Acute Iron Deficiency Research Articles

Antimicrobial Potency of Nor-Pyochelin Analogues and Their Cation Complexes against Multidrug-Resistant Pathogens.

The opportunistic pathogen Pseudomonas aeruginosa develops increasing resistance toward even the most potent antibiotics. Like other bacteria, the pathogen produces a number of virulence factors including metallophores, which constitute an important group. Pseudomonads produce the iron-chelating metallophore (siderophore) pyochelin, which, in addition to its iron-scavenging ability, is an effector for the transcriptional regulator PchR in its FeIII-bound form (ferripyochelin). In the present study, docking studies predicted a major ferripyochelin binding site in PchR, which prompted the exploration of nor-pyochelin analogues to produce tight binding to PchR, and thereby upregulation of the pyochelin metabolism. In addition, we investigated the effects of using the analogues to bind the antimicrobial cations GaIII and InIII. Selected analogues of nor-pyochelin were synthesized, and their GaIII- and InIII-based complexes were assessed for antimicrobial activity. The results indicate that the GaIII complexes inhibit the pathogens under iron-limited conditions, while the InIII-based systems are more effective in iron-rich media. Several of the GaIII complexes were shown to be highly effective against a multidrug-resistant P. aeruginosa clinical isolate, with minimum inhibitory concentrations (MICs) of ≤1 μg/mL. Similarly, two of the InIII-based systems were particularly effective against the isolate, with an MIC of 8 μg/mL. These results show high promise in comparison with other, traditionally potent antibiotics, as the compounds generally indicated low cytotoxicity toward mammalian cells. Preliminary mechanistic investigations using pseudomonal transposon mutants suggested that the inhibitory effects of the InIII-based systems could be due to acute iron deficiency as a result of InIII-bound bacterioferritin.

Quantitative Proteome and Transcriptome Dynamics Analysis Reveals Iron Deficiency Response Networks and Signature in Neuronal Cells.

Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.

The Ideal Time for Iron Administration in Anemia Secondary to Blood Loss-An Experimental Animal Model.

Background: Anemia and iron deficiency are two of the main public health problems worldwide, associated with negative outcomes in surgical patients. This experimental study aimed to create a model of acute iron deficiency with anemia through blood loss and extensive surgery. Afterwards, intravenous iron was administered to correct the iron deficiency and to improve the hematological parameters in distinct moments regarding the surgical time. To assess the optimum time for therapeutic intervention, experimental subjects were compared, performing clinical, paraclinical, and histological examinations, as well. Methods: Male rats (n = 35), aged 11–13 months, were randomly designated into six groups. Anemia and iron deficiency were obtained through a 15% blood volume loss, followed by major surgical intervention (femur fracture and osteosynthesis using Kirschner wire). Therapeutic intervention was obtained with an intravenous ferric carboxymaltose infusion, as follows: group II: intraoperative (n = 7), group III: 48 h after surgery (n = 7), group IV: 48 h before surgery (n = 5), and group V: seven days before surgery (n = 6). Group I (n = 5) was left anemic, while group 0 (n = 5) was nonanemic without therapeutic intervention. Results and Discussion: In group I, serum iron lower than in group 0 (27.04 ± 6.92 μg/dL versus 60.5 ± 2.34 μg/dL), as well as hemoglobin (10.4 ± 0.54 g/dL versus 14.32 ± 2.01 g/dL) and ferritin values (22.52 ± 0.53 ng/mL versus 29.86 ± 3.97 ng/mL), validated the experimental model. Regarding wound healing after surgical trauma, we observed that neovascularization was more significant in group III, followed by group V, with fewer neutrophils, a well-represented and rich in lymphomonocytes inflammatory infiltrate associated with the biggest collagen fiber dimensions. The periosteal reaction and callus area presented thicker trabeculae in groups II and III compared to the anemic group. Conclusions: This original experimental study assessed the effect of perioperative intravenous iron administration at a specific time by comparing the weight, hematological, and iron status-defining parameters, as well as histological characteristics of the included subjects. The present findings highlight that correcting the iron deficiency in emergency settings through intravenous iron administration intraoperatively or 48 h postoperatively could determine the improved bioumoral parameters, as well as a better evolution of the postoperative wound and bone healing compared to the anemic group or subjects that received therapeutic intervention 48 h before surgery.

Iron-deficient diet induces distinct protein profile related to energy metabolism in the striatum and hippocampus of adult rats

ABSTRACT Iron deficiency is a public health problem that affects all age groups. Its main consequence is anemia, but it can also affect cognitive functions. Although the negative effects of iron deficiency on cognitive function have been extensively described, the underlying mechanism has not been fully investigated. Thus, to gain an unbiased insight into the effects of iron deficiency (ID) on discrete brain regions, we performed a proteomic analysis of the striatum and hippocampus of adult rats subjected to an iron restricted (IR) diets for 30 days. We found that an IR diet caused major alterations in proteins related to glycolysis and lipid catabolism in the striatum. In the hippocampus, a larger portion of proteins related to oxidative phosphorylation and neurodegenerative diseases were altered. These alterations in the striatum and hippocampus occurred without a reduction in local iron levels, although there was a drastic reduction in liver iron and ferritin. Moreover, the IR group showed higher fasting glycaemia than the control group. These results suggest that brain iron content is preserved during acute iron deficiency, but the alterations of other systemic metabolites such as glucose may trigger distinct metabolic adaptations in each brain region. Abnormal energy metabolism precedes and persists in many neurological disorders. Thus, altered energy metabolism can be one of the mechanisms by which iron deficiency affects cognitive functions.

Acute loss of iron–sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells

Iron-sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant-negative variants of the primary Fe-S biogenesis scaffold protein iron-sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming associated with loss of Fe-S-containing proteins in several major cellular compartments. Using multiple metabolomics platforms, we observed a ∼12-fold increase in intracellular citrate content in Fe-S-deficient cells, a surge that was due to loss of aconitase activity. The excess citrate was generated from glucose-derived acetyl-CoA, and global analysis of cellular lipids revealed that fatty acid biosynthesis increased markedly relative to cellular proliferation rates in Fe-S-deficient cells. We also observed intracellular lipid droplet accumulation in both acutely Fe-S-deficient cells and iron-starved cells. We conclude that deficient Fe-S biogenesis and acute iron deficiency rapidly increase cellular citrate concentrations, leading to fatty acid synthesis and cytosolic lipid droplet formation. Our findings uncover a potential cause of cellular steatosis in nonadipose tissues.

Perioperatives Vorgehen bei Restless-legs-Syndrom

Restless legs syndrome (RLS) is one of the most common neurological disorders. The key feature is the urge to move, especially in the legs. New onset RLS can develop perioperatively or an existing RLS can be exacerbated. Severe insomnia, forced immobilization and acute iron deficiency are common trigger factors. Medicinal treatment can also be an important triggering or exacerbating factor. Drugs with dopamine antagonistic, serotonergic and opioid antagonistic effects should be avoided. The long-term medicinal treatment should be terminated as quickly as possible and if necessary bridged non-orally. For diseases which can be associated with secondary RLS a provocation or an exacerbation of RLS should be taken into consideration. This is particularly true for Parkinson's disease, diabetes mellitus, terminal renal insufficiency, spinal cord lesions and pregnancy. So far, there is not sufficient evidence that any form of anesthesia has a negative influence on RLS.

Atypical clinical course of pneumonia in a patient with ummunodeficiency, iron-deficient anemia and dietary supplement intake

A clinical case pneumonia and multiple organ dysfunction syndrome in a patient with iron-deficiency anemia and previous intake of a dietary supplement for weight loss is presented, including results of examinations, observation and treatment. A 22 years old female was admitted with complaints on dyspnea, dry cough, malaise, «pulsing» head ache at the back of the head, vertigo while walking, fever up to 39 °С during the previous 3 days. Basing on the results of chest X-ray and laboratory examination the diagnosis of «Community-acquired subtotal right-sided pneumonia of mixed origin, severe clinical course, respiratory failure grade III, complicated by toxic shock syndrome, toxic pulmonary edema, disseminated intravascular coagulopathy stage I. Acute cardiac failure, acute respiratory distress syndrome. Acute iron-deficiency anemia. Acute erosive hemorrhagic gastritis. Obesity, II degree» was set up. In spite of active treatment patient’s condition deteriorated due to intoxication, cardiac failure and respiratory distress progress. Autopsy revealed that the patient has died of severe viral pneumonia, although such an extensive pneumonia is not typical for a 22-year old patient. Severe pneumonia development may be explained by immunodeficiency intensified by acute iron-deficiency anemia, which can be a possible side effect of previous intake of a dietary supplement for weight loss and alimentary factors.

Suppression of hepatic hepcidin expression in response to acute iron deficiency is correlated with an increase of matripatase‐2 protein in the liver

Recent studies demonstrate a pivotal role of bone morphogenic protein‐6 (BMP6) and matriptase‐2, a protein encoded by the TMPRSS6 gene, in the induction and suppression of hepatic hepcidin expression, respectively. We examined their expression profiles in isolated liver cells and found an exclusive expression of TMPRSS6 mRNA in hepatocytes. In rats fed an iron deficient (ID) diet for 24 hrs, the rapid decrease of transferrin saturation from 71% to 24% (control versus ID diet) was associated with a marked decrease of hepatic hepcidin mRNA, by approximately 100‐fold in comparison with the corresponding controls. These results indicated a close correlation of low transferrin saturation with the decrease of hepcidin mRNA. The decrease of phosphorylated Smad1/5/8 detected in the ID rat livers suggests that the suppressed hepcidin expression resulted from the inhibition of BMP signaling. qRT‐PCR analysis revealed no significant change in either BMP6 or TMPRSS6 mRNA in the liver. However, an increase of matriptase‐2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deficiency is mediated by the increase of matriptase‐2 protein levels.

Intestinal Hypoxia-Inducible Transcription Factors Are Essential for Iron Absorption following Iron Deficiency

Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. Duodenal cytochrome b (DcytB) and divalent metal transporter 1 (DMT1) are regulators of iron absorption. Their expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. Hypoxia-inducible factor (HIF) signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2alpha target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis.

Helicobacter felis Infection Causes an Acute Iron Deficiency in Nonpregnant and Pregnant Mice

The role of Helicobacter pylori infection in iron deficiency during pregnancy is limited. The aim of the present study was to assess the relationship between Helicobacter infection and levels of iron stores in pregnant mice. Female C57BL/6 mice were either inoculated with 10(8) H. pylori, Helicobacter felis or water. In the nonpregnant study, 15 mice from each group were sacrificed after 4 and 20 weeks of infection. In the pregnancy study, after 6 weeks of infection all female mice were mated and approximately 2 weeks after mating, half of the pregnant mice (n = 9/group) from each group were sacrificed. The remaining mice were allowed to give birth, and approximately 4 weeks after birth, mice were asphyxiated with CO2, followed by heart puncture, and killed by cervical dislocation. Serum ferritin and iron were determined with a micro-particle enzyme immunoassay method and by a timed-endpoint method. Serum iron levels in mice infected with H. felis were significantly (p < .05) lowered compared to control (24%) and H. pylori (27%)-infected mice at 4 weeks of infection. Serum iron in the control, H. pylori and H. felis groups were significantly (p < .05) elevated at 20 weeks by 39, 26 and 77%, respectively, compared to 4 weeks of infection. H. felis-infected mice had a significantly (p < .05) decreased serum ferritin level during pregnancy (61%) compared to H. pylori-infected mice. These results suggest that H. felis but not H. pylori infection causes an acute iron deficiency in normal and pregnant mice.

Treatment of Kidney Disease and Anemia in Elderly, Long-Term Care Residents

Given the surprising prevalence of anemia in the elderly population, particularly those individuals in long-term care settings, the differential diagnosis and treatment of this disorder have assumed a more prominent position in health-care management in recent years, with good reason. Whether caused by acute iron deficiency or chronic disease such as chronic kidney disease, anemia has been associated with significant clinical outcomes, including disability, dementia, congestive heart failure, and even mortality.

Treatment of kidney disease and anemia in elderly, long-term care residents.

Given the surprising prevalence of anemia in the elderly population, particularly those individuals in long-term care settings, the differential diagnosis and treatment of this disorder have assumed a more prominent position in health-care management in recent years, with good reason. Whether caused by acute iron deficiency or chronic disease such as chronic kidney disease, anemia has been associated with significant clinical outcomes, including disability, dementia, congestive heart failure, and even mortality.

Expression of genes involved in iron metabolism in mouse intestine.

Intestinal nonheme iron levels and mRNA levels of genes implicated in iron metabolism were measured in mice with altered iron metabolism [chronic (4 wk) and acute (4 days) dietary iron deficiency; iron overload and hypoxia] to investigate their role in the process and regulation of intestinal iron absorption. Mucosal nonheme iron levels were decreased by both chronic and acute iron deficiency and increased by iron overload but were not affected by hypoxia. There was evidence of a gradient of mucosal nonheme iron along the small intestine (duodenum, jejunum > ileum). There were also regional differences in H-ferritin (duodenum > ileum) and transferrin receptor (ileum > duodenum) mRNA levels. Iron overload produced a decrease in transferrin receptor (TfR) mRNA in the duodenum, with ferritin mRNA levels unaffected in both the duodenum and ileum. Chronic iron deficiency induced a twofold increase in TfR mRNA levels in both the duodenum and ileum, whereas H- and L-ferritin mRNA levels did not change significantly. The ratio of H- to L-ferritin mRNA decreased significantly during exposure to hypoxia; however, individual ferritin and TfR mRNA levels were not significantly altered. Calreticulin (mobilferrin), cysteine-rich intestinal protein, and H(+)-adenosinetriphosphatase mRNA levels were virtually unchanged in all models. A comparison with previously published data on changes in iron absorption leads us to conclude that 1) iron absorption can be altered independently of effects on transcripts of genes for iron-related proteins, and 2) it is not essential for iron absorption to be coordinated with regulation of mucosal iron metabolism.

Abnormal rat brain monoamine metabolism in iron deficiency anemia

Iron deficiency in rats produces numerous alterations in brain metabolism as assessed by in vitro techniques. We used a new method of in vivo microdialysis to study the effect of acute iron deficiency anemia on rat brain monoamine metabolism. This method was used to sample extracellular fluid from an implanted microdialysis probe in the caudate putamen from freely moving animals. Method validation experiments showed that steady-state levels of dopamine, norepinephrine, and their metabolites were obtained only after 5 to 7 days of surgical recovery and with prior perfusion of the brain region. Caudate putamen dopamine was significantly increased 30% and 40% in fasted light-exposed and 2-hr-fed dark-exposed iron deficient anemic rats (hemoglobin in vitro demonstrations of down-regulation of dopamine D 2 receptors, they also suggest that uptake and processing of monoamines is significantly perturbed by iron deficiency.

Chapter I: Prevention of iron deficiency with hemoglobin‐iron. A review of studies of the absorption of heme and non‐heme iron.

AbstractThe relative roles of non‐heme and heme iron in preventing iron deficiency are reviewed. While it has been difficult to demonstrate, in different population groups, any correlation between the intake of non‐heme iron and iron deficiency, such correlations have been found between the intake of meat and iron deficiency. Alternative interpretations of the these findings are discussed.The absorption of non‐heme iron under experimental and physiological conditions is reviewed. Under experimental conditions, and in acute iron deficiency absorption is invariably very good, but under long‐term conditions of prophylaxis absorption is reduced and side effects lead to non‐compliance of patients. This suggests studies of heme iron for prophylactic purposes.Repeated studies between 1945 and 1978 have failed to prove the efficacy of iron fortification, and some suggest that even tablets may not be efficient in the prevention of iron deficiency. Concern about possible negative effects of prophylaxis with non‐heme iron has increased lately, particularly when iron tablets mask the anemia of gastrointestinal cancer. Heme iron has only a small advantage in these respects, namely that doses and the maximal absorption are lower.In different studied meals, the heme iron absorption is usually higher than the non‐heme iron absorption, probably because the absorption of non‐heme iron is inhibited by several constituents of the meal.The prevalence of iron deficiency is reviewed. It is suggested that directed prophylaxis with heme iron in tablet form, which can be directed towards at‐risk groups and away from groups in the gastrointestinal cancer age, tablets which can be taken with meals and without side effects should be studied as an alternative to generalized iron fortification.