Iron Deficiency in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a complex cardiovascular condition that is characterized by elevated pulmonary arterial pressure, which leads to significant morbidity and mortality. Among the various factors that influence the pathophysiology and progression of PH, iron deficiency has become a critical, yet often overlooked, element. In this review, the prevalence, implications, and therapeutic potential of addressing iron deficiency in patients with PH are elucidated.Iron deficiency, which is prevalent in a significant proportion of patients with PH, has been associated with worsened clinical outcomes, including diminished exercise capacity, impaired oxygen transport and utilization, and compromised right ventricular function. The pathophysiological linkages between iron deficiency and PH are multifaceted and involve alterations in oxygen sensing, endothelial function, and metabolic disturbances.In this review, the evidence from recent clinical trials and studies that assess the impact of iron supplementation, both oral and intravenous, on PH outcomes is critically analyzed. Although some studies suggest improvements in exercise capacity and hemodynamic parameters following iron repletion, the responses appear variable and are not universally beneficial. This review highlights the complexities of iron metabolism in PH and the challenges in effectively diagnosing and treating iron deficiency in this patient population.Furthermore, the potential mechanisms through which iron supplementation might influence pulmonary vascular and right ventricular function, emphasizing the need for personalized treatment approaches are discussed. In this review, the importance of recognizing iron deficiency in the management of patients with PH is highlighted, and further research is warranted to establish comprehensive, evidence-based guidelines for iron supplementation in this unique patient cohort. The ultimate goal of this review is to improve clinical outcomes and quality of life for patients suffering from this debilitating condition.

Iron and ferritin deficiency in women with hypothyroidism and chronic lymphocytic thyroiditis - systematic review.

Iron is one of the essential microelements necessary for maintaining the body's homeostasis. It serves various roles, including being a crucial component in the proper structure of many enzymes and supporting the transport of oxygen and electrons. Its deficiency can lead to anaemia, which is a common clinical condition often associated with thyroid diseases. Iron deficiency is one of the most common nutritional deficiencies, and its prevalence is strongly associated with socioeconomic status. It is the primary cause of anaemia in 42% of children and 50% of women. Importantly, iron deficiency is placed among the top 5 causes of disability in women. Thyroid peroxidase (TPO) is an enzyme essential for the production of thyroid hormones, and iron is a key factor in its proper functioning. Therefore, in the case of iron deficiency, the activity of this enzyme is also reduced. Iron is also a factor that is important in epigenetic modification processes, and its deficiency may contribute to genomic changes potentially promoting the development of autoimmune thyroid diseases. Adequate supplementation in patients with Hashimoto's disease is one of the crucial elements of effective therapy. In addition to iodine, selenium, and magnesium supplementation, attention should be paid to proper iron intake. Iron is an element that is a component of the heme enzyme- thyroid peroxidase, which owes its activity to the binding of haem, and its function is the production of thyroid hormones. Iron can be delivered to the body in haem and non-haem forms. The haem form is found particularly in haemoglobin-rich red meat, but also in eggs, fish, and poultry. On the other hand, non-haem iron can be found in legumes, grains, fruits, and vegetables. Our study aimed to gather and summarise knowledge from scientific literature regarding iron deficiency anaemia and its association with hypothyroidism in women, as well as the possible mechanisms and pathogenesis of these conditions. The paper also aims to highlight that considering the high risk of iron deficiency, assessing iron status along with ferritin should be an integral part of additional diagnostic measures in cases of hypothyroidism, particularly Hashimoto's disease.

Iron deficiency anemia and platelet dysfunction: A comprehensive analysis of the underlying mechanisms.

AIMS: This research aimed to study the changes in platelet function and their underlying mechanisms in iron deficiency anemia. MAIN METHODS: Initially, we evaluated platelet function in an IDA mice model. Due to the inability to accurately reduce intracellular Fe2+ concentrations, we investigated the impact of Fe2+ on platelet function by introducing varying concentrations of Fe2+. To probe the underlying mechanism, we simultaneously examined the dynamics of calcium in the cytosol, and integrin αIIbß3 activation in Fe2+-treated platelets. Ferroptosis inhibitors Lip-1 and Fer-1 were applied to determine whether ferroptosis was involved in this process. KEY FINDINGS: Our study revealed that platelet function was suppressed in IDA mice. Fe2+ concentration-dependently facilitated platelet activation and function in vitro. Mechanistically, Fe2+ promoted calcium mobilization, integrin αIIbß3 activation, and its downstream outside-in signaling. Additionally, we also demonstrated that ferroptosis might play a role in this process. SIGNIFICANCE: Our data suggest an association between iron and platelet activation, with iron deficiency resulting in impaired platelet function, while high concentrations of Fe2+ contribute to platelet activation and function by promoting calcium mobilization, αIIbß3 activation, and ferroptosis.

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron-deficient heart failure.

The available evidence suggests that the kidney may contribute importantly to the development of an iron deficiency state in patients with heart failure and may be injured by therapeutic efforts to achieve iron repletion. The exceptional workload of the proximal renal tubule requires substantial quantities of iron for ATP synthesis, which it derives from Fe3+ bound to transferrin in the bloodstream. Following ferrireduction, Fe2+ is conveyed by divalent transporters (e.g. DMT1) out of the endosome of the proximal renal tubule, and highly reactive Fe2+ can be directed to the mitochondria, sequestered safely in a ferritin nanocage or exported through the actions of hepcidin-inhibitable ferroportin. The actions of ferroportin, together with transferrin endocytosis and DMT1-mediated transport, play a key role in the recycling of iron from the tubular fluid into the bloodstream and preventing the loss of filtered iron in the urine. Activation of endogenous neurohormonal systems and proinflammatory signalling in heart failure decrease megalin-mediated uptake and DMT1 expression, and increase hepcidin-mediated suppression of ferroportin, promoting the loss of iron in the urine and contributing to the development of an iron deficiency state. Furthermore, the failure of ferroportin-mediated efflux at the basolateral membrane heightens the susceptibility of the renal tubules to cytosolic excesses of Fe2+, causing lipid peroxidation and synchronized cell death (ferroptosis) through the iron-dependent free radical theft of electrons from lipids in the cell membrane. Ferroptosis is a central mechanism to most disorders that can cause acute and chronic kidney disease. Short-term bolus administration of intravenous iron can cause oxidative stress and is accompanied by markers of renal injury. Experimentally, long-term maintenance of an iron-replete state is accompanied by accelerated loss of nephrons, oxidative stress, inflammation and fibrosis. Intravenous iron therapy increases glomerular filtration rate rapidly in patients with heart failure (perhaps because of a haemodynamic effect) but not in patients with chronic kidney disease, and the effects of intravenous iron on the progression of renal dysfunction in the long-term trials - AFFIRM-AHF, IRONMAN and HEART-FID - have not yet been reported. Given the potential role of dysregulated renal iron homeostasis in the pathogenesis of iron deficiency and the known vulnerability of the kidney to intravenous iron, the appropriate level of iron repletion with respect to the risk of acute and chronic kidney injury in patients with heart failure requires further study.

Role of BACH1 in multiple myeloma.

OBJECTIVE: Examine Bach1 protein expression in bone marrow biopsy specimens obtained from newly diagnosed multiple myeloma (NDMM) and iron deficiency anemia (IDA) patients. Conduct a thorough analysis to explore the potential connection between Bach1 and the onset as well as treatment response of NDMM. METHODS: This study investigated Bach1 expression in bone marrow biopsy tissues from NDMM and IDA patients. Immunohistochemical staining and Image-pro Plus software were utilized for quantitatively obtaining the expression level of Bach1 protein. Arrange Bach1 expression levels from high to low, and use its median expression level as the threshold. Samples with Bach1 expression level above the median are categorized as the high-expression group, while those below the median are categorized as the low-expression group. Under this grouping, a detailed discussion was conducted to explore relationship of the Bach1 expression level with the patients' gender, ISS stage, and survival rate based on the Bortezomib (Btz) therapy. RESULTS: Our experiment indicates that the expression level of Bach1 in NDMM patients is significantly higher than in IDA patients. Furthermore, we discovered that patients in the high-expression group exhibit better prognosis compared to those in the low-expression group after Btz-treatment. Bioinformatics analysis further confirms this conclusion. CONCLUSION: By categorizing Bach1 expression level as high and low, our study offers a unique perspective on understanding the relationship between Bach1 and NDMM.

Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia.

OBJECTIVE: To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia. MATERIALS AND METHODS: A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR. RESULTS: Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN. CONCLUSION: The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery. WHAT DOES THIS STUDY ADDS TO THE CLINICAL WORK: Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

Identification of three mechanistic pathways for iron-deficient heart failure.

Current understanding of iron-deficient heart failure is based on blood tests that are thought to reflect systemic iron stores, but the available evidence suggests greater complexity. The entry and egress of circulating iron is controlled by erythroblasts, which (in severe iron deficiency) will sacrifice erythropoiesis to supply iron to other organs, e.g. the heart. Marked hypoferraemia (typically with anaemia) can drive the depletion of cardiomyocyte iron, impairing contractile performance and explaining why a transferrin saturation < ≈15%-16% predicts the ability of intravenous iron to reduce the risk of major heart failure events in long-term trials (Type 1 iron-deficient heart failure). However, heart failure may be accompanied by intracellular iron depletion within skeletal muscle and cardiomyocytes, which is disproportionate to the findings of systemic iron biomarkers. Inflammation- and deconditioning-mediated skeletal muscle dysfunction-a primary cause of dyspnoea and exercise intolerance in patients with heart failure-is accompanied by intracellular skeletal myocyte iron depletion, which can be exacerbated by even mild hypoferraemia, explaining why symptoms and functional capacity improve following intravenous iron, regardless of baseline haemoglobin or changes in haemoglobin (Type 2 iron-deficient heart failure). Additionally, patients with advanced heart failure show myocardial iron depletion due to both diminished entry into and enhanced egress of iron from the myocardium; the changes in iron proteins in the cardiomyocytes of these patients are opposite to those expected from systemic iron deficiency. Nevertheless, iron supplementation can prevent ventricular remodelling and cardiomyopathy produced by experimental injury in the absence of systemic iron deficiency (Type 3 iron-deficient heart failure). These observations, taken collectively, support the possibility of three different mechanistic pathways for the development of iron-deficient heart failure: one that is driven through systemic iron depletion and impaired erythropoiesis and two that are characterized by disproportionate depletion of intracellular iron in skeletal and cardiac muscle. These mechanisms are not mutually exclusive, and all pathways may be operative at the same time or may occur sequentially in the same patients.

The Puzzle of Aspirin and Iron Deficiency: The Vital Missing Link of the Iron-Chelating Metabolites.

Acetylsalicylic acid or aspirin is the most commonly used drug in the world and is taken daily by millions of people. There is increasing evidence that chronic administration of low-dose aspirin of about 75-100 mg/day can cause iron deficiency anaemia (IDA) in the absence of major gastric bleeding; this is found in a large number of about 20% otherwise healthy elderly (>65 years) individuals. The mechanisms of the cause of IDA in this category of individuals are still largely unknown. Evidence is presented suggesting that a likely cause of IDA in this category of aspirin users is the chelation activity and increased excretion of iron caused by aspirin chelating metabolites (ACMs). It is estimated that 90% of oral aspirin is metabolized into about 70% of the ACMs salicyluric acid, salicylic acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. All ACMs have a high affinity for binding iron and ability to mobilize iron from different iron pools, causing an overall net increase in iron excretion and altering iron balance. Interestingly, 2,3-dihydroxybenzoic acid has been previously tested in iron-loaded thalassaemia patients, leading to substantial increases in iron excretion. The daily administration of low-dose aspirin for long-term periods is likely to enhance the overall iron excretion in small increments each time due to the combined iron mobilization effect of the ACM. In particular, IDA is likely to occur mainly in populations such as elderly vegetarian adults with meals low in iron content. Furthermore, IDA may be exacerbated by the combinations of ACM with other dietary components, which can prevent iron absorption and enhance iron excretion. Overall, aspirin is acting as a chelating pro-drug similar to dexrazoxane, and the ACM as combination chelation therapy. Iron balance, pharmacological, and other studies on the interaction of iron and aspirin, as well as ACM, are likely to shed more light on the mechanism of IDA. Similar mechanisms of iron chelation through ACM may also be implicated in patient improvements observed in cancer, neurodegenerative, and other disease categories when treated long-term with daily aspirin. In particular, the role of aspirin and ACM in iron metabolism and free radical pathology includes ferroptosis, and may identify other missing links in the therapeutic effects of aspirin in many more diseases. It is suggested that aspirin is the first non-chelating drug described to cause IDA through its ACM metabolites. The therapeutic, pharmacological, toxicological and other implications of aspirin are incomplete without taking into consideration the iron binding and other effects of the ACM.

Brain Iron Dysregulation in Iron Deficiency Anemia-Related Restless Leg Syndrome Revealed by Neuron-Derived Extracellular Vesicles: A Case-Control Study.

Brain iron deficiency (ID) and, to a degree, systemic ID have been implicated in restless leg syndrome (RLS) pathogenesis. Previously, we found increased ferritin in neuron-derived extracellular vesicles (NDEVs) in RLS, suggesting a mechanism for depleting intracellular iron by secreting ferritin-loaded NDEVs. In this study, we hypothesized that increased NDEV ferritin occurs even in RLS accompanied by systemic ID and that neuronal intracellular iron depletion in RLS also manifests as NDEV abnormalities in other iron regulatory proteins, specifically, decreased transferrin receptor (TfR) and increased ferroportin. To address these hypotheses, we studied 71 women with ID anemia, 36 with RLS, and 35 without RLS. Subjects with RLS again showed higher NDEV ferritin and also decreased TfR, suggesting diminished neuronal capacity for iron uptake. Findings inform a more complete understanding of the pathogenic role of neuronal iron homeostasis and dissociate it from peripheral ID. ANN NEUROL 2024;96:560-564.

Fibroblast growth factor 23 is pumping iron: C-terminal-fibroblast growth factor 23 cleaved peptide and its function in iron metabolism.

PURPOSE OF REVIEW: Iron deficiency regulates the production of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) but also its cleavage, to generate both intact (iFGF23) and C-terminal (Cter)-FGF23 peptides. Novel studies demonstrate that independently of the phosphaturic effects of iFGF23, Cter-FGF23 peptides play an important role in the regulation of systemic iron homeostasis. This review describes the complex interplay between iron metabolism and FGF23 biology. RECENT FINDINGS: C-terminal (Cter) FGF23 peptides antagonize inflammation-induced hypoferremia to maintain a pool of bioavailable iron in the circulation. A key mechanism proposed is the down-regulation of the iron-regulating hormone hepcidin by Cter-FGF23. SUMMARY: In this manuscript, we discuss how FGF23 is produced and cleaved in response to iron deficiency, and the principal functions of cleaved C-terminal FGF23 peptides. We also review possible implications anemia of chronic kidney disease (CKD).

Molecular Mechanisms of Iron Transport and Homeostasis Regulated by Antarctic Krill-Derived Heptapeptide-Iron Complex.

In this study, the molecular mechanisms of iron transport and homeostasis regulated by the Antarctic krill-derived heptapeptide-iron (LVDDHFL-iron) complex were explored. LVDDHFL-iron significantly increased the hemoglobin, serum iron, total iron binding capacity levels, and iron contents in the liver and spleen to normal levels, regulated the gene expressions of iron homeostasis, and enhanced in vivo antioxidant capacity in iron-deficiency anemia mice (P < 0.05). The results revealed that iron ions within LVDDHFL-iron can be transported via the heme transporter and divalent metal transporter-1, and the absorption of LVDDHFL-iron involved receptor-mediated endocytosis. We also found that the transport of LVDDHFL-iron across cells via phagocytosis was facilitated by the up-regulation of the high mobility group protein, heat shock protein ß, and V-type proton ATPase subunit, accompanied by the regulatory mechanism of autophagy. These findings provided deeper understandings of the mechanism of LVDDHFL-iron facilitating iron absorption.

Efficacy of polysaccharide iron complex in IDA rats: A comparative study with iron protein succinylate and ferrous succinate.

Iron deficiency anemia (IDA) is the most common nutrient-related health problem in the world. There is still a lack of comprehensive comparative study on the efficacies of commonly used iron supplements such as polysaccharide iron complex (PIC), iron protein succinylate (IPS) and ferrous succinate (FS) for IDA. In this study, we compared the PIC, IPS and FS efficacies in IDA rats via intragastric administration. The results showed that the three iron supplements had similar efficacies. PIC/IPS/FS at a dose of 15 mg Fe/kg/d for 10 d increased the hematological and serum biochemical parameters to 2.15/2.12/2.18 (Hb), 1.71/1.67/1.69 (RBC), 2.10/2.11/2.12 (HCT), 1.26/1.22/1.22 (MCV), all 1.34 (MCH), 1.15/1.15/1.14 (MCHC), 1.94/1.82/1.91 (SF), 9.75/9.67/9.53 (SI), and 23.30/22.68/21.64 (TS) times, and reduced TIBC to 0.42/0.43/0.44 times, compared to untreated IDA rats. PIC performed slightly better than IPS and FS in restoring MCV level. Meanwhile, the heart, spleen and kidney coefficients reduced to 67%/74%/65% (heart), all 59% (spleen) and 87%/88%/88% (kidney), and the liver coefficient increased to 116%/115%/116%, compared to untreated IDA rats. The liver iron content was found to be more affected by IDA than the spleen iron content. PIC/IPS/FS at 15 mg Fe/kg/d increased organ iron contents to 4.20/3.97/4.03 times (liver) and 1.36/1.24/1.41 times (spleen) within 10 d compared to untreated IDA rats, and PIC-H and FS were slightly better than IPS in restoring spleen iron content. The results of this study can provide useful data information for the comparison of three iron supplements, PIC, IPS and FS.

Characterization of Oyster Protein Hydrolysate-Iron Complexes and their In Vivo Protective Effects against Iron Deficiency-Induced Symptoms in Mice.

Iron is one of the trace mineral elements, and iron deficiency is a common phenomenon that negatively influences human health. Food-derived iron supplements were considered excellent candidates for improving this syndrome. In this work, oyster-protein hydrolysates (OPH) and ferrous chloride successfully formed the OPH-Fe complex (6 mg/mL, 40 °C, 30 min), where the main binding sites involved were the carboxyl and amino groups. The OPH-Fe complex showed no obvious changes in the secondary structure, while the iron changed the morphological appearance and also showed fluorescence quenching, an ultraviolet shift, and an increase in size distribution. The OPH-Fe complex showed better dynamic absorption of iron (64.11 µmol/L) than ferrous sulfate (46.90 µmol/L), and the medium dose had better protective effects against iron-deficiency anemia in vivo. Three representative peptides (DGKGKIPEE, FAGDDAPRA, and VLDSGDGVTH) that were absorbed intact were identified. This experiment provided a theoretical foundation for further study of the digestion and absorption of the OPH-Fe complex.

Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia.

Iron deficiency is a potent stimulator of fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism, that is classically thought to be produced by bone-embedded osteocytes. Here, we show that iron-deficient transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibit elevated circulating FGF23 and Fgf23 messenger RNA (mRNA) upregulation in the bone marrow (BM) but not the cortical bone. To clarify sites of Fgf23 promoter activity in Tmprss6-/- mice, we introduced a heterozygous enhanced green fluorescent protein (eGFP) reporter allele at the endogenous Fgf23 locus. Heterozygous Fgf23 disruption did not alter the severity of systemic iron deficiency or anemia in the Tmprss6-/- mice. Tmprss6-/-Fgf23+/eGFP mice showed green fluorescence in the vascular regions of BM sections and showed a subset of BM endothelial cells that were GFPbright by flow cytometry. Mining of transcriptomic data sets from mice with normal iron balance revealed higher Fgf23 mRNA in BM sinusoidal endothelial cells (BM-SECs) than that in other BM endothelial cell populations. Anti-GFP immunohistochemistry of fixed BM sections from Tmprss6-/-Fgf23+/eGFP mice revealed GFP expression in BM-SECs, which was more intense than in nonanemic controls. In addition, in mice with intact Tmprss6 alleles, Fgf23-eGFP reporter expression increased in BM-SECs following large-volume phlebotomy and also following erythropoietin treatment both ex vivo and in vivo. Collectively, our results identified BM-SECs as a novel site for Fgf23 upregulation in both acute and chronic anemia. Given the elevated serum erythropoietin in both anemic models, our findings raise the possibility that erythropoietin may act directly on BM-SECs to promote FGF23 production during anemia.

THE FEATURES OF LIMITED PROTEOLYSIS IN PLACENTAL FIBRINOID IN COMBINATION WITH INFLAMMATION AND IRON DEFICIENCY ANEMIA OF PREGNANT WOMEN.

OBJECTIVE: The aim: To establish the features of limited proteolysis in fibrinoid of the chorionic and basal plates of the placenta in acute and chronic chorioamnionitis, as well as basal deciduitis on the background of iron deficiency anemia in pregnant women. PATIENTS AND METHODS: Materials and methods: The histochemical procedure was performed using the ninhydrin-Schiff response to free amino groups of proteins by the method of A. Yasuma and T. Ichikava, and Bonheg bromophenol blue. RESULTS: Results: With iron deficiency anemia of pregnant women, the relative units of optical density in the chorionic plate were 0.312±0.0026, and with basal one - 0.310±0.0024 (with indicators of physiological pregnancy 0.285±0.0024 and 0.289±0.002.1). In the observations of acute chorioamnionitis, the quantitative indicators were 0.311±0.0024, chronic one - 0.311±0.0024, and with inflammation on the background of anemia of pregnant women - 0.315±0.0031 and 0.339±0.0036, respectively. With acute basal deciduitis - 0.316±0.0027, chronic one - 0.326±0.0034, and with inflammation of the basal plate of the placenta on the background of anemia of pregnant women - 0.320±0.0031 and 0.341±0.0038, respectively. CONCLUSION: Conclusions: With anemia of pregnant women, the processes of limited proteolysis are intensified in accordance with the indicators of optical density of histochemical staining in the fibrinoid of the chorionic and basal plates of the placenta compared with physiological pregnancy. In case of acute and chronic forms of chorioamnionitis and basal deciduitis, quantitative indicators of optic density of histochemical staining increase compared with physiological preg¬nancy. Comorbid anemia of pregnant women activates the processes of limited proteolysis only in the chronic form of chorioamnionitis and basal deciduitis.

Effects of food-derived oligopeptide iron chelates on liver injury and gut microbiota homeostasis in iron-deficiency anemia female rats: a pilot study.

Iron deficiency (ID) is the biggest cause of anemia. This pilot study aimed to investigate the effects of food-derived oligopeptide iron chelates on ameliorating liver injury and restoring gut microbiota homeostasis in iron-deficiency anemia (IDA) female rats. Female Sprague-Dawley rats at 21 days old were selected and randomly divided into a control group (N = 4) and an ID model group (N = 16). The ID model group was fed an iron-deficient diet containing 4 mg kg-1 iron for 28 days to generate the IDA rat model and then randomly subdivided into four groups (N = 4 for each group): ID group, ferrous sulfate group, marine fish oligopeptide iron chelate (MCOP-Fe) group, and whey protein oligopeptide iron chelate (WPP-Fe) group. Iron supplements were given to rats in the three intervention groups once per day via intragastric administration for three weeks. After iron supplementation, the hemoglobin levels in the three intervention groups were significantly improved, with the MCOP-Fe and WPP-Fe groups returning to normal. The ALT and AST levels in the ID group increased significantly, while levels in all intervention groups decreased to normal levels. Liver glutathione in the WPP-Fe group was increased, while the activity of superoxide dismutase also tended to be higher. In addition, 16S rRNA gene sequencing showed that IDA resulted in changes to intestinal microbiota. After intervention, the WPP-Fe group showed increased alpha diversity of intestinal microbes. Therefore, MCOP-Fe and WPP-Fe may improve the iron status of IDA female rats as well as ameliorate liver damage, with WPP-Fe showing a greater potential in improving gut microbiota imbalance.

Influence of exopolysaccharide EPSKar1-iron complexation on iron bioavailability and alleviating iron deficiency anaemia in Wistar rats.

The prevalence of iron deficiency anaemia is a significant issue worldwide, affecting individuals of all ages and often associated with inadequate iron bioavailability. Despite the use of ferrous salt supplements to address anaemia, their limited bioaccessibility and bioavailability in human GIT and adverse impact on food properties remain significant challenges. Hence, this study aims to explore the iron chelation mechanism of an exopolysaccharide EPSKar1 to enhance iron bioaccessibility, bioavailability, and anti-anaemic effects using cell culture and an anaemic rat model. EPSKar1 was extracted from Lacticaseibacillus rhamnosus Kar1 and complexed with FeSO4 to form "EPSKar1-iron". This novel complex, besides being bio-accessible after in vitro gastric digestion, demonstrated 61.27 ± 1.96% iron bioavailability to the Caco-2 cells. In line with these in vitro findings, intragastric administration of the EPSKar1-iron complex to anaemic Wistar rats at 25 and 50 mg per kg body weight significantly restored blood haemoglobin levels and re-established the morphological features of red blood cells. Furthermore, the apparent digestibility co-efficient and iron uptake improved significantly without adversely affecting the serum biochemical parameters in these anaemic rats. The levels of iron-transport proteins including serum transferrin and ferritin in tissue and plasma have increased remarkably upon oral administration of EPSKar1-iron at a higher dose of 50 mg per kg body weight. Oral supplementation of EPSKar1-iron did not foster adverse histological changes in the liver, kidneys, and spleen. In fact, the treatment with the EPSKar1-iron complex had a restitution effect on the tissue architecture, thereby ameliorating the tissue lesions. These findings collectively indicate that the EPSKar1-iron complex shows nutraceutical potential in enhancing the bioavailability of iron and could be a promising approach to tackle iron deficiency anaemia.

Cerebral iron deficiency may induce depression through downregulation of the hippocampal glucocorticoid-glucocorticoid receptor signaling pathway.

BACKGROUND: Iron is a trace essential element to sustain the normal neurological function of human. Many researches had reported the involvement of iron deficiency (ID) in neural development and cognitive functions. However, the role of ID in pathogenesis of depression and its underlying mechanism are still unclear. METHODS: In this study, we first used chronic unpredicted mild stress (CUMS) and iron deprivation mouse models to clarify the pathogenesis role of cerebral ID in depression. Then the role of hippocampal glucocorticoid (GC)-glucocorticoid receptor (GR) pathway in cerebral ID induced depression were elucidated in iron deprivation mice and iron deficiency anemia patients. RESULTS: Our results revealed that both CUMS and iron deprivation could induce cerebral ID in mice, and combination of iron deprivation and CUMS could accelerate the onset and aggravate the symptoms of depression in mice. In hippocampus, ID led to neuronal injury and neurogenesis decrease, which might be related to downregulation of GC-GR signaling pathway caused GR dysfunction, thereby inhibiting the negative feedback regulation function of hippocampus on hypothalamic-pituitary-adrenal (HPA) axis. Moreover, the overactivity of HPA axis in iron deprivation mice and iron deficiency anemia patients also confirmed GR dysfunction. LIMITATIONS: Iron deprivation led to food and water intake decrease of mice, which may affect the behavioral test. In addition, we mainly evaluated the role of hippocampal ID in depression, and the number of iron deficiency anemia patients was limited. CONCLUSIONS: Our results identified that cerebral iron homeostasis was a key factor for maintaining mental stability.

A Role of Sodium-Glucose Co-Transporter 2 in Cardiorenal Anemia Iron Deficiency Syndrome.

Heart failure, renal dysfunction, anemia, and iron deficiency affect each other and form a vicious cycle, a condition referred to as cardiorenal anemia iron deficiency syndrome. The presence of diabetes further accelerates this vicious cycle. Surprisingly, simply inhibiting sodium-glucose co-transporter 2 (SGLT2), which is expressed almost exclusively in the proximal tubular epithelial cells of the kidney, not only increases glucose excretion into the urine and effectively controls blood glucose levels in diabetes but can also correct the vicious cycle of cardiorenal anemia iron deficiency syndrome. This review describes how SGLT2 is involved in energy metabolism regulation, hemodynamics (i.e., circulating blood volume and sympathetic nervous system activity), erythropoiesis, iron bioavailability, and inflammatory set points in diabetes, heart failure, and renal dysfunction.