Assuntos
Transfusão de Sangue/métodos , COVID-19/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Adolescente , Criança , Ensaios Clínicos como Assunto , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoterapia Adotiva , Ensaios Clínicos Controlados Aleatórios como Assunto , Talassemia/terapia , Condicionamento Pré-Transplante/métodosAssuntos
Transplante de Células-Tronco Hematopoéticas , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Benzoatos/uso terapêutico , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hidrazinas/uso terapêutico , Imunossupressores/uso terapêutico , Pirazóis/uso terapêutico , Sociedades MédicasAssuntos
Oncologia , Sociedades Médicas , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Estados UnidosRESUMO
Somatic LINE-1 (L1) retrotransposition is a source of genomic mosaicism and potential phenotypic diversity among neurons during brain development. In the adult brain, L1 expression can be triggered by different environmental alterations, but its functional role in this context remains unknown. Here we demonstrate a neural activation-dependent increase in the number of L1 retrotransposon insertions in the hippocampus. Using both pharmacologic and genetic approaches in mice, we demonstrate that L1 expression in the adult hippocampus enables long-term memory formation. These results provide experimental evidence that L1 retrotransposition-induced genomic mosaicism is involved in cognitive processes such as memory formation.
Assuntos
Hipocampo/metabolismo , Elementos Nucleotídeos Longos e Dispersos , Memória de Longo Prazo , Retroelementos , Animais , Genômica , Masculino , Camundongos , MosaicismoRESUMO
During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-ß-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization.
Assuntos
Células-Tronco Neoplásicas/metabolismo , Trombospondinas/metabolismo , Animais , Benzocicloeptenos/toxicidade , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Camundongos Transgênicos , Metástase Neoplásica , Células-Tronco Neoplásicas/citologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Trombospondinas/antagonistas & inibidores , Trombospondinas/genética , Fator de Crescimento Transformador beta/metabolismo , Transplante Heterólogo , Triazóis/toxicidade , Receptor Tirosina Quinase AxlRESUMO
Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that mitochondrial dysfunction and oxidative stress may have a role in the pathophysiology of FM. Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ10 levels have been detected in patients with FM, and a significant decrease of clinical symptoms has been reported after oral CoQ10 supplementation. In this report, we show the effect of CoQ10 treatment on clinical symptoms, blood mononuclear cells, and mitochondrial and oxidative stress markers from a woman with FM. After CoQ10 treatment, the patient reported a significant improvement of clinical symptoms. At the cellular level, CoQ10 treatment restored mitochondrial dysfunction and the mtDNA copy number, decreased oxidative stress, and increased mitochondrial biogenesis. Our results suggest that CoQ10 could be an alternative therapeutic approach for FM.
Assuntos
Ataxia/dietoterapia , Suplementos Nutricionais , Fibromialgia/complicações , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/dietoterapia , Debilidade Muscular/dietoterapia , Ubiquinona/análogos & derivados , Ataxia/complicações , Feminino , Fibromialgia/sangue , Fibromialgia/metabolismo , Fibromialgia/fisiopatologia , Humanos , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Renovação Mitocondrial , Debilidade Muscular/complicações , Estresse Oxidativo , Índice de Gravidade de Doença , Resultado do Tratamento , Ubiquinona/deficiência , Ubiquinona/uso terapêuticoRESUMO
Memory formation requires changes in gene expression, which are regulated by the activation of transcription factors and by changes in epigenetic factors. Poly[ADP]-ribosylation of nuclear proteins has been postulated as a chromatin modification involved in memory consolidation, although the mechanisms involved are not well characterized. Here we demonstrate that poly[ADP]-ribose polymerase 1 (PARP-1) activity and the poly[ADP]-ribosylation of proteins over a specific time course is required for the changes in synaptic plasticity related to memory stabilization in mice. At the molecular level, histone H1 poly[ADP]-ribosylation was evident in the hippocampus after the acquisition period, and it was selectively released in a PARP-1-dependent manner at the promoters of cAMP response element-binding protein and nuclear factor-κB dependent genes associated with learning and memory. These findings suggest that histone H1 poly[ADP]-ribosylation, and its loss at specific loci, is an epigenetic mechanism involved in the reprogramming of neuronal gene expression required for memory consolidation.
Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Aprendizagem/fisiologia , Poli Adenosina Difosfato Ribose/metabolismo , Proteínas/metabolismo , Animais , Cromatina/genética , Epigênese Genética/genética , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/fisiologia , Loci Gênicos/genética , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Histonas/fisiologia , Masculino , Memória/fisiologia , Camundongos , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Poli(ADP-Ribose) Polimerase-1 , Poli Adenosina Difosfato Ribose/fisiologia , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/fisiologia , Regiões Promotoras Genéticas/genética , Proteínas/fisiologia , Transmissão Sináptica/genéticaRESUMO
Memory deficits in aging affect millions of people and are often disturbing to those concerned. Dissection of the molecular control of learning and memory is paramount to understand and possibly enhance cognitive functions. Old-age memory loss also has been recently linked to altered Ca(2+) homeostasis. We have previously identified DREAM (downstream regulatory element antagonistic modulator), a member of the neuronal Ca(2+) sensor superfamily of EF-hand proteins, with specific roles in different cell compartments. In the nucleus, DREAM is a Ca(2+)-dependent transcriptional repressor, binding to specific DNA signatures, or interacting with nucleoproteins regulating their transcriptional properties. Also, we and others have shown that dream mutant (dream(-/-)) mice exhibit marked analgesia. Here we report that dream(-/-) mice exhibit markedly enhanced learning and synaptic plasticity related to improved cognition. Mechanistically, DREAM functions as a negative regulator of the key memory factor CREB in a Ca(2+)-dependent manner, and loss of DREAM facilitates CREB-dependent transcription during learning. Intriguingly, 18-month-old dream(-/-) mice display learning and memory capacities similar to young mice. Moreover, loss of DREAM protects from brain degeneration in aging. These data identify the Ca(2+)-regulated "pain gene" DREAM as a novel key regulator of memory and brain aging.