Iron Stores Research Articles

#2264 Efficacy and safety of oral iron supplementation with liposomal iron in non-dialysis chronic kidney disease patients with iron deficiency

Abstract Background and Aims Iron deficiency (ID) is very common in patients with non-dialysis dependent chronic kidney disease (NDD-CKD). In these patients, oral iron supplementation is recommended as first-line treatment for ID. However, the efficacy of oral iron supplementation is frequently impaired by a higher incidence of adverse gastrointestinal side effects. Liposomal iron is a compound with ferric pyrophosphate enclosed in a phospholipid nucleus, providing high gastrointestinal absorption and bioavailability and a lower incidence of side effects. However, few data are available on its efficacy in patients with NDD-CKD. Method This single-arm pilot study was carried out in in patients with NDD-CKD stages 1-5 and ID, defined as serum ferritin (SF)<100 ng/mL and/or transferrin saturation (TSAT)< 20%, consecutively seen in two Nephrology units (Naples and Bari) from 01/12/2022 to 01/04/2023. We assessed the efficacy of six months of liposomal iron therapy in correcting ID across three visits after baseline (month 1, 3 and 6). All patients received liposomal iron (30 mg/day twice daily for the first month followed by 30 mg daily for the remaining five months). The primary endpoints were the achievement of SF ≥100 ng/mL and TSAT ≥20%. Secondary outcomes were hemoglobin (Hb) changes and safety of liposomal iron; adherence to the iron supplementation was assessed by monthly pill counting. Changes of continuous variables during the study were analyzed by linear mixed models assuming an unstructured covariance matrix; this was done to take into account the correlation between repeated measures and missing points for patients not completing the study. Change of prevalence of corrected SF and TSAT values from baseline to month 1, 3 and 6 was analyzed by McNemar test. Results 38 patients (65.3 ± 15.2 years, 52.6% males, 35.1% diabetes, eGFR 38.5 ± 28.8 mL/min/1.73 m2) received at least one dose of liposomal iron (safety population). Efficacy population included 34 patients with at least one control visit after baseline. Clinical characteristics of patients enrolled in the two clinics did not differ. In efficacy population, baseline SF was 44 (IQR 19-82) ng/mL and TSAT 14.3 ± 5.9%, corresponding to a percentage of SF<100 ng/mL of 78.9%, and TSAT<20% in 89.5%; 64.7% had both parameters below the cut-offs. Anemia (defined as Hb<12 g/dL in women and <13 g/dL in men) was detected in 22/34 patients. Liposomal iron induced a progressive increase of TSAT from 14.3 ± 5.9%, at baseline to 20.0 ± 7.6% at month-6 (P = 0.009) whereas no difference was detected for SF (Fig. 1A and 1C). Accordingly, at the end of study, the prevalence of TSAT>20% significantly increased from 11.8% to 50.0% (P = 0.002) while correction of SF, mildly improved (from 23.5% to 30.0%, P = 0.214, Fig. 1B and 1D). When patients were stratified by anemia, a significant improvement of TSAT was observed in anemic patients (from 13.3 ± 5.8% to 20.2 ± 8.1%, P = 0.012), whereas no significant improvement was found in patients without anemia (P = 0.093). Adherence to iron supplementation was 100% in patients completing the study. Hb values did not significantly increase at month-6 in either anemic (+0.60 ± 1.39 g/dL, P = 0.258) or non-anemic (+0.08 ± 0.78 g/dL, P = 1.0) patients. In safety population (n = 38), 7 patients dropped out (18.4%). In particular, treatment was discontinued in 4 patients in the first month (2 for diarrhea, 1 for dyspepsia and constipation, and 1 for death), 1 patient after 3 months (switch to intravenous iron for symptomatic anemia), and 2 after five months (1 for dyspepsia and 1 for death). Conclusion The use of liposomal iron in patients with NDD-CKD is associated with a partial correction of functional ID (TSAT<20%), with no significant effect on iron storage. The small sample size prevents any causative conclusion, though it may provide some insights into using these compounds in patients with CKD.

Myeloid-specific ferritin light chain deletion does not exacerbate sepsis-associated AKI.

Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life-threatening sequelae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprising ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed that myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, although sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evidenced by a rise in serum creatinine and cystatin C and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy postsepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NF-κB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, the loss of FtL did not influence sepsis pathogenesis.NEW & NOTEWORTHY Hyperferritinemia in sepsis is often associated with a proinflammatory phenotype and poor prognosis. We previously showed the myeloid deletion of FtH results in a compensatory increase in FtL and is associated with reduced circulating cytokines and decreased rates of SA-AKI in animal sepsis models. Here, we show that myeloid deletion of FtL does not impact the severity of SA-AKI following CLP or LPS, suggesting that FtH plays the predominant role in propagating myeloid-induced proinflammatory pathways.

Validation of an automated iron stain process for use with bone marrow aspirate smear slides.

The assessment of bone marrow iron stores is typically performed on an aspirate smear slide that has been manually stained by a technologist using a commercially available kit. This approach can contribute to inconsistent results and limit the broad use of iron staining in bone marrow specimens, particularly when laboratories have low staffing and/or high specimen volumes. Here, we describe the adaptation and validation of the Ventana Benchmark automated stainer and iron stain kit for routine clinical use of staining iron in bone marrow aspirate smear slides. We assessed accuracy and precision of the Ventana automated iron staining protocol compared to the Perls Prussian blue manual iron staining index method. Hematopathologists assigned Gale scores and enumerated the percentages of erythroid sideroblasts on paired patient bone marrow aspirate smear slides stained by the automated method and the manual iron staining method. We found a similar level of performance of the Ventana automated iron stain relative to the index manual method (as assessed by Pearson correlation and Bland-Altman analyses). In addition, there was low imprecision between replicates performed via the automated iron stain protocol. We also report superior qualitative findings of the automated method in ease of localization of iron storage, visualization of sideroblasts, and counterstain consistency. Automated iron staining of bone marrow aspirate smear slides performed similarly to the manual method and may allow for accurate routine evaluation of bone marrow iron stores as part of bone marrow analysis.

Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice.

Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.

Lamprey--an excellent model for iron metabolism.

After 500 million years of evolution, lamprey is in a natural environment characterized by low temperature and high iron content, and its unique adaptive evolution mode has developed its organizational structure and life mechanism in the process of metamorphosis, which provides a new direction for people to further study the origin and evolution of life. Iron is one of the essential nutrients for the human body and plays an important role in metabolic processes, but when exceeded, it can lead to iron toxicity. For example, the serum iron concentration of pre-metamorphosis larvae is 149 times that of normal males, and the iron content in the liver of juveniles is about 2-3 times that of normal humans. Lamprey has a complete biochemical system to tolerate high concentrations of free iron in the body, and high expression of important genes for iron homeostasis, such as transferrin, ferritin heavy chain, superoxide dismutase, etc., improves iron transport, iron storage and antioxidant capacity. Lamprey has an IRE/IRP regulatory system, which is an important protection mechanism for lamprey to adapt to the high iron content environment in the organization. In addition, lampreys gradually form oral glands during metamorphosis and development, which become the unique iron metabolism organs of lampreys. In this review, we mainly summarize the distribution of iron in various tissues of lamprey and the potential mechanism of adapting to the content of iron in the body, so as to provide a theoretical basis for the subsequent search for the molecular mechanism of iron metabolism.

Leading with dysphagia… An unusual view of a common symptom.

Plummer-Vinson syndrome (PVS) is characterized by the classic triad of post-cricoid dysphagia, iron-deficiency anemia and esophageal webs. PVS is commonly found in women of middle age especially in the fourth and fifth decade of life. The prevalence of PVS has decreased due to early detection of iron deficiency and repletion of iron stores. We report a case of a 81-year-old female patient who had a classic presentation of PVS, treated successfully with endoscopic procedure. To our knowledge, the current case is the fourth case of dysphagia related to Plummer-Vinson syndrome reported in an octogenarian in the literature so far. Iron supplementation can resolve dysphagia in many patients, but dilation of esophageal webs may sometimes be required. PVS should be part of the differential diagnosis of sideropenic dysphagia, especially due the risk of pharyngeal and esophageal epidermoid neoplasia.

Casein phosphopeptide interferes the interactions between ferritin and ion irons

Ferritin, a vital protein required to store iron in a cage-like structure, is critical for maintaining iron balance. Ferritin can be attacked by free radicals during iron reduction and release, thereby leading to oxidative damage. Whether other biomacromolecules such as casein phosphopeptides (CPP) could influence the ferritin's function in iron oxidation and release and affect the ferritin stability remains unclear. This study aims to investigate the effect of CPP on the ferritin‑iron ion interaction, thereby focusing on role of CPP on ferritin stability. Results showed that CPP weakened the iron oxidation activity of ferritin but promoted iron release. Moreover, CPP could effectively chelate iron, capture hydroxyl radicals, and reduce the degradation of ferritin. This study highlights the role of CPP in the ferritin‑iron relationship, and lays a foundation for understanding the interaction between ferritin, peptides, and metal ions.

The relationship of hypothyroidism to iron deficiency in the body: Review Article

The lack of iron storage has a significant impact on the thyroid gland's efficiency, and its synthesis of hormones, which are required for biological activities in the body, has been compromised. Furthermore, thyroid issues have a negative impact on iron levels in the body and the amount of iron stored. Inactivity of the gland leads to poor iron absorption, and it is frequently misdiagnosed with hypothyroidism due to similar symptoms. Although hypothyroidism and iron insufficiency are distinct illnesses, they are sometimes linked. Hypothyroidism can impair the body's ability to absorb iron, resulting in iron deficiency anemia. Furthermore, because both illnesses can induce symptoms like weariness, weakness, and pale skin, it's critical to receive a good diagnosis to discover the underlying source of these symptoms. Iron deficiency is commonly connected with hypothyroidism. Current research has demonstrated that adding iron to hormonal therapy for the treatment of pathological hypothyroidism situations improved the pathological condition as compared to using hormonal therapy for the thyroid gland alone.

Myxococcus xanthus encapsulin cargo protein EncD is a flavin-binding protein with ferric reductase activity

Encapsulins are protein nanocompartments that regulate cellular metabolism in several bacteria and archaea. Myxococcus xanthus encapsulins protect the bacterial cells against oxidative stress by sequestering cytosolic iron. These encapsulins are formed by the shell protein EncA and three cargo proteins: EncB, EncC, and EncD. EncB and EncC form rotationally symmetric decamers with ferroxidase centers (FOCs) that oxidize Fe+2 to Fe+3 for iron storage in mineral form. However, the structure and function of the third cargo protein, EncD, have yet to be determined. Here, we report the x-ray crystal structure of EncD in complex with flavin mononucleotide. EncD forms an α-helical hairpin arranged as an antiparallel dimer, but unlike other flavin-binding proteins, it has no β-sheet, showing that EncD and its homologs represent a unique class of bacterial flavin-binding proteins. The cryo-EM structure of EncA-EncD encapsulins confirms that EncD binds to the interior of the EncA shell via its C-terminal targeting peptide. With only 100 amino acids, the EncD α-helical dimer forms the smallest flavin-binding domain observed to date. Unlike EncB and EncC, EncD lacks a FOC, and our biochemical results show that EncD instead is a NAD(P)H-dependent ferric reductase, indicating that the M. xanthus encapsulins act as an integrated system for iron homeostasis. Overall, this work contributes to our understanding of bacterial metabolism and could lead to the development of technologies for iron biomineralization and the production of iron-containing materials for the treatment of various diseases associated with oxidative stress.

Comparative evaluation of different oral iron salts in the management of iron deficiency anemia.

Anemia affects one-fourth of the world's population and is caused mostly by iron deficiency. Iron supplementation is the most essential strategy for preventing iron deficiency anemia. Conventional oral iron salts have many drawbacks such as poor absorption & bioavailability, and poor tolerability resulting in poor clinical outcomes. To compare the effectiveness and safety of ferrous ascorbate, ferrous fumarate, ferrous bis-glycinate, and Sucrosomial iron in the management of iron deficiency anemia. The study is a retrospective observational clinical study comprising 260 subjects with hemoglobin between 7-10g/dl. The patients were divided into four groups I, II, III, and IV, and received ferrous fumarate, ferrous ascorbate, ferrous bis-glycinate, and Sucrosomial iron respectively. Hematological profile and iron store indices were measured at baseline and month 3. One-way ANOVA followed by Tukey multiple comparison test was used to assess statistical significance (P < 0.05) using GraphPad Prism V.9.3.1 software. The observational study showed that hemoglobin levels were significantly increased in the ferrous ascorbate group (11.86 ± 0.09; P < 0.0001), ferrous fumarate group (11.72 ± 0.08; P < 0.0001), ferrous bis-glycinate group (11.69 ± 0.11; P = 0.0003) and Sucrosomial iron group (12.20 ± 0.1; P < 0.0001) compared to the baseline. The Sucrosomial iron-supplemented group showed significantly higher improvement in hemoglobin levels and serum ferritin levels compared to conventional oral iron salts (P < 0.05) with a better safety profile. The Sucrosomial iron showed significantly higher improvement in hemoglobin levels and higher improvement in iron store indices parameters along with a good tolerability profile compared to other conventional oral iron salts.

Obesity modifies the association between diabetes and iron biomarkers and red cell indices in reproductive-aged women in the United States.

Obesity and diabetes are associated with impaired iron metabolism. We aimed to examine the independent relationship between diabetes and iron after controlling for body weight (or obesity) in women aged 20-49 years. The National Health and Nutrition Examination Survey data from 2015 to 2018 were used in this investigation. Body composition data, HbAc1, iron biomarkers (serum ferritin (SF), soluble transferrin receptor (sTfR), and body iron index (BII)), mean corpuscular volume (MCV), mean hemoglobin concentration (MCH), red cell distribution width (RDW), and hemoglobin were used. Linear regression models were used to examine how and to what extent body mass index (BMI) modified the relationship between diabetes and iron status biomarkers. A total of 1834 women aged 20-49 were included in the analysis with a mean (SD) age of 32 .2 ± 6.1 years and BMI of 29.5 ± 6.9 kg/m2. The mean SF (p = 0.014) and BII (p < 0.001) were lower, while sTfR (p < 0.001) was higher in women with diabetes than those with no diabetes. Mean estimates for MCV and MCH were lower, while RDW (p = 0.001) was higher in diabetes patients (all p < 0.001). Women with diabetes were more likely to have iron deficiency, anemia, and iron deficiency anemia than those without diabetes (18.1% vs 8.6%, p < 0.001), (24.4% vs 8.4%, p < 0.001), and (14.8% vs 5.2%, p < 0.001), respectively. Among women with obesity, those with diabetes had lower predicted ferritin (β = -0.19, p = 0.016), BII (β = -0.99, p = 0.016), and hemoglobin (β = -0.27, p = 0.042) than those without diabetes. The study shows that diabetes is linked to lower iron stores; this is exacerbated in those with obesity.

Defective ferritinophagy and imbalanced iron metabolism in PBDE-47-triggered neuronal ferroptosis and salvage by Canolol

The brominated flame retardant 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) is a ubiquitous environmental pollutant that causes neurotoxicity. However, incomplete understanding of the underlying mechanisms has hampered the development of effective intervention strategies. Oxidative stress and related cell death are the modes of action for PBDE-47 neurotoxicity, which are also the characteristics of ferroptosis. Nonetheless, the role of ferroptosis in PBDE-47-induced neurotoxicity remains unclear. In the present study, we found that PBDE-47 triggered ferroptosis in neuron-like PC12 cells, as evidenced by intracellular iron overload, lipid peroxidation, and mitochondrial damage. This was confirmed by ferroptosis inhibitors including the lipid reactive oxygen species scavenger ferrostatin-1 and iron chelator deferoxamine mesylate. Mechanistically, PBDE-47 impaired ferritinophagy by disrupting nuclear receptor coactivator 4-mediated lysosomal degradation of the iron storage protein ferritin. Moreover, PBDE-47 disturbed iron metabolism by increasing cellular iron import via upregulation of transferrin receptor 1 and decreasing cellular iron export via downregulation of ferroportin 1 (FPN1). Intriguingly, rescuing lysosomal function by overexpressing cathepsin B (CatB) mitigated PBDE-47-induced ferroptosis by partially restoring dysfunctional ferritinophagy and enhancing iron excretion via the upregulation of FPN1. However, FPN1 knockdown reversed the beneficial effects of CatB overexpression on the PBDE-47-induced iron overload. Finally, network pharmacology integrated with experimental validation revealed that Canolol, the main phenolic compound in canola oil, protected against PBDE-47-evoked iron overload, resulting in ferroptosis by restoring defective ferritinophagy and improving abnormal iron metabolism via lowering iron uptake and facilitating iron excretion. Overall, these data suggest that ferroptosis is a novel mechanism of PBDE-47-induced neuronal death and that manipulation of ferritinophagy and iron metabolism via Canolol represents a promising therapeutic strategy.

Redefining Iron Deficiency in Patients With Chronic Heart Failure.

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.

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.

Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte

IntroductionDuring postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN. MethodsCSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk. ResultsBMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05). ConclusionOur study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.

Effects of iron supplements in individuals with erythropoietic protoporphyria

BackgroundProtoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of PPIX, causing photosensitivity and increased liver disease risk. Many also have iron deficiency and anemia. We investigated outcomes of oral iron supplements in individuals with EPP. MethodsA systematic review identified literature on oral iron supplements in EPP patients. Subsequently, we administered iron supplements to EPP patients with iron deficiency. The primary outcome was impact on PPIX level. Secondary outcomes were adverse events and relative differences in hemoglobin and iron parameters. ResultsThe systematic review found 13 case reports and one uncontrolled clinical trial with uncertain results. From our department 10 patients with EPP and iron deficiency took daily dosages of 330 mg of ferrous fumarate for two months. Five of our patients had anemia at baseline. After 2 months of supplementation seven patients had increased PPIX level compared to baseline, two had decrease, one remained unchanged. The administration of iron led to a rise in ferritin, and in four of the anemic patients also to an improvement in blood hemoglobin. A small transiently elevation in plasma alanine transaminase concentration was observed during supplementation. ConclusionsOverall, iron supplementation in EPP patients replenished iron stores and elevated erythrocyte PPIX and plasma alanine transaminase. For anemic patients, there was some degree of normalization of the hemoglobin level. If iron therapy is needed for EPP patients, monitoring of photosensitivity, PPIX, hemoglobin, and plasma liver enzymes is advisable.

Urinary Ferritin as a Noninvasive Means of Assessing Iron Status in Young Children

BackgroundIron deficiency (ID) is the most common nutritional deficiency affecting young children. Serum ferritin concentration is the preferred biomarker for measuring iron status because it reflects iron stores; however, blood collection can be distressing for young children and can be logistically difficult. A noninvasive means to measure iron status would be attractive to either diagnose or screen for ID in young children. ObjectivesThis study aimed to determine the correlation between urinary and serum ferritin concentrations in young children; to determine whether correcting urinary ferritin for creatinine and specific gravity improves the correlation; and to determine a urine ferritin cut point to predict ID. MethodsValidation study was conducted using paired serum and urine collected from 3-y-old children (n = 142) participating in a longitudinal birth cohort study: the ORIGINS project in Perth, Western Australia. We calculated the sensitivity, specificity, positive, and negative predictive values of urinary ferritin amount in identifying those with ID at the clinical cut point used by the World Health Organization (serum ferritin concentration of <12 ng/mL). ResultsUrine ferritin, corrected for creatinine, correlated moderately with serum ferritin [r = 0.53 (0.40–0.64)] and performed well in predicting those with ID (area under the curve: 0.85; 95% confidence interval: 0.75, 0.94). Urine ferritin <2.28 ng/mg creatinine was sensitive (86%) and specific (77%) in predicting ID and had a high negative predictive value of 97%; however, the positive predictive value was low (40%) owing to the low prevalence of ID in the sample (16%). ConclusionsUrine ferritin shows good diagnostic performance for ID. This noninvasive biomarker maybe a useful screening tool to exclude ID in healthy young children; however, further research is needed in other populations.

Structural basis for the intracellular regulation of ferritin degradation

The interaction between nuclear receptor coactivator 4 (NCOA4) and the iron storage protein ferritin is a crucial component of cellular iron homeostasis. The binding of NCOA4 to the FTH1 subunits of ferritin initiates ferritinophagy—a ferritin-specific autophagic pathway leading to the release of the iron stored inside ferritin. The dysregulation of NCOA4 is associated with several diseases, including neurodegenerative disorders and cancer, highlighting the NCOA4-ferritin interface as a prime target for drug development. Here, we present the cryo-EM structure of the NCOA4-FTH1 interface, resolving 16 amino acids of NCOA4 that are crucial for the interaction. The characterization of mutants, designed to modulate the NCOA4–FTH1 interaction, is used to validate the significance of the different features of the binding site. Our results explain the role of the large solvent-exposed hydrophobic patch found on the surface of FTH1 and pave the way for the rational development of ferritinophagy modulators.

Hyperthermia/glutathione-triggered ferritin nanoparticles amplify the ferroptosis for synergistic tumor therapy

Breast cancer is the most diagnosed malignancy in women globally, and drug resistance is among the major obstacles to effective breast cancer treatment. Emerging evidence indicates that photothermal therapy and ferroptosis are both promising therapeutic techniques for the treatment of drug-resistant breast tumors. In this study, we proposed a thermal/ferroptosis/magnetic resonance imaging (MRI) triple functional nanoparticle (I@P-ss-FRT) in which ferritin, an iron storage material with excellent cellular uptake capacity, was attached via disulfide bonds onto polydopamine coated iron oxide nanoparticle (I@P) as photothermal transduction agent and MRI probe. I@P-ss-FRT converted the near-infrared light (NIR) into localized heat which accelerated the release of ferrous ions from ferritin accomplished by glutathione reduction and subsequently induced ferroptosis. The drug-resistant cancer cell lines exhibited a more significant uptake of I@P-ss-FRT and sensitivity to PTT/ferroptosis compared with normal cancer cell lines. In vivo, I@P-ss-FRT plus NIR displayed the best tumor-killing potential with inhibitory rate of 83.46 %, along with a decline in GSH/GPX-4 content and an increase in lipid peroxides generation at tumor sites. Therefore, I@P-ss-FRT can be applied to combat drug-resistant breast cancer.

Selection of parenteral iron supplement for iron deficiency anemia: A review

The article reviews medicinal products for the treatment of iron deficiency conditions and iron deficiency anemia, the prevalence of which is about 30% among the world population. Iron deficiency is a significant cause of anemia, which can lead to hospitalization and even death. In case of intolerance or ineffectiveness of oral formulations of iron supplements, if it is necessary to replenish the iron level quickly, trivalent iron formulations for intravenous administration are used. These supplements are iron complexes with an iron hydroxide core surrounded by a carbohydrate shell. Iron formulations for intravenous administration can be divided into drugs of the "old" and "new" generation. One of the most studied and popular representatives of the "new" generation is iron carboxymaltose (ICM). The results of clinical studies showed that ICM better and faster increases hemoglobin concentration and replenishes iron stores in patients compared to the "old" generation formulations and also has a more favorable safety profile. Large doses of ICM can be administered in a short time, saving resources and increasing patient satisfaction. The injection of large doses of iron with a small number of infusions in the case of ICM is more economically beneficial for all departments of medical institutions, as it significantly reduces the total cost of medical care. Intravenous iron plays an essential role in the perioperative treatment of iron deficiency anemia, especially in elective surgery. Currently, there is a reliable evidence base confirming the efficacy and safety of intravenous iron formulations in chronic kidney disease, inflammatory bowel disease, heart failure, gynecological and obstetric diseases, and cancer.