RESUMO
Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and differentiation factor 10 (GDF10) is induced in peri-infarct neurons in mice, non-human primates and humans. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFßRI and TGFßRII signaling. Using pharmacogenetic gain- and loss-of-function studies, we found that GDF10 produced axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocked axonal sprouting and reduced recovery. RNA sequencing from peri-infarct cortical neurons revealed that GDF10 downregulated PTEN, upregulated PI3 kinase signaling and induced specific axonal guidance molecules. Using unsupervised genome-wide association analysis of the GDF10 transcriptome, we found that it was not related to neurodevelopment, but may partially overlap with other CNS injury patterns. Thus, GDF10 is a stroke-induced signal for axonal sprouting and functional recovery.
Assuntos
Axônios/metabolismo , Fator 10 de Diferenciação de Crescimento/biossíntese , Fator 10 de Diferenciação de Crescimento/genética , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Recém-Nascidos , Axônios/patologia , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/patologiaRESUMO
The synthesis and the biological evaluation of a new family diterpenes are presented. The synthetic studies were inspired by the structural framework of acanthoic acid (1) and yielded a family of compounds that were evaluated as anti-inflammatory agents. Among them, compounds 2, 10, 12, and 16 exhibited a very low nonspecific cytotoxicity and inhibited the synthesis of TNF-alpha with greater than 65 % efficacy at low micromolar concentrations. Cytokine-specificity studies revealed that these compounds also inhibited the synthesis of the proinflammatory cytokines IL-1beta and IL-6, while inhibition of IL-1ra and IL-8 synthesis was marginal and only occurred at high concentrations. Further studies, through EMSA and Western blot analyses, indicated that these compounds decreased the extent of phosphorylation of IkappaBalpha; this suggests that they exert their anti-inflammatory profile by inhibiting NF-kappaB-mediated cytokine synthesis. These findings imply that these diterpenes represent promising leads for the development of novel anti-inflammatory agents.
Assuntos
Citocinas/biossíntese , Diterpenos/síntese química , Diterpenos/farmacologia , Proteínas I-kappa B/antagonistas & inibidores , Diterpenos/química , Humanos , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Fosforilação , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Breakdown of peripheral T cell regulation due to defective antigen-activated apoptosis may lead to autoimmunity. In the nonobese diabetic (NOD) mouse model of type 1 diabetes mellitus, we have demonstrated defects in T cell activation and peripheral apoptosis. Stimulation of the Fas pathway by a Fas receptor agonist led to enhanced in vitro apoptosis and in vivo selective apoptosis of islet-infiltrating lymphocytes. Administration of the Fas agonist immediately after onset of diabetes led to reversal of diabetes in NOD mice. Inducing peripheral T cell apoptosis may be a potential method for reversal of autoimmune diabetes.
