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1.
World J Clin Cases ; 12(19): 3961-3970, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38994316

RESUMO

BACKGROUND: Juvenile hemochromatosis (JH) is an early-onset, rare autosomal recessive disorder of iron overload observed worldwide that leads to damage in multiple organs. Pathogenic mutations in the hemojuvelin (HJV) gene are the major cause of JH. CASE SUMMARY: A 34-year-old male Chinese patient presented with liver fibrosis, diabetes, hypogonadotropic hypogonadism, hypophysis hypothyroidism, and skin hyperpigmentation. Biochemical test revealed a markedly elevated serum ferritin level of 4329 µg/L and a transferrin saturation rate of 95.4%. Targeted exome sequencing and Sanger sequencing revealed that the proband had a novel mutation c.863G>A (p.R288Q) in the HJV gene which was transmitted from his father, and two known mutations, c.18G>C (p.Q6H) and c.962_963delGCinsAA (p.C321*) in cis, which were inherited from his mother. The p.R288W mutation was previously reported to be pathogenic for hemochromatosis, which strongly supported the pathogenicity of p.R288Q reported for the first time in this case. After 72 wk of intensive phlebotomy therapy, the patient achieved a reduction in serum ferritin to 160.5 µg/L. The patient's clinical symptoms demonstrated a notable improvement. CONCLUSION: This study highlights the importance of screening for hemochromatosis in patients with diabetes and hypogonadotropic hypogonadism. It also suggests that long-term active phlebotomy could efficiently improve the prognosis in severe JH.

2.
J Alzheimers Dis ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39031369

RESUMO

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-ß (Aß) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aß plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

3.
Chem Biol Interact ; : 111135, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38971422

RESUMO

Iron overload is a risk factor for osteoporosis due to its oxidative toxicity. Previous studies have demonstrated that an excessive amount of iron increases osteocyte apoptosis and receptor activator of nuclear factor κ-B ligand (RANKL) production, which stimulates osteoclast differentiation in vitro. However, the effects of exogenous iron supplementation-induced iron overload on osteocytes in vivo and its role in iron overload-induced bone loss are unknown. This work aimed to develop an iron overloaded murine model of C57BL/6 mice by intraperitoneal administration of iron dextran for two months. The iron levels in various organs, bone, and serum, as well as the microstructure and strength of bone, apoptosis of osteocytes, oxidative stress in bone tissue, and bone formation and resorption, were assessed. The results showed that 2 months of exogenous iron supplementation significantly increased iron levels in the liver, spleen, kidney, bone tissue, and serum. Iron overload negatively affected bone microstructure and strength. Osteocyte apoptosis and empty lacunae rate were elevated by exogenous iron. Iron overload upregulated RANKL expression but had no significant impact on osteoprotegerin (OPG) and sclerostin levels. Static and dynamic histologic analyses and serum biochemical assay showed that iron overload increased bone resorption without significantly affecting bone formation. Exogenous iron promoted oxidative stress in osteocytes in vivo and in vitro. Additional supplementation of iron chelator (deferoxamine) or N-acetyl-L-cysteine (NAC) partially alleviated bone loss, osteocyte apoptosis, osteoclast formation, and oxidative stress due to iron overload. These findings, in line with prior in vitro studies, suggest that exogenous iron supplementation induces osteoclastogenesis and osteoporosis by promoting osteocyte apoptosis and RANKL production via oxidative stress.

4.
Expert Rev Hematol ; : 1-12, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39037857

RESUMO

INTRODUCTION: Ineffective erythropoiesis and subsequent anemia as well as primary and secondary (transfusional) iron overload are key drivers for morbidity and mortality outcomes in patients with ß-thalassemia. AREAS COVERED: In this review, we highlight evidence from observational studies evaluating the association between measures of anemia and iron overload versus outcomes in both non-transfusion-dependent and transfusion-dependent forms of ß-thalassemia. EXPERT OPINION: Several prognostic thresholds have been identified with implications for patient management. These have also formed the basis for the design of novel therapy clinical trials by informing eligibility and target endpoints. Still, several data gaps persist in view of the challenge of assessing prospective long-term outcomes in a chronic disease. Pooling insights on the prognostic value of different measures of disease mechanism will be key to design future scoring systems that can help optimize patient management.

5.
Heliyon ; 10(13): e33707, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39044986

RESUMO

Background: ß-thalassemia major is microcytic hypochromic anemia disorder inherited from parents, resulting from a mutation in the ß-globin locus. As a result, a quantitative defective hemoglobin synthesis and relative excess in α-globin is occurred. As such, frequent blood transfusion is required, that leads to iron overload. Iron overload results in several pathological complications, including cell death, tissue injury, organ dysfunction, and liver fibrosis. The present study examined the effectiveness of nigella Sativa and manuka honey combination or manuka honey alone to the conventional therapy (Deferasirox + blood transfusion) used for preventing and managing iron overload in pediatric ß-thalassemia major patients. Methods: One hundred sixty-five patients participated in this randomized, double-blind, standard therapy-controlled, parallel-design multisite trial. The patients were randomly allocated into three groups, receiving either 500 mg nigella sativa oil combined with manuka honey lozenge (344 mg) daily or manuka honey alone plus the conventional therapy for ten treatment months. Ferritin level, serum iron, transferrin saturation, total iron binding capacity, alanine transaminase, and aspartate transaminase were determined at baseline and month 10. Results: Eventually, serum ferritin and iron were decreased significantly in the nigella sativa + manuka honey group as compared with the control group. Other clinical parameters were significantly impacted. The level of alanine transaminase and aspartate transaminase were significantly decreased in the nigella sativa plus manuka honey group compared with the control group. Conclusion: Results showed that nigella sativa plus manuka honey was more effective than manuka alone or the conventional treatment alone in managing iron overload of ß-thalassemia major patients.

6.
Pediatr Gastroenterol Hepatol Nutr ; 27(4): 215-223, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39035402

RESUMO

Purpose: Patients who receive frequent blood transfusions are at an elevated risk of developing hepatic fibrosis due to iron overload in the liver. In this study, we evaluated the effectiveness of transient elastography (TE) (FibroScan®) for assessing liver fibrosis in patients with pediatric cancer. Methods: We enrolled 106 consecutive cases of acute leukemia in individuals under 21 years of age. The participants were followed for 2 years. Based on their serum ferritin (SF) levels, the patients were divided into two groups: group 1 (SF≥300 ng/mL) and group 2 (SF<300 ng/mL). A liver FibroScan® was performed, and a p-value of less than 0.05 was considered statistically significant. Results: Among the various parameters in the liver function test (LFT), alkaline phosphatase was significantly higher in a subgroup of patients aged 5-8 years in group 2 compared to those in group 1. The indices of liver fibrosis determined by TE, including the FibroScan score, controlled attenuation parameter score, steatosis percentage, and meta-analysis of histological data in viral hepatitis score, as well as indirect serum markers of liver fibrosis such as the aminotransferase (AST)/alanine aminotransferase (ALT) ratio, Fibrosis 4 score, and AST to platelet ratio index, did not differ significantly between the two groups. The association between the TE results and LFT parameters was only significant for ALT. Conclusion: Transfusion-associated iron overload does not have a significant correlation with severe liver fibrosis. FibroScan® is not a sensitive tool for detecting early stages of fibrosis in survivors of pediatric leukemia.

7.
Asian J Transfus Sci ; 18(1): 73-78, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39036689

RESUMO

INTRODUCTION: Hepcidin is the key regulator of systemic iron homeostasis. In iron-loading anemias, hepcidin levels are regulated by opposite forces of erythropoiesis and iron overload. In ß-thalassemia major patients, transfusions are the predominant cause of iron overload; in such chronically transfused patients, hepcidin concentrations are significantly higher than nontransfused patients, due to both increased iron load of transfusions and the suppression of ineffective erythropoiesis. AIM: This study aims to evaluate the effect of blood transfusions on serum hepcidin levels in chronically transfused patients of ß-thalassemia major and correlate with hemoglobin and serum ferritin levels of pre- and posttransfusion. MATERIALS AND METHODS: Thirty-three ß-thalassemia major patients requiring monthly transfusions were included in the study. Blood samples, collected pretransfusion and 7 days posttransfusion, were evaluated for hemoglobin, serum ferritin, and serum hepcidin using enzyme immunoassay. STATISTICAL ANALYSIS: Data were statistically analyzed through SPSS software and P < 0.05 is considered statically significant. RESULTS: Posttransfusion levels of hemoglobin, serum ferritin, and serum hepcidin increased. Posttransfusion levels of hepcidin were near normal levels. Pre- and posttransfusion hepcidin concentrations were significantly associated with hemoglobin levels. CONCLUSION: Serum hepcidin concentrations vary depending on the degree of erythropoiesis drive and level of anemia. We found that the serum hepcidin levels decrease over the inter-transfusion interval and transfusions cause suppression of ineffective erythropoiesis by the increase in hemoglobin. Posttransfusion values of hepcidin in our study were closer to normal levels which may be due to lower erythropoietic drive posttransfusion. We suggest that the measurement of serum hepcidin in chronically transfused ß-thalassemia patients can be used as a follow-up investigation for better management of these patients.

8.
Arch Toxicol ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987487

RESUMO

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.

9.
Biomed Environ Sci ; 37(6): 617-627, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38988112

RESUMO

Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.


Assuntos
Modelos Animais de Doenças , Ferroptose , Sobrecarga de Ferro , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Dióxido de Silício , Silicose , Animais , Ferroptose/efeitos dos fármacos , Masculino , Camundongos , Sobrecarga de Ferro/metabolismo , Dióxido de Silício/toxicidade , Silicose/metabolismo , Silicose/tratamento farmacológico , Silicose/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Desferroxamina/farmacologia , Fenilenodiaminas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Ferro/metabolismo , Cicloexilaminas/farmacologia
10.
Abdom Radiol (NY) ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38990302

RESUMO

PURPOSE: To assess the feasibility and performance of MR elastography (MRE) for quantifying liver fibrosis in patients with and without hepatic iron overload. METHODS: This retrospective single-center study analyzed 139 patients who underwent liver MRI at 3 Tesla including MRE (2D spin-echo EPI sequence) and R2* mapping for liver iron content (LIC) estimation. MRE feasibility and diagnostic performance between patients with normal and elevated LIC were compared. RESULTS: Patients with elevated LIC (21%) had significantly higher MRE failure rates (24.1% vs. 3.6%, p < 0.001) compared to patients with normal LIC (79%). For those with only insignificant to mild iron overload (LIC < 5.4 mg/g; 17%), MRE failure rate did not differ significantly from patients without iron overload (8.3% vs. 3.6%, p = 0.315). R2* predicted MRE failure with fair accuracy at a threshold of R2* ≥ 269 s-1 (LIC of approximately 4.6 mg/g). MRE showed good diagnostic performance for detecting significant (≥ F2) and severe fibrosis (≥ F3) in patients without (AUC 0.835 and 0.900) and with iron overload (AUC 0.818 and 0.889) without significant difference between the cohorts (p = 0.884 and p = 0.913). For detecting cirrhosis MRE showed an excellent diagnostic performance in both groups (AUC 0.944 and 1.000, p = 0.009). CONCLUSION: Spin-echo EPI MRE at 3 Tesla is feasible in patients with mild iron overload with good to excellent performance for detecting hepatic fibrosis with a failure rate comparable to patients without iron overload.

11.
Int J Cardiol ; 413: 132319, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38971535

RESUMO

BACKGROUND: The aim of this cross-sectional study was to investigate the association of left ventricular (LV) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrhythmias) in patients with ß-thalassemia major (ß-TM). METHOD: We considered 266 ß-TM patients (134 females, 37.08 ± 11.60 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project and 80 healthy controls (50 females, mean age 39.77 ± 11.29 years). The CMR protocol included cine images for the assessment of global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) using feature tracking (FT) and for the quantification of LV function parameters, the T2* technique for the assessment of myocardial iron overload, and late gadolinium enhancement (LGE) technique. RESULTS: In comparison to the healthy control group, ß-TM patients showed impaired GLS, GCS, and GRS values. Among ß-TM patients, sex was identified as the sole independent determinant of all LV strain parameters. All LV strain parameters displayed a significant correlation with LV end-diastolic volume index, end-systolic volume index, mass index, and ejection fraction, and with the number of segments exhibiting LGE. Only GLS exhibited a significant correlation with global heart T2* values and the number of segments with T2* < 20 ms. Patients with cardiac complications exhibited significantly impaired GLS compared to those without cardiac complications. CONCLUSION: In patients with ß-TM, GLS, GCS, and GRS were impaired in comparison with control subjects. Among LV strain parameters, only GLS demonstrated a significant association with cardiac iron levels and complications.

12.
J Clin Med ; 13(13)2024 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-38999226

RESUMO

Hemochromatosis (HC) is the main genetic disorder of iron overload and is regarded as metal-related human toxicosis. HC may result from HFE and rare non-HFE gene mutations, causing hepcidin deficiency or, sporadically, hepcidin resistance. This review focuses on HFE-related HC. The illness presents a strong biochemical penetrance, but its prevalence is low. Unfortunately, the majority of patients with HC remain undiagnosed at their disease-curable stage. The main aim of HC management is to prevent iron overload in its early phase and remove excess iron from the body by phlebotomy in its late stage. Raising global awareness of HC among health staff, teaching them how not to overlook early HC manifestations, and paying attention to careful patient monitoring remain critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.

13.
Cells ; 13(13)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38994998

RESUMO

Iron is often accumulated in the liver during pathological conditions such as cirrhosis and cancer. Elevated expression of glucose transporters GLUT1 and GLUT3 is associated with reduced overall survival in patients with hepatocellular carcinoma. However, it is not known whether iron can regulate glucose transporters and contribute to tumor proliferation. In the present study, we found that treatment of human liver cell line HepG2 with ferric ammonium citrate (FAC) resulted in a significant upregulation of GLUT3 mRNA and protein in a dose-dependent manner. Similarly, iron accumulation in mice fed with high dietary iron as well as in mice injected intraperitoneally with iron dextran enhanced the GLUT3 expression drastically in the liver. We demonstrated that iron-induced hepatic GLUT3 upregulation is mediated by the LKB1/AMPK/CREB1 pathway, and this activation was reversed when treated with iron chelator deferiprone. In addition, inhibition of GLUT3 using siRNA prevented iron-mediated increase in the expression of cell cycle markers and cellular hyperproliferation. Furthermore, exogenous sodium beta-hydroxybutyrate treatment prevented iron-mediated hepatic GLUT3 activation both in vitro and in vivo. Together, these results underscore the importance of iron, AMPK, CREB1 and GLUT3 pathways in cell proliferation and highlight the therapeutic potential of sodium beta-hydroxybutyrate in hepatocellular carcinoma with high GLUT3 expression.


Assuntos
Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Transportador de Glucose Tipo 3 , Ferro , Fígado , Proliferação de Células/efeitos dos fármacos , Animais , Humanos , Transportador de Glucose Tipo 3/metabolismo , Transportador de Glucose Tipo 3/genética , Células Hep G2 , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ferro/metabolismo , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Compostos de Amônio Quaternário/farmacologia , Compostos Férricos/farmacologia , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética
14.
Med Clin (Barc) ; 2024 Jul 12.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-39003111

RESUMO

BACKGROUND: The main genetic cause of iron overload is haemochromatosis (HC). In recent years, the study of non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6) has become relevant thanks to next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) techniques. Our objectives were to estimate the prevalence of both HFE (C282Y/HY63D variants) and non-HFE variants attending a tertiary hospital in Aragón, to predict the effect of the variants on the protein, and to establish a genotype-phenotype correlation evaluating with the clinical context. METHODS: Retrospective descriptive study from 2006 to 2020 of patients attended at genetic consultation in a reference hospital for HC in Aragon. We calculated prevalence of HFE and non-HFE variants. We analysed non-HFE genes (HFE2, HJV, HAMP, TRF2, SLC40A1, and BMP6), used bioinformatics tools, consulted different databases and measured clinical parameters (laboratory and imaging). RESULTS: The prevalence of C282Y homozygous was 5.95% respect the total of cases and 0.025% respect our population. The prevalence of non-HFE HC variants was 1.94% respect the total of cases and 0.008% respect our population. We found 27 variants in non-HFE genes and 4 in HFE gene, of which 6 were classified as variant of uncertain clinical significance (VUS), or likely pathogenic or pathogenic according to the ACMG classification criteria. CONCLUSION: Our prevalence results are as expected, and similar to those obtained by other studies. Although some of the genetic findings explain the clinical symptoms of some of our patients, we remain have a high number of patients without a clear molecular diagnosis.

15.
Biomed Pharmacother ; 177: 117112, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39018869

RESUMO

Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues.

16.
Genet Test Mol Biomarkers ; 28(7): 289-296, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38980801

RESUMO

Introduction: The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as "suspected cases of HH," to a diagnostic laboratory in Iran over a 12-year period. Materials and Methods: From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of HFE exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the HFE, TFR2, and FPN1(SLC40A1) genes and 733 cases were screened using this method. Results: From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for HFE:C282Y and five homozygotes for TFR2:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other HFE variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). Conclusion: This study showed that the spectrum of genetic variants of HH in the Iranian population includes HFE and TFR2 variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue.


Assuntos
Testes Genéticos , Proteína da Hemocromatose , Hemocromatose , Receptores da Transferrina , Humanos , Hemocromatose/genética , Hemocromatose/diagnóstico , Irã (Geográfico)/epidemiologia , Proteína da Hemocromatose/genética , Masculino , Feminino , Testes Genéticos/métodos , Adulto , Pessoa de Meia-Idade , Receptores da Transferrina/genética , Homozigoto , Idoso , Éxons/genética , Genótipo , Antígenos de Histocompatibilidade Classe I/genética , Mutação , Proteínas de Transporte de Cátions
17.
JBMR Plus ; 8(8): ziae064, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38957399

RESUMO

Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents-particularly maltoses-of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.

18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(3): 449-457, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-38953270

RESUMO

Long-term treatment of anemia involving frequent blood transfusions and intravenous iron administration increases the risks of hepatic iron overload and steatosis in the patients undergoing hemodialysis.Pathological accumulation of iron damages hepatocytes,not only elevating the risks of progressive hepatic fibrosis and cirrhosis but also potentially accelerating the process of hepatic steatosis.Iron overload and steatosis may interact with each other,exacerbating liver damage and ultimately leading to further deterioration of hepatic fibrosis and cirrhosis.MRI characterized by non-invasiveness and high repeatability,enables the simultaneous quantitative assessment of hepatic iron and fat content,providing crucial information for early diagnosis and intervention of liver diseases.In recent years,researchers have achieved significant advances in the application of MRI in the diagnosis and treatment of liver diseases.MRI can accurately reflect the extent of hepatic iron overload and steatosis in patients and predict the risk of liver diseases.This article reviews the latest advances,challenges,and perspectives in the application of MRI in assessing hepatic iron overload and steatosis in the patients undergoing hemodialysis,aiming to offer valuable references for clinical practice.


Assuntos
Fígado Gorduroso , Sobrecarga de Ferro , Imageamento por Ressonância Magnética , Diálise Renal , Humanos , Sobrecarga de Ferro/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/metabolismo , Fígado/diagnóstico por imagem , Fígado/metabolismo , Fígado/patologia
19.
Inflammation ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954261

RESUMO

Peroxiredoxin 6 (PRDX6) has a protective effect on pulmonary epithelial cells against cigarette smoke (CS)-induced ferroptosis. This study investigates the role of PRDX6 in the development of chronic obstructive pulmonary disease (COPD) and its possibility as a target. We observed that PRDX6 was downregulated in lung tissues of COPD patients and in CS-stimulated cells. The degradation of PRDX6 could be through the lysosomal pathway. PRDX6 deficiency exacerbated pulmonary inflammation and mucus hypersecretion in vivo. Overexpression of PRDX6 in Beas-2B cells ameliorated CS-induced cell death and inflammation, suggesting its protective role against CS-induced damage. Furthermore, PRDX6 deficiency promoted ferroptosis by adding the content of iron and reactive oxygen species, while iron chelation with deferoxamine mitigated CS-induced ferroptosis, cell death, and inflammatory infiltration both in vitro and in vivo. The critical role of PRDX6 in regulating ferroptosis suggests that targeting PRDX6 or iron metabolism may represent a promising strategy for COPD treatment.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38961821

RESUMO

Alzheimer's Disease (AD) is the 5th leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.

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