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1.
J Gastrointest Surg ; 28(2): 108-114, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38445931

RESUMO

BACKGROUND: Occult cystobiliary fistula (CBF) is a common complication of hepatic hydatid cyst (HHC). It is often the cause of high morbidity of conservative treatment of HHC. This study aimed to determine the predictive factors of occult CBF to establish the indications for the investigation and treatment of these CBFs. METHODS: This was a prospective study that included all operated HHCs over a 3-year period. HHCs complicated with large CBFs were not included in the study. Systematic cholecystectomy and methylene blue test for all cysts were performed. RESULTS: A total of 46 patients operated on with 113 cysts were included in this study. The median cyst size was 6.7 cm (IQR, 1-38). A total of 114 CBFs were detected in 51 cysts (45.1%). The postoperative course was simple in 95.0% of cases. The specific morbidity rate was 2.7%. In a bivariate study, absence of mass and abdominal pain on palpation, hemoglobin level >11.55 g/dL, negative hydatid serology, cyst size, absence of calcifications, vascular compression, existence of a single cyst, and localization at segment VIII were predictive factors of occult CBF. At the end of the multivariate study, cyst size was determined to be the only predictive factor for occult CBF. A threshold of 3 cm was used. CONCLUSION: Cyst size is a major predictive factor for occult CBF.


Assuntos
Catarata/congênito , Cistos , Equinococose Hepática , Fístula , Distúrbios do Metabolismo do Ferro/congênito , Humanos , Tratamento Conservador , Estudos Prospectivos , Equinococose Hepática/complicações , Equinococose Hepática/cirurgia
2.
Commun Biol ; 7(1): 140, 2024 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291108

RESUMO

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.


Assuntos
Ceruloplasmina , Distúrbios do Metabolismo do Ferro , Doenças Neurodegenerativas , Proteoma , Adulto , Humanos , Animais , Camundongos , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Proteoma/metabolismo , Doenças Raras , Resíduos Industriais
3.
Mov Disord Clin Pract ; 11(1): 53-62, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38291840

RESUMO

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.


Assuntos
Hemocromatose , Distúrbios do Metabolismo do Ferro , Doenças Neurodegenerativas , Neurodegeneração Associada a Pantotenato-Quinase , Transtornos Parkinsonianos , Humanos , Feminino , Encéfalo , Espasticidade Muscular , Caminhada , Ferro
6.
Int J Mol Sci ; 24(15)2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37569253

RESUMO

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.


Assuntos
Catarata , Hiperferritinemia , Distúrbios do Metabolismo do Ferro , Humanos , Brasil , Linhagem , Distúrbios do Metabolismo do Ferro/patologia , Catarata/patologia , Mutação
7.
J Trace Elem Med Biol ; 79: 127259, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37413927

RESUMO

AIM: Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) improved iron metabolism disorder in obese rats through the downregulation of hepcidin. This study aimed to observe the molecular mechanism of CIHH in improving iron metabolism disorders, especially by Janus kinase/signal transducer and activation of the transcription (JAK/STAT) signaling pathway in metabolic syndrome (MS) rats. METHODS: Six-week-old male Sprague-Dawley rats were randomly divided into four groups: CON, CIHH (subjected to hypobaric hypoxia simulating 5000-m altitude for 28 days, 6 h daily), MS (induced by high fat diet and fructose water), and MS+CIHH. The serum levels of glucose, lipid metabolism, iron metabolism, interleukin-6 (IL-6), erythropoietin (Epo) and hepcidin were measured. The protein expressions of JAK2, STAT3, STAT5, bone morphogenetic protein 6 (BMP6), small mothers against decapentaplegic 1 (SMAD1) and hepcidin were examined. The mRNA expressions of erythroferrone (ERFE) and hepcidin were analyzed. RESULTS: The MS rats displayed obesity, hyperglycemia, hyperlipidemia, iron metabolism disorder, increased IL-6 and hepcidin serum levels, upregulation of JAK2/STAT3 signaling pathway, decreased Epo serum levels, downregulation of STAT5/ERFE signaling pathway in spleen, upregulation of BMP/SMAD signaling pathway in liver, and increased hepcidin mRNA and protein expression compared to CON rats. All the aforementioned abnormalities in MS rats were ameliorated in MS + CIHH rats. CONCLUSIONS: CIHH improved iron metabolism disorders, possibly by inhibiting IL-6/JAK2/STAT3 and activating Epo/STAT5/ERFE signaling pathway, thus downregulating hepcidin in MS rats.


Assuntos
Distúrbios do Metabolismo do Ferro , Síndrome Metabólica , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Interleucina-6/metabolismo , Hepcidinas/metabolismo , Fator de Transcrição STAT5/metabolismo , Hipóxia , Transdução de Sinais , RNA Mensageiro
8.
Front Immunol ; 14: 1100725, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37304284

RESUMO

Background: We explored the prognostic and immunogenic characteristics of iron pendant disease regulators in colon cancer to provide a scientific basis for the prediction of tumor prognosis-related markers and potential immunotherapeutic drug targets. Methods: RNA sequencing and matched complete clinical information of colon cancer (COAD) were retrieved from the UCSC Xena database, and genomic and transcriptomic data of colon cancer from the TCGA database were downloaded. Then univariate and multifactorial Cox regression were used to process these data. The prognostic factors were analyzed by single-factor and multi-factor Cox regression, followed by Kaplan-Meier survival curves with the aid of R software "survival" package. Then we use FireBrowse online analysis tool to analyze the expression variation of all cancer genes, and draw a histogram according to the influencing factors to predict the 1, 3, and 5 year survival rates of patients. Results: The results show that age, tumor stage and iron death score were significantly correlated with prognosis (p<0.05). Further multivariate cox regression analysis confirmed that age, tumor stage and iron death score were still significantly correlated with prognosis (p<0.05); The calibration curve results show that the deviation between the predicted values of 1 year, 3 years and 5 years and the diagonal of the figure is very small; the ROC curve results show that the AUC values of the 1-year and 5-year ROC curves of the bar graph are high; the DCA curve results show that the net yield of the bar graph is the largest; The scores of T cells and B cells in the high iron death score group were significantly lower than those in the low iron death score group, and the activities of immune related pathways were significantly reduced. There was a significant difference in the iron death score between the iron death molecular subtype and the gene cluster subtype. Conclusions: The model showed a superior response to immunotherapy in the high-risk group, revealing a potential relationship between iron death and tumor immunotherapy, which will provide new ideas for the treatment and prognostic assessment of colon cancer patients.


Assuntos
Neoplasias do Colo , Distúrbios do Metabolismo do Ferro , Humanos , Prognóstico , Ferro , Oncogenes , Neoplasias do Colo/genética , Biomarcadores Tumorais/genética
9.
PLoS One ; 18(6): e0282218, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37347744

RESUMO

Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters.


Assuntos
Anemia Ferropriva , Anemia , Distúrbios do Metabolismo do Ferro , Paracoccidioidomicose , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Ferro/metabolismo , Ferritinas , Anemia/tratamento farmacológico , Hemoglobinas/metabolismo , Receptores da Transferrina , Distúrbios do Metabolismo do Ferro/tratamento farmacológico
10.
Small Methods ; 7(9): e2300183, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37291735

RESUMO

ESX-3 is a secretion pathway which is essential for mycobactin-mediated iron acquisition under iron-limited conditions. Although present in all Mycobacterium sp., ESX-3 remains to be elucidated in Mycobacterium abscessus. In the study reported here, impaired ESX-3 seriously restricts the growth of M. abscesses under iron-limited conditions; growth is salvaged by functional ESX-3 or iron supplementation. Notably, impaired ESX-3 does not kill M. abscesses when environmental iron is insufficient but induces persistence to bedaquiline, a diarylquinoline class antibiotic used to treat multidrug-resistant mycobacteria. One potential mechanism contributing to persistence is the iron deficiency due to impaired ESX-3 suppressing succinate dehydrogenase activity, which dysregulates the tricarboxylic acid cycle and inactivates bedaquiline. Experiments conducted here also demonstrate that the regulator, MtrA, can bind ESX-3 and promote the survival of M. abscessus. As such, this study suggests that a novel pathway involving MtrA, ESX-3, iron metabolism, and the TCA cycle contributes to bedaquiline persistence in M. abscesses growing under iron-limited conditions.


Assuntos
Distúrbios do Metabolismo do Ferro , Mycobacterium abscessus , Mycobacterium , Humanos , Mycobacterium abscessus/metabolismo , Diarilquinolinas/farmacologia , Diarilquinolinas/metabolismo , Abscesso , Mycobacterium/metabolismo , Ferro/farmacologia
11.
J Ethnopharmacol ; 313: 116559, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37116730

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri grandis (ECG, Huajuhong in Chinese), the epicarp of C. grandis 'Tomentosa', has been used for hundreds of years as an anti-inflammatory, expectorant, hypoglycemic, and lipid-lowering medication in China. Nevertheless, there have been few papers that have explored the mechanism behind ECG's hypolipidemic characteristics from the perspective of treating nonalcoholic fatty liver disease (NAFLD). AIM OF STUDY: The purpose of our study was to confirm the therapeutic and preventative effects of ECG in NAFLD by regulating lipid accumulation and iron metabolism, and to explore the specific mechanism of ECG in enhancing hepatic iron transport and excretion capabilities. STUDY DESIGN: We constructed a NAFLD model by feeding male C57BL/6 J mice with a high-fat diet for 12 weeks. Mice were gavaged with ECG beginning in the seventh week of modeling, and three dosage gradients were established: low dose group (2.5 g/kg/d), medium dose group (5 g/kg/d) y, and high dose group (10 g/kg/d) until the end of model construction in week 12. MATERIALS AND METHODS: We used network pharmacology to analyze the relationship between ECG and NAFLD. In addition, we constructed a nonalcoholic fatty liver disease model by feeding male C57BL/6 J mice a high-fat diet for 12 weeks. Finally, lipid accumulation, iron accumulation, inflammation and oxidative stress were evaluated by serological index detection, histological detection, immunofluorescent and immunohistochemical staining, and western blotting. RESULTS: Network pharmacology confirmed the treatment effect of ECG in NAFLD. Three active components of ECG, including Naringenin, Naringin and Neohesperidin, were detected by UHPLC-HRMS analysis. The results of serum TC, TG, LDL concentration, HE staining, Oil red staining and Nile red staining demonstrated that ECG could improve lipid metabolism disorders. The results of serum iron concentration, liver tissue iron concentration, iron metabolism-related proteins Ferritin light chain, Ferroportin1, Transferrin receptor, and Transferrin demonstrated that ECG improved the iron transport and storage capacities of hepatic cells. CONCLUSIONS: Our results demonstrated that ECG relieved liver injury by inhibiting lipid accumulation and iron accumulation in NAFLD.


Assuntos
Distúrbios do Metabolismo do Ferro , Hepatopatia Gordurosa não Alcoólica , Camundongos , Masculino , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/patologia , Ferro/metabolismo , Lipídeos/farmacologia , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos
12.
Am J Med Genet A ; 191(5): 1384-1387, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36750760

RESUMO

Beta-propeller protein-associated neurodegeneration (BPAN), a subgroup of neurodegeneration with brain iron accumulation, is typically characterized by non-progressive global developmental delay and seizures in childhood, followed by progressive neurological decline with parkinsonism and dementia in adolescence or early adulthood. It is difficult to clinically identify a patient with BPAN in childhood. Recent studies reported that serum levels of neuron-specific enolase (NSE) were elevated in children with BPAN. We reviewed the time course of serum NSE levels in a 21-year-old female patient genetically diagnosed (a de novo WDR45 variant c.268A > T) with BPAN, which was suspected based on prolonged elevation of serum NSE. There was an overall tendency for serum NSE levels to decrease in a stepwise fashion. The peak serum NSE level was observed during the first 2 years of age and then decreased rapidly in 1 year. High serum NSE levels persisted between 3 and 11 years of age. Subsequently, serum NSE levels decreased and plateaued after 13 years of age. There were tendencies for both blood AST and LDH levels to decrease over time in parallel with serum NSE levels. Serum NSE levels may be a diagnostic biomarker of BPAN in children but becomes of less value in identifying a patient with BPAN after childhood.


Assuntos
Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Criança , Adolescente , Humanos , Feminino , Lactente , Adulto , Adulto Jovem , Proteínas de Transporte , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Fosfopiruvato Hidratase/genética , Convulsões
14.
Biometals ; 36(3): 391-416, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36214975

RESUMO

Iron is by far the most widespread and essential transition metal, possessing crucial biological functions for living systems. Despite chemical advantages, iron biology has forced organisms to face with some issues: ferric iron insolubility and ferrous-driven formation of toxic radicals. For these reasons, acquisition and transport of iron constitutes a formidable challenge for cells and organisms, which need to maintain adequate iron concentrations within a narrow range, allowing biological processes without triggering toxic effects. Higher organisms have evolved extracellular carrier proteins to acquire, transport and manage iron. In recent years, a renewed interest in iron biology has highlighted the role of iron-proteins dysregulation in the onset and/or exacerbation of different pathological conditions. However, to date, no resolutive therapy for iron disorders has been found. In this review, we outline the efficacy of Lactoferrin, a member of the transferrin family mainly secreted by exocrine glands and neutrophils, as a new emerging orchestrator of iron metabolism and homeostasis, able to counteract iron disorders associated to different pathologies, including iron deficiency and anemia of inflammation in blood, Parkinson and Alzheimer diseases in the brain and cystic fibrosis in the lung.


Assuntos
Anemia , Distúrbios do Metabolismo do Ferro , Humanos , Lactoferrina/química , Ferro/metabolismo , Transferrina/metabolismo , Homeostase
16.
Zhen Ci Yan Jiu ; 47(12): 1073-9, 2022 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-36571222

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Weizhong" (BL40) on the disorder of iron metabolism and the level of oxidative stress after lumbar multifidus muscle injury (LMMI), so as to explore its mechanisms underlying promoting the repair of LMMI. METHODS: Male SD rats were randomly divided into normal, model and EA groups (6 rats in each group). The LMMI model was established by injecting 0.5% bupivacaine (BPVC) solution (400 µL) into the lumbar multifidus muscle with the syringe-needle close to the spinous process (L4-L5). Twenty-four hours after successful establishment of the model, EA (2 Hz/15 Hz, 2 mA) was applied to bilateral BL40 for 30 min, once a day for 2 days. Histopathological changes of the multifid muscle were observed under microscope after H.E. staining, and the iron granules in the multifid muscle tissue observed after Prussian blue staining. The expression of glutathione synthase (GSS) was detected by Western blot, and the expressions of iron regulatory protein 1 (IRP1), ferroportin (Fpn), ferritin heavy chain 1 (FTH1, iron metabolism-related proteins) and gluta-thione peroxidase 4 (GPX4, functions in protecting cells against detrimental lipid peroxidation and governing a novel form of regulated necrotic cell death, called ferroptosis) mRNAs were detected by quantitative real-time PCR. The contents of glutathione (GSH) and malondialdehyde (MDA) were measured by biochemical methods. RESULTS: H.E. staining showed large areas of necrosis and breakage of muscle fibers, disordered arrangement of muscle fibers, widened muscle cell space, accompanying with a large number of inflammatory cell infiltration in the multifidus muscle tissue of the model group, which was relatively milder in the EA group. Outcomes of Prussian blue staining showed that compared with the normal group, there were more iron particles in the multifidus muscle tissue and enlarged muscle fiber gaps, which was also milder in the EA group. Compared with the normal group, the expression level of IRP1 mRNA and content of MDA were significantly increased (P<0.001), the expression levels of Fpn, FTH1 and GPX4 mRNAs and GSS protein, and the content of GSH were considerably decreased (P<0.001) in the model group. In comparison with the model group, the increase of IRP1 mRNA expression and MDA content, as well as the decrease of Fpn, FTH1 and GPX4 mRNAs expressions and GSH content were reversed in the EA group (P<0.001,P<0.05,P<0.01). CONCLUSION: EA of BL40 has a protect effect in BPVC-induced injury of lumbar multifidus muscle in rats, which may be related to its functions in improving iron metabolism to reduce oxidative damage by regulating expression of IRP1, Fpn and FTH1.


Assuntos
Eletroacupuntura , Distúrbios do Metabolismo do Ferro , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Músculos Paraespinais , Músculos/lesões , Bupivacaína , Ferro
17.
Mov Disord ; 37(9): 1948-1952, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35996824

RESUMO

BACKGROUND: Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders. No treatment is currently available. OBJECTIVE: We assessed conservative iron chelation with deferiprone at 30 mg/kg/day on the disease progression with controlled periods of discontinuation. METHODS: Four patients with confirmed molecular diagnosis of neuroferritinopathy were given deferiprone at different stages of disease progression and with clinical and biological monitoring to control benefit and risk. RESULTS: The four patients showed slight to high improvement. In one case, we managed to stabilize disease progression for more than 11 years. In another case, we were able to reverse symptoms after a few months of treatment. The earliest the treatment was started, the most efficient it was on disease progression. CONCLUSIONS: Conservative iron chelation should be further assessed in neuroferritinopathy. © 2022 International Parkinson and Movement Disorder Society.


Assuntos
Quelantes de Ferro , Doenças Neurodegenerativas , Deferiprona/uso terapêutico , Progressão da Doença , Humanos , Quelantes de Ferro/uso terapêutico , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Doenças Neurodegenerativas/tratamento farmacológico , Piridonas/uso terapêutico
18.
Pharmacol Res ; 183: 106386, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35933006

RESUMO

Iron participates in myriad processes necessary to sustain life. During the past decades, great efforts have been made to understand iron regulation and function in health and disease. Indeed, iron is associated with both physiological (e.g., immune cell biology and function and hematopoiesis) and pathological (e.g., inflammatory and infectious diseases, ferroptosis and ferritinophagy) processes, yet few studies have addressed the potential functional link between iron, the aforementioned processes and extramedullary hematopoiesis, despite the obvious benefits that this could bring to clinical practice. Further investigation in this direction will shape the future development of individualized treatments for iron-linked diseases and chronic inflammatory disorders, including extramedullary hematopoiesis, metabolic syndrome, cardiovascular diseases and cancer.


Assuntos
Ferroptose , Hematopoese Extramedular , Distúrbios do Metabolismo do Ferro , Homeostase , Humanos , Ferro/metabolismo
19.
Stem Cell Res ; 63: 102856, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35868289

RESUMO

Aceruloplasminemia is a rare autosomal recessive disorder caused by mutations in the CP gene, encoding the copper-binding protein ceruloplasmin. A mutation in the CP gene results in brain and systemic iron overload, which is classified as a rare subtype of neurodegeneration with brain iron accumulation (NBIA). Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells from peripheral blood mononuclear cells of a patient carrying the CP c.607+1 delG homozygous splicing mutation. The generated cell line retained the original genotype, expressed pluripotency markers, and differentiated into cells of the three germ layers.


Assuntos
Linhagem Celular , Ceruloplasmina , Células-Tronco Pluripotentes Induzidas , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Humanos , Distúrbios do Metabolismo do Ferro , Leucócitos Mononucleares , Mutação , Doenças Neurodegenerativas
20.
Mol Genet Metab ; 137(1-2): 26-32, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35878504

RESUMO

BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.


Assuntos
Distúrbios do Metabolismo do Ferro , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Psicometria , Estudos Prospectivos , Estudos Retrospectivos , Proteínas de Transporte/genética , Ferro/metabolismo , Avaliação de Resultados em Cuidados de Saúde
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