of abdominal adipose tissue weight relative to BW (P < 0.01). Adipocyte size and DNA content in abdominal adipose tissue were also lower (P < 0.001) in the high-iron treatment group than in the control group. High dietary iron decreased the concentrations of triglyceride (TAG) and total fatty acids in the liver, and the concentration of very-low-density lipoprotein in the serum, the major vehicle for TAG from the liver to the peripheral tissues. In the liver, the activities of lipogenic enzymes including acetyl-coenzyme A carboxylase, fatty acid synthase (FAS), and stearoyl-coenzyme A desaturase 1 (SCD1) were lower in the high-iron treatment group than in the control group (P < 0.05). High dietary iron decreased the activities of lipolytic enzymes such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in the abdominal adipose tissue (P < 0.05). Simultaneously, high dietary iron decreased the mRNA abundance of FAS, SCD1, and sterol regulatory element–binding transcription factor (SREBP) 1 in the liver and that of peroxisome proliferator–activated receptor γ, CCAAT/enhancer-binding protein (C/EBP) α, and C/EBPβ in the abdominal adipose tissue (P < 0.05). These results suggested that high dietary iron reduced abdominal adipose fat deposition and hepatic TAG accumulation in broiler chickens, which was at least partly due to the reduction in hepatic de novo lipogenesis in broiler chickens.