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1.
Nat Commun ; 11(1): 708, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024842

RESUMO

The metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis in order to provide cancer cells with energy and substrates of biosynthesis. Therefore, it is important to elucidate mechanisms controlling the cancer metabolic switch. MTR4 is a RNA helicase associated with a nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrate that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and is an independent diagnostic marker predicting the poor prognosis of HCC patients. MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. c-Myc binds to the promoter of the MTR4 gene and is important for MTR4 expression in HCC cells, indicating that MTR4 is a mediator of the functions of c-Myc in cancer metabolism. These findings reveal important roles of MTR4 in the cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.

2.
Cancer Cell ; 35(2): 191-203.e8, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30712844

RESUMO

The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier (MPC) through PUMA-MPC interaction, which depends on IκB kinase-mediated phosphorylation of PUMA at Ser96/106. High expression levels of PUMA are correlated with decreased mitochondrial pyruvate uptake and increased glycolysis in HCCs and poor prognosis of HCC patients. These findings are instrumental for cancer drug discovery aiming at activating WTp53 or restoring WTp53 activity to p53 mutants.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Neoplasias Hepáticas/metabolismo , Fosforilação Oxidativa , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Glicólise , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Quinase I-kappa B/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas/genética , Ácido Pirúvico/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 206: 97-103, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30086452

RESUMO

In this work, gold-silver alloy nanoclusters (AuAg NCs) were demonstrated as a novel probe for fluorescent detection of cysteine (Cys). The alloy nanoclusters were fabricated by bovine serum albumin as a template and NaBH4 as a reducer. They showed a red emission at 650 nm. The interaction between AuAg NCs and Cys was investigated. The thiol group in Cys molecules has strong affinity on the surface of metals, which results in variation of fluorescence peak wavelength. It was further demonstrated that this red-shift of fluorescence had a good linear relationship with the concentration of Cys in the range of 2-100 µM. The method was successfully applied for human plasma analysis with satisfactory results. This novel strategy was expected to provide a potential opportunity for extending the application of novel metal nanoclusters in fluorescence.


Assuntos
Cisteína/análise , Corantes Fluorescentes/química , Ouro/química , Nanopartículas Metálicas/química , Prata/química , Espectrometria de Fluorescência/métodos , Cisteína/sangue , Cisteína/química , Corantes Fluorescentes/síntese química , Humanos , Limite de Detecção , Modelos Lineares , Tamanho da Partícula , Reprodutibilidade dos Testes , Soroalbumina Bovina
4.
Nat Commun ; 9(1): 4176, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301979

RESUMO

Long non-coding RNAs (lncRNAs) have emerged as a new class of gene expression regulators playing key roles in many biological and pathophysiological processes. Here, we identify cardiac conduction regulatory RNA (CCRR) as an antiarrhythmic lncRNA. CCRR is downregulated in a mouse model of heart failure (HF) and in patients with HF, and this downregulation slows cardiac conduction and enhances arrhythmogenicity. Moreover, CCRR silencing induces arrhythmias in healthy mice. CCRR overexpression eliminates these detrimental alterations. HF or CCRR knockdown causes destruction of intercalated discs and gap junctions to slow longitudinal cardiac conduction. CCRR overexpression improves cardiac conduction by blocking endocytic trafficking of connexin43 (Cx43) to prevent its degradation via binding to Cx43-interacting protein CIP85, whereas CCRR silence does the opposite. We identified the functional domain of CCRR, which can reproduce the functional roles and pertinent molecular events of full-length CCRR. Our study suggests CCRR replacement a potential therapeutic approach for pathological arrhythmias.


Assuntos
Acoplamento Excitação-Contração/genética , Espaço Extracelular/metabolismo , Sistema de Condução Cardíaco/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Arritmias Cardíacas/genética , Conexina 43/metabolismo , Junções Comunicantes/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Insuficiência Cardíaca/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , RNA Longo não Codificante/genética , Transdução de Sinais , Frações Subcelulares/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
5.
Front Chem ; 6: 393, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333968

RESUMO

BiOCl/NaNbO3 p-n heterojunction photocatalysts with significantly improved photocatalytic performance were fabricated by a facile in-situ growth method. The obtained BiOCl/NaNbO3 samples were characterized by UV-vis absorption spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), photocurrent (PC) and photoluminescence spectroscopy (PL). The photocatalytic activity of the BiOCl/NaNbO3 samples was investigated by the degradation of a typical antibiotic Ofloxacin (OFX). The experimental results showed that BiOCl/NaNbO3 composites exhibited much higher photocatalytic activity for OFX degradation compared to pure NaNbO3 and BiOCl. The degradation percent of OFX reached 90% within 60 min, and the apparent rate constant was about 8 times as that of pure NaNbO3 and BiOCl. The improved activity can be attributed to the formation of p-n junction between NaNbO3 and BiOCl. The formed p-n junction facilitated the separation of photogenerated holes and electrons, thereby enhancing photocatalytic activity. In addition, the composite photocatalyst showed satisfactory stability for the degradation of OFX. Due to the simple synthesis process, high photocatalytic activity, and the good recyclability of these composite photocatalysts, the results of this study would provide a good example for the rational design of other highly efficient heterojunction photocatalytic materials.

6.
Medicine (Baltimore) ; 96(45): e8549, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29137068

RESUMO

RATIONALE: Carnitine-acylcarnitine translocate deficiency (CACTD) is a rare and life-threatening, autosomal recessive disorder of fatty acid ß-oxidation characterized by hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, liver dysfunction, and muscle weakness; culminating in early death. To date, CACTD cases screened from the Chinese mainland population, especially patient with compound heterozygote with c.199-10T>G and a novel c.1A>G mutation in the SLC25A20 gene has never been described. PATIENT CONCERNS: Herein, we report 2 neonatal cases of CACTD identified from the mainland China. These 2 patients were presented with severe metabolic crisis and their clinical conditions deteriorate rapidly and both died of cardiorespiratory collapse in the first week of life. We present the clinical and biochemical features of 2 probands and a brief literature review of previously reported CACTD cases with the c.199-10T>G mutation. DIAGNOSES: The acylcarnitine profiles by tandem-mass-spectrometry and the mutation analysis of SLC25A20 gene confirmed the diagnosis of CACTD in both patients. Mutation analysis demonstrated that patient No. 1 was homozygous for c.199-10T>G mutation, while patient No. 2 was a compound heterozygote for 2 mutations, a maternally-inherited c.199-10T>G and a paternally-inherited, novel c.1A>G mutation. INTERVENTIONS: Both patients were treated with an aggressive treatment regimen include high glucose and arginine infusion, respiratory, and circulatory support. OUTCOMES: The first proband died 3 days after delivery due to sudden cardiac arrest. The second patient's clinical condition, at one time, was improved by high glucose infusion, intravenous arginine, and circulatory support. However, the patient failed to wean from mechanical ventilation. Unfortunately, her parents refused further treatment due to fear of financial burdens. The patient died of congestive heart failure in the 6th day of life. LESSONS: We report the first 2 cases of CACTD identified from the mainland China. Apart from a founder mutation c.199-10T>G, we identified a novel c.1A>G mutation. Patients with CACTD with a genotype of c.199-10T>G mutation usually presents with a severe clinical phenotype. Early recognition and appropriate treatment is crucial in this highly lethal disorder. This case series highlights the importance of screening for metabolic diseases including CACTD in cases of sudden infant death and unexplained abrupt clinical deterioration in the early neonatal period.


Assuntos
Carnitina Aciltransferases/deficiência , Efeito Fundador , Erros Inatos do Metabolismo Lipídico/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Carnitina Aciltransferases/genética , China , Análise Mutacional de DNA , Evolução Fatal , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino
7.
J Cell Mol Med ; 21(9): 1803-1814, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28296001

RESUMO

This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for heart failure (HF). We measured the circulating levels of 13 individual lncRNAs which are known to be relevant to cardiovascular disease in the plasma samples from 72 HF patients and 60 non-HF control participants using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) methods. We found that out of the 13 lncRNAs tested, non-coding repressor of NFAT (NRON) and myosin heavy-chain-associated RNA transcripts (MHRT) had significantly higher plasma levels in HF than in non-HF subjects: 3.17 ± 0.30 versus 1.0 ± 0.07 for NRON (P < 0.0001) and 1.66 ± 0.14 versus 1.0 ± 0.12 for MHRT (P < 0.0001). The area under the ROC curve was 0.865 for NRON and 0.702 for MHRT. Univariate and multivariate analyses identified NRON and MHRT as independent predictors for HF. Spearman's rank correlation analysis showed that NRON was negatively correlated with HDL and positively correlated with LDH, whereas MHRT was positively correlated with AST and LDH. Hence, elevation of circulating NRON and MHRT predicts HF and may be considered as novel biomarkers of HF.


Assuntos
Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , RNA Longo não Codificante/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Prognóstico , Curva ROC , Análise de Regressão , Estatísticas não Paramétricas
8.
Fish Shellfish Immunol ; 35(2): 581-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23765116

RESUMO

Cathepsin L (CTSL) is a lysosomal cysteine protease involved in immune responses in vertebrates. However, few studies exist regarding the role of cathepsin L in bivalves. In this study, we isolated and characterized four cathepsin L genes from the razor clam Sinonovacula constricta, referred to as CTSL1, CTSL2, CTSL3 and CTSL4. These four genes contained typical papain-like cysteine protease structure and enzyme activity sites with ERWNIN-like and GNFD-like motifs in the proregion domain and an oxyanion hole (Gln) and a catalytic triad (Cys, His and Asn) in the mature domain. Expression analysis of the four transcripts revealed a tissue-specific pattern with high expression of CTSL1 and CTSL3 in liver and gonad tissues and high expression of CTSL2 and CTSL4 in liver and gill tissues. During the developmental stages, the four transcripts showed the highest expression in the juvenile stage; however, CTSL3 had a much higher expression level than the other three transcripts during embryogenesis. The four transcripts showed significant changes in expression as early as 4 h or 8 h after infection with Vibrio anguillarum. The fact that bacterial infection can induce expression of the four CTSL transcripts suggests that these transcripts are important components of the innate immunity system of the clam.


Assuntos
Bivalves/genética , Bivalves/imunologia , Catepsina L/genética , Regulação da Expressão Gênica , Imunidade Inata , Sequência de Aminoácidos , Animais , Bivalves/microbiologia , Catepsina L/química , Catepsina L/metabolismo , DNA Complementar/genética , DNA Complementar/metabolismo , Dados de Sequência Molecular , Especificidade de Órgãos , Filogenia , Estrutura Terciária de Proteína , Alinhamento de Sequência , Vibrio/fisiologia
9.
Mar Biotechnol (NY) ; 12(3): 282-91, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19590922

RESUMO

The Agamaki clam (Sinonovacula constricta) is an economically important shellfish in Asia. However, genomic research on this species is still in its infancy, and genomic resources are largely unavailable. The objective of this study was to generate expressed sequence tags (ESTs) from a normalized liver complementary DNA library and to identify genes that function in immune defense. A total of 5,296 ESTs were sequenced, from which 540 contigs and 3,473 singletons were identified. BLAST homology analysis indicated that only 20.7% of these ESTs were homologues of known genes while the remaining 79.3% appeared to be novel sequences. Based on sequence similarities, 43 putative immune genes were identified that encode proteases and protease inhibitors, adhesive proteins, stress proteins, lysosomal enzymes, and signal transduction regulators. Our study thus provides both a large collection of novel transcripts and a detailed annotation of immune genes for an important bivalve species.


Assuntos
Bivalves/genética , Bivalves/imunologia , Biologia Computacional/métodos , Etiquetas de Sequências Expressas , Animais , Perfilação da Expressão Gênica , Dados de Sequência Molecular
10.
J Biomol Screen ; 10(5): 447-55, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16093554

RESUMO

The currently approved kinase inhibitors for therapeutic uses and a number of kinase inhibitors that are undergoing clinical trials are directed toward the adenosine triphosphate (ATP) binding site of protein kinases. The 5'-fluorosulfonylbenzoyl 5'-adenosine (FSBA) is an ATP-affinity reagent that covalently modifies a conserved lysine present in the nucleotide-binding site of most kinases. The authors have developed a liquid chromatography/mass spectrometry-based method to monitor binding of ATP competitive protein kinase inhibitors using FSBA as a nonselective activity-based probe for protein kinases. Their method provides a general, rapid, and reproducible means to screen and validate selective ATP competitive inhibitors of protein kinases.


Assuntos
Cromatografia Líquida/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Espectrometria de Massas/métodos , Adenosina/análogos & derivados , Adenosina/farmacologia , Trifosfato de Adenosina/química , Marcadores de Afinidade/farmacologia , Apoptose , Autorradiografia , Sítios de Ligação , Ligação Competitiva , CDC2-CDC28 Quinases/metabolismo , Diferenciação Celular , Quinase 2 Dependente de Ciclina , Eletroforese em Gel de Poliacrilamida , Modelos Químicos , Fosfotransferases/metabolismo , Transdução de Sinais , Fatores de Tempo
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