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1.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

2.
Chem Commun (Camb) ; 55(58): 8359-8373, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31264670

RESUMO

Photo-switched spin-crossover (SCO) complexes, especially iron(ii)-based ones, have been widely studied in the past few decades owing to their promising applications in high density information storage, optical memory materials, magneto-optical devices and light-responsive switches. In particular, photo-induced spin-crossover involves not only the changing of the spin state and magnetic anisotropy of metal centers, but also the magnetic coupling interactions between neighbouring metal centers, which is also of vital importance to the overall magnetic properties. The exchange interactions can be reversibly switched on and off via light-induced excited spin-state trapping (LIESST) and reverse processes, leading to an abrupt changing of the magnetization value, spontaneous magnetization, and even molecular nanomagnet properties, depending on their dimensionalities and topologies. In this feature article, we will discuss the recent progress on the photoswitchable magnetic coupling in spin-crossover complexes reported by both our group and other groups and highlight the role of magnetic coupling in determining their magnetic properties. The design strategy of magnetically coupled photo-switched SCO complexes will be discussed. Finally, a perspective with respect to the remaining challenges and growing trends in this field will be given.

3.
J Exp Clin Cancer Res ; 37(1): 204, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157922

RESUMO

BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry. RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs. CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.


Assuntos
Citarabina/administração & dosagem , Células-Tronco Hematopoéticas/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Espécies Reativas de Oxigênio/metabolismo , Nicho de Células-Tronco/genética
4.
Clin Cancer Res ; 23(22): 7108-7118, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28912140

RESUMO

Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-ß-activated kinase 1 (TAK1) and NF-κB signaling by SAFB The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-κB signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1- and NF-κB-related genes.Conclusions: Our results show that SAFB regulated the activity of NF-κB signaling in CRC by targeting TAK1 This novel mechanism provides a comprehensive understanding of both SAFB and the NF-κB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-κB axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108-18. ©2017 AACR.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , MAP Quinase Quinase Quinases/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , NF-kappa B/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Receptores Estrogênicos/genética , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Prognóstico , Ligação Proteica , Receptores Estrogênicos/metabolismo , Transcrição Genética
5.
Cell Res ; 27(5): 606-625, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28418038

RESUMO

5-methylcytosine (m5C) is a post-transcriptional RNA modification identified in both stable and highly abundant tRNAs and rRNAs, and in mRNAs. However, its regulatory role in mRNA metabolism is still largely unknown. Here, we reveal that m5C modification is enriched in CG-rich regions and in regions immediately downstream of translation initiation sites and has conserved, tissue-specific and dynamic features across mammalian transcriptomes. Moreover, m5C formation in mRNAs is mainly catalyzed by the RNA methyltransferase NSUN2, and m5C is specifically recognized by the mRNA export adaptor ALYREF as shown by in vitro and in vivo studies. NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling, RNA-binding affinity and associated mRNA export. Dysregulation of ALYREF-mediated mRNA export upon NSUN2 depletion could be restored by reconstitution of wild-type but not methyltransferase-defective NSUN2. Our study provides comprehensive m5C profiles of mammalian transcriptomes and suggests an essential role for m5C modification in mRNA export and post-transcriptional regulation.


Assuntos
5-Metilcitosina/metabolismo , Metiltransferases/metabolismo , Proteínas Nucleares/metabolismo , Transporte de RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Células HeLa , Humanos , Masculino , Modelos Biológicos , Proteínas Nucleares/química , Especificidade de Órgãos/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Testículo/embriologia , Testículo/metabolismo , Fatores de Transcrição/química
7.
J Exp Clin Cancer Res ; 35(1): 152, 2016 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-27669982

RESUMO

BACKGROUND: Transducin-like enhancer of Split3 (TLE3) serves as a transcriptional corepressor during cell differentiation and shows multiple roles in different kinds of cancers. Recently, TLE3 together with many other genes involved in Wnt/ß-catenin pathway were detected hyper-methylated in colorectal cancer (CRC). However, the potential role and the underlying mechanism of TLE3 in CRC progression remain scarce. METHODS: Gene expression profiles were analyzed in The Cancer Genome Atlas (TCGA) microarray dataset of 41 normal colorectal intestine tissues and 465 CRC tissues. Western blot and Real-time Quantitative PCR (RT-qPCR) were respectively performed to detect protein and mRNA expression in 8 pairs of CRC tissue and matched adjacent normal mucosa. Immunohistochemistry (IHC) was conducted to evaluate TLE3 protein expression in 105 paraffin-embedded, archived human CRC tissues from patients, whose survival data were analyzed with Kaplan-Meier method. In vitro experiments including MTT assay, colony formation assay, and soft agar formation assay were used to investigate the effects of TLE3 on CRC cell growth and proliferation. Additionally, subcutaneous tumorigenesis assay was performed in nude mice to confirm the effects of TLE3 in vivo. Furthermore, gene set enrichment analysis (GSEA) was run to explore potential mechanism of TLE3 in CRC, and then we measured the distribution of CRC cell cycle phases and apoptosis by flow cytometry, as well as the impacts of TLE3 on MAPK and AKT signaling pathways by Western blot and RT-qPCR. RESULTS: TLE3 was significantly down-regulated in 465 CRC tissues compared with 41 normal tissues. Both protein and mRNA expressions of TLE3 were down-regulated in CRC compared with matched adjacent normal mucosa. Lower expression of TLE3 was significantly associated with poorer survival of patients with CRC. Besides, knock down of TLE3 promoted CRC cell growth and proliferation, while overexpression of TLE3 showed suppressive effects. Furthermore, overexpression of TLE3 caused G1-S phase transition arrest, inhibition of MAPK and AKT pathways, and up-regulation of p21Cip1/WAF1 and p27Kip1. CONCLUSION: This study indicated that TLE3 repressed CRC proliferation partly through inhibition of MAPK and AKT signaling pathways, suggesting the possibility of TLE3 as a biomarker for CRC prognosis.

8.
Mol Cell ; 61(4): 507-519, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26876937

RESUMO

The regulatory role of N(6)-methyladenosine (m(6)A) and its nuclear binding protein YTHDC1 in pre-mRNA splicing remains an enigma. Here we show that YTHDC1 promotes exon inclusion in targeted mRNAs through recruiting pre-mRNA splicing factor SRSF3 (SRp20) while blocking SRSF10 (SRp38) mRNA binding. Transcriptome assay with PAR-CLIP-seq analysis revealed that YTHDC1-regulated exon-inclusion patterns were similar to those of SRSF3 but opposite of SRSF10. In vitro pull-down assay illustrated a competitive binding of SRSF3 and SRSF10 to YTHDC1. Moreover, YTHDC1 facilitates SRSF3 but represses SRSF10 in their nuclear speckle localization, RNA-binding affinity, and associated splicing events, dysregulation of which, as the result of YTHDC1 depletion, can be restored by reconstitution with wild-type, but not m(6)A-binding-defective, YTHDC1. Our findings provide the direct evidence that m(6)A reader YTHDC1 regulates mRNA splicing through recruiting and modulating pre-mRNA splicing factors for their access to the binding regions of targeted mRNAs.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Processamento de RNA , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Sítios de Ligação , Éxons , Células HeLa , Humanos , Fatores de Processamento de RNA , RNA Mensageiro/metabolismo , Fatores de Processamento de Serina-Arginina
9.
Org Lett ; 17(8): 1914-7, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25826709

RESUMO

A multicomponent reaction has been developed for the synthesis of polyfunctional pyrazole derivatives from readily available arylglyoxal monohydrates, tosylhydrazine, and aldehydes or ketones. This synthetic method has significant advantages in broad substrate scope, excellent regioselectivity, and simple operation.


Assuntos
Pirazóis/síntese química , Aldeídos/química , Glioxal/análogos & derivados , Glioxal/química , Hidrazinas/química , Cetonas/química , Estrutura Molecular , Pirazóis/química , Estereoisomerismo
10.
Sheng Li Ke Xue Jin Zhan ; 37(4): 335-8, 2006 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-17262968

RESUMO

Dehydroepiandrosterone is the precursor of sex hormone, and can be synthesized in the brain de novo, which means it is a kind of neurosteroid. Animal experiments and clinical researches have proved that DHEA exhibits a variety of functional activities in the nervous system, including neurotrophic, neuroprotective effects and enhancement' of learning and memory, which suggests that it may be useful in preventing and treating some neural diseases such as neurodegenerative diseases, cerebral ischemia, trauma, psychosis and so on. The mechanisms of the effect of DHEA on protection against oxidative stress, excitotoxicity, apoptosis etc. were found to be through both genomic and nongenomic way. These effects and mechanisms in nervous system were summarized in the present paper.


Assuntos
Desidroepiandrosterona/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Desidroepiandrosterona/biossíntese , Desidroepiandrosterona/metabolismo , Sulfato de Desidroepiandrosterona/farmacologia , Humanos , Doenças Neurodegenerativas , Estresse Oxidativo/efeitos dos fármacos
11.
Acta Biochim Biophys Sin (Shanghai) ; 37(2): 119-25, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15685369

RESUMO

Neuroprotective effects of dehydroepiandrosterone (DHEA) have been shown to be associated with its antioxidant properties, but the mechanisms remain unknown. Considering that the thioredoxin (Trx) system, an important cellular redox modulation system, changes under oxidative stress and could exert protective effects, the relationship between the antioxidant effects of DHEA and the Trx system regulation was explored. Using MTT assay and morphological observation, the effects of DHEA in the model of H2O2-induced oxidative stress in SH-SY5Y cells were analyzed, then RT-PCR and Western blot assay were used to detect the alteration in mRNA and protein level of Trx. The results showed that a pre-treatment of DHEA (10-100 nM) protected cells against the toxicity induced by H2O2 in a dose-dependent manner, which could be confirmed in morphological observation by phase-contract microscope. In addition, Trx mRNA transcription was inhibited by H2O2 (300 microM), which could be reversed by the pre-administration of DHEA in various concentrations (0.1100 nM). Western blot assay confirmed that protein level of Trx could be elevated by the pre-treatment of DHEA (10100 nM) with the exposure of H2O2. Taken together, these data suggest that DHEA may be useful in treating age-related neurodegenerative diseases based on its up-regulating effects on an antioxidant and neuroprotective protein thioredoxin, a substrate in the Trx redox system.


Assuntos
Antioxidantes/farmacologia , Desidroepiandrosterona/farmacologia , Tiorredoxinas/metabolismo , Regulação para Cima/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Neuroblastoma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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