Cardamonin attenuates iron overload-induced osteoblast oxidative stress through the HIF-1α/ROS pathway.

BACKGROUND: Osteoporosis(OP) is a bone disease under research. Iron overload is a significant risk factor. Iron balance is crucial for bone metabolism and biochemical processes. When there is an excess of iron in the body, it tends to produce reactive oxygen species (ROS) which can cause oxidative damage to cells. The flavonoid compound, Cardamonin (CAR), possesses potent anti-inflammatory and anti-iron overload properties that can be beneficial in mitigating the risk of OP. PURPOSE: This study investigates the potential therapeutic interventions and underlying mechanisms of CAR for treating OP in individuals with iron overload. METHODS: The model of iron-overloaded mice was established by intraperitoneally injecting iron dextran(ID) into the mice. OP severity was evaluated with micro-CT and Hematoxylin-Eosin (HE) staining in vivo. In vitro, the iron-overloaded osteoblast model was induced by ferric ammonium citrate. Cell counting kit 8 assay to evaluate cell viability, Annexin V-FITC/PI assay to detect cell apoptosis. A range of cellular markers were detected, including the variation in mitochondrial membrane potential (MMP), levels of malondialdehyde (MDA), ROS, and lipid hydroperoxide (LPO). RESULTS: CAR can reverse bone loss in iron overload-induced OP mouse models in vivo. CAR attenuates the impairment of iron overload on the activity and apoptosis of MC3T3-E1 cells as well as the accumulation of ROS and LPO activation via HIF-1α/ROS pathways. CONCLUSION: CAR downregulating HIF-1α pathways prevents inhibition of iron overload-induced osteoblasts dysfunctional by attenuating ROS accumulation, reducing oxidative stress, promotes bone formation, and alleviates OP.

Advances in Oral Exfoliative Cytology: From Cancer Diagnosis to Systemic Disease Detection.

Oral exfoliative cytology has emerged as a valuable tool in the early detection of oral cancer and other systemic diseases. This review comprehensively examines the current applications and recent advancements in oral exfoliative cytology techniques. We analyzed published literature from the past decade, focusing on methodological improvements, diagnostic accuracy, and emerging applications. Key findings include: (1) Enhanced cell collection and preparation methods have significantly improved sample quality and diagnostic reliability. (2) Integration of molecular markers and DNA analysis with traditional cytomorphological assessment has increased diagnostic sensitivity and specificity for oral cancer detection. (3) Novel applications in systemic disease detection, including diabetes and iron overload disorders, demonstrate the expanding utility of this technique. (4) Computer-assisted analysis and deep learning algorithms show promise in improving diagnostic accuracy and efficiency. Despite these advancements, challenges remain in standardization and widespread clinical implementation. This review provides a critical evaluation of oral exfoliative cytology's current status and future potential in oral and systemic disease diagnosis.

Nanoparticle-delivered quercetin exhibits enhanced efficacy in eliminating iron-overloaded senescent chondrocytes.

Aim: The therapeutic potential of senolytic drugs in osteoarthritis (OA) is poorly known. Quercetin, a senolytic agent exhibits promising potential to treat OA, having limited bioavailability. We investigated the effects of Quercetin-loaded nanoparticles (Q-NP) with enhanced bioavailability in human chondrocytes mimicking OA phenotype.Materials & methods: The C-20/A4 chondrocytes were exposed to ferric ammonium citrate to induce OA phenotype, followed by treatment with free Quercetin/Q-NP for 24 and 48-h. Q-NP were synthesized by nanoprecipitation method. Following treatment chondrocytes were assessed for drug cellular bioavailability, viability, cell cycle, apoptosis, oxidative stress and expression of key senescence markers.Results: Q-NP exhibited 120.1 ± 1.2 nm particle size, 81 ± 2.4% encapsulation efficiency, increased cellular bioavailability and selective apoptosis of senescent chondrocytes compared with free Quercetin. Q-NP treatment also induced oxidative stress and reduced the expressions of senescence markers, including TRB3, p16, p62 and p21 suggesting their ability to eliminate senescent cells. Last, Q-NP arrested the cell cycle in the sub-G0 phase, potentially creating a beneficial environment for tissue repair.Conclusion: Q-NP propose a promising delivery system for treating OA by eliminating senescent chondrocytes through apoptosis. Furthermore, their enhanced cellular bioavailability and capacity to modify cell cycle and senescent pathways warrant further investigations.

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Risk of transfusion-related iron overload varies based on oncologic diagnosis and associated treatment: Retrospective analysis from a single pediatric cancer center.

BACKGROUND: Transfusion-related iron overload (TRIO) is a widely acknowledged late effect of antineoplastic therapy in pediatric cancer survivors, but firm guidelines as to screening protocols or at-risk populations are lacking in the literature. PROCEDURE: We performed retrospective analysis of all oncology patients diagnosed at our center from 2014 to 2019, who underwent TRIO screening as part of an internal quality improvement project. Correlations of MRI-confirmed TRIO with patient-, disease-, and treatment-specific features were evaluated. RESULTS: We show that a tiered screening algorithm for TRIO, when followed as intended, led to the identification of the highest proportion of patients with TRIO. We confirm that cardiac TRIO is quite rare in the oncology patient population. However, accepted surrogate markers including red blood cell transfused volume and ferritin only modestly correlated with TRIO in our patient cohort. Instead, we found that older age, leukemia diagnosis, anthracycline exposure, and receipt of stem cell transplant were most strongly associated with risk for TRIO. CONCLUSIONS: We describe associations between TRIO and patient, disease, and treatment characteristics in a multivariate risk model that could lead to an improved risk stratification of off-therapy patients, and which should be validated in a prospective manner.

Comorbidities and complications in adult and paediatric patients with pyruvate kinase deficiency: Analysis from the Peak Registry.

Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.

A Rare Case of Iron Overload in Hereditary Spherocytosis: A Case Report.

Hereditary spherocytosis (HS) is a hereditary hematologic disorder characterized by fragile spherical red blood cells that are susceptible to hemolysis. HS patients are often asymptomatic or present with anemia; however, serious complications of chronic hemolysis can include cholelithiasis and aplastic crisis. Splenectomy is considered the standard surgical treatment in moderate and severe forms of HS, with the main complication being a life-long risk of infection. Interestingly, our case suggests a possibility of secondary hemochromatosis as a complication of chronic hemolysis seen in HS. A vast majority of hemochromatosis patients possess a genetic predisposition, which increases their serum iron level and iron storage within the reticuloendothelial system. However, we present a case in which the genetic panel for common mutations associated with hemochromatosis resulted as negative. This case emphasizes the need for increased awareness regarding the potential development of idiopathic hemochromatosis in patients with long-standing HS, allowing for prompt intervention and preventing the associated complications.

A two-pronged approach to inhibit ferroptosis of MSCs caused by the iron overload in postmenopausal osteoporosis and promote osseointegration of titanium implant.

Postmenopausal osteoporosis (PMOP) is a prevalent condition among elderly women. After menopause, women exhibit decreased iron excretion, which is prone to osteoporosis. To design a specific titanium implant for PMOP, we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis. The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP. Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs, thus breaking bone homeostasis. Based on the findings above, we have designed a novel Ti implant coated with nanospheres of caffeic acid (CA) and deferoxamine (DFO). CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid (PCA) dimer, as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units. DFO was grafted with PCA through borate ester bonds. The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways. Firstly, DFO was released under high oxidative stress, chelating with excess iron and decreasing the labile iron pool in MSCs. Meanwhile, CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation. So, the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway. Furthermore, the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level. This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP.

Transfusional hemosiderosis in childhood cancer patients and survivors.

BACKGROUND: Children treated for cancer are at risk for adverse effects of iron due to transfusions administered during prolonged marrow suppression, which may increase exposure to toxic forms of iron, extrahepatic iron accumulation, and long-term organ damage. OBJECTIVE: This study aimed to characterize the severity and organ distribution of clinically significant, multisystem iron overload (IO) in an at-risk cohort of pediatric cancer patients. METHODS: This was a retrospective, cross-sectional study of childhood cancer patients who underwent a magnetic resonance imaging (MRI) due to clinical concern for IO. Data regarding cancer type and treatment, transfusion history, MRI and laboratory results, and treatment for IO were collected. Severity of IO was analyzed by non-parametric tests with respect to clinical characteristics. RESULTS: Of the 103 patients, 98% of whom had a Cancer Intensity Treatment Rating (ITR-3) of 3 or higher, 53% (54/102) had moderate or greater hepatic siderosis, 80% (77/96) had pancreatic siderosis, 4% (3/80) had cardiac siderosis, and 45% (13/29) had pituitary siderosis and/or volume loss. Pancreatic iron was associated with both cardiac (p = .0043) and pituitary iron (p = .0101). In the 73 off-therapy patients, ferritin levels were lower (p = .0008) with higher correlation with liver iron concentration (LIC) (p = .0016) than on-therapy patients. Fifty-eight subjects were treated for IO. CONCLUSION: In this heavily treated cohort of pediatric cancer patients, more than 80% had extrahepatic iron loading, which occurs with significant exposure to toxic forms of iron related to decreased marrow activity in setting of transfusions. Further studies should examine the effects of exposure to reactive iron on long-term outcomes and potential strategies for management.

The effect of iron supplementation in preterm infants at different gestational ages.

BACKGROUND: Iron deficiency (ID) is the most prevalent nutritional deficiency disease in preterm infants, significantly affecting their growth and development. For preterm infants to flourish physically and neurologically, timely iron supplementation is essential. The main goals of this study were to determine whether the present iron supplementation regimen results in iron overload in late preterm infants and whether it can meet the growth requirements of early preterm infants for catch-up. METHODS: We conducted a prospective follow-up study on preterm infants at the Department of Child Health, West China Second University Hospital, Sichuan University, from January 1, 2020, to August 31, 2020. In this study, 177 preterm infants were divided into two groups based on gestational age-early preterm infants (gestational age < 34 weeks) and late preterm infants (gestational age ≥ 34 weeks and < 37 weeks)-to compare the incidence of iron deficiency, iron status, and physical growth of preterm infants receiving iron supplements (2-4 mg/kg/d). RESULTS: Iron supplementation considerably reduced the incidence of iron deficiency in preterm infants. The prevalence of iron deficiency in early preterm infants and late preterm infants was 11.3% and 5.1%, respectively, at the corrected gestational age of 3 months; at the corrected gestational age of 6 months, the prevalence was 5.3% and 6.3%, respectively. No preterm infants with iron deficiency were detected in either group at the corrected gestational age of 12 months. Ferritin was substantially lower in early preterm infants (36.87 ± 31.57 ng/ml) than in late preterm infants (65.78 ± 75.76 ng/ml) at the corrected gestational age of 3 months (p < 0.05). A multifactorial regression analysis of factors influencing iron metabolism levels in preterm infants revealed a positive relationship between log10hepcidin, birth weight, and ferritin, with higher birth weights resulting in higher ferritin levels. CONCLUSIONS: Postnatal iron supplementation at 2-4 mg/kg/d in preterm infants significantly decreases the incidence of ID. There were substantial differences in iron levels across preterm infants of varying gestational ages. A tailored iron supplementation plan based on growth, birth weight, and gestational age may be a more suitable route for iron supplementation. Although the current study found that the postnatal iron status of early preterm infants differed from that of late preterm infants, the actual mechanism of action remains unknown, and large-sample, multicenter clinical studies are required to investigate this further.

Ubiquitin-specific protease 38 promotes atrial fibrillation in diabetic mice by stabilizing iron regulatory protein 2.

BACKGROUND: Atrial fibrillation (AF) is a common cardiovascular disease often observed in diabetes mellitus, and there is currently no satisfactory therapeutic option. Ubiquitin-specific protease 38 (USP38) has been implicated in the degradation of numerous substrate proteins in the myocardium. Herein, we aim to investigate the role of USP38 in AF induced by diabetes. METHODS: Cardiac-specific transgenic USP38 mice and cardiac-specific knockout USP38 mice were constructed, and streptozotocin was used to establish diabetic mouse model. Functional, electrophysiological, histologic, biochemical studies were performed. RESULTS: The expression of USP38 was upregulated in atrial tissues of diabetic mice and HL-1 cells exposed to high glucose. USP38 overexpression increased susceptibility to AF, accompanied by aberrant expression of calcium-handling protein, heightened iron load and oxidation stress in diabetic mice. Conversely, USP38 deficiency reduced vulnerability to AF by hampering ferroptosis. Mechanistically, USP38 bound to iron regulatory protein 2 (IRP2), stabilizing it and remove K48-linked polyubiquitination chains, thereby increasing intracellular iron overload, lipid peroxidation, and ultimately contributing to ferroptosis. In addition, reduced iron overload by deferoxamine treatment alleviated oxidation stress and decreased vulnerability to AF in diabetic mice. CONCLUSION: Overall, our findings reveal the detrimental role of USP38 in diabetes-related AF, manifested by increased level of iron overload and oxidation stress.

Ferroptosis promotes valproate-induced liver steatosis in vitro and in vivo.

Valproic acid (VPA), a common antiepileptic drug, can cause liver steatosis after long-term therapy. However, an impact of ferroptosis on VPA-induced liver steatosis has not been investigated. In the study, treatment with VPA promoted ferroptosis in the livers of mice by elevating ferrous iron (Fe2+) levels derived from the increased absorption by transferrin receptor 1 (TFR1) and the decreased storage by ferritin (FTH1 and FTL), disrupting the redox balance via reduced levels of solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPX4), and augmenting acyl-CoA synthetase long-chain family member 4 (ACSL4) -mediated lipid peroxide generation, accompanied by enhanced liver steatosis. All the changes were significantly reversed by co-treatment with an iron-chelating agent, deferoxamine mesylate (DFO) and a ferroptosis inhibitor, ferrostatin-1 (Fer-1). Similarly, the increases in Fe2+, TFR1, and ACSL4 levels, as well as the decreases in GSH, GPX4, and ferroportin (FPN) levels, were detected in VPA-treated HepG2 cells. These changes were also attenuated after co-treatment with Fer-1. It demonstrates that ferroptosis promotes VPA-induced liver steatosis through iron overload, inhibition of the GSH-GPX4 axis, and upregulation of ACSL4. It offers a potential therapy targeting ferroptosis for patients with liver steatosis following VPA treatment.

Iron Overloading Potentiates the Antitumor Activity of 5-Fluorouracil by Promoting Apoptosis and Ferroptosis in Colorectal Cancer Cells.

Resistance to 5-fluorouracil (5-FU) remains a significant challenge in colorectal cancer (CRC) treatment. Ferric ammonium citrate (FAC) is commonly used as an iron supplement due to its food-fortification properties; however, its potential role as a chemosensitizer in cancer therapy has not been studied. In this study, we explored the ability of FAC to sensitize CRC cells and increase their susceptibility to 5-FU-mediated anticancer effects. We assessed cell viability, cell cycle progression, apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, ferroptosis, and iron metabolism-related protein expression using two CRC cell lines. Additionally, we conducted in silico analyses to compare iron markers in normal colon and CRC tumor tissues. Compared to controls, CRC cells pretreated with FAC and then treated with 5-FU exhibited significantly reduced growth and viability, along with increased ROS-mediated ferroptosis. Mechanistically, FAC-pretreated then 5-FU-treated CRC cells showed enhanced apoptosis, increased Bak/Bax expression, MMP depolarization, and decreased antiapoptotic protein levels (Bcl-2 and Bcl-xL). This combined treatment also led to G2/M cell cycle arrest, upregulation of p21 and p27, and downregulation of cyclin D1, c-Myc, survivin, and GPX4. Analysis of human colon tumor tissue revealed decreased expression of IRP-1, HMOX-1, and FTH1 but increased HAMP expression. In contrast, FAC-pretreated/5-FU-treated CRC cells exhibited a reverse pattern, suggesting that FAC-induced chemosensitization enhances 5-FU-mediated anticancer activity in CRC by disrupting iron homeostasis. These findings highlight the potential of iron overload as a chemosensitization strategy for improving CRC chemotherapy.

Quantification of Cardiac Iron Overload at 3 T MRI in a Rabbit Model Utilizing ME-GRE T2* Sequence.

BACKGROUND: Myocardial iron overload can lead to myocardial dysfunction, muscle cell injury, and end-stage heart failure. The enhanced signal-to-noise ratio and technical advancements have made 3 T magnetic resonance imaging (MRI) more accessible in clinical settings. However, 3 T assessments for early diagnosis of myocardial iron overload are scarce. PURPOSE: To evaluate the feasibility of myocardial iron quantification using 3 T MRI in a rabbit model of iron overload. STUDY TYPE: Animal model. ANIMAL MODEL: Overall, 40 male New Zealand white rabbits were categorized into control (N = 8; no treatment) and experimental (N = 32; weekly 200 mg/kg iron dextran injections) groups. SEQUENCE: 3 T MRI with multi-echo gradient echo (ME-GRE) T2* sequence. ASSESSMENT: Each week, two experimental rabbits were randomly selected for blood collection to determine serum iron (SI) levels; their tissue was harvested to assess myocardial and hepatic iron deposition. STATISTICAL TESTS: Spearman's rank correlation tests were used to evaluate the correlations among R2*, cardiac iron concentration (CIC), liver iron concentration (LIC), total amount of iron injected, and SI levels. P ≤ 0.05 was considered statistically significant. RESULTS: The myocardial T2* value in the experimental group was significantly lower than that of the control group. An excellent correlation was observed between R2* values and CIC (r = 0.854). CIC moderately correlated with LIC (r = 0.712) and the total amount of iron injected (r = 0.698). A strong correlation was observed between the total amount of iron injected and LIC (r = 0.866). SI levels poorly correlated with the total amount of iron injected (r = 0.205, P = 0.277) and LIC (r = 0.170, P = 0.370) but fairly correlated with CIC (r = 0.415, P = 0.022). DATA CONCLUSION: A 3 T MRI with an ME-GRE sequence may serve as a noninvasive method for evaluating cardiac iron content. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 1.

Protocatechualdehyde inhibits iron overload-induced bone loss by inhibiting inflammation and oxidative stress in senile rats.

The accumulating evidence has made it clear that iron overload is a crucial mechanism in bone loss. Protocatechualdehyde (PCA) has also been used to prevent osteoporosis in recent years. Whether PCA can reverse the harmful effects of iron overload on bone mass in aged rats is still unknown. Therefore, this study aimed to assess the role of PCA in iron overload-induced bone loss in senile rats. In the aged rat model, we observed that iron overload affects bone metabolism and bone remodeling, manifested by bone loss and decreased bone mineral density. The administration of PCA effectively mitigated the detrimental effects caused by iron overload, and concomitant reduction in MDA serum levels and elevation of SOD were noted. In addition, PCA-treated rats were observed to have significantly increased bone mass and elevated expression of SIRT3，BMP2，SOD2 and reduced expression of TNF-α in bone tissue. We also observed that PCA was able to reduce oxidative stress and inflammation and restore the imbalance in bone metabolism. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclasts differentiation, PCA intervention could significantly recover the restriction of osteogenic differentiation and up-regulation of osteoclast differentiation treated by iron overload. Further, by detecting changes in ROS, SOD, MDA, expression of SIRT3 and mitochondrial membrane potentials, we confirm that the damage caused to cells by iron overload is associated with decreased SIRT3 activity, and that 3-TYP have similar effects on oxidative stress caused by FAC. In conclusion, PCA can resist iron overload-induced bone damage by improving SIRT3 activity, anti-inflammatory and anti-oxidative stress.

Iron-laden macrophage-mediated paracrine pro-fibrotic signaling induces lung fibroblast activation.

Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. While elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-ß1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-ß1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When co-cultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this pro-fibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-ß receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-ß1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages.

Comparative evaluation of the effects of deferiprone and/or resveratrol in alleviating iron overload-induced tongue injury in rats.

Iron overload causes excessive iron deposition in extrahepatic organs, including the tongue. This study aims to compare the deferiprone and/or resveratrol treatments for the alleviation of iron overload-induced tongue injury in rats. Rats were divided into 6 groups: control group, iron-overloaded group, recovery group where rats were left to recover from iron overload, deferiprone-treated group, resveratrol-treated group, and combined deferiprone/resveratrol-treated group. Iron was administered for 4 weeks, while all treatment options were given for the subsequent 4 weeks. After 8 weeks, all rats were sacrificed; the serum iron profile was estimated, and the tongues were assessed by histopathological, tumour necrosis factor alpha (TNF-α) immunohistochemical, histomorphometric, and ultrastructural evaluations. Serum iron parameters were significantly increased in iron-overloaded rats and decreased to control levels only in the combined group. The iron-overloaded tongues demonstrated lost lingual papillae, coarse keratohyalin granules, vacuolated epithelial cells, degenerated muscle fibers, and congested blood vessels. Compared to the control rats, this group revealed a significant decrease in the epithelial layer thickness (550.7 vs. 763.4 µm), papillae height (441.4 vs. 849.7 µm), and myofiber diameter (58.5 vs. 98.6 µm), and increased lamina propria thickness (305.1 vs. 176.8 µm), fibrosis index (33.4 vs. 8.6 %), and TNF-α immunoexpression (1.16 vs. 0.63 optical density). Additionally, the ultrastructure showed hyperkeratinized papillae, wide interpapillary spaces, flat fungiform papillae, and lost gustatory pores. All these parameters were improved in the recovery, deferiprone, and resveratrol groups to different degrees, while the combined deferiprone/resveratrol treatment was the best option.

Macrophage-derived extracellular vesicles represent a promising endogenous iron-chelating therapy for iron overload and cardiac injury in myocardial infarction.

BACKGROUND: Cardiac iron overload and ferroptosis greatly contribute to the poor prognosis of myocardial infarction (MI). Iron chelator is one of the most promising strategies for scavenging excessive iron and alleviating cardiac dysfunction post MI. However, various side effects of existing chemical iron chelators restrict their clinical application, which calls for a more viable and safer approach to protect against iron injury in ischemic hearts. RESULTS: In this study, we isolated macrophage-derived extracellular vesicles (EVs) and identified macrophage-derived EVs as a novel endogenous biological chelator for iron. The administration of macrophage-derived EVs effectively reduced iron overload in hypoxia-treated cardiomyocytes and hearts post MI. Moreover, the oxidative stress and ferroptosis induced by excessive iron were considerably suppressed by application of macrophage-derived EVs. Mechanistically, transferrin receptor (TfR), which was inherited from macrophage to the surface of EVs, endowed EVs with the ability to bind to transferrin and remove excess protein-bound iron. EVs with TfR deficiency exhibited a loss of function in preventing MI-induced iron overload and protecting the heart from MI injury. Furthermore, the iron-chelating EVs were ultimately captured and processed by macrophages in the liver. CONCLUSIONS: These results highlight the potential of macrophage-derived EVs as a powerful endogenous candidate for iron chelation therapy, offering a novel and promising therapeutic approach to protect against iron overload-induced injury in MI and other cardiovascular diseases.

Impact of Serum Ferritin and Iron Overload on Acute Myeloid Leukemia Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the iron overload among individuals with acute myeloid leukemia (AML) who have not received red blood cell transfusions. METHODS: A comprehensive search was conducted in Embase, PubMed, PubMed Central, Web of Science, NIH, and Blood Library databases up to September 2023. The search strategy included keywords related to AML, iron overload, serum ferritin, survival, outcomes, and inflammation. Manual searches through included articles and relevant references were also performed. From 1650 initial articles, 16 studies involving 8752 patients met the inclusion criteria for systematic review. Statistical analysis used hazard ratios (HR) and confidence intervals (CI).  Results: The systematic review and meta-analysis revealed a statistically significant association between high serum ferritin (SF) levels and poor outcomes in AML patients before starting chemotherapy. Elevated SF levels (>1000 mg/L) were associated with lower overall survival (OS) and event-free survival (EFS) (HR for OS: 1.99, 95% CI: 1.48-2.66; HR for EFS: 2.29, 95% CI: 1.73-3.05). Elevated SF levels were inversely correlated with the gradual onset of infections, indicating an increased risk of early mortality (p<0.05). CONCLUSION: Elevated serum ferritin levels are significantly associated with poor outcomes in AML patients before treatment initiation. These findings highlight the importance of monitoring iron levels in these patients to improve prognostic assessments and treatment strategies.

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.

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.