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1.
Stem Cell Res Ther ; 14(1): 45, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36941658

RESUMO

BACKGROUND: Cholestatic liver fibrosis (CLF) is caused by inflammatory destruction of the intrahepatic bile duct and abnormal proliferation of the small bile duct after cholestasis. Activation of the Notch signaling pathway is required for hepatic stem cells to differentiate into cholangiocytes during the pathogenesis of CLF. Our previous research found that the expression of the Numb protein, a negative regulator of Notch signaling, was significantly reduced in the livers of patients with primary biliary cholangitis and CLF rats. However, the relationship between the Numb gene and CLF is largely unclear. In this study, we investigated the role of the Numb gene in the treatment of bile duct ligation (BDL)-induced CLF. METHODS: In vivo, bone marrow-derived mesenchymal stem cells (BM-MSCs) with Numb gene overexpression or knockdown obtained using lentivirus transfection were transplanted into the livers of rats with BDL-induced CLF. The effects of the Numb gene on stem cell differentiation and CLF were evaluated by performing histology, tests of liver function, and measurements of liver hydroxyproline, cytokine gene and protein levels. In vitro, the Numb gene was overexpressed or knocked down in the WB-F344 cell line by lentivirus transfection, Then, cells were subjected immunofluorescence staining and the detection of mRNA levels of related factors, which provided further evidence supporting the results from in vivo experiments. RESULTS: BM-MSCs overexpressing the Numb gene differentiated into hepatocytes, thereby inhibiting CLF progression. Conversely, BM-MSCs with Numb knockdown differentiated into biliary epithelial cells (BECs), thereby promoting the ductular reaction (DR) and the progression of CLF. In addition, we confirmed that knockdown of Numb in sodium butyrate-treated WB-F344 cells aggravated WB-F344 cell differentiation into BECs, while overexpression of Numb inhibited this process. CONCLUSIONS: The transplantation of BM-MSCs overexpressing Numb may be a useful new treatment strategy for CLF.


Assuntos
Colestase , Células-Tronco Mesenquimais , Ratos , Animais , Ratos Endogâmicos F344 , Cirrose Hepática/genética , Cirrose Hepática/terapia , Colestase/genética , Colestase/terapia , Colestase/complicações , Fígado/metabolismo , Células-Tronco Mesenquimais/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
2.
Neural Regen Res ; 18(9): 1884-1889, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36926704

RESUMO

At the level of in vitro drug screening, the development of a phenotypic analysis system with high-content screening at the core provides a strong platform to support high-throughput drug screening. There are few systematic reports on brain organoids, as a new three-dimensional in vitro model, in terms of model stability, key phenotypic fingerprint, and drug screening schemes, and particularly regarding the development of screening strategies for massive numbers of traditional Chinese medicine monomers. This paper reviews the development of brain organoids and the advantages of brain organoids over induced neurons or cells in simulated diseases. The paper also highlights the prospects from model stability, induction criteria of brain organoids, and the screening schemes of brain organoids based on the characteristics of brain organoids and the application and development of a high-content screening system.

3.
Sci Rep ; 10(1): 17486, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060633

RESUMO

Numb is a negative regulator of Notch signal pathway. Previous study has demonstrated that Notch signal pathway activation is required for hepatic progenitor cell (HPC) differentiating into cholangiocytes in cholestatic liver fibrosis (CLF), and Huang Qi Decoction (HQD) could prevent CLF through inhibition of the Notch signal pathway. However, the role of Numb in HQD against CLF is yet unclear. Thus, CLF rats transplanted into rat bone marrow-derived mesenchymal stem cells with knocked down Numb gene (BMSCNumb-KD) were treated with HQD. Simultaneously, Numb gene knockdown was also performed in WB-F344 cell line and then treated with refined HQD in vitro. In vivo study revealed that liver fibrosis was inhibited by HQD plus BMSCNumb-KD treatment, while Hyp content in liver tissue, the gene and protein expression of α-SMA, gene expression of Col I, TNF-α, and TGF-ß1 were increased compared to that in HQD group. Furthermore, Notch signal pathway was inhibited by HQD plus BMSCNumb-KD, while the protein expression of Numb was decreased and RBP-Jκ and Hes1 was increased compared to that in HQD group. In vitro, HQD reduced the differentiation of WB-F344 cells into cholangiocyte phenotype, while this effect was attenuated after Numb-knockdown. This study highlights that the absence of hepatic stem cell Numb gene decreases effect of HQD against CLF, which give rise the conclusion that Numb might be a potential target for HQD against CLF.


Assuntos
Colestase/genética , Medicamentos de Ervas Chinesas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cirrose Hepática/genética , Células-Tronco Mesenquimais/metabolismo , Animais , Astragalus propinquus , Células da Medula Óssea/citologia , Linhagem Celular , Colestase/tratamento farmacológico , Fibrose , Técnicas de Silenciamento de Genes , Lentivirus , Cirrose Hepática/tratamento farmacológico , Masculino , Células-Tronco Mesenquimais/citologia , Fenótipo , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Transdução de Sinais
4.
Eur J Cell Biol ; 94(12): 626-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26518113

RESUMO

Tetramethylpyrazine (TMP) is an active compound extracted from the traditional Chinese medicinal herb Chuanxiong. Previously, we have shown that TMP induces human SH-SY5Y neuroblastoma cell differentiation toward the neuronal phenotype by targeting topoisomeraseIIß (TopoIIß), a protein implicated in neural development. In the present study, we aimed to elucidate whether the transcriptional factors specificity protein 1 (Sp1) and nuclear factor Y (NF-Y), in addition to the upstream signaling pathways ERK1/2 and PI3K/Akt, are involved in modulating TopoIIß expression in the neuronal differentiation process. We demonstrated that SH-SY5Y cells treated with TMP (80µM) terminally differentiated into neurons, characterized by increased neuronal markers, tubulin ßIII and microtubule associated protein 2 (MAP2), and increased neurite outgrowth, with no negative effect on cell survival. TMP also increased the expression of TopoIIß, which was accompanied by increased expression of Sp1 in the differentiated neuron-like cells, whereas NF-Y protein levels remained unchanged following the differentiation progression. We also found that the phosphorylation level of Akt, but not ERK1/2, was significantly increased as a result of TMP stimulation. Furthermore, as established by chromatin immunoprecipitation (ChIP) assay, activation of the PI3K/Akt pathway increased Sp1 binding to the promoter of the TopoIIß gene. Blockage of PI3K/Akt was shown to lead to subsequent inhibition of TopoIIß expression and neuronal differentiation. Collectively, the results indicate that the PI3K/Akt/Sp1/TopoIIß signaling pathway is necessary for TMP-induced neuronal differentiation. Our findings offer mechanistic insights into understanding the upstream regulation of TopoIIß in neuronal differentiation, and suggest potential applications of TMP both in neuroscience research and clinical practice to treat relevant diseases of the nervous system.


Assuntos
DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neurônios/enzimologia , Pirazinas/farmacologia , Transdução de Sinais , Fator de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Transdiferenciação Celular , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Avaliação Pré-Clínica de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular , Expressão Gênica , Humanos , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição Sp1/metabolismo , Ativação Transcricional
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