RESUMO
Niemann-Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and ß-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.
Assuntos
Doenças por Armazenamento dos Lisossomos , Doença de Niemann-Pick Tipo C , Humanos , Proteostase , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Dobramento de Proteína , ProteóliseRESUMO
Establishing the role of non-coding RNA (ncRNA), especially microRNAs (miRNAs), in the regulation of cell function constitutes a current research challenge. Two to six miRNAs can act in clusters; particularly, the miR-17-92 family, composed of miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a is well-characterized. This cluster functions during embryonic development in cell differentiation, growth, development, and morphogenesis and is an established oncogenic cluster. However, its role in the regulation of cellular metabolism, mainly in lipid metabolism and autophagy, has received less attention. Here, we argue that the miR-17-92 cluster is highly relevant for these two processes, and thus, could be involved in the study of pathologies derived from lysosomal deficiencies. Lysosomes are related to both processes, as they control cholesterol flux and regulate autophagy. Accordingly, we compiled, analyzed, and discussed current evidence that highlights the cluster's fundamental role in regulating cellular energetic metabolism (mainly lipid and cholesterol flux) and atherosclerosis, as well as its critical participation in autophagy regulation. Because these processes are closely related to lysosomes, we also provide experimental data from the literature to support our proposal that the miR-17-92 cluster could be involved in the pathogenesis and effects of lysosomal storage diseases (LSD).
Assuntos
Aterosclerose , Doenças por Armazenamento dos Lisossomos , MicroRNAs , Humanos , Aterosclerose/genética , Autofagia , Colesterol , Lipídeos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Rhipicephalus microplus is a hematophagous ectoparasite that significantly affects parasitized cattle. As a one-host tick its entire life cycle consists of free-living and parasitic forms. Its extraordinary ability to survive during prolonged off-host periods has been related to the process of cytoplasmic degradation called autophagy. In order to deepen our understanding of this process during R. microplus non-parasitic stages, we determined the expression dynamics of a set of five autophagy-related genes (ATG genes) during embryonic development and over an increasing larval starvation period of 50 days. We found two apparent successive waves of ATG genes transcriptional activation, which paralleled key embryonic changes such as cellularization and organogenesis, as well as nutrient utilization. Moreover, during increasing larval starvation, ATG genes were up-regulated cyclically every 10-15 days. Taken together, our results suggest that autophagy is playing a major role in embryo development and energy metabolism during starvation in R. microplus.
Assuntos
Proteínas de Artrópodes/genética , Autofagia/genética , Expressão Gênica , Rhipicephalus/genética , Animais , Proteínas de Artrópodes/metabolismo , Bovinos/parasitologia , Desenvolvimento Embrionário/genética , Larva/genética , México , Rhipicephalus/embriologia , Rhipicephalus/crescimento & desenvolvimentoRESUMO
In mammals, the neural control of breathing is attributed to circuits distributed along the ventral respiratory column (VRC) in the ventrolateral medulla. The VRC contains the kernel for generation of the inspiratory phase of respiratory rhythm and nuclei involved in central chemoreception. During development, the respiratory rhythm, as well as central chemosensitivity, adjusts to meet the changing physiological requirements associated with increased body weight and size. Gene expression in VRC ontogeny is well characterized. However, little is known about gene expression in the VRC during postnatal development. Here, we sought to characterize the changes in gene expression that occur in the VRC of the adult rat (5-6 months of age) in comparison with the VRC of neonate rat (1-4 days old). We isolated total RNA from VRC tissue punches collected from thick transversal slices. We hybridized cDNA to a 5000-oligonucleotide rat microarray. We found that 218 genes (4.4%) of the 5000 genes in the microarray changed their expression in adult VRC with respect to that from neonate. To further analyze the modified expression of specific genes, we quantified the differential expression of 84 genes of neuronal ion channels using a quantitative RT-PCR array. This analysis confirmed the overexpression of 68 genes and the underexpression of 14 genes in the VRC from adult compared with that from neonate. Our findings may help to explain the functional changes in respiratory rhythm and chemosensitivity occurring throughout life.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Canais Iônicos/genética , Centro Respiratório/metabolismo , Animais , Canais Iônicos/metabolismo , Masculino , Ratos , Ratos Wistar , Centro Respiratório/crescimento & desenvolvimentoRESUMO
Pleiotrophin (PTN) is a secreted growth factor recently proposed to act as a neuromodulatory peptide in the Central Nervous System. PTN appears to be involved in neurodegenerative diseases and neural disorders, and it has also been implicated in learning and memory. Specifically, PTN-deficient mice exhibit a lower threshold for LTP induction in the hippocampus, which is attenuated in mice overexpressing PTN. However, there is little information about the signaling systems recruited by PTN to modulate neural activity. To address this issue, the gene expression profile in hippocampus of mice lacking PTN was analyzed using microarrays of 22,000 genes. In addition, we corroborated the effect of the absence of PTN on the expression of these genes by silencing this growth factor in primary neuronal cultures in vitro. The microarray analysis identified 102 genes that are differentially expressed (z-score>3.0) in PTN null mice, and the expression of eight of those modified in the hippocampus of KO mice was also modified in vitro after silencing PTN in cultured neurons with siRNAs. The data obtained indicate that the absence of PTN affects AKT pathway response and modulates the expression of genes related with neuroprotection (Mgst3 and Estrogen receptor 1, Ers 1) and cell differentiation (Caspase 6, Nestin, and Odz4), both in vivo and in vitro.
Assuntos
Proteínas de Transporte/metabolismo , Cerebelo/metabolismo , Citocinas/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Transcriptoma , Animais , Proteínas de Transporte/genética , Caspase 6/genética , Caspase 6/metabolismo , Células Cultivadas , Cerebelo/citologia , Citocinas/deficiência , Citocinas/genética , Hipocampo/citologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Ribossômico 18S/genética , RNA Ribossômico 18S/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMO
Bovine respiratory disease (BRD) complex is a major cause of economic losses for the cattle backgrounding and feedlot industries. Mannheimia haemolytica is considered the most important pathogen associated with this disease. Vaccines against M. haemolytica have been prepared and used for many decades, but traditional bacterins have failed to demonstrate effective protection and their use has often exacerbated disease in vaccinated animals. Thus, the BRD complex continues to exert a strong adverse effect on the health and wellbeing of stocker and feeder cattle. Therefore, generation of recombinant proteins has been helpful in formulating enhanced vaccines against M. haemolytica, which could confer better protection against BRD. In the present study, we formulated a vaccine preparation enriched with recombinant small fragments of leukotoxin A (LKTA) and outer-membrane lipoprotein (PlpE) proteins, and demonstrated its ability to generate high antibody titers in rabbits and sheep, which protected against M. haemolytica bacterial challenge in mice.
Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Proteínas Hemolisinas/imunologia , Lipoproteínas/imunologia , Mannheimia haemolytica/imunologia , Infecções por Pasteurellaceae/veterinária , Animais , Anticorpos Antibacterianos , Proteínas da Membrana Bacteriana Externa/química , Proteínas de Bactérias/química , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática/veterinária , Proteínas Hemolisinas/química , Lipoproteínas/química , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pasteurellaceae/prevenção & controle , Coelhos , Proteínas Recombinantes , OvinosAssuntos
Humanos , Masculino , Feminino , Dieta , Doença , Saúde , Ciências da Nutrição/educação , Política Nutricional , Medicina , VenezuelaRESUMO
Durante la niñez cobra particular importancia el establecimiento de hábitos alimentarios, por ser ésta una etapa de aprendizaje y formación, las costumbres adquiridas durante este lapso repercutirán en el crecimiento y desarrollo y en la prevención de enfermedades del niño y del adolescente. De allí se desprende la importancia de conocer las necesidades nutricionales del individuo en las primeras etapas de su vida así como las particularidades del desarrollo en las mismas, con el fin de introducirlo paulatina y adecuadamente en la dieta familiar. En atención a estas características, esta revisión espera ofrecer al personal de la salud las bases prácticas que luego le permitan orientar a los padres para que éstos, a su vez sean capaces de formar hábitos saludables en sus hijos
Assuntos
Humanos , Masculino , Adolescente , Feminino , Lactente , Pré-Escolar , Cálcio da Dieta , Cultura , Comportamento Alimentar/fisiologia , Ferro da Dieta , Medicina , VenezuelaRESUMO
La interleuquina-1 (IL-1) es un medidor soluble con propíedades inmunoreguladoras, inflamatorias, anorexígenas y antianabólicas, secretado principalmente por macrófagos activados. Evaluamos los niveles séricos de IL-1alfa en 54 lactantes y preescolares con desnutrición leve, moderada o grave con o sin infección clínica asociada y en 40 cintroles eutróficos de edad, sexo, raza y condición socioeconómica comparables, mediante ensayo inmunoenzimático con un nivel inferior de detección de 37.5 pg/ml. El porcentaje de sueros con niveles detectables de la citoquina fue similar en el grupo total de niños desnutridos y en los eutróficos. Sin embargo, cuando se analizaron los valores promedio de IL-1 alfa en los sueros con niveles detectables de la citoquina se observó que: 1) El nivel de IL-1 alfa fué significativamente mayor en los desnutridos totales que en los eutróficos. 2) Cuando el grupo de niños desnutridos se subdividió de acuerdo a la severidad del déficit nutricional, cada subgrupo (desnutridos leves, moderados o graves) mostró una media de IL-1 alfa mayor a la del grupo control. No hubo diferencias en los nivles promedios de IL-1 alfa en sueros de desnutridos con infección clínica asociada o sin infección aparente. Se concluye que en la desnutrición primaria persiste la capacidad para sintetizar IL-1 alfa y 2) que los valores aumentados de IL-1 alfa observados en desnutridos serías causados por la alta prevalencia de infecciones clínicas asociadas. A su vez, los niveles elevados de IL-1 alfa en los desnutridos sin infección clínica asociada serían determinados por infecciones latentes, y/o traslocación de bacterias y endotoxina través de la mucosa intestinal atrófica