RESUMO
The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Encefalopatias Metabólicas , Glutaril-CoA Desidrogenase , Oligodendroglia , Substância Branca , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Glutaril-CoA Desidrogenase/metabolismo , Humanos , Animais , Substância Branca/patologia , Substância Branca/metabolismo , Encefalopatias Metabólicas/patologia , Encefalopatias Metabólicas/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/patologiaRESUMO
Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.
Assuntos
Moléculas de Adesão Celular Neuronais , Endossomos , Proteínas da Matriz Extracelular , Proteínas Relacionadas a Receptor de LDL , Proteínas do Tecido Nervoso , Neurônios , Monoéster Fosfórico Hidrolases , Transporte Proteico , Proteína Reelina , Serina Endopeptidases , Humanos , Monoéster Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/deficiência , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/deficiência , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/deficiência , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/deficiência , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/deficiência , Endossomos/metabolismo , Neurônios/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Transdução de Sinais , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismoRESUMO
BACKGROUND: Giardiasis and zinc deficiency have been identified as serious health problems worldwide. Although Zn depletion is known to occur in giardiasis, no work has investigated whether changes occur in brain structures. METHODS: Three groups of gerbils were used: control (1), orogastrically inoculated on day 3 after birth with trophozoites of two isolates of Giardia intestinalis (HGINV/WB) group (2 and 3). Estimates were made at five ages covering: establishment of infection, Giardia population growth, natural parasite clearance and a post-infection age. QuantiChrome zinc assay kit, cresyl violet staining and TUNEL technique were used. RESULTS: A significant decrease (p<0.01) in tissue zinc was observed and persisted after infection. Cytoarchitectural changes were observed in 75% of gerbils in the HGINV or WB groups. Ectopic pyramidal neurons were found in the cornus ammonis (CA1-CA3). At 60 and 90 days of age loss of lamination was clearly visible in CA1. In the dentate gyrus (DG), thinning of the dorsal lamina and abnormal thickening of the ventral lamina were observed from 30 days of age. In the cerebellum, we found an increase (p<0.01) in the thickness of the external granular layer (EGL) at 14 days of age that persisted until day 21 (C 3 ± 0.3 µm; HGINV 37 ± 5 µm; WB 28 ± 3 µm); Purkinje cell population estimation showed a significant decrease; a large number of apoptotic somas were observed scattered in the molecular layer; in 60 and 90 days old gerbils we found granular cell heterotopia and Purkinje cell ectopia. The pattern of apoptosis was different in the cerebellum and hippocampus of parasitized gerbils. CONCLUSION: The morphological changes found suggest that neuronal migration is affected by zinc depletion caused by giardiasis in early postnatal life; for the first time, the link between giardiasis-zinc depletion and damaged brain structures is shown. This damage may explain the psychomotor/cognitive delay associated with giardiasis. These findings are alarming. Alterations in zinc metabolism and signalling are known to be involved in many brain disorders, including autism.
Assuntos
Cerebelo , Gerbillinae , Giardia lamblia , Giardíase , Hipocampo , Zinco , Animais , Gerbillinae/parasitologia , Zinco/deficiência , Zinco/metabolismo , Giardíase/parasitologia , Giardíase/patologia , Cerebelo/patologia , Cerebelo/parasitologia , Hipocampo/patologia , Hipocampo/parasitologia , Giardia lamblia/crescimento & desenvolvimento , Masculino , Modelos Animais de DoençasRESUMO
The moral imperative of public health systems is to maximize the health and welfare of the population to the extent possible. Constraints often include a lack of resources, political will, popular acceptance, or an acceptable safety margin. Major agencies have established iron, iodine, and vitamin A as the principal elements for micronutrients, with folate and zinc on the second plane. As the armamentarium of interventions to favor micronutrient nutrition, for example, preventive health measures, dietary improvement, forms of fortification, and nutrient supplements, is offered in public health policy. The utility of their merger with other nutrients, emergent nutrients, has been considered. The Latin America and Caribbean Region has unique characteristics. The scientific and epidemiology considerations for action in the Region's health concern on 4 emergent nutrient deficiencies of public health-vitamins D and E, essential fatty acids, and choline-are reviewed.
Plain language titleMicronutrient Deficiencies of Interest in Latin America and the CaribbeanPlain language summaryThe diets consumed in the diverse corners and societies in the nations of Latin America and the Caribbean area do not fully supply the vitamins and minerals needed by people of all ages and conditions. Some public health actions are being taken, but only against a limited selection of such nutrients as iron, vitamin A, iodine, and folic acid. The composition of diets and environmental conditions across the region suggests that 4 additional nutrients might be candidates for public health efforts. These include vitamin D, vitamin E, certain large fatty acid molecules, and choline.
Assuntos
Micronutrientes , Humanos , Região do Caribe/epidemiologia , Suplementos Nutricionais , Ácidos Graxos Essenciais/deficiência , América Latina/epidemiologia , Micronutrientes/deficiência , Política Nutricional , Saúde PúblicaRESUMO
Herein, we present a thorough examination of the impact of maternal nutrition on fetal and infant neurodevelopment, focusing on specific nutrients and their critical roles in perinatal and pediatric health. Through a comprehensive narrative review of the literature, this study highlights the importance of a balanced maternal diet rich in nutrients like eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), folic acid, iron, and iodine in shaping children's neurological functions. Key findings underscore the influence of maternal nutrition during pregnancy and the peri-gestational period on children's cognitive, motor, speech, and socio-emotional development. Deficiencies in essential nutrients, such as DHA, are linked to adverse long-lasting outcomes such as premature birth and intrauterine growth restriction, where a suitable intake of iron and folic acid is vital to prevent neural tube defects and promote healthy brain development. We highlight areas requiring further investigation, particularly regarding iodine's impact and the risks associated with alcohol consumption during pregnancy. In conclusion, this research sheds light on our current understanding of maternal nutrition and child neurodevelopment, offering valuable insights for health professionals and researchers.
Assuntos
Desenvolvimento Infantil , Desenvolvimento Fetal , Fenômenos Fisiológicos da Nutrição Materna , Humanos , Gravidez , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Desenvolvimento Fetal/fisiologia , Desenvolvimento Infantil/efeitos dos fármacos , Desenvolvimento Infantil/fisiologia , Iodo/deficiência , Iodo/administração & dosagem , Dieta/métodos , Lactente , Recém-Nascido , Encéfalo/crescimento & desenvolvimento , Encéfalo/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Estado Nutricional , Ácidos Docosa-Hexaenoicos/administração & dosagemRESUMO
Blood selenium (Se) concentrations differ substantially by population and could be influenced by genetic variants, increasing Se deficiency-related diseases. We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with serum Se deficiency in 382 adults with admixed ancestry. Genotyping arrays were combined to yield 90,937 SNPs. R packages were applied to quality control and imputation. We also performed the ancestral proportion analysis. The Search Tool for the Retrieval of Interacting Genes was used to interrogate known protein-protein interaction networks (PPIs). Our ancestral proportion analysis estimated 71% of the genome was from Caucasians, 22% was from Africans, and 8% was from East Asians. We identified the SNP rs1561573 in the TraB domain containing 2B (TRABD2B), rs425664 in MAF bZIP transcription factor (MAF), rs10444656 in spermatogenesis-associated 13 (SPATA13), and rs6592284 in heat shock protein nuclear import factor (HIKESHI) genes. The PPI analysis showed functional associations of Se deficiency, thyroid hormone metabolism, NRF2-ARE and the Wnt pathway, and heat stress. Our findings show evidence of a genetic association between Se deficiency and metabolic pathways indirectly linked to Se regulation, reinforcing the complex relationship between Se intake and the endogenous factors affecting the Se requirements for optimal health.
Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Selênio , Humanos , Selênio/sangue , Selênio/deficiência , Masculino , Feminino , Adulto , Brasil , Pessoa de Meia-Idade , Predisposição Genética para Doença , População Branca/genética , Genótipo , Mapas de Interação de Proteínas/genéticaRESUMO
BACKGROUND: Gestational weight gain below or above the Institute of Medicine recommendations has been associated with adverse perinatal and neonatal outcomes. Very few studies have evaluated the association between serum and red blood cell folate concentrations and gestational weight gain in adolescents. Additionally, zinc deficiency during pregnancy has been associated with impaired immunity, prolonged labor, preterm and post-term birth, intrauterine growth restriction, low birth weight, and pregnancy-induced hypertension. OBJECTIVE: The purpose of our study is to evaluate the association between serum concentrations of zinc, serum folate, and red blood cell folate, with the increase in gestational weight and the weight and length of the newborn in a group of adolescent mothers from Mexico City. RESULTS: In our study, 406 adolescent-neonate dyads participated. The adolescents' median age was 15.8 years old. The predominant socioeconomic level was middle-low (57.8%), single (57%), 89.9% were engaged in home activities, and 41.3% completed secondary education. Excessive gestational weight gain was observed in 36.7% of cases, while insufficient gestational weight gain was noted in 38.4%. Small for gestational age infants were observed in 20.9% of the sample. Low serum folate (OR 2.1, 95% CI 1.3-3.3), decreased red blood cell folate (OR 1.6, 95% CI 1.0-2.6), and reduced serum zinc concentrations (OR 3.3, 95% CI 2.1-5.2) were associated with insufficient gestational weight gain. Decreased serum zinc levels (OR 1.2, 95% CI 1.2-3.4) were linked to an increased probability of delivering a baby who is small for their gestational age. CONCLUSIONS: Low serum folate, red blood cell folate, and serum zinc concentrations were associated with gestational weight gain and having a small gestational age baby. Both excessive and insufficient gestational weight gain, as well as having a small gestational age baby, are frequent among adolescent mothers.
Assuntos
Peso ao Nascer , Eritrócitos , Ácido Fólico , Ganho de Peso na Gestação , Zinco , Humanos , Feminino , Zinco/sangue , Zinco/deficiência , Adolescente , Gravidez , Ácido Fólico/sangue , Recém-Nascido , México , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Gravidez na Adolescência/sangueRESUMO
Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE-/-) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.
Assuntos
Anti-Inflamatórios , Aterosclerose , Nippostrongylus , Uridina , Animais , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/deficiência , Aterosclerose/metabolismo , Aterosclerose/genética , Modelos Animais de Doenças , Canais KATP/metabolismo , Canais KATP/genética , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Uridina/farmacologiaRESUMO
In rare instances, patients with SLE may exhibit atypical clinical manifestations, such as Hypocomplementemic Urticarial Vasculitis, which can pose diagnostic challenges. Here, we present a case report of a 28-year-old female with a history of SLE with lupus nephritis clase IV who developed HUV-like symptoms, ultimately leading to a diagnosis of C1q Vasculitis. This case underscores the importance of considering C1q Vasculitis in SLE patients presenting with HUV-like features and highlights Rituximab as a promising therapeutic option for managing this rare condition.