14,379 results on '"Iron overload"'
Search Results
2. Neurodegenerative Diseases Progression Markers (MARKERS-NDD) (MARKERS-NDD)
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IRCCS San Raffaele Roma, San Raffaele Telematic University, University of Urbino 'Carlo Bo', University of Cassino and Southern Lazio, University of Roma La Sapienza, and Politecnico di Milano
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- 2024
3. Study to Evaluate Treatment Compliance, Efficacy and Safety of an Improved Deferasirox Formulation (Granules) in Pediatric Patients (2
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- 2024
4. N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma
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Geroyska, Sofia, Mejia, Isabel, Chan, Alfred A, Navarrete, Marian, Pandey, Vijaya, Kharpatin, Samuel, Noguti, Juliana, Wang, Feng, Srole, Daniel, Chou, Tsui-Fen, Wohlschlegel, James, Nemeth, Elizabeta, Damoiseaux, Robert, Shackelford, David B, Lee, Delphine J, and Díaz, Begoña
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Digestive Diseases ,Cancer ,Lung ,Genetics ,Lung Cancer ,Orphan Drug ,Rare Diseases ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Humans ,Lung Neoplasms ,Animals ,Mitochondrial Precursor Protein Import Complex Proteins ,Mitochondria ,Acyltransferases ,Mice ,Iron Overload ,Cell Line ,Tumor ,Kelch-Like ECH-Associated Protein 1 ,Membrane Transport Proteins ,Protein Serine-Threonine Kinases ,AMP-Activated Protein Kinase Kinases ,Proto-Oncogene Proteins p21(ras) ,Xenograft Model Antitumor Assays ,Mutation ,Oxidative Stress - Abstract
Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity to NMT inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that NMTs are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS-mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation, and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter translocase of inner mitochondrial membrane 17 homolog A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis NMT-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.SignificanceKRAS-mutant lung carcinomas with LKB1 and/or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos and thus has the potential to kill apoptosis and ferroptosis-resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas.
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- 2024
5. A Study to Test the Safety, Tolerability, and Efficacy of an Antibody, REGN7999, Injected Under the Skin for the Treatment of Iron Overload in Adult Participants With Non-Transfusion Dependent β-thalassemia, Using MRI Scans to Measure Iron Levels in the Body (FERVENT-1)
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- 2024
6. Comparison of Deferasirox and Desferoxamine in Patients of β-Thalassemia Major With Iron Overload
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- 2024
7. Survey to Assess Physicians' Knowledge of Exjade Posology and Biological Monitoring Recommendations as Described in the Educational Materials
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- 2024
8. MRI QSM Imaging for Iron Overload
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Stanford University and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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- 2024
9. Iron Fortification and Inulin Supplementation in Early Infancy: Evaluating the Impact on Iron Metabolism and Trace Mineral Status in a Piglet Model.
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Park, Jungjae, Wickramasinghe, Saumya, Lönnerdal, Bo, Mills, David, and Ji, Peng
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infant formula ,inulin ,iron fortification ,iron overload ,pig model ,prebiotic ,trace mineral - Abstract
BACKGROUND: Infant formula in the United States contains abundant iron, raising health concerns about excess iron intake in early infancy. OBJECTIVES: Using a piglet model, we explored the impact of high iron fortification and prebiotic or synbiotic supplementation on iron homeostasis and trace mineral bioavailability. METHODS: Twenty-four piglets were stratified and randomly assigned to treatments on postnatal day 2. Piglets were individually housed and received an iron-adequate milk diet (AI), a high-iron milk diet (HI), HI supplemented with 5% inulin (HI with a prebiotic [HIP]), or HIP with an oral gavage of Ligilactobacillus agilis YZ050, an inulin-fermenting strain, every third day (HI with synbiotic [HIS]). Milk was provided in 14 meals daily, mimicking formula feeding in infants. Fecal consistency score and body weight were recorded daily or every other day. Blood and feces were sampled weekly, and tissues collected on postnatal day 29. Data were analyzed using mixed model analysis of variance with repeated measures whenever necessary. RESULTS: Diet did not affect growth. HI increased hemoglobin, hematocrit, and serum iron compared to AI. Despite marginal adequacy, AI upregulated iron transporter genes and maintained satisfactory iron status in most pigs. HI upregulated hepcidin gene expression in liver, caused pronounced tissue iron deposition, and markedly increased colonic and fecal iron. Inulin supplementation, regardless of L. agilis YZ050, not only attenuated hepatic iron overload but also decreased colonic and fecal iron without altering pH or the expression of iron regulatory genes. HI lowered zinc (Zn) and copper (Cu) in the duodenum and liver compared to AI, whereas HIP and HIS further decreased Zn and Cu in the liver and diminished colonic and fecal trace minerals. CONCLUSIONS: Early-infancy excessive iron fortification causes iron overload and compromises Zn and Cu absorption. Inulin decreases trace mineral absorption likely by enhancing gut peristalsis and stool frequency.
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- 2024
10. Treatment of Iron Overload With Deferasirox (Exjade) in Hereditary Hemochromatosis and Myelodysplastic Syndrome (DefeHEMY)
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Novartis
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- 2024
11. Safety and Efficacy of Early Treatment With Deferiprone in Infants and Young Children (START)
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- 2024
12. Heme and Non-heme Iron Intakes, Gut Microbiota, and Influence on Host Iron Absorption (FeMicrobiome)
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- 2024
13. Ethnic Differences in Iron Absorption (FeGenes) (FeGenes)
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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institutes of Health (NIH)
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- 2024
14. Long-term Clinical Study of CN128 in Thalassemia With Sever Liver Iron Overloaded Patients
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- 2024
15. Fully Automated High-Throughput Quantitative MRI of the Liver
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National Institute for Biomedical Imaging and Bioengineering (NIBIB)
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- 2024
16. Elevated Plasma Atherogenic and Triglyceride-Glucose Indices: Markers of Cardiovascular Risk in Transfusion-Dependent Thalassemia.
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Yalcin, Nazif, Sadri, Sevil, Ertınmaz Özkan, Ayşegül, Gürsoy, Vildan, and Koca, Nizameddin
- Abstract
AbstractBackgroundMethodsResultsConclusionTransfusion-dependent thalassemia (TDT) is an autosomal recessive disorder characterized by defective hemoglobin synthesis, leading to severe complications such as iron overload and multi-organ dysfunction. This study aims to elucidate the distinctive clinical and biochemical profiles of TDT patients compared to healthy controls, with an emphasis on cardiovascular risk assessment using novel markers such as the Plasma Atherogenic Index (PAI) and Triglyceride-Glucose (TyG) index.This cross-sectional study included 32 TDT patients and 36 healthy controls, matched for age and gender. Comprehensive demographic, laboratory, and imaging data were collected and analyzed. TDT patients were further stratified based on cardiac involvement and ferritin levels. Key assessments included hemoglobin levels, liver enzymes, lipid profiles, and cardiac imaging. The PAI and TyG index were calculated to evaluate cardiovascular risks. Statistical analyses were performed using SPSS 27.0, employing Student’s
t -test, Mann–WhitneyU test, and Pearson chi-square test as appropriate.No significant differences in basic demographic parameters were observed between groups; however, TDT patients exhibited significant clinical and laboratory differences. Notably, these patients had lower hemoglobin levels, higher platelet counts, elevated liver enzymes (ALT and AST), and markedly increased ferritin levels. Lipid profiles were significantly altered, with lower levels of total cholesterol, HDL, and LDL but elevated triglycerides. Importantly, the PAI was significantly higher in TDT patients, suggesting an increased atherosclerotic risk. Subgroup analysis revealed that patients with cardiac involvement had worse metabolic profiles, higher TyG indices, and prolonged QT intervals, indicating heightened cardiovascular risk. As the iron burden increases, the TyG index and PAI may lose their sensitivity in distinguishing between varying levels of iron overload, suggesting that their effectiveness plateaus beyond a certain threshold of iron accumulation.TDT patients show significant hematological and metabolic deviations, including elevated cardiovascular risk markers like PAI and TyG index. As iron burden increases, these markers lose discriminative power, and cardiac involvement escalates rapidly once a critical iron threshold is surpassed, as supported by studies showing a non-linear relationship between iron load and cardiac complications. Comprehensive cardiovascular risk assessment and tailored management are essential for these patients. Future studies should focus on tracking cardiovascular risk progression and the effects of targeted interventions. [ABSTRACT FROM AUTHOR]- Published
- 2024
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17. Iron overload regulates cognitive function in rats with minimal hepatic encephalopathy by inducing an increase in frontal butyrylcholinesterase activity.
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Hua Lan, Xuhong Yang, Minxing Wang, Minglei Wang, Xueying Huang, and Xiaodong Wang
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BRAIN metabolism ,IRON metabolism ,CHOLINESTERASES ,PEARSON correlation (Statistics) ,COGNITIVE testing ,PHYSIOLOGIC salines ,COMPUTER software ,T-test (Statistics) ,DATA analysis ,ERYTHROCYTES ,RESEARCH funding ,IRON overload ,STATISTICAL sampling ,ENZYME-linked immunosorbent assay ,LEARNING ,MAGNETIC resonance imaging ,AMIDES ,DESCRIPTIVE statistics ,MANN Whitney U Test ,HEPATIC encephalopathy ,FRONTAL lobe ,ANIMAL experimentation ,COGNITION disorders ,MEMORY ,ANIMAL behavior ,STATISTICS ,SPACE perception ,COLLECTION & preservation of biological specimens ,DATA analysis software ,STAINS & staining (Microscopy) - Abstract
Background and aims: This study aimed to investigate the effect of iron overload on acetylcholinesterase activity in the frontal lobe tissue of rats with minimal hepatic encephalopathy (MHE) and its relation to cognitive ability. By elucidating the potential mechanisms of cognitive impairment, this study may offer insights into novel therapeutic targets for MHE. Materials and methods: Twelve Sprague-Dawley rats were purchased and randomly assigned to either the experimental or control group with six rats in each group. Following the induction of MHE, the Morris Water Maze (MWM) was utilized to assess spatial orientation and memory capacity. Subsequently, Magnetic Resonance Imaging (MRI) scans were performed to capture Quantitative Susceptibility Mapping (QSM) images of all rats' heads. Results: Compared to the control group rats, the MHE model rats showed significantly reduced learning and memory capabilities as well as spatial orientation abilities (P < 0.05). Furthermore, the susceptibility values in the frontal lobe tissue of MHE model rats was significantly higher than that of the control group rats (P < 0.05), and the corresponding BuChE activity in the frontal lobe extract of model rats was significantly increased while BuChE activity in the peripheral blood serum was significantly decreased compared to the control group rats (P < 0.05). Meanwhile, our findings indicate a significant positive correlation between latency period and BuChE activity with susceptibility values in the MHE group. Conclusion: The changes in BuChE activity in frontal lobe extract may be related to changes in spatial orientation and behavioral changes in MHE, and iron overload in the frontal lobe tissue may regulate changes in BuChE activity, BuChE levels appear to be iron-dependent. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Differential gut microbiota composition in β-Thalassemia patients and its correlation with iron overload.
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Nonejuie, Poochit, Wilantho, Alisa, McDonald, Daniel, Htoo, Htut Htut, Chalerm, Jenjira, Tripathi, Anupriya, Ngamphiw, Chumpol, Tongsima, Sissades, Knight, Rob, Paiboonsukwong, Kittiphong, and Fucharoen, Suthat
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SHORT-chain fatty acids , *IRON overload , *IRON in the body , *GUT microbiome , *DISEASE susceptibility - Abstract
Recent research highlights the significant impact of the gut microbiota on health and disease. Thalassemia, a hereditary blood disorder, requires regular blood transfusions, leading to an accumulation of iron in the body. Such changes could potentially alter the intestinal microbiota, thereby increasing the susceptibility of thalassemic patients to infection. In this study, we analyzed the fecal microbiota of 70 non-transfusion-dependent (NTDT) β-thalassemia/HbE patients and 30 healthy controls. Our findings indicate that iron chelation intervention had no detectable effect on the microbiome profile of thalassemic patients. However, the cross-sectional analysis revealed that the bacterial diversity and community structure in patients were significantly less diverse and distinct compared to those of healthy subjects. Using reference frames, we were also able to demonstrate that bacterial taxa that are known to produce short chain fatty acids, from the genera Alistipes, Coprococcus, and Oscillospira, and those from the family Ruminococcaceae, were less prevalent in the patients. In contrast, bacterial taxa associated with an unhealthy gut, including the genus Clostridium and those from the families Fusobacteriaceae, Enterobacteriaceae, and Peptostrptococcaceae, were more prevalent in patients and found to be correlated with higher levels of ferritin. Collectively, these changes in the microbiota could be regarded as markers of raised ferritin levels, and therefore, awareness should be exercised as they could interfere, albeit indirectly, with the treatment of the co-morbidities of thalassemia. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Automated red blood cell exchange with a post‐procedure haematocrit targeted at 34% in the chronic management of sickle cell disease.
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M. Ross, Jules, Forté, Stéphanie, Mercure‐Corriveau, Nicolas, Lemay, Anne‐Sophie, Rioux‐Massé, Benjamin, Potter, Brian J., and Soulières, Denis
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Summary: Optimal targets for red blood cell exchange (RCE) are not well defined in the chronic management of sickle cell disease. We analysed transfusion requirements and iron‐related outcomes in 101 patients on chronic RCE with a post‐procedure haematocrit (Ht) targeted at 34%, which is higher than typically used. A majority were of HbSS/HbSβ0 genotype (n = 72) and enrolled for neurological complications (n = 53). Fifty patients had a positive Ht balance with RCE (>2% mean increase from pre‐procedure level), while 43 patients maintained a neutral balance. The first group required fewer red blood cell units/year (65 vs. 80, p < 0.001), but a significant proportion were iron overloaded based on R2* with liver MRI (32% vs. none performed) and prescription of iron chelation (52% vs. 0%, p < 0.001, after a median of 19 months). The second group was more likely to receive iron supplementation (6% vs. 56%, p < 0.001). Chronic automated RCE with a post‐procedure Ht targeted at 34% is not iron‐neutral, and personalized Ht goals may be more appropriate in certain settings. This higher target should be compared with a lower Ht strategy in individuals with similar baseline red cell volumes to assess iron homeostasis and blood product requirements. [ABSTRACT FROM AUTHOR]
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- 2024
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20. MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import.
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Xu, Tao and Chen, Guilan
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Ferroptosis is a recently identified iron-dependent programmed cell death with lipid peroxide accumulation and condensation and compaction of mitochondria. A recent study indicated that ferroptosis plays a pivotal role in ischemic cardiac injury with the mechanisms remain largely unknown. This study demonstrates that when an iron overload occurs in the ischemia/reperfusion cardiac tissues, which initiates myocardial ferroptosis, the expression levels of mitochondrial inner membrane protein MPV17 are reduced. Overexpression of MPV17 delivered via adenovirus significantly reduced ferroptosis in both cardiomyocytes with high levels of iron and cardiac I/R tissues. Mitochondrial glutathione (mtGSH), crucial for reactive oxygen species scavenging and mitochondrial homeostasis maintenance, is depleted in myocardial ferroptosis caused by iron overload. This mechanistic study shows that MPV17 can increase mitochondrial glutathione levels through maintaining the protein homeostasis of SLC25A10, which is a mitochondrial inner-membrane glutathione transporter. The absence of MPV17 in iron overload resulted in the ubiquitination-dependent degradation of SLC25A10, leading to impaired mitochondrial glutathione import. Moreover, we found that MPV17 was the targeted gene of Nrf2, which plays a pivotal role in preventing lipid peroxide accumulation and ferroptosis. The decreased expression levels of Nrf2 led to the inactivation of MPV17 in iron overload-induced myocardial ferroptosis. In summary, this study demonstrates the critical role of MPV17 in protecting cardiomyocytes from ferroptosis and elucidates the Nrf2-MPV17-SLC25A10/mitochondrial glutathione signaling pathway in the regulation of myocardial ferroptosis. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Neutrophil Diversity (Immature, Aged, and Low-Density Neutrophils) and Functional Plasticity: Possible Impacts of Iron Overload in β-Thalassemia.
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Sae-Khow, Kritsanawan, Charoensappakit, Awirut, and Leelahavanichkul, Asada
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Neutrophil dysfunction is a form of immune suppression in patients with β-thalassemia (Beta-thal), although data on this are limited. In this study, blood from patients and healthy volunteers was analyzed. Flow cytometry analysis demonstrated an increase in immature neutrophils (CD16− CD62L+) and aged (senescent) neutrophils (CD16+ CD62L−) in Beta-thal patients compared to healthy volunteers. The Beta-thal neutrophils demonstrated less prominent chemotaxis and phagocytosis than healthy neutrophils at the baseline. With phorbol myristate acetate (PMA) or lipopolysaccharide (LPS) stimulations, some of the indicators, including the flow cytometry markers (CD11b, CD62L, CD66b, CD63, apoptosis, and reactive oxygen species) and neutrophil extracellular traps (NETs; detected by anti-citrullinated histone 3 immunofluorescence), were lower than the control. Additionally, low-density neutrophils (LDNs), which are found in the peripheral blood mononuclear cell (PBMC) fraction, were observed in Beta-thal patients but not in the control group. The expression of CD11b, CD66b, CD63, arginase I, and ROS in LDNs was higher than the regular normal-density neutrophils (NDNs). The proliferation rate of CD3+ T cells isolated from the PBMC fraction of healthy volunteers was higher than that of the cells from patients with Beta-thal. The incubation of red blood cell (RBC) lysate plus ferric ions with healthy NDNs transformed the NDNs into the aged neutrophils (decreased CD62L) and LDNs. In conclusion, iron overload induces neutrophil diversity along with some dysfunctions. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Osteocyte ferroptosis induced by ATF3/TFR1 contributes to cortical bone loss during ageing.
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Yin, Ying, Chen, Guang‐Jin, Yang, Chen, Wang, Jia‐Jia, Peng, Jin‐Feng, Huang, Xiao‐Fei, Tang, Qing‐Ming, and Chen, Li‐Li
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COMPACT bone , *TRANSCRIPTION factors , *IRON overload , *OLDER people , *OSTEOCYTES , *TRANSFERRIN receptors - Abstract
Cortical bone loss is intricately associated with ageing and coincides with iron accumulation. The precise role of ferroptosis, characterized by iron overload and lipid peroxidation, in senescent osteocytes remains elusive. We found that ferroptosis was a crucial mode of osteocyte death in cortical bone during ageing. Using a single‐cell transcriptome analysis, we identified activating transcription factor 3 (ATF3) as a critical driver of osteocyte ferroptosis. Elevated ATF3 expression in senescent osteocytes promotes iron uptake by upregulating transferrin receptor 1 while simultaneously inhibiting solute carrier family 7‐member 11‐mediated cystine import. This process leads to an iron overload and lipid peroxidation, culminating in ferroptosis. Importantly, ATF3 inhibition in aged mice effectively alleviated ferroptosis in the cortical bone and mitigated cortical bone mass loss. Taken together, our findings establish a pivotal role of ferroptosis in cortical bone loss in older adults, providing promising prevention and treatment strategies for osteoporosis and fractures. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Targeting ferroptosis by natural products in pathophysiological conditions.
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Zheng, Daheng, Jin, Shikai, Liu, Pu-Ste, Ye, Jianping, and Xie, Xin
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DRUG discovery , *ACUTE kidney failure , *NATURAL products , *DRUG repositioning , *IRON overload - Abstract
Ferroptosis is a form of cell death that is induced by iron-mediated accumulation of lipid peroxidation. The involvement of ferroptosis in different pathophysiological conditions has offered new perspectives on potential therapeutic interventions. Natural products, which are widely recognized for their significance in drug discovery and repurposing, have shown great promise in regulating ferroptosis by targeting various ferroptosis players. In this review, we discuss the regulatory mechanisms of ferroptosis and its implications in different pathological conditions. We dissect the interactions between natural products and ferroptosis in cancer, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury, liver injury, and cardiomyopathy, with an emphasis on the relevance of ferroptosis players to disease targetability. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Evaluation of iron overload in visceral organs in thalassemia patients by point shear-wave elastography.
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Hattapoğlu, Salih and Çetinçakmak, Mehmet Güli
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Introduction: The aim of this study was to investigate the value of point shear-wave elastography (pSWE) in the measurement of iron overload in the liver and other visceral organs in patients with beta thalassemia major (BTM). Materials and methods: The study included 103 patients diagnosed with BTM who were referred to our clinic for cardiac and liver T2* measurement and a control group of 120 age- and gender-matched healthy volunteers. Cardiac and hepatic T2* measurements were performed in the patient group. Hepatic, pancreatic, splenic, and renal pSWE values were measured in both groups. The pSWE values were compared between the two groups. In the patient group, correlations between pSWE values, cardiac-hepatic T2* values and hepatic size, patient age, and serum ferritin levels were analyzed. Results: Hepatic, pancreatic, splenic, and renal pSWE values were significantly higher in the patient group compared to the control group (p ≤ 0.001, < 0.001, 0.014, 0.026, respectively). In the patient group, hepatic pSWE values established a significant correlation with cardiac T2* values, liver size-T2*, pancreatic pSWE values, serum ferritin levels, and age (p = 0.006, < 0.001, 0.001, 0.042, 0.001, 0.032, respectively). In the ROC analysis, the area under the ROC curve was 0.807 for hepatic pSWE in the discrimination of thalassemia patients and healthy controls, and the cut-off value was 1.42, which gave a sensitivity and specificity of 75.7% and 75%, respectively. Conclusıon: Point shear-wave elastography can be a useful technique in the clinical measurement of iron overload in the liver, pancreas, spleen, and kidney. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Evaluation of some heart enzymes and Iron levels in β-thalassemia patients in Thi-Qar City, Iraq.
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ibrahim, Ahmed jaber and AL–Saeed, Arwa H. M.
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TROPONIN I ,IRON overload ,BETA-Thalassemia ,GENETIC disorders ,PEARSON correlation (Statistics) ,FERRITIN ,ASPARTATE aminotransferase - Abstract
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- 2024
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26. Mechanism of HDAC1 Regulating Iron Overload-Induced Neuronal Oxidative Damage After Cerebral Hemorrhage.
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Han, Jing, Zhang, Jinnan, Yao, Xiaojuan, Meng, Meng, Wan, Yahui, and Cheng, Yan
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Iron overload is associated with brain edema in the context of intracerebral hemorrhage (ICH). Here, we investigated the role of histone deacetylase 1 (HDAC1) in mediating oxidative damage induced by iron overload after ICH. Utilizing ICH mouse models and FeCl
2 -induced HT-22 cell models, we assessed HDAC1 expression and its impact on iron overload and oxidative damage. We examined the levels of Kruppel like factor 4 (KLF4), RAN binding protein 9 (RANBP9), as well as the acetylation levels of HDAC1 and histones H3 and H4 in the KLF4 promoter, and the KLF4 level in the RANBP9 promoter. Additionally, we investigated the binding relationships between KLF4 and the RANBP9 promoter, HDAC1 and miR-129-5p. Our results demonstrated elevated HDAC1 expression in ICH mice and FeCl2 -induced HT-22 cells. HDAC1 silencing improved neurological function in mice, reduced brain edema, and alleviated iron overload and oxidative damage in vitro. HDAC1 downregulated KLF4 expression by reducing acetylation levels in the KLF4 promoter, leading to decreased KLF4 enrichment in the RANBP9 promoter and increased RANBP9 expression. Furthermore, upstream miR-129-5p inhibited HDAC1, and the downregulation of miR-129-5p mitigated the protective effect of HDAC1 silencing. Collectively, our findings highlight the significant role of HDAC1 in exacerbating iron overload-induced oxidative damage following ICH and its regulation by miR-129-5p. [ABSTRACT FROM AUTHOR]- Published
- 2024
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27. Deferasirox, an iron chelator, impacts myeloid differentiation by modulating NF‐kB activity via mitochondrial ROS.
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Jeffries, Nathan E., Sadreyev, Daniel, Trull, Elizabeth C., Chetal, Kashish, Yvanovich, Emma E., Mansour, Michael K., Sadreyev, Ruslan I., and Sykes, David B.
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ERYTHROCYTES , *IRON chelates , *MYELOID cells , *IRON overload , *GENE expression - Abstract
Summary The iron chelator deferasirox (DFX) is effective in the treatment of iron overload. In certain patients with myelodysplastic syndrome, DFX can also provide a dramatic therapeutic benefit, improving red blood cell production and decreasing transfusion requirements. Nuclear Factor‐kappa B (NF‐kB) signalling has been implicated as a potential mechanism behind this phenomenon, with studies focusing on the effect of DFX on haematopoietic progenitors. Here, we examine the phenotypic and transcriptional effects of DFX throughout myeloid cell maturation in both murine and human model systems. The effect of DFX depends on the stage of differentiation, with effects on mitochondrial reactive oxygen species (ROS) production and NF‐kB pathway regulation that vary between progenitors and neutrophils. DFX triggers a greater increase in mitochondrial ROS production in neutrophils and this phenomenon is mitigated when cells are cultured in hypoxic conditions. Single‐cell transcriptomic profiling revealed that DFX decreases the expression of NF‐kB and MYC (c‐Myc) targets in progenitors and decreases the expression of PU.1 (SPI1) gene targets in neutrophils. Together, these data suggest a role of DFX in impairing terminal maturation of band neutrophils. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Role of ferroptosis in the pathogenesis of heart disease.
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Fatima, Sulail, Haiyan Zhou, Yi Chen, and Qinghang Liu
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CARDIAC hypertrophy ,IRON overload ,CARDIOMYOPATHIES ,HEART diseases ,MYOCARDIAL infarction ,LIPID peroxidation (Biology) ,HEART failure - Abstract
Ferroptosis is a new form of regulated necrosis characterized by iron-dependent lipid peroxidation, leading to irreparable lipid damage, membrane permeabilization, and necrotic cell death. Ferroptosis has recently been implicated in the pathogenesis of multiple forms of heart disease such as myocardial infarction, cardiac hypertrophy, heart failure, and various cardiomyopathies. Important progress has also been made regarding how ferroptosis is regulated in vitro and in vivo as well as its role in cardiac homeostasis and disease pathogenesis. In this review, we discuss molecular mechanisms that regulates ferroptosis in the heart, including pathways leading to iron overload and lipid peroxidation as well as the roles of key organelles in this process. We also discuss recent findings pertaining to the new pathogenic role of ferroptosis in various forms of heart disease as well as genetic and pharmacologic strategies targeting ferroptosis in the heart. [ABSTRACT FROM AUTHOR]
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- 2024
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29. 8-weeks aerobic exercise ameliorates cognitive deficit and mitigates ferroptosis triggered by iron overload in the prefrontal cortex of APPSwe/PSEN1dE9 mice through Xc-/GPx4 pathway.
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Chaoyang Li, Kaiyin Cui, Xinyuan Zhu, Shufan Wang, Qing Yang, and Guoliang Fang
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IRON in the body ,HEMOPROTEINS ,AEROBIC exercises ,IRON overload ,ALZHEIMER'S disease - Abstract
Background: Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of APPSwe/PSEN1dE9 (APP/PS1) mice. Methods: Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, ironmetabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice. Results: In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc-/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice. Conclusion: 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc-pathway in PFC to reduce ferroptosis induced by AD. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Fetal hemochromatosis: rare case of hepatic and extrahepatic siderosis involving thyroid on fetal MRI.
- Author
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Natarajan, Sumathi, Kashyap, Ravindar, Rajan, Saira, and Muthusamy, Dhivakar
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HEMOCHROMATOSIS diagnosis ,INBORN errors of metabolism diagnosis ,INBORN errors of metabolism ,FETAL growth retardation ,MAGNETIC resonance imaging ,FETAL ultrasonic imaging ,TREATMENT effectiveness ,PRENATAL diagnosis ,HEMOCHROMATOSIS ,THYROID gland ,WATER-electrolyte balance (Physiology) ,LIVER ,HEMOSIDEROSIS ,AMNIOTIC liquid ,PREGNANCY complications ,EARLY diagnosis - Abstract
Background: Neonatal hemochromatosis (NH) is a rare condition that is characterized by severe neonatal liver disease in association with hepatic and extrahepatic excess iron deposition (siderosis), while sparing the reticuloendothelial system. The most common cause of fetal liver injury leading to the NH phenotype (accounting for over 95% of cases) is gestational alloimmune liver disease. This condition is caused by the transfer of maternal IgG antibodies through the placenta, targeting a fetal hepatocyte antigen. Prenatal diagnosis, particularly the identification of iron overload involving both liver and thyroid, is of significant importance and can have a profound impact on patient care. To our knowledge, no case has been reported on prenatal diagnosis of iron overload involving both liver and thyroid. Case presentation: We present an exceptionally rare case of fetal hemochromatosis in a primigravida, a case that significantly contributes to our understanding of this condition. The diagnosis was made with the presence of hepatic and extrahepatic siderosis involving the thyroid using Ultrasonography (USG) and fetal Magnetic Resonance Imaging (MRI) findings. A 23-year-old primigravida was referred to our center in view of oligohydramnios, Intrauterine Growth Restriction (IUGR) and echogenic bowel at 29 weeks of gestation. USG and fetal MRI showed features of coarse liver echotexture and iron overload involving the liver and thyroid; this is the first case describing iron accumulation in the fetal thyroid gland diagnosed in utero. Conclusion: This case underscores the critical importance of performing MRI in suspected cases of fetal hemochromatosis for early diagnosis and intervention, emphasizing the potential to significantly improve patient outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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31. The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease.
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Carolin, Agnes, Frazer, David, Kexin Yan, Bishop, Cameron R., Bing Tang, Nguyen, Wilson, Helman, Sheridan L., Horvat, Jay, Larcher, Thibaut, Rawle, Daniel J., and Suhrbier, Andreas
- Subjects
SARS-CoV-2 ,COVID-19 ,IRON overload ,IRON deficiency ,SARS-CoV-2 Omicron variant - Abstract
Introduction: The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish. Methods: Here we generate iron deficient and iron loaded C57BL/6 J mice by feeding standard low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary SARS-CoV-2 omicron XBB isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq. Results: Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial. Discussion: Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations. [ABSTRACT FROM AUTHOR]
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- 2024
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32. MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.
- Author
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Tam, Eddie, Nguyen, Khang, Sung, Hye Kyoung, and Sweeney, Gary
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MITOCHONDRIAL dynamics , *IRON overload , *TYPE 2 diabetes , *INSULIN sensitivity , *INSULIN resistance - Abstract
Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron–sulfur domain‐containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO‐induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p‐Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1‐dependent mitochondrial fission, mitophagy, FUN14 domain‐containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO‐induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi‐1, prevented IO‐induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO‐induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Antioxidant Effects of Cactus Seed Oil against Iron-Induced Oxidative Stress in Mouse Liver, Brain and Kidney.
- Author
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Bouchab, Habiba, Ishaq, Abbas, Limami, Youness, Saretzki, Gabriele, Nasser, Boubker, and El Kebbaj, Riad
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RAPESEED oil , *FERROUS sulfate , *REACTIVE oxygen species , *IRON overload , *DNA damage - Abstract
In recent times, exploring the protective potential of medicinal plants has attracted increasing attention. To fight reactive oxygen species (ROS), which are key players in hepatic, cerebral and renal diseases, scientists have directed their efforts towards identifying novel compounds with antioxidant effects. Due to its unique composition, significant attention has been given to Cactus Seed Oil (CSO). Iron, as a metal, can be a potent generator of reactive oxygen species, especially hydroxyl radicals, via the Fenton and Haber–Weiss reactions. Here, we employed ferrous sulfate (FeSO4) to induce oxidative stress and DNA damage in mice. Then, we used CSO and Colza oil (CO) and evaluated the levels of the antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GPx] and glutathione [GSH]) as well as a metabolite marker for lipid peroxidation (malondialdehyde [MDA]) relating to the antioxidant balance in the liver, brain and kidney. In addition, we measured DNA damage levels in hepatic tissue and the effects of CSO on it. Our study found that iron-dependent GPx activity decreases in the liver and the kidney tissues. Additionally, while iron decreased SOD activity in the liver, it increased it in the kidney. Interestingly, iron treatment resulted in a significant increase in hepatic MDA levels. In contrast, in brain tissue, there was a significant decrease under iron treatment. In addition, we found varying protective effects of CSO in alleviating oxidative stress in the different tissues with ameliorating DNA damage after iron overload in a mouse liver model, adding compelling evidence to the protective potential of CSO. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Ferroptosis in Ischemic Stroke and Related Traditional Chinese Medicines.
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Ma, Runchen, Sun, Xiaohui, Liu, Zhaofeng, Zhang, Jianzhao, Yang, Gangqiang, Tian, Jingwei, and Wang, Yunjie
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- *
TISSUE plasminogen activator , *CHINESE medicine , *ISCHEMIC stroke , *STROKE , *IRON overload - Abstract
Stroke is a severe neurological disorder resulting from the rupture or blockage of blood vessels, leading to significant mortality and disability worldwide. Among the different types of stroke, ischemic stroke (IS) is the most prevalent, accounting for 70–80% of cases. Cell death following IS occurs through various mechanisms, including apoptosis, necrosis, and ferroptosis. Ferroptosis, a recently identified form of regulated cell death characterized by iron overload and lipid peroxidation, was first described by Dixon in 2012. Currently, the only approved pharmacological treatment for IS is recombinant tissue plasminogen activator (rt-PA), which is limited by a narrow therapeutic window and often results in suboptimal outcomes. Recent research has identified several traditional Chinese medicines (TCMs) that can inhibit ferroptosis, thereby mitigating the damage caused by IS. This review provides an overview of stroke, the role of ferroptosis in IS, and the potential of certain TCMs to inhibit ferroptosis and contribute to stroke treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Fatigue Assessment in Patients with Hereditary Hemochromatosis: First Use of the Popular Diagnostic Tools.
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Świątczak, Michał, Raczak, Alicja, Świątczak, Agata, Młodziński, Krzysztof, Sikorska, Katarzyna, Jaźwińska, Anna, Kaufmann, Damian, and Daniłowicz-Szymanowicz, Ludmiła
- Subjects
- *
IRON overload , *FATIGUE (Physiology) , *CRONBACH'S alpha , *HEMOCHROMATOSIS , *BLOOD donors - Abstract
Background: Hereditary hemochromatosis (HH) is a genetic condition with fatigue as an essential but not precisely assessed symptom. While some well-specified scales for fatigue assessment in some pathologies exist, data on their usefulness in HH need to be collected. This research aimed to evaluate fatigue in HH using the Fatigue Assessment Scale (FAS), Fatigue Severity Scale (FSS), and Chalder Fatigue Scale (CFQ). Methodology: Seventy-nine HH patients underwent a questionnaire containing items about detailed medical history and the FAS, FSS, and CFQ scales. Twenty-five sex- and age-matched healthy persons constituted the control group (controls); additionally, thirty blood donors (donors) were compared. Results: The fatigue indices were significantly worse in the HH patients than in the controls and donors (HH vs. controls p-value: FAS = 0.003, FSS < 0.001, and CFQ = 0.003; HH vs. donors p-value: FAS = 0.025, FSS < 0.001, and CFQ = 0.041). There were no differences between the severity of fatigue and the specific genotype or the age of the patients. The HH women presented more severe fatigue than the men. High internal consistency and reliability for each scale were revealed: the Cronbach alpha values were as follows: FAS 0.92, FSS 0.95, and CFQ 0.93. Additionally, the construct validity and factorial validity of the implemented scales were confirmed. Conclusions: The HH patients exhibited significantly worse fatigue across all the scales. The FAS, FSS, and CFQ are simple and reliable diagnostic tools for assessing and quantifying fatigue for clinical and research purposes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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36. Dysregulated S100A9 Expression Impairs Matrix Deposition in Chronic Wounds.
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Franz, Sandra, Torregrossa, Marta, Anderegg, Ulf, Ertel, Anastasia, and Saalbach, Anja
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- *
CHRONIC wounds & injuries , *IRON overload , *SKIN injuries , *EXTRACELLULAR matrix , *WOUND healing ,LEG ulcers - Abstract
Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of S100A9 overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of S100A8 and S100A9 that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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37. Research progress of ferroptosis in female infertility.
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peiyin, Fan, yuxian, Wang, jiali, Zhang, and jian, Xu
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FEMALE infertility , *IRON overload , *APOPTOSIS , *LITERATURE reviews , *INFERTILITY - Abstract
Ferroptosis is a novel type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides in cells and is closely related to various diseases. Female infertility is a global health concern, which is associated with a variety of factors. The etiology remains unknown in many women with infertility. With further investigation into the pathogenesis of infertility, a growing number of studies have demonstrated the close connections between infertility and ferroptosis. Through a literature review, it is found that ferroptosis is closely involved in endometriosis- and polycystic ovarian syndrome (PCOS)-associated infertility and tubal factor infertility. Iron overload increases the resistance to ferroptosis, and ferroptosis in some cells accelerates endometrial lesion growth. Moreover, iron overload may be hazardous to oocytes. This review may shed some light on the diagnosis and treatment of female infertility. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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38. Ovarian Insufficiency in Adolescent Females with Transfusion-Dependent β-Thalassemia: Pituitary versus Ovarian Iron Overload.
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Matter, Randa M., Farid, Laila A., Madkour, Sherihane S., Yassin, Alshimaa H., and Salah, Nouran Y.
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- *
OVARIAN reserve , *OVARIAN follicle , *TEENAGE girls , *HYPERFERRITINEMIA , *IRON overload , *FERRITIN - Abstract
Females with transfusion-dependent β-thalassemia (TDT) display menstrual irregularities and subfertility at certain points in their lives, even if well-chelated, representing a significant physical and psychological burden. Little is known about the effects of pituitary and ovarian iron contents on ovarian reserve and function. Hence, this study aimed to assess ovarian reserve and pituitary-gonadal axis function in adolescent females with TDT and correlate them with pituitary and ovarian volume, pituitary iron load, and serum ferritin.Introduction: Fifty adolescent females with TDT were compared to 50 age-matched healthy females. Age of diagnosis of TDT, transfusion index, type of chelation therapy, age at menarche, and Tanner breast stage were assessed. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and ferritin were measured. Magnetic resonance imaging (MRI) pituitary iron content R2* and T2* were measured, and 3-D transabdominal ovarian ultrasound performed.Methods: The mean age of the studied females with TDT was 14.54 ± 2.24 years. Ovarian insufficiency was found in 20 of them (40%). Compared to controls, adolescent females with TDT had significantly delayed age of menarche, AMH, FSH, LH, antral follicle count (AFC), and ovarian volume. Upon comparing those with ovarian insufficiency and those without, adolescents with TDT having ovarian insufficiency had significantly higher serum ferritin and pituitary MRI-R2* than those without insufficiency. Multivariate-logistic regression showed that pituitary MRI-R2* was the most significant independent variable associated with ovarian insufficiency among adolescent females with TDT.Results: Adolescent females with TDT have decreased ovarian reserve, AFC, and gonadotropins that are correlated with serum ferritin, pituitary iron load, and ovarian volume. Hence, regular ovarian reserve assessment should be implemented as a part of endocrinological follow-up of females with TDT advising procedures to preserve fertility to those who are likely to have ovarian insufficiency. [ABSTRACT FROM AUTHOR]Conclusion: - Published
- 2024
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39. Ferroptosis as a molecular target of epigallocatechin gallate in diseases.
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Wang, Lili, Tang, Chunlian, Zhang, Qizhi, and Pan, Qun
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NUCLEAR factor E2 related factor , *TREATMENT effectiveness , *EPIGALLOCATECHIN gallate , *IRON overload , *GREEN tea - Abstract
AbstractContextObjectiveMethodsResults and conclusionFerroptosis is a novel form of cell death characterised by iron overload and lipid peroxidation. It is closely associated with many diseases, including cardiovascular diseases, tumours, and neurological diseases. The use of natural chemicals to modulate ferroptosis is of great concern because of the critical role ferroptosis plays in disease. The main active ingredient in green tea is epigallocatechin gallate (EGCG), which is the most abundant catechin in green tea. EGCG shows a wide range of biological and therapeutic effects in various diseases, including anti-inflammatory, antioxidant, anticancer, and cardioprotective.The purpose of this article is to summarise the existing information on the relationship between EGCG and ferroptosis.Articles related to EGCG and ferroptosis were searched in PubMed and Web of Science databases, and the literature was analysed.EGCG could improve ferroptosis-related diseases and affect the development of ferroptosis by regulating the nuclear factor erythroid 2-related factor 2, autophagy, microRNA, signal transducer and activator of transcription 1, and protein kinase D1 signalling pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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40. The effect of iron status on gadolinium deposition in the rat brain: mechanistic implications.
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Prybylski, John P., Jastrzemski, Olivia, and Jay, Michael
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IRON in the body ,IRON overload ,GLOBUS pallidus ,IRON deficiency ,OLFACTORY bulb - Abstract
Introduction: Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure. Methods: Female Sprague-Dawley rats were given diets with controlled iron levels at 2-6 ppm, 6 ppt (20 g/kg Fe carbonyl) or 48 ppm for 3 weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10 mmol/kg dose of gadodiamide intravenously over 2 weeks, then left to washout gadodiamide for 3 days or 3 weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS. Results: There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a nonsignificant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron. Discussion: Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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41. Iron-depleting nutritional immunity controls extracellular bacterial replication in Legionella pneumophila infections.
- Author
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Torres-Escobar, Ascención, Wilkins, Ashley, Juárez-Rodríguez, María D., Circu, Magdalena, Latimer, Brian, Dragoi, Ana-Maria, and Ivanov, Stanimir S.
- Subjects
LEGIONNAIRES' disease ,LEGIONELLA pneumophila ,ALVEOLAR macrophages ,BACTERIAL proteins ,SECRETION ,IRON overload - Abstract
The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires' disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus—a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell—is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz's group unequivocally established that Legionella does not replicate extracellularly during infection—a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires' disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis. In this work, authors indicate a cooperation between nutritional immunity and interferon limits Legionella replication during infection and compromised nutritional immunity may increase severity by allowing the bacteria to replicate outside of host cells. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
42. Preliminary screening of biomarkers and drug candidates in a mouse model of β-thalassemia based on quasi-targeted metabolomics.
- Author
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Xianfeng Guo, Xuchao Zhang, Min Li, Yuanliang Peng, Zi Wang, and Jing Liu
- Subjects
MACHINE learning ,IRON overload ,BLOOD plasma ,METABOLIC disorders ,HEMOLYTIC anemia - Abstract
Background: β-thalassemia (β-TH) is a hereditary hemolytic anemia that results in deficient hemoglobin (Hb) synthesis. It is characterized by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload. Exploration new potential biomarkers and drug candidates is important to facilitate the prevention and treatment of β-TH. Methods: We applied quasi-targeted metabolomics between wild type (Wt) and heterozygous β-TH mice (Th3/+), a model of non-transfusion-dependent β-TH intermedia, in plasma and peripheral blood (PB) cells. Futher data was deeply mined by Kyoto Encyclopedia of Genomes (KEGG) and machine algorithms methods. Results: Using KEGG enrichment analysis, we found that taurine and hypotaurine metabolism disorders in plasma and alanine, aspartate and glutamate metabolism disorders in PB cells. After systematically anatomize the metabolites by machine algorithms, we confirmed that alpha-muricholic acid
UP and N-acetyl-DL-phenylalanineUP in plasma and Dl-3-hydroxynorvalineUP , O-acetyl-L-serineUP , H-abu-OHUP , S-(Methyl) glutathioneUP , sepiapterinDOWN, and imidazoleacetic acidDOWN in PB cells play key roles in predicting the occurrence of β-TH. Furthermore, Sepiapterin, Imidazoleacetic acid, Methyl alpha-Dglucopyranoside and alpha-ketoglutaric acid have a good binding capacity to hemoglobin E through molecular docking and are considered to be potential drug candidates for β-TH. Conclusion: Those results may help in identify useful molecular targets in the diagnosis and treatment of β-TH and lays a strong foundation for further research. [ABSTRACT FROM AUTHOR]- Published
- 2024
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43. Ultrasound targeted microbubble destruction assisted exosomal delivery of siHmox1 effectively inhibits doxorubicin-induced cardiomyocyte ferroptosis.
- Author
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Chen, Jianmei, Qiu, Shuo, Liu, Yang, Sun, Wenqi, Zhou, Tian, Zhao, Lianbi, Li, Zhelong, and Duan, Yunyou
- Subjects
- *
IRON overload , *EXOSOMES , *CARDIOTOXICITY , *SMALL interfering RNA , *CARDIOMYOPATHIES - Abstract
Ferroptosis, triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DOX-induced cardiomyopathy (DIC), and thus limits the use of doxorubicin (DOX) in clinic. Here, we further showed that cardiac ferroptosis induced by DOX in mice was attributed to up-regulation of Hmox1, as knockdown of Hmox1 effectively inhibited cardiomyocyte ferroptosis. To targeted delivery of siRNA into cardiomyocytes, siRNA-encapsulated exosomes were injected followed by ultrasound microbubble targeted destruction (UTMD) in the heart region. UTMD greatly facilitated exosome delivery into heart. Consistently, UTMD assisted exosomal delivery of siHomox1 nearly blocked the ferroptosis and the subsequent cardiotoxicity induced by doxorubicin. In summary, our findings reveal that the upregulation of HMOX1 induces ferroptosis in cardiomyocytes and UTMD-assisted exosomal delivery of siHmox1 can be used as a potential therapeutic strategy for DIC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. First Report of Hb Youngstown in Capillary Electrophoresis and Overlapping Hb Analysis Findings with Hb Rush.
- Author
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Poh, Kim Yan and Bee, Ping Chong
- Subjects
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CAPILLARY electrophoresis , *HIGH performance liquid chromatography , *GLOBIN genes , *IRON overload , *GLUTAMIC acid - Abstract
AbstractHb Youngstown [
HBB: c.305A > C] is a rare unstable hemoglobin caused by the substitution of glutamic acid with alanine at codon 101 of the Beta globin chain. It causes hemolytic anemia in the heterozygous state. This is a case of a six-year-old Chinese-Javanese girl with heterozygous Hb Youngstown and clinical features of chronic hemolysis and iron overload. Hb Youngstown appears at the S window near to 4.6 minutes on high-performance liquid chromatography (HPLC) and can form a hybrid tetramer on alkaline gel electrophoresis seen as two distinct bands cathodal to A and close to F. For the first time, Hb Youngstown is captured with capillary electrophoresis (CE) and shown to be eluted at zone 8. Clinical presentation and Hb analysis results of this heterozygous Hb Youngstown overlap with heterozygous Hb Rush. They can only be differentiated at molecular level by Beta globin gene sequencing or intact mass spectrometry. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
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45. Polystyrene nanoplastic exposure actives ferroptosis by oxidative stress-induced lipid peroxidation in porcine oocytes during maturation.
- Author
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He, Yijing, Yu, Tianhang, Li, Heran, Sun, Qinfeng, Chen, Miaoyu, Lin, Yiyi, Dai, Jianjun, Wang, Weihan, Li, Qiao, and Ju, Shiqiang
- Subjects
- *
POISONS , *IRON overload , *TRANSFERRIN receptors , *REACTIVE oxygen species , *PLASTICS - Abstract
Background: Polystyrene nanoplastics (PS-NPs) are becoming increasingly prevalent in the environment with great advancements in plastic products, and their potential health hazard to animals has received much attention. Several studies have reported the toxicity of PS-NPs to various tissues and cells; however, there is a paucity of information about whether PS-NPs exposure can have toxic effects on mammalian oocytes, especially livestock. Herein, porcine oocytes were used as the model to investigate the potential effects of PS-NPs on mammalian oocytes. Results: The findings showed that different concentrations of PS-NPs (0, 25, 50 and 100 μg/mL) entering into porcine oocytes could induce mitochondrial stress, including a significant decrease in mitochondrial membrane potential (MMP), and the destruction of the balance of mitochondrial dynamic and micromorphology. Furthermore, there was a marked increase in reactive oxygen species (ROS), which led to oocyte lipid peroxidation (LPO). PS-NPs exposure induced abnormal intracellular iron overload, and subsequently increased the expression of transferrin receptor (TfRC), solute carrier family 7 member 11 (SLC7a11), and acyl-CoA synthetase long-chain family member 4 (ACSL4), which resulted in ferroptosis in oocytes. PS-NPs also induced oocyte maturation failure, cytoskeletal dysfunction and DNA damage. Cotreatment with 5 μmol/L ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) alleviated the cellular toxicity associated with PS-NPs exposure during porcine oocyte maturation. Conclusions: In conclusion, PS-NPs caused ferroptosis in porcine oocytes by increasing oxidative stress and altering lipid metabolism, leading to the failure of oocyte maturation. PS-NPs could enter oocytes, caused mitochondrial dysfunction and oxidative stress, induced lipid peroxidation and ferroptosis, which eventually resulted in failure of oocyte maturation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. The predicting formula and scoring system for cardiac iron overload for thalassaemia children: Study from a middle-income country.
- Author
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Rohimi, Syarif, Siswanto, Bambang Budi, Mansyur, Muchtaruddin, Gatot, Djajadiman, Sutanto, Ina, Pandelaki, Jacub, Soesanto, Amiliana M., and Ontoseno, Teddy
- Subjects
- *
IRON overload , *TRICUSPID valve insufficiency , *MAGNETIC resonance imaging , *MIDDLE-income countries , *ODDS ratio , *DOPPLER echocardiography - Abstract
Magnetic resonance imaging T2* screening is the gold standard for detecting cardiac iron overload in thalassemia, but its implementation in Indonesia is limited by the high costs. A predicting formula and scoring system based on low-cost investigations is needed. This cross-sectional study was conducted among thalassemia aged 6–18 years at Rumah Sakit Anak dan Bunda RSAB Harapan Kita Indonesia, during October 2017 to April 2019. All subjects were scheduled for clinical examination, laboratory tests, ECGs, echocardiography, tissue Doppler imaging, and MRIT2*. Multivariate logistic regression was used to identify the formula, simplifying to a scoring system, and risk classification for myocardial iron overload using odds ratio (OR) and 95% confidence interval (CI). Significance was set as p<0,05. We recruited 80 children, of those, 8 (10%) were classified as cardiac iron overload based on MRI T2* screening. Multivariate logistic regression showed determinant factors for cardiac iron overload were hemoglobin (95% CI:1.92–369.14), reticulocyte (95% CI:1.14–232.33), mitral deceleration time (DT) (95% CI:1.80–810.62,), and tricuspid regurgitation (TR Vmax) (95% CI:1.87–1942.56) with aOR of 26.65, 14.27, 38.22, and 60.27 respectively. The formula for cardiac iron overload was decided as 9.32 + 3.28 (Hb) + 2.9 (reticulocyte) + 3.64 (DT) + 4.1 (TR Vmax). A scoring system was defined by simplifying the formula of Hb ≤ 8.2 g/L, reticulocyte ≤0.33%, DT ≤ 114.5 cm/s, and TR Vmax ≥ 2.37 m/s were given a score of 1, while others were assigned 0. Total scores of 0 or 1, 2 and 3 or 4 were categorized as low, moderate, and high risk for iron cardiac overload. The cardiac iron overload formula was 9.32 + 3.28 (Hb) + 2.9 (reticulocyte) + 3.64 (DT) + 4.1 (TR Vmax). Variables of Hb ≤ 8.2 g/L, reticulocyte ≤0.33%, DT ≤ 114.5 cm/s, and TR Vmax ≥ 2.37 m/s were given a score of 1, while others were assigned 0. Total scores of 0 or 1, 2, and 3 or 4 were categorized as low, moderate, and high risk for iron cardiac overload. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Evaluation the salivary anti-Porphyromonas gingivalis (IgA and IgG) response in relation to sera levels of Ferritin and Vitamin D in Patients with Beta-Thalassemia Major.
- Author
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abd, Shahad fayiz and Mahmood, Maha Adel
- Abstract
Beta-thalassemia major is a severe hereditary anemia that necessitates regular blood transfusions, leading to iron overload. This condition also affects various biological markers, including ferritin and vitamin D levels, and can influence immune responses and oral health. The Aim of Study To examine the relationship between salivary Porphyromonas gingivalis IgA and IgG levels with the concentrations of ferritin and vitamin D in adolescent affected by Beta-Thalassemia Major. A case-control study was conducted from November 2023 to June 2024, involving 45 beta-thalassemia major adolescents and 45 healthy controls. All subjects were within ages ranged between 12-17 years. Saliva sample was collected and analyzed for estimation of salivary anti-Porphyromonas gingivalis IgA and IgG by using ELISA and blood collected and analyzed to measures s.ferritin and s.vitamin D by Cobas E411 system. The study group exhibited significantly lower mean salivary anti-Porphyromonas gingivalis IgA and IgG levels (40.59± 16.71 pg/ml), (15.23±3.21 pg/ml) compared to the control group (93.06± 55.25pg/ml), (18.92±3.32 pg/ml) (p=0.000) respectively. Serum ferritin (4158.37±542.64 ng/ml vs. 25.11±10.93 ng/ml), and vitamin D levels (9.83±4.69 ng/ml vs. 16.40±12.93 ng/ml) showed significant differences (p<0.05) between study and control groups. Beta-thalassemia major significantly impacts salivary and serum biochemical markers, highlighting the importance of regular monitoring and potential targeted therapies to manage iron overload and associated complications. The reduced immune response against Porphyromonas gingivalis in these patients suggests a need for enhanced oral health care and possibly prophylactic measures. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
48. Iron supplementation and iron accumulation promote adipocyte thermogenesis through PGC1a-ATGL–mediated lipolysis.
- Author
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Xudong Mai, Yifan Liu, Jigang Fan, Lanling Xiao, Miaomiao Liao, Zhipeng Huang, Zijian Chen, Shaojun Huang, Rui Sun, Xiaowan Jiang, Liujing Huang, Jia Sun, Liwei Xie, and Hong Chen
- Subjects
- *
IRON in the body , *IRON supplements , *HOMEOSTASIS , *IRON overload , *OXYGEN consumption , *LIPOLYSIS , *FAT cells - Abstract
Iron homeostasis is essential for maintaining metabolic health and iron disorder has been linked to chronic metabolic diseases. Increasing thermogenic capacity in adipose tissue has been considered as a potential approach to regulate energy homeostasis. Both mitochondrial biogenesis and mitochondrial function are iron-dependent and essential for adipocyte thermogenic capacity, but the underlying relationships between iron accumulation and adipose thermogenesis is unclear. Firstly, we confirmed that iron homeostasis and the iron regulatory markers (e.g., Tfr1 and Hfe) are involved in cold-induced thermogenesis in subcutaneous adipose tissues using RNA-seq and bioinformatic analysis. Secondly, an Hfe (Hfe−/−)-deficient mouse model, in which tissues become overloaded with iron, was employed. We found iron accumulation caused by Hfe deficiency enhanced mitochondrial respiratory chain expression in subcutaneous white adipose in vivo and resulted in enhanced tissue thermogenesis with upregulation of PGC-1α and adipose triglyceride lipase, mitochondrial biogenesis and lipolysis. To investigate the thermogenic capacity in vitro, stromal vascular fraction from adipose tissues was isolated, followed with adipogenic differentiation. Primary adipocyte from Hfe−/− mice exhibited higher cellular oxygen consumption, associated with enhanced expression of mitochondrial oxidative respiratory chain protein, while primary adipocytes or stromal vascular fractions from WT mice supplemented with iron citrate) exhibited similar effect in thermogenic capacity. Taken together, these findings indicate iron supplementation and iron accumulation (Hfe deficiency) can regulate adipocyte thermogenic capacity, suggesting a potential role for iron homeostasis in adipose tissues. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. 铁死亡在多囊卵巢综合征中的研究进展.
- Author
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李轩昂, 王婷婷, 相珊, 赵帅, and 连方
- Abstract
Polycystic ovary syndrome (PCOS) is a common metabolic disorder of the reproductive system in women of adolescent and childbearing age. In addition to ovulatory dysfunction, menstrual dysfunction and infertility, most patients suffer from endocrine abnormalities such as insulin resistance (IR), hyperandrogenemia (HA) and abdominal obesity. Ferroptosis, a highly iron-dependent programmed cell death mediated by the lipid peroxidation and the imbalance in the oxidative -antioxidant system is a hot research topic in reproductive medicine. The relevance of ferroptosis in PCOS has received much attention in recent years, and recent studies suggest that ferroptosis may be involved in the regulation of PCOS -associated metabolic disorders and affect reproductive function in women with PCOS by disrupting oocyte quality and uteroplacental function. To further enrich and improve the system of diagnosis, prevention, and prognosis assessment of PCOS, we summarize the mechanisms related to ferroptosis, systematically discusses the correlation between ferroptosis and the pathophysiology of PCOS, and its research progress in the treatment of PCOS. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
50. How We Treat Hemolytic Anemia Due to Pyruvate Kinase Deficiency.
- Author
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Tama-Shekan, Sara, Moreno, Valeria, Saba, Ludovic, and Chaulagain, Chakra P.
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PYRUVATE kinase , *IRON overload , *HEMOLYTIC anemia , *FATIGUE (Physiology) , *ERYTHROCYTES - Abstract
Background: Pyruvate kinase (PK) deficiency is an inherited red blood cell (RBC) enzyme disorder that results in non-immune chronic hemolytic anemia. Characteristic symptoms of PK deficiency include anemia, fatigue, splenomegaly, jaundice, gallstones, thrombosis, and transfusional iron overload. Previously, treatments aimed at symptomatic management with RBC transfusions, phototherapy, folic acid supplementation, splenectomy, and iron chelation therapy when iron overload was documented. Mitapivat, a recently approved medication for treatment of PK-deficiency hemolytic anemia, is an oral allosteric activator of wild-type and mutant RBC PK enzymes. In this paper, we describe three cases of PK-deficiency anemia treated with mitapivat and describe modern management of this rare hemolytic disorder. Methods: A retrospective healthcare database analysis was conducted to extract relevant information. Both quantitative and qualitative methods were integrated to provide a more comprehensive understanding of the cases. Results: Two patients responded well to treatment with mitapivat, noted by an increase in hemoglobin levels, improvements in hemolytic markers, less frequent or no RBC transfusion requirements, and improvements in fatigue. One patient carrying two non-missense mutations of the PKLR gene did not respond to treatment with mitapivat. As variations in patient-specific factors (including genotype) can lead to different clinical manifestations and responses to treatment, we recommend considering both the phenotype (clinical symptoms and signs) and the genotype of the PKLR gene when making therapeutic decisions about starting a patient on mitapivat. Conclusions: While mitapivat addresses the previously unmet needs of most patients with PK deficiency as the first and only disease-modifying medication to receive approval for this condition, not all patients with PK deficiency are amenable to treatment with mitapivat. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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