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1.
PLoS Genet ; 17(2): e1009357, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33591966

RESUMO

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show that Lzp deletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.


Assuntos
Apolipoproteínas B/metabolismo , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Proteínas de Membrana/genética , Triglicerídeos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/sangue , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Triglicerídeos/sangue , Ubiquitina-Proteína Ligases , Ubiquitinação
2.
J Org Chem ; 88(5): 2832-2840, 2023 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-36791405

RESUMO

A commercially available and versatile dehydrative amidation catalyst, featuring a thianthrene boron acid structure, has been developed. The catalyst shows high catalytic activity to both aliphatic and less reactive aromatic carboxylic acid substrates, including several bioactive or clinical molecules with a carboxylic acid group.

3.
FASEB J ; 33(3): 3784-3794, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30496701

RESUMO

Dendritic cells (DCs) have crucial roles in immune-related diseases. However, it is difficult to explore DCs because of their rareness and heterogeneity. Although previous studies had been performed to detect the phenotypic characteristics of DC populations, the functional diversity has been ignored. Using a combination of flow cytometry, single-cell quantitative PCR, and bioinformatic analysis, we depicted the DC panorama with not only phenotypic but also functional markers. Functional classification of DCs in mouse lymphoid tissue (spleen) and nonlymphoid tissue (liver) was performed. The results revealed that expression of macrophage scavenger receptor 1 ( MSR1) and C-C motif chemokine receptors ( CCR) 1, CCR2, and CCR4 were elevated in liver DCs, suggesting increased lipid uptake and migration abilities. The enriched expression of costimulatory molecule CD80, TLR9, and TLR adaptor MYD88 in spleen DCs indicated a more-mature phenotype, enhanced pathogen recognition, and T-cell stimulation abilities. Furthermore, we compared DCs in the atherosclerotic mouse models with healthy controls. In addition to the quantitative increase in DCs in the liver and spleen of the apolipoprotein E-knockout ( ApoE-/-) mice, the functional expression patterns of the DCs also changed at the single-cell level. These results promote our understanding of the participation of DCs in inflammatory diseases and have potential applications in DC clinical assessment.-Shi, Q., Zhuang, F., Liu, J.-T., Li, N., Chen, Y.-X., Su, X.-B., Yao, A.-H., Yao, Q.-P., Han, Y., Li, S.-S., Qi, Y.-X., Jiang, Z.-L. Single-cell analyses reveal functional classification of dendritic cells and their potential roles in inflammatory disease.


Assuntos
Células Dendríticas/patologia , Inflamação/patologia , Animais , Células Dendríticas/metabolismo , Citometria de Fluxo/métodos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR1/metabolismo , Receptores Depuradores Classe A/metabolismo , Análise de Célula Única/métodos , Baço/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia
4.
Proc Natl Acad Sci U S A ; 114(20): 5237-5242, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28461508

RESUMO

DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin-Sca1+cKit+ cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G2/M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3aR878H/WT mice.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Leucemia Mieloide Aguda/genética , Animais , Sequência de Bases , Diferenciação Celular , Metilação de DNA , DNA Metiltransferase 3A , Metilases de Modificação do DNA/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Técnicas de Introdução de Genes/métodos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Mutação , Serina-Treonina Quinases TOR/metabolismo , Transcriptoma
5.
Yi Chuan ; 42(7): 703-712, 2020 Jul 20.
Artigo em Zh | MEDLINE | ID: mdl-32694109

RESUMO

The analysis of genomic point mutations is one of the research strategies to explore the clonal evolution of tumor cells. At present, clonal evolution of tumor cells is mainly determined by bulk sampling and sequencing of different sections of the tumor. Since this approach analyzes a mixture of different cell types, it may not accurately represent the clonal evolution of specific tumor cell populations and likely miss low frequency mutations, especially when the sequencing depths are not sufficient. To address this issue, we have developed a strategy to analyze genomic point mutations from prostate basal cell carcinoma (BCC) tissues at single-cell resolution. Firstly, we optimized the single-cell whole genome amplification procedure with HepG2 cells. Then the single cells from BCC tissue were captured by a microfluidic chip of Fluidigm and processed for whole-genome amplification. Both SCUBE3 and MST1L genomic mutations were obtained by whole exome sequencing. Finally, we examined the genomic mutations through single-cell targeted amplification and Sanger sequencing. The established method successfully reconfirmed the mutations of SCUBE3 and MST1L in BCC at single cell level. The strategy established in this study could provide a useful tool for determining the clonal evolution of tumor cells based on genomic mutations at single-cell resolution.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mutação Puntual , Projetos de Pesquisa , Proteínas de Ligação ao Cálcio/genética , Genoma , Genômica , Humanos , Masculino , Mutação , Receptores Proteína Tirosina Quinases/genética , Análise de Célula Única
6.
Org Lett ; 24(41): 7492-7496, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36215416

RESUMO

Herein, we report a convenient solvent-controlled regioselective esterification to access two types of carboxylate esters without any additive or non-green activation strategy. In this transformation, 2-methyleneaziridines served as an ester reagent, providing two alternative electrophilic carbon centers. Notably, this protocol is suitable for some structure-complicated clinical molecules with a carboxylic acid group, presenting remarkable application potential.


Assuntos
Aziridinas , Ésteres , Solventes , Acetona , Ácidos Carboxílicos , Carbono
7.
Cancer Lett ; 546: 215869, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35964817

RESUMO

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.


Assuntos
Neoplasias Hepáticas , Proteínas Nucleares , Cromatina , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA , Humanos , Células-Tronco , Fatores de Transcrição
8.
Front Pharmacol ; 12: 775602, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925034

RESUMO

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor, and almost half of the patients carrying EGFR-driven tumor with PTEN deficiency are resistant to EGFR-targeted therapy. EGFR amplification and/or mutation is reported in various epithelial tumors. This series of studies aimed to identify a potent compound against EGFR-driven tumor. We screened a chemical library containing over 600 individual compounds purified from Traditional Chinese Medicine against GBM cells with EGFR amplification and found that cinobufagin, the major active ingredient of Chansu, inhibited the proliferation of EGFR amplified GBM cells and PTEN deficiency enhanced its anti-proliferation effects. Cinobufagin also strongly inhibited the proliferation of carcinoma cell lines with wild-type or mutant EGFR expression. In contrast, the compound only weakly inhibited the proliferation of cancer cells with low or without EGFR expression. Cinobufagin blocked EGFR phosphorylation and its downstream signaling, which additionally induced apoptosis and cytotoxicity in EGFR amplified cancer cells. In vivo, cinobufagin blocked EGFR signaling, inhibited cell proliferation, and elicited apoptosis, thereby suppressing tumor growth in both subcutaneous and intracranial U87MG-EGFR xenograft mouse models and increasing the median survival of nude mice bearing intracranial U87MG-EGFR tumors. Cinobufagin is a potential therapeutic agent for treating malignant glioma and other human cancers expressing EGFR.

9.
Sci Rep ; 6: 35270, 2016 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-27762310

RESUMO

Somatic mutations of many cancer genes tend to co-occur (termed co-mutations) in certain patterns during tumor initiation and progression. However, the genetic and epigenetic mechanisms that contribute to the co-mutations of these cancer genes have yet to be explored. Here, we systematically investigated the association between the somatic co-mutations of cancer genes and high-order chromatin conformation. Significantly, somatic point co-mutations in protein-coding genes were closely associated with high-order spatial chromatin folding. We propose that these regions be termed Spatial Co-mutation Hotspots (SCHs) and report their occurrence in different cancer types. The conserved mutational signatures and DNA sequences flanking these point co-mutations, as well as CTCF-binding sites, are also enriched within the SCH regions. The genetic alterations that are harboured in the same SCHs tend to disrupt cancer driver genes involved in multiple signalling pathways. The present work demonstrates that high-order spatial chromatin organisation may contribute to the somatic co-mutations of certain cancer genes during tumor development.


Assuntos
Fator de Ligação a CCCTC/genética , Cromatina/química , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias/genética , Oncogenes , Fator de Ligação a CCCTC/metabolismo , Cromatina/ultraestrutura , Montagem e Desmontagem da Cromatina , Progressão da Doença , Epigênese Genética , Loci Gênicos , Genoma Humano , Humanos , Neoplasias/classificação , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Transdução de Sinais , Biologia de Sistemas/métodos
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