Tissue Iron Research Articles

Iron accumulation/overload and Alzheimer's disease risk factors in the precuneus region: A comprehensive narrative review

AbstractAlzheimer's disease (AD) is a neurodegenerative disease that is characterized by amyloid plaques, neurofibrillary tangles, and neuronal loss. Early cerebral and body iron dysregulation and accumulation interact with AD pathology, particularly in the precuneus, a crucial functional hub in cognitive functions. Quantitative susceptibility mapping (QSM), a novel post‐processing approach, provides insights into tissue iron levels and cerebral oxygen metabolism and reveals abnormal iron accumulation early in AD. Increased iron deposition in the precuneus can lead to oxidative stress, neuroinflammation, and accelerated neurodegeneration. Metabolic disorders (diabetes, non‐alcoholic fatty liver disease (NAFLD), and obesity), genetic factors, and small vessel pathology contribute to abnormal iron accumulation in the precuneus. Therefore, in line with the growing body of literature in the precuneus region of patients with AD, QSM as a neuroimaging method could serve as a non‐invasive biomarker to track disease progression, complement other imaging modalities, and aid in early AD diagnosis and monitoring.

Dietary superdosing of phytase positively affects growth, mineral utilization and amino acid availability of channel catfish (Ictalurus punctatus)

The present study investigated the effects of supplementing high levels (superdosing) of dietary phytase on growth performance, mineral utilization and digestibility of amino acids in different regions of the gastrointestinal (GI) tract of fingerling channel catfish. The negative control (NC) diet was formulated with primarily soybean meal as a protein feedstuff which contributed 0.61 % total phosphorus (P) but was deficient in available P at 0.11 % of diet. Five other diets were formulated either with supplemental monocalcium phosphate at 1 % of diet in the positive control (PC), or supplemented with Quantum Blue phytase (AB Vista, Plantation, Florida) at 1000, 2000, 4000, or 8000 phytase units (FTU)/kg of diet. Groups of 20 catfish were each stocked into 24 aquaria operated as a closed, recirculating system with biological and mechanical filtration. All dietary treatments were assigned randomly to quadruplicate aquaria and initially fed at 6 % of total body weight per day. Feed quantities were adjusted weekly after weighing all fish in each aquarium as a group, and feeding levels were maintained close to apparent satiation throughout the 8-week feeding trial. Phytase supplementation significantly (P < 0.05) increased various responses of channel catfish including weight gain, feed efficiency, and protein retention compared to catfish fed the NC diet, resulting in values that were similar to catfish fed the PC diet. Moreover, catfish fed the phytase-supplemented diets had higher bone ash, calcium (Ca), magnesium (Mg), P, manganese (Mn), and zinc (Zn), as well as retention of Ca, Mg, P, iron (Fe), Mn, and Zn in whole-body tissues. Additionally, apparent availability of P from the posterior intestinal region increased with dietary phytase supplementation, with reduced excretion of nitrogen, Ca, Mg, P, copper (Cu), Mn, and Zn observed in comparison to fish fed the NC diet. Apparent digestibility coefficients for many of the indispensable and dispensable amino acids were increased by phytase supplementation, except for histidine, methionine, threonine, and taurine. This improvement in amino acid availability occurred only in the posterior region of the gastrointestinal tract. Channel catfish fed the diet containing 4000 FTU/kg diet had the highest postprandial plasma phosphorus level most of the time, except at 24 h after feeding. Based on these various responses, the optimal dietary phytase dosage was determined to average 5492 FTU/kg diet.

8283 Diabetes Mellitus in Patients with Hemochromatosis- A Diagnostic and Therapeutic Challenge

Abstract Disclosure: U. Rafat: None. M. Siddiqui: None. J.L. Gilden: Other; Self; Novartis Pharmaceuticals. A. Moid: Other; Self; Novartis Pharmaceuticals. Background: Primary Hemochromatosis is a genetic condition most commonly due to two sets of mutations in the Human homeostatic iron regular Protein (HFE) gene. HFE modulates the expression of hepcidin, which regulates intestinal iron absorption, plasma iron concentration and distribution of iron in tissues. Hemochromatosis patients are at high risk for developing diabetes mellitus (DM) due to iron overload in the pancreas with damage to Beta cells and impaired insulin secretory capacity. Hemochromatosis is often called Bronze Diabetes due to brown discoloration of the skin from accumulation of iron, and is characterized by hepatic fibrosis, fatigue, arthralgias, cirrhosis, DM, arthropathy, pigmentation and cardiomyopathy. Case: We present a Caucasian male with homozygous hereditary hemochromatosis, diagnosed by liver biopsy at age 40 due to transaminitis and Ferritin level of 1500 ng/mL and Genetic testing- 2 copies of HFE gene pathogenic variant (C282Y). He was later diagnosed with DM age 51, started on Metformin and referred to Endocrine clinic with abdominal bloating, and polyarticular arthralgias. Physical exam=Vital Signs normal (WT. 231lbs, BMI 34), with splenomegaly, but normal musculoskeletal exam and skin without bronze discoloration. Both parents had T2DM. Lab- Hb a1c 8.7% (0.0-5.6), Iron saturation 71% (10-50), Ferritin 66.3 ng/mL (26-388), C-Peptide 3.30 ng/ml (0.81-3.85), with glucose level of 119 mg/dL, and negative IA-2 &amp;lt;5.4 U/mL, negative Islet cell antibody, GAD 65 &amp;lt;5 IU/mL (nl &amp;lt;5), Insulin Autoantibody &amp;lt;0.4 U/mL (nl &amp;lt;0.4), and Zinc Transporter 8 antibodies &amp;lt;10 U/mL (nl &amp;lt;15). Liver tests- AST 39 U/L(10-37), ALT 77 U/L (10-65), ALP 89 U/L (45-117), total bilirubin 1.1 mg/dL(0.2-1.2). Hormonal evaluation included TSH 1.2 uIU/mL (0.55-4.78), ACTH 19 pg/mL (0-47), AM Cortisol 16.28 ug/d (5.30-22.50) IGF1 158 ng/mL (50-317) FSH 9.6 mIU/mL(l.40-18.10), LH 5.09 mIU/mL (1.50-9.30), Prolactin 7.40 ng/mL(2.10-17.70), total testosterone 374 ng/dL(250-1100), free testosterone 66.2 pg/mL (35.0-155.0). Echocardiogram-left ventricular hypertrophy and thick right ventricular wall with concerns for iron overload. Hba1c improved to 6.6% on Metformin. Fructosamine 351umol/L (151-300). In the absence of advanced cardiac, hepatic and other organ involvement, and presence of elevated C-peptide and high BMI, this patient is being managed as T2DM, with low threshold to initiate insulin therapy considering possibility of concomitant Bronze DM. Conclusion: It is important to determine type of DM, so appropriate management options can be devised. While insulin is recommended for management in Bronze Diabetes, insulin sensitizers, such as metformin and/or GLP 1 agonists can be used in type 2 DM. One must also consider therapy based upon the risk of cancer and acute pancreatitis in the setting of pancreatic iron overload, when considering antihyperglycemic therapies. Presentation: 6/2/2024

Appraisal on heavy metal contamination in tissues (gills, intestine, liver, and fillet) of &lt;i&gt;Parachanna obscura&lt;/i&gt; and the physicochemical properties of Oguta Lake, South-Eastern Nigeria.

The aim of this study is to provide baseline data on the investigation of concentrations of copper (Cu), lead (Pb), iron (Fe), manganese (Mn), and zinc (Zn) in various tissues (gills, intestine, liver, and fillet) of Parachanna obscura in Oguta Lake, and to assess physicochemical properties of Oguta lake to determine level of pollution and contamination. Twenty fish samples in total were collected at the fishermen landing site of the lake and analyzed using the Atomic Absorption Spectroscopy (AAS). Dissolved oxygen and temperature were measured on site using dissolved Oxygen meter (model 5509) and Mercury-in-glass thermometer respectively, while other parameters were analyzed in the laboratory. Results indicated Fe had the highest concentrations (1.479±0.003 mg/kg) especially in the gills, while Mn recorded least concentrations (0.001±0.000) mg/kg) of all metals analyzed. Values for Cu (0.026±0.002 mg/kg), Mn (0.001±0.000 mg/kg), Zn (.782±0.015 mg/kg), and Fe (1.479±0.030 mg/kg) levels were within FAO/WHO permissible limits in all tissues, whereas Pb (1.438±0.015 mg/kg) exceeded standard limits especially in the gills and intestines, indicating potential contamination and threats to aquatic and human health. Heavy metal concentrations in the tissues followed the order: gills &gt; intestine &gt; fillet &gt; liver. The physicochemical properties assessment of Oguta Lake indicated a stable temperature with mean value of (28.02±022 C). The lake's temperature supports aquatic life, but challenges like low transparency (1.22±0.13 m), acidic pH levels (5.83±0.09), elevated ammonium levels (0.63±0.03 mg/l), low nitrate-nitrogen levels (0.0±50.00 mg/l), and fluctuating dissolved oxygen (6.50±0.29 mg/l) levels suggests pollution from agricultural runoff or sewage. The findings proffer effective management through pollution control, enhanced buffering capacity, and rigorous monitoring to safeguard biodiversity and ensure longterm ecological health.

Bioaccumulation of iron (Fe) and lead (Pb) in various body tissues of Telescopium telescopium in Peninsular Malaysia: Implications for biomonitoring and sustainability

Bioaccumulation of iron (Fe) and lead (Pb) in various body tissues of Telescopium telescopium in Peninsular Malaysia: Implications for biomonitoring and sustainability

TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe2+) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.

Leveraging ultra-high field (7T) MRI in psychiatric research.

Non-invasive brain imaging has played a critical role in establishing our understanding of the neural properties that contribute to the emergence of psychiatric disorders. However, characterizing core neurobiological mechanisms of psychiatric symptomatology requires greater structural, functional, and neurochemical specificity than is typically obtainable with standard field strength MRI acquisitions (e.g., 3T). Ultra-high field (UHF) imaging at 7 Tesla (7T) provides the opportunity to identify neurobiological systems that confer risk, determine etiology, and characterize disease progression and treatment outcomes of major mental illnesses. Increases in scanner availability, regulatory approval, and sequence availability have made the application of UHF to clinical cohorts more feasible than ever before, yet the application of UHF approaches to the study of mental health remains nascent. In this technical review, we describe core neuroimaging methodologies which benefit from UHF acquisition, including high resolution structural and functional imaging, single (1H) and multi-nuclear (e.g., 31P) MR spectroscopy, and quantitative MR techniques for assessing brain tissue iron and myelin. We discuss advantages provided by 7T MRI, including higher signal- and contrast-to-noise ratio, enhanced spatial resolution, increased test-retest reliability, and molecular and neurochemical specificity, and how these have begun to uncover mechanisms of psychiatric disorders. Finally, we consider current limitations of UHF in its application to clinical cohorts, and point to ongoing work that aims to overcome technical hurdles through the continued development of UHF hardware, software, and protocols.

An Insight in to Cadaveric Ectopic Calcification: A Case Report

Abstract: Pathological Calcification is an anomalous accumulation of calcium salts along with minimal quantities of iron, magnesium and other minerals in bodily tissues except teeth and bone causing hardening of the affected tissues. The location of the calcification and the presence or absence of mineral balance can be used to categorize it. The atypical mineral deposition processes in biological systems can sometimes be referred to as pathological calcification. During the routine dissection in National Institute of Ayurveda, Jaipur it was observed that numerous pathological calcifications were present both on osseous and extra osseous sites which were different from the normal human anatomy. The subject was a 90-year-old male of North Indian origin. Case examples illustrate different types and locations of calcification, shedding light on the anatomical distribution and potential clinical relevance.

Galangin alleviated Doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through GSTP1/JNK pathway

BackgroundDoxorubicin (DOX) is a potent anticancer medication, but its significant cardiotoxicity poses a challenge in clinical practice. Galangin (Gal), a flavonoid compound with diverse pharmacological activities, has shown potential in exerting cardioprotective effects. However, the related molecular mechanism has not been fully elucidated. PurposeCombined with bioinformatics and experimental verification methods to investigate Gal's potential role and underlying mechanisms in mitigating DOX-induced cardiotoxicity (DIC). MethodsC57BL/6 mice received a single dose of DOX via intraperitoneal injection 4 days before the end of the gavage period with Gal. Myocardial injury was evaluated using echocardiography, myocardial injury biomarkers, Sirius Red and H&E staining. H9c2 cells were stimulated with DOX to mimic DIC in vitro. The potential therapeutic target of Gal was identified through network pharmacology, molecular docking and cellular thermal shift assay (CETSA), complemented by an in-depth exploration of the GSTP1/JNK signaling pathway using immunofluorescence. Subsequently, the GSTP1 inhibitor Ezatiostat (Eza) substantiated the signaling pathway. ResultsGal administration considerably raised DOX-inhibited the left ventricular ejection fractions (LVEF), reduced levels of myocardial injury markers (c-TnI, c-TnT, CKMB, LDH, and AST), and alleviated DOX-induced myocardial histopathological injury and fibrosis in mice, thereby improving cardiac dysfunction. The ferroptosis induced by DOX was inhibited by Gal treatment. Gal remarkably ameliorated the DOX-induced lipid peroxidation, accumulation of iron and Ptgs2 expression both in H9c2 cells and cardiac tissue. Furthermore, Gal effectively rescued the DOX-inhibited crucial regulators of ferroptosis such as Gpx4, Nrf2, Fpn, and Slc7a11. The mechanistic investigations revealed that Glutathione S-transferase P1 (GSTP1) may be a potential target for Gal in attenuating DIC. Gal act on GSTP1 by stimulating its expression, thereby enhancing the interaction between GSTP1 and c-Jun N-terminal kinase (JNK), leading to the deactivation of JNK/c-Jun pathway. Furthermore, interference of GSTP1 with inhibitor Eza abrogated the cardioprotective and anti-ferroptotic effects of Gal, as evidenced by decreased cell viability, reduced expression of GSTP1 and Gpx4, elevated MDA levels, and promoted phosphorylation of JNK and c-Jun compared with Gal treatment. ConclusionGal could inhibit ferroptosis and protect against DIC through regulating the GSTP1/JNK pathway. Our research has identified a novel pathway through which Gal regulates DIC, providing valuable insights into the potential therapeutic efficacy of Gal in mitigating cardiotoxic effects.

The potency of Thymus vulgaris seed extract in alleviating obesity complications and iron overload in obese rats

Natural products have long been recognized as valuable sources of bioactive compounds in therapeutic agents. Thymus vulgaris, commonly known as thyme and belonging to the Lamiaceae family, is widely distributed and extensively used in Egyptian folk medicine for its antibroncholitic, antispasmodic, carminative, and diuretic properties. However, there is a lack of research on the effects of T. vulgaris seed extract in mitigating obesity-induced iron overload in rats. Given its potent bioactive constituents, this study aimed to investigate the impact of T. vulgaris seed extract on iron overload associated with obesity by evaluating lipid profiles, iron status parameters—including plasma ferritin, total iron-binding capacity (TIBC), plasma transferrin, transferrin saturation percentage (TS%), and hepcidin gene expression in adipose tissue. About 30 flavonoids were identified in T. vulgaris seed extract using LC-MS. Among these, methoxyflavonoids were the most abundant metabolites. The administration of T. vulgaris seed extract to obese rats resulted in significant reductions in anthropometric features, hepcidin gene expression, cholesterol, triglycerides, low-density lipoprotein (LDL), TIBC, plasma ferritin, leptin, and iron and copper content in adipose tissue. Moreover, treatment with T. vulgaris extract led to a notable decrease in interleukin-6 (IL-6) levels (76.33 ± 4.31 ng/L and 40.83 ± 1.82 ng/L for low and high doses, respectively) compared to the obese control group (110.83 ± 5.82 ng/L). Conversely, plasma adiponectin levels were significantly increased with T. vulgaris supplementation (123.6 ± 7.9 µg/L and 217.4 ± 6.1 µg/L for low and high doses, respectively) compared to the obese group (54.6 ± 4.9 µg/L). Additionally, adipose tissue zinc levels were significantly elevated in response to T. vulgaris supplementation (2.54 ± 0.20 µg/g and 3.75 ± 0.14 µg/g for low and high doses, respectively) compared to the obese group (1.45 ± 0.23 µg/g). Our findings suggest that T. vulgaris could be a promising novel therapeutic agent for managing obesity-induced iron overload.

Iron and Manganese concentrations in leaf tissues of Rhizophora mangle (Rhizophoraceae): implications for energetic metabolism

Introduction: Iron (Fe) and manganese (Mn) are bioessential micronutrients for plants but can impair the energetic metabolism when present at high levels. Objective: To assess the photosynthetic performance and oxidative damages in Rhizophora mangle L. leaf tissues at low and high concentrations of Fe (74 and 195 mg kg-1; Feleaf) and Mn (65 and 414 mg kg-1; Mnleaf). Methods: Photosynthetic pigments, chlorophyll a fluorescence, leaf CO2 assimilation and gas exchange and DPPH• radical scavenging capacity were sampled in R. mangle growing in estuarine forests in the North region of Espírito Santo State and the extreme South of Bahia State (Brazil) showing low and high Feleaf and Mnleaf. Results: Effects of high Fe and Mn were not identified on pigment levels. The increase in Feleaf and Mnleaf at the levels observed in this assessment had a positive effect on the number of reaction centers and on the efficiency of the oxygen-evolving complex, evaluated as K-band, while no changes were found in the parameters related to the excitation trapping efficiency at the active center of photosystem II. Distinct interference patterns of Fe and Mn on the functional processes of photosynthesis were identified, especially on CO2 assimilation and reactive oxygen species metabolism, with major effects on CO2 assimilation and carboxylation efficiency of Rubisco at high Mnleaf. Conclusion: These findings demonstrate the efficiency of R. mangle in positively regulating the electron transport chain in response to high Fe and Mn, at least in terms of the preservation of structure and functionality of the plant photosynthetic apparatus. Moreover, interference of high Mnleaf in R. mangle occurs at non-stomatal and biochemical levels. There is an antagonistic interference of these trace elements with the physiology of R. mangle, which is a dominant species in Brazilian mangroves.

GGC repeat expansions in NOTCH2NLC cause uN2CpolyG cerebral amyloid angiopathy.

The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. H&E staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.

Magnetic Resonance Evaluation of Tissue Iron Deposition and Cardiac Function in Adult Regularly Transfused Thalassemia Intermedia Compared with Thalassemia Major Patients.

Objectives: This multicenter, retrospective, population-based, matched-cohort study compared clinical characteristics and magnetic resonance imaging (MRI) findings, including hepatic, pancreatic, and cardiac iron levels and cardiac function, between 135 adult regularly transfused thalassemia intermedia (TI) patients (44.73 ± 12.16 years, 77 females) and 135 age- and sex-matched thalassemia major (TM) patients (43.35 ± 9.83 years, 77 females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Methods: The MRI protocol included the quantification of hepatic, pancreatic, and cardiac iron levels (R2* technique), the assessment of biventricular function parameters (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Results: Age, sex, frequency of splenectomy and chelation, and serum ferritin levels were not significantly different (p > 0.05) between the two groups, but TI patients started regular transfusions significantly later (p < 0.0001) and showed significantly lower pre-transfusion hemoglobin levels (p = 0.005). No difference was found in hepatic iron levels (p = 0.853). TI patients exhibited significantly lower pancreatic R2* values (p < 0.0001), also correcting for the duration of regular transfusions, and significantly lower cardiac R2* values (p < 0.0001). In the receiver operating characteristic analysis, pancreatic iron was the strongest discriminator between the two diseases. Left and right ventricular end-diastolic volume indexes were significantly higher in TI than in TM patients (p = 0.003 and p = 0.046, respectively), but the correction for the duration of regular transfusions removed the disease-specific differences (p > 0.05). Left ventricular (LV) mass index was significantly higher in TI (p = 0.049), while no difference (p > 0.05) was found in biventricular ejection fractions and replacement myocardial fibrosis. Conclusions: TI patients showed lower pancreatic and cardiac iron burden and more pronounced LV hypertrophy. These differences could not be explained by the different duration of the transfusional regimen.

Prognostic Role of Tissue Iron Deficiency Measured by sTfR Levels in Heart Failure Patients without Systemic Iron Deficiency or Anemia.

Background. Iron deficiency (ID) is a significant, high-prevalence comorbidity in chronic heart failure (HF) that represents an independent predictor of a worse prognosis. However, a clear-cut diagnosis of ID in HF patients is not assured. The soluble transferrin receptor (sTfR) is a marker that reflects tissue-level iron demand and may be an early marker of ID. However, the impact of sTfR levels on clinical outcomes in non-anemic HF patients with a normal systemic iron status has never been evaluated. Methods. This is a post hoc analysis of an observational, prospective cohort study of 1236 patients with chronic HF of which only those with normal hemoglobin levels and a normal systemic iron status were studied. The final cohort consisted of 215 patients. Tissue ID was defined as levels of sTfR > 75th percentile (1.65 mg/L). Our aim was to describe the association between sTfR and clinical outcomes (all-cause death and HF hospitalization) and to explore its association with a wide array of serum biomarkers. Results. The sTfR level (HR 1.48, 95% CI 1.13-1.96, p = 0.005) and tissue ID (HR 2.14, 95% CI 1.22-3.75, p = 0.008) was associated with all-cause death. However, we found no association between sTfR levels and the risk of HF hospitalization. Furthermore, high sTfR levels were associated with a worse biomarker profile indicating myocardial damage (troponin and NT-proBNP), systemic inflammation (CRP and albumin), and impaired erythropoiesis (erythropoietin). Conclusions. In this cohort, the presence of tissue ID defined by sTfR levels is an independent factor for all-cause death in patients with normal systemic iron parameters.

Role of Cardiac Magnetic Resonance in Inflammatory and Infiltrative Cardiomyopathies: A Narrative Review.

Cardiac magnetic resonance (CMR) has acquired a pivotal role in modern cardiology. It represents the gold standard for biventricular volume and systolic function assessment. Moreover, CMR allows for non-invasive myocardial tissue evaluation, highlighting tissue edema, fibrosis, fibro-fatty infiltration and iron overload. This manuscript aims to review the impact of CMR in the main inflammatory and infiltrative cardiomyopathies, providing details on specific imaging patterns and insights regarding the most relevant trials in the setting.

The influence of iron nutrition on the development of intestine and immune cell divergency in neonatal pigs

BackgroundAppropriate iron supplementation is essential for neonatal growth and development. However, there are few reports on the effects of iron overload on neonatal growth and immune homeostasis. Thus, the aim of this study was to investigate the effects of iron nutrition on neonatal growth and intestinal immunity by administering different levels of iron to neonatal pigs.ResultsWe found that iron deficiency and iron overload resulted in slow growth in neonatal pigs. Iron deficiency and iron overload led to down-regulation of jejunum intestinal barrier and antioxidant marker genes, and promoted CD8+ T cell differentiation in jejunum and mesenteric lymph nodes (MLN) of pigs, disrupting intestinal health. Moreover, iron levels altered serum iron and tissue iron status leading to disturbances in redox state, affecting host innate and adaptive immunity.ConclusionsThese findings emphasized the effect of iron nutrition on host health and elucidated the importance of iron in regulating redox state and immunity development. This study provided valuable insights into the regulation of redox state and immune function by iron metabolism in early life, thus contributing to the development of targeted interventions and nutritional strategies to optimize iron nutrition in neonates.

Iron regulatory protein 1 is required for the propagation of inflammation in inflammatory bowel disease

Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Metformin enhances endogenous neural stem cells proliferation, neuronal differentiation, and inhibits ferroptosis through activating AMPK pathway after spinal cord injury

BackgroundInadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated.MethodsThe proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot.ResultsMetformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK).ConclusionMetformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.

Autophagy-mediated ferroptosis is involved in development of severe acute pancreatitis

BackgroundFerroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated.MethodsWe established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy.ResultsOur study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP.ConclusionsOur results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.

Sex similarities and divergences in systemic and muscle iron metabolism adaptations to extreme physical inactivity in rats.

Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI. Eight-week-old male and female Wistar rats were assigned to control (CTL) or hindlimb unloading (HU) conditions (n=12/group). After 7days of HU, serum, liver, spleen, and soleus muscle were removed. Iron parameters were measured in serum samples, and ICP-MS was used to quantify iron in tissues. Iron metabolism genes and proteins were analysed by RT-qPCR and Western blot. Compared with control males, control females exhibited higher iron concentrations in serum (+43.3%, p<0.001), liver (LIC; +198%, P<0.001), spleen (SIC; +76.1%, P<0.001), and transferrin saturation (TS) in serum (+53.3%, P<0.001), contrasting with previous observations in humans. HU rat males, but not females, exhibited an increase of LIC (+54% P<0.001) and SIC (+30.1%, P=0.023), along with a rise of H-ferritin protein levels (+60.9% and +134%, respectively, in liver and spleen; P<0.05) and a decrease of TFRC protein levels (-36%; -50%, respectively, P<0.05). HU males also exhibited an increase of splenic HO-1 and NRF2 mRNA levels, (p<0.001), as well as HU females (P<0.001). Concomitantly to muscle atrophy observed in HU animals, the iron concentration increased in soleus in females (+26.7, P=0.004) while only a trend is observed in males (+17.5%, P=0.088). In addition, the H-ferritin and myoglobin protein levels in soleus were increased in males (+748%, P<0.001, +22%, P=0.011, respectively) and in females (+369%, P<0.001, +21.9%, P=0.007, respectively), whereas TFRC and ferroportin (FPN) protein levels were reduced in males (-68.9%, P<0.001, -76.8%, P<0.001, respectively) and females (-75.9%, P<0.001, -62.9%, P<0.001, respectively). Interestingly, in both sexes, heme exporter FLVCR1 mRNA increased in soleus, while protein levels decreased (-39.9% for males P=0.010 and -49.1% for females P<0.001). Taken together, these data support that, in rats (1) extreme physical inactivity differently impacts the distribution of iron in both sexes, (2) splenic erythrophagocytosis could play a role in this iron misdistribution. The higher iron concentrations in atrophied soleus from both sexes are associated with a decoupling between the increase in iron storage proteins (i.e., ferritin and myoglobin) and the decrease in levels of iron export proteins (i.e., FPN and FLVCR1), thus supporting an iron sequestration in skeletal muscle under extreme physical inactivity.