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1.
EMBO Rep ; 24(12): e57176, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37870400

RESUMO

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. ß-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress.


Assuntos
Resistência à Insulina , Núcleo Hipotalâmico Paraventricular , Ratos , Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos Sprague-Dawley , Depressão , Obesidade/metabolismo , Adipocinas/metabolismo , Adipocinas/farmacologia
2.
Biochem Biophys Res Commun ; 469(4): 1111-6, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26740175

RESUMO

Chromatinassembly factor 1 subunit A (CHAF1A) has been reported to be involved in several human diseases including cancer. However, the biological and clinical significance of CHAF1A in glioblastoma progression remains largely unknown. In this study, we found that up-regulation of CHAF1A happens frequently in glioblastoma tissues and is associated with glioblastoma prognosis. Knockout of CHAF1A by CRISPR/CAS9 technology induce G1 phase arrest and apoptosis in glioblastoma cell U251 and U87. In addition, inhibition of CHAF1A influenced the signal transduction of the AKT/FOXO3a/Bim axis, which is required for glioblastoma cell proliferation. Taken together, these results show that CHAF1A contributes to the proliferation of glioblastoma cells and may be developed as a de novo drug target and prognosis biomarker of glioblastoma.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Fator 1 de Modelagem da Cromatina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Apoptose , Proteína 11 Semelhante a Bcl-2 , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Proteína Forkhead Box O3 , Humanos , Transdução de Sinais , Fatores de Transcrição , Regulação para Cima
3.
Nat Commun ; 11(1): 4063, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792525

RESUMO

The neuroendocrine hypothalamus is the central regulator of vital physiological homeostasis and behavior. However, the cellular and molecular properties of hypothalamic neural progenitors remain unexplored. Here, hypothalamic radial glial (hRG) and hypothalamic mantle zone radial glial (hmRG) cells are found to be neural progenitors in the developing mammalian hypothalamus. The hmRG cells originate from hRG cells and produce neurons. During the early development of hypothalamus, neurogenesis occurs in radial columns and is initiated from hRG cells. The radial glial fibers are oriented toward the locations of hypothalamic subregions which act as a scaffold for neuronal migration. Furthermore, we use single-cell RNA sequencing to reveal progenitor subtypes in human developing hypothalamus and characterize specific progenitor genes, such as TTYH1, HMGA2, and FAM107A. We also demonstrate that HMGA2 is involved in E2F1 pathway, regulating the proliferation of progenitor cells by targeting on the downstream MYBL2. Different neuronal subtypes start to differentiate and express specific genes of hypothalamic nucleus at gestational week 10. Finally, we reveal the developmental conservation of nuclear structures and marker genes in mouse and human hypothalamus. Our identification of cellular and molecular properties of neural progenitors provides a basic understanding of neurogenesis and regional formation of the non-laminated hypothalamus.


Assuntos
Hipotálamo/citologia , Hipotálamo/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Animais , Análise por Conglomerados , Feminino , Genes Supressores de Tumor , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Hibridização In Situ , Mamíferos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neurogênese/genética , Neurogênese/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Gravidez
4.
Int J Biol Sci ; 13(3): 276-285, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28367092

RESUMO

Growing evidence shows that protein kinase D (PKD) plays an important role in the development of pressure overload-induced cardiac hypertrophy. However, the mechanisms involved are not clear. This study tested our hypothesis that PKD might mediate cardiac hypertrophy by negatively regulating autophagy using the technique of PKD knockdown by siRNA. Cardiac hypertrophy was induced in 8-week old male C57BL/6 mice by transverse aortic constriction (TAC). TAC mice were then divided into five groups receiving the treatments of vehicle (DMSO), an autophagy inducer rapamycin (1 mg/kg/day, i.p.), control siRNA, lentiviral PKD siRNA (2×108 transducing units/0.1 ml, i.v. injection in one day after surgery, and repeated in 2 weeks after surgery), and PKD siRNA plus 3-methyladenine (3-MA, an autophagy inhibitor, 20 mg/kg/day, i.p.), respectively. Four weeks after TAC surgery, echocardiographic study, hematoxylin and eosin (HE) staining, and Masson's staining showed mice with TAC had significantly hypertrophy and remodeling compared with sham animals. Treatments with PKD siRNA or rapamycin significantly ameliorated the cardiac hypertrophy and dysfunction. Moreover, PKD siRNA increased cardiac autophagic activity determined by electron micrographic study and the biomarkers by Western blot, accompanied with the downregulated AKT/mTOR/S6K signaling pathway. All the cardiac effects of PDK knockdown were inhibited by co-treatment with 3-MA. These results suggest that PKD is involved in the development of cardiac hypertrophy by inhibiting cardiac autophagy via AKT/mTOR pathway.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/terapia , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Cardiomegalia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética
5.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(3): 2188-9, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-25492533

RESUMO

In this article we have reported the complete mitochondrial genome sequence of rat C6 glioma cell line for the first time. The total length of the mitogenome was 16,314 bp, with coding 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes. This sequence was deposited in the GenBank (Accession No. KM820837).


Assuntos
Genoma Mitocondrial/genética , Glioma/genética , Animais , Composição de Bases/genética , Sequência de Bases/genética , Linhagem Celular , DNA Mitocondrial/genética , Ordem dos Genes/genética , Genes Mitocondriais/genética , Genoma/genética , Mitocôndrias/genética , Ratos , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
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