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1.
J Int Med Res ; 52(3): 3000605241232920, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38518199

RESUMO

OBJECTIVE: This study was performed to examine the possible association of iron overload with infectious complications and survival among liver transplant recipients. METHODS: We conducted a systematic review and meta-analysis of studies published in the PubMed, Embase, Web of Science, and Cochrane Library databases up to September 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted to estimate the association of iron overload with infectious outcomes and overall survival after liver transplantation. RESULTS: Eight studies involving 2817 recipients met the inclusion criteria. Iron overload was strongly associated with an increased risk of infection after liver transplantation (HR, 1.66; 95% CI, 1.03-2.68). An increase in the serum ferritin level was associated with an increased risk of infection after liver transplantation (HR, 1.44; 95% CI, 1.09-1.91). Iron overload was a significant predictor of worse overall survival (HR, 1.35; 95% CI, 1.11-1.64). In addition, a high serum ferritin level was significantly associated with an increased risk of death (HR, 1.34; 95% CI, 1.10-1.64). CONCLUSION: Iron overload may be associated with a higher risk of infectious complications and a worse prognosis among liver transplant recipients.


Assuntos
Sobrecarga de Ferro , Transplante de Fígado , Humanos , Ferro/metabolismo , Transplante de Fígado/efeitos adversos , Sobrecarga de Ferro/complicações , Prognóstico , Ferritinas
2.
Medicine (Baltimore) ; 103(11): e37421, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489713

RESUMO

BACKGROUND: Endometriosis (EMT) a common gynecological condition in women, an inflammatory disease characterized by the presence of endometrial tissue on organs and tissues in the pelvis, and is mainly associated with chronic pelvic pain and infertility. As the etiology has not been fully elucidated, current treatment is limited to surgery, hormones and painkillers, with more side effects and difficulty in achieving long-term relief. Oxidative stress manifests itself as an overproduction of reactive oxygen species, which has an integral impact in the pathology of female reproductive disorders. In this review, we evaluate the mechanisms of iron overload-induced oxidative stress and ferroptosis in EMT and their pathophysiological implications. METHODS: Because the etiology has not been fully elucidated, current treatments are limited to surgery, hormones, and painkillers, which have many side effects and are difficult to achieve long-term relief. RESULTS: We interpreted that antioxidants as well as ferroptosis inducers show promising results in the treatment of EMT, but their application in this population needs to be further investigated. CONCLUSION: In combination with the interpretation of previous studies, it was shown that iron overload is present in the peritoneal fluid, endometriotic lesions, peritoneum and macrophages in the abdominal cavity. However, the programmed cellular ferroptosis associated with iron overload is resisted by endometriotic foci, which is critical to the pathophysiology of EMT with local iron overload and inflammation.


Assuntos
Endometriose , Ferroptose , Sobrecarga de Ferro , Feminino , Humanos , Endometriose/patologia , Estresse Oxidativo/fisiologia , Sobrecarga de Ferro/complicações , Hormônios
3.
Toxicology ; 504: 153766, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38432408

RESUMO

Blood transfusion-requiring diseases such as sickle cell anemia and thalassemia are characterized by an imbalance between iron intake and excretion, resulting in an iron overload (IOL) disorder. Hepatotoxicity is prevalent under the IOL disorder because of the associated hepatocellular redox and inflammatory perturbation. The current work was devoted to investigate the potential protection against the IOL-associated hepatotoxicity using chrysin, a naturally-occurring flavone. IOL model was created in male Wistar rats by intraperitoneal injection of 100 mg/kg elemental iron subdivided on five equal injections; one injection was applied every other day over ten days. Chrysin was administered in a daily dose of 50 mg/kg over the ten-day iron treatment period. On day eleven, blood and liver samples were collected and subjected to histopathological, biochemical, and molecular investigations. Chrysin suppressed the IOL-induced hepatocellular damage as revealed by decreased serum activity of the intracellular liver enzymes and improved liver histological picture. Oxidative damage biomarkers, and pro-inflammatory cytokines were significantly suppressed. Mechanistically, the levels of the redox and inflammation-controlling proteins SIRT1 and PPARγ were efficiently up-regulated. The liver iron load, NLRP3 inflammasome activation, and NF-κB acetylation and nuclear shift were significantly suppressed in the iron-intoxicated rats. Equally important, the level of the antioxidant protein Nrf2 and its target HO-1 were up-regulated. In addition, chrysin significantly ameliorated the IOL-induced apoptosis as indicated by reduction in caspase-3 activity and modulation of BAX and Bcl2 protein abundance. Together, these findings highlight the alleviating activity of chrysin against the IOL-associated hepatotoxicity and shed light on the role of SIRT1, NLRP3 inflammasome, and Nrf2 signaling as potential contributing molecular mechanisms.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Flavonoides , Inflamassomos , Fator 2 Relacionado a NF-E2 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos Wistar , Transdução de Sinais , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Masculino , Flavonoides/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transdução de Sinais/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Ratos , Ferro/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/complicações
4.
Cell Biochem Funct ; 42(2): e3958, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38396357

RESUMO

Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.


Assuntos
Acetilcisteína , Sobrecarga de Ferro , Oligopeptídeos , Animais , Masculino , Ratos , Acetilcisteína/farmacologia , Acetilcisteína/metabolismo , Caspases/metabolismo , Claudinas/genética , Giro Denteado/metabolismo , Giro Denteado/patologia , Dextranos/metabolismo , Dextranos/farmacologia , Regulação para Baixo , Glutationa/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Ferro/metabolismo , Ferro/farmacologia , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/farmacologia , Nestina/genética , Nestina/metabolismo , Nestina/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-1/farmacologia , Regulação para Cima , Oligopeptídeos/farmacologia , Heme Oxigenase-1/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo
5.
Toxicol Appl Pharmacol ; 484: 116845, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38331104

RESUMO

Liver fibrosis could progress to liver cirrhosis with several contributing factors, one being iron overload which triggers ferroptosis, a form of regulated cell death. Rifaximin, a non-absorbable antibiotic, has shown promise in mitigating fibrosis, primarily by modulating gut microbiota. This study investigated the effects and mechanisms of rifaximin on iron overload-related hepatic fibrosis and ferroptosis. In an iron overload-induced liver fibrosis model in mice and in ferric ammonium citrate (FAC)-stimulated primary hepatocytes, treatment with rifaximin showed significant therapeutic effects. Specifically, it ameliorated the processes of ferroptosis triggered by iron overload, reduced liver injury, and alleviated fibrosis. This was demonstrated by decreased iron accumulation in the liver, improved liver function, and reduced fibrotic area and collagen deposition. Rifaximin also modulated key proteins related to iron homeostasis and ferroptosis, including reduced expression of TFR1, a protein facilitating cellular iron uptake, and increased expression of Fpn and FTH, proteins involved in iron export and storage. In the context of oxidative stress, rifaximin treatment led to a decrease in lipid peroxidation, evidenced by reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and an increase in the reduced glutathione (GSH) and decrease in oxidized glutathione (GSSG). Notably, rifaximin's potential functions were associated with the TGF-ß pathway, evidenced by suppressed Tgfb1 protein levels and ratios of phosphorylated to total Smad2 and Smad3, whereas increased Smad7 phosphorylation. These findings indicate rifaximin's therapeutic potential in managing liver fibrosis by modulating the TGF-ß pathway and reducing iron overload-induced damage. Further research is required to confirm these results and explore their clinical implications.


Assuntos
Ferroptose , Sobrecarga de Ferro , Animais , Camundongos , Rifaximina/efeitos adversos , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Cirrose Hepática/metabolismo , Ferro/metabolismo , Fator de Crescimento Transformador beta
6.
Biochim Biophys Acta Mol Basis Dis ; 1870(4): 167058, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38331112

RESUMO

INTRODUCTION: Excess iron contributes to Hemophilic Arthropathy (HA) development. Divalent metal transporter 1 (DMT1) delivers iron into the cytoplasm, thus regulating iron homeostasis. OBJECTIVES: We aimed to investigate whether DMT1-mediated iron homeostasis is involved in bleeding-induced cartilage degeneration and the molecular mechanisms underlying iron overload-induced chondrocyte damage. METHODS: This study established an in vivo HA model by puncturing knee joints of coagulation factor VIII gene knockout mice with a needle, and mimicked iron overload conditions in vitro by treatment of Ferric ammonium citrate (FAC). RESULTS: We demonstrated that blood exposure caused iron overload and cartilage degeneration, as well as elevated expression of DMT1. Furthermore, DMT1 silencing alleviated blood-induced iron overload and cartilage degeneration. In hemophilic mice, articular cartilage degeneration was also suppressed by intro-articularly injection of DMT1 adeno-associated virus 9 (AAV9). Mechanistically, RNA-sequencing analysis indicated the association between iron overload and cGAS-STING pathway. Further, iron overload triggered mtDNA-cGAS-STING pathway activation, which could be effectively mitigated by DMT1 silencing. Additionally, we discovered that RU.521, a potent Cyclic GMP-AMP Synthase (cGAS) inhibitor, successfully suppressed the downward cascades of cGAS-STING, thereby protecting against chondrocyte damage. CONCLUSION: Taken together, DMT1-mediated iron overload promotes chondrocyte damage and murine HA development, and targeted DMT1 may provide therapeutic and preventive approaches in HA.


Assuntos
Sobrecarga de Ferro , Artropatias , Animais , Camundongos , Cartilagem , DNA Mitocondrial/genética , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Camundongos Knockout , Nucleotidiltransferases/metabolismo
7.
Sci Rep ; 14(1): 4887, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418857

RESUMO

Iron is an essential nutrient for all living organisms. Both iron deficiency and excess can be harmful. Bone, a highly metabolic active organ, is particularly sensitive to fluctuations in iron levels. In this study, we investigated the effects of dietary iron overload on bone homeostasis with a specific focus on two frequently utilized mouse strains: 129/Sv and C57BL/6J. Our findings revealed that after 6 weeks on an iron-rich diet, 129/Sv mice exhibited a decrease in trabecular and cortical bone density in both vertebral and femoral bones, which was linked to reduced bone turnover. In contrast, there was no evidence of bone changes associated with iron overload in age-matched C57BL/6J mice. Interestingly, 129/Sv mice exposed to an iron-rich diet during their prenatal development were protected from iron-induced bone loss, suggesting the presence of potential adaptive mechanisms. Overall, our study underscores the critical role of genetic background in modulating the effects of iron overload on bone health. This should be considered when studying effects of iron on bone.


Assuntos
Sobrecarga de Ferro , Ferro da Dieta , Gravidez , Feminino , Camundongos , Animais , Camundongos Endogâmicos C57BL , Osso e Ossos , Camundongos Endogâmicos , Sobrecarga de Ferro/complicações , Ferro
8.
BMJ Case Rep ; 17(2)2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38367998

RESUMO

This is the case of a gravida 3 para 1 woman in her late 20s with underlying haemoglobin constant spring who visited a healthcare clinic for an antenatal check-up. Towards the end of her second trimester, she experienced lethargy. During her antenatal booking, she was diagnosed with mild asymptomatic anaemia, high serum ferritin, T saturation of 88% and abnormal liver function tests. She was referred to a hospital where an MRI scan revealed over 2 g of iron deposits in her liver, leading to a revised diagnosis of iron overload. Treatment included deferoxamine and expectant management throughout her antenatal period, and her delivery was uncomplicated. While iron deficiency anaemia is common in pregnancy, it is crucial not to overlook iron deposition and the distinction from acute fatty liver during pregnancy to prevent treatment delays.


Assuntos
Anemia Ferropriva , Anemia , Hemoglobinas Anormais , Sobrecarga de Ferro , Complicações Hematológicas na Gravidez , Feminino , Gravidez , Humanos , Mães , Anemia/etiologia , Ferro/uso terapêutico , Anemia Ferropriva/complicações , Anemia Ferropriva/diagnóstico , Complicações Hematológicas na Gravidez/diagnóstico , Sobrecarga de Ferro/complicações , Atenção Primária à Saúde
9.
Rev Invest Clin ; 76(1): 18-28, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38262366

RESUMO

Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.


Assuntos
Hemocromatose , Sobrecarga de Ferro , Hepatopatias , Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Hemocromatose/complicações , Hemocromatose/epidemiologia , Hemocromatose/patologia , Estudos Retrospectivos , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/complicações , Hepatopatias/complicações , Hepatopatias/metabolismo , Hepatopatias/patologia , Fígado/metabolismo
10.
Mol Nutr Food Res ; 68(4): e2300123, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38196088

RESUMO

SCOPE: Age-related increases in retinal iron are involved in the development of retinal degeneration. The recently discovered iron-dependent mechanism of cell death known as ferroptosis has been linked to a wide range of pathologies. However, its role in iron overload-induced retinal degeneration is still uncertain. Puerarin has been associated with retinal protection. The purpose of this research is to determine how puerarin prevents retinal ferroptosis under iron overload conditions. METHODS AND RESULTS: Models of iron overload in Kunming mice, 661W cell, and ARPE-19 cell are established. Increased iron deposition significantly worsens retinal pathology, decreases cell viability, and induces ferroptotic changes. Puerarin mitigates iron overload-induced ferroptosis by decreasing excessive iron through the regulation of iron handling proteins and lowering lipid peroxidation through the inhibition of cyclooxygenase 2 expression and activation of the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway and downstream ferroptosis-related proteins (solute carrier family 7 member 11, glutathione peroxidase 4 and heme oxygenase-1). The protective effect of puerarin on ferroptosis is diminished by the Nrf2-specific inhibitor ML385. CONCLUSION: These findings suggest targeting ferroptosis may be a novel strategy for the management of retinal degeneration. Puerarin may exert some of its ocular benefits by attenuating ferroptosis.


Assuntos
Ferroptose , Sobrecarga de Ferro , Isoflavonas , Degeneração Retiniana , Camundongos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Degeneração Retiniana/complicações , Ferroptose/fisiologia , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Retina/metabolismo , Ferro/metabolismo
11.
Liver Int ; 44(3): 838-847, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38263707

RESUMO

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.


Assuntos
Carcinoma Hepatocelular , Hemocromatose , Sobrecarga de Ferro , Neoplasias Hepáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemocromatose/epidemiologia , Hemocromatose/genética , Hemocromatose/complicações , Penetrância , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/complicações , Estudos de Coortes , Incidência , Antígenos de Histocompatibilidade Classe I/genética , Proteína da Hemocromatose/genética , Sobrecarga de Ferro/complicações , Homozigoto , Cirrose Hepática/complicações , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/complicações , Mutação
12.
Ann N Y Acad Sci ; 1532(1): 50-62, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38270933

RESUMO

Health-related quality of life (HRQOL) is a patient-reported outcome that assesses the impact of a disease or illness on different domains of a patient's life. Different general and disease-specific measures can be used to evaluate HRQOL. This article aimed to summarize the evidence for HRQOL among patients with transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT). We included HRQOL data related to standard therapy with blood transfusions, iron chelation, and/or luspatercept in TDT and NTDT, as well as curative therapies for TDT, including hematopoietic stem cell transplant (HSCT) and gene therapy. Patients with thalassemia had worse HRQOL scores compared to the general population, and chronic pain was seen to increase in frequency and severity over time with age. NTDT patients reported worse physical health and functioning, mental health, general health, and vitality than TDT patients. However, TDT patients reported worse pain, change in health, and social support than NTDT. Most therapies improved overall HRQOL among thalassemia patients. Deferasirox, an oral iron chelator, was associated with more HRQOL benefits compared to deferoxamine, an intravenous iron chelator. Luspatercept showed clinically meaningful improvement in physical functioning among TDT and NTDT. Furthermore, HSCT and gene therapy were associated with better physical, emotional, and mental domains scores.


Assuntos
Dor Crônica , Sobrecarga de Ferro , Talassemia , Humanos , Qualidade de Vida , Talassemia/terapia , Talassemia/complicações , Quelantes de Ferro/uso terapêutico , Transfusão de Sangue , Sobrecarga de Ferro/complicações
13.
Haemophilia ; 30(1): 195-203, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38058260

RESUMO

AIM: Haemophiliac arthritis (HA) is caused by spontaneous intra-articular hemorrhage and repeated intra-articular hematomas, leading to iron overload, which, in turn, induces M1 macrophage polarisation and inflammatory cytokine secretion, resulting in synovitis. Here, we explored the mechanism by which iron overload in HA induces the polarisation of M1 macrophages, providing a new approach for the treatment of HA synovitis. METHODS: The synovium from the knee joints of normal amputees and patients with HA was collected. Pathological changes in the synovial tissues were analysed using hematoxylin and eosin staining. Iron tissue deposition was evaluated using the iron assay kit and Prussia Blue staining, while macrophage phenotype was determined using immunofluorescence. The levels of pro-inflammatory cytokines and p53 acetylation were determine using western blotting. An in vitro iron overload model was established by inducing THP-1 macrophages with ferric ammonium citrate, and the involvement of acetylated p53 in M1 macrophage polarisation was investigated. RESULTS: Compared to control samples, the iron content in the synovium of patients with HA was significantly increased. The protein levels of M1 macrophage markers, pro-inflammatory cytokines, and acetylated p53, were also significantly elevated in the synovial tissues of patients with HA. Similar results were observed in the in vitro iron overload model. Furthermore, the inhibition of p53 acetylation in vitro reversed these iron overload-induced effects. CONCLUSION: In patients with HA, iron overload induced synovial p53 acetylation, leading to macrophage polarisation toward the M1 phenotype and increased inflammatory cytokine secretion, resulting in synovitis. HIGHLIGHTS: Synovial iron overload is associated with changes in P53 acetylation in hemophiliac arthritis (HA). Acetylated p53, a known regulator of macrophage polarization, is highly expressed in HA synovium, suggesting a potential role in M1 polarization. HA synovial macrophages predominantly polarize into the pro-inflammatory M1 phenotype, secreting elevated levels of pro-inflammatory cytokines.


Assuntos
Sobrecarga de Ferro , Osteoartrite , Sinovite , Humanos , Proteína Supressora de Tumor p53/metabolismo , Membrana Sinovial/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Sinovite/complicações , Osteoartrite/patologia , Fenótipo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Ferro/metabolismo , Citocinas/metabolismo
14.
Chem Biol Interact ; 388: 110827, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38081572

RESUMO

Recently, more and more studies have revealed that iron overload can lead to osteoporosis by inducing oxidative stress. Niacin (NAN), also known as nicotinate or vitamin B3, has been confirmed to possess potent antioxidative effects. In addition, very little is currently known about the protective effects of NAN on iron overload in osteoporotic bone tissue. Therefore, we aimed to evaluate the protective effect of niacin on iron overload-induced bone injury and to investigate the effect and underlying mechanisms of the niacin and iron overload on intracellular antioxidant properties. When MC3T3-E1 and RAW264.7 cells were cultured in the presence of ammonium ferric citrate(FAC), NAN therapy could increase the matrix mineralization and promote expression of osteogenic markers in MC3T3-E1, inhibit osteoclastic differentiation of RAW264.7 cells, while increasing intracellular reactive oxygen species (ROS) levels and strengthening mitochondrial membrane potential (MMP). In the ovariectomized (OVX) rat model, NAN had an obvious protective effect against iron-overloaded injury. Meanwhile, superoxide dismutase 2 (SOD2), intracellular antioxidant enzymes and silent information regulator type 1 (SIRT1), were up-regulated in response to NAN exposures in MC3T3-E1. Furthermore, SIRT1 inhibitor EX527 attenuated the protective effects of NAN. Results revealed that NAN could stimulate osteogenic differentiation, inhibit osteoclastic differentiation and markedly increased antioxidant properties in cells through the induction of SIRT1. Studies suggest that niacin is a promising agent for preventing bone loss in iron overload conditions.


Assuntos
Sobrecarga de Ferro , Niacina , Animais , Ratos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Niacina/farmacologia , Niacina/uso terapêutico , Osteogênese , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo
15.
Neurocrit Care ; 40(1): 225-236, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37208490

RESUMO

BACKGROUND: Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. METHODS: There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28. RESULTS: Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. CONCLUSIONS: AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.


Assuntos
Hidrocefalia , Sobrecarga de Ferro , Niacinamida , Tiadiazóis , Animais , Ratos , Aquaporina 4/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Hidrocefalia/etiologia , Injeções Intraventriculares , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Niacinamida/análogos & derivados , Ratos Sprague-Dawley
16.
Osteoporos Int ; 35(2): 243-253, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37857915

RESUMO

Iron is a necessary trace element in the human body, and it participates in many physiological processes. Disorders of iron metabolism can cause lesions in many tissues and organs, including bone. Recently, iron has gained attention as an independent factor influencing bone metabolism disorders, especially the involvement of iron overload in osteoporosis. The aim of this review was to summarize the findings from clinical and animal model research regarding the involvement of iron in bone metabolism disorders and to elucidate the mechanisms behind iron overload and osteoporosis. Lastly, we aimed to describe the association between bone loss and iron overload. We believe that a reduction in iron accumulation can be used as an alternative treatment to assist in the treatment of osteoporosis, to improve bone mass, and to improve the quality of life of patients.


Assuntos
Sobrecarga de Ferro , Osteoporose , Animais , Humanos , Ferro/metabolismo , Qualidade de Vida , Sobrecarga de Ferro/complicações , Osso e Ossos/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/metabolismo
17.
J Nutr Biochem ; 125: 109499, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37875229

RESUMO

Transfusional therapy is used to cure anemia but raises the risk of hepatic iron overload (IO), which triggers oxidative stress damage, inflammation, and failure even fibrosis. microRNAs play a vital role in developing hepatic diseases. This study presented the mechanism by which IO induce hepatic inflammation through microRNAs. In this study, microRNA expression profiling in the liver was observed after IO for 2 weeks, in which the target microRNA will be found. IO activating the miR-146α/TRAF6/NF-κB pathway was validated, and the molecular mechanism of the IO-induced decrease of miR-146α in the liver was studied in vivo and in vitro. The expression of TRAF6/NF-κB (p65)-dependent inflammatory factors increased, whereas the expression of miR-146α decreased during the IO-induced inflammatory response in the liver. The reduced expression of HNF4α caused by HIF1α and miR-34α may decrease the expression of miR-146α. Overexpression of miR-146α alleviated the hepatic inflammatory response caused by IO. Our findings indicate that miR-146α is a key factor in inducing hepatic IO inflammation, which will be another potential target to prevent IO-induced hepatic damage.


Assuntos
Sobrecarga de Ferro , MicroRNAs , Humanos , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/metabolismo , Transdução de Sinais , MicroRNAs/genética , MicroRNAs/metabolismo , Inflamação/prevenção & controle , Sobrecarga de Ferro/complicações
18.
Eur J Pediatr ; 183(2): 875-882, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37938353

RESUMO

Magnetic resonance imaging (MRI) T2* is the gold standard for detecting iron deposition in cardiac tissue, but the technique has limitations and cannot be fully performed in paediatric thalassemia patients. The aim of this study was to analyse clinical data to identify other predictors of cardiac iron deposition. A retrospective analysis was performed on 370 children with ß-TM. According to the cardiac MRI results, patients were allocated to a cardiac deposition group and noncardiac deposition group. Multivariate analysis revealed that genotype and corrected QT interval were associated with cardiac iron deposition, indicating that the-ß0/ß0 genotype conferred greater susceptibility to cardiac iron deposition. Receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) of genotype was 0.651. The AUC for the corrected QT interval was 0.711, at a cut-off value of 418.5 ms. ROC analysis of the combined genotype and corrected QT interval showed an AUC of 0.762 with 81.3% sensitivity and 64.7% specificity. Compared to patients with the ß+/ß+ and ß0ß+ genotypes, ß0ß0 children with ß-TM were more likely to have cardiac iron deposition.  Conclusion: The genotype and QTc interval can be used to predict cardiac iron deposition in children with ß-TM who are unable to undergo MRI T2 testing.


Assuntos
Sobrecarga de Ferro , Talassemia beta , Humanos , Criança , Talassemia beta/complicações , Talassemia beta/diagnóstico , Talassemia beta/genética , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/patologia , Estudos Retrospectivos , Curva ROC , Imageamento por Ressonância Magnética/métodos , Ferro , Miocárdio/patologia
19.
Life Sci ; 340: 122370, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38141854

RESUMO

Iron is an essential trace element for organisms. However, iron overload, which is common in haematological disorders (e.g. haemochromatosis, myelodysplastic syndromes, aplastic anaemia, and thalassaemia, blood transfusion-dependent or not), can promote reactive oxygen species generation and induce ferroptosis, a novel form of programmed cell death characterised by excess iron and lipid peroxidation, thus causing cell and tissue damage. Infertility is a global health concern. Recent evidence has indicated the emerging role of iron overload and ferroptosis in female infertility by inducing hypogonadism, causing ovary dysfunction, impairing preimplantation embryos, attenuating endometrial receptivity, and crosstalk between subfertility-related disorders, such as polycystic ovary syndrome and endometriosis. In addition, gut microbiota and their metabolites are involved in iron metabolism, ferroptosis, and female infertility. In this review, we systematically elaborate on the current research progress in female infertility with a novel focus on iron overload and ferroptosis and summarise promising therapies targeting iron overload and ferroptosis to recover fertility in women. In summary, our study provides new insights into female infertility and offers literature references for the clinical management of female infertility associated with iron overload and ferroptosis, which may be beneficial for females with haematopoietic disorders suffering from both iron overload and infertility.


Assuntos
Ferroptose , Infertilidade Feminina , Sobrecarga de Ferro , Feminino , Humanos , Sobrecarga de Ferro/complicações , Fertilidade , Ferro
20.
Mol Hum Reprod ; 30(1)2023 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-38113413

RESUMO

Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.


Assuntos
Endometriose , Ferroptose , Sobrecarga de Ferro , Feminino , Animais , Camundongos , Humanos , Fator 4 Ativador da Transcrição/metabolismo , Endometriose/metabolismo , Ferroptose/genética , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Ferro/metabolismo , Autofagia/genética , Células Estromais/metabolismo
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