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1.
Mol Cell ; 82(21): 4080-4098.e12, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36272410

RESUMO

Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.


Assuntos
Neoplasias , Corpos Nucleares , Humanos , Domínios Proteicos , Cromatina/genética , Mutação , Neoplasias/genética
2.
Blood ; 142(11): 973-988, 2023 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-37235754

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin-really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane-associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Linfoma Difuso de Grandes Células B , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Ubiquitina , Proteômica , Recidiva Local de Neoplasia/tratamento farmacológico , Rituximab/uso terapêutico , Vincristina , Ciclofosfamida , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Prednisona , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor Notch2/genética
3.
J Sci Food Agric ; 104(2): 716-726, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37658829

RESUMO

BACKGROUND: The demand for food-based anti-photoaging products is surging because of the rising recognition of health and beauty, as well as enhanced comprehension of the detrimental impact of ultraviolet (UV) radiation. This study aimed to investigate the potential of bioactive peptides derived from bovine elastin, specifically focusing on identifying novel elastase inhibitory peptides and assessing their photoprotective properties using bioinformatics techniques. RESULTS: A total of 48 bioactive peptides were screened in bovine elastin hydrolysate (EH) utilizing Peptide Ranker analysis. Three novel elastase inhibitory peptides, GAGQPFPI, FFPGAG and FPGIG (in descending order of activity), exhibited potent inhibitory effects on elastase in vitro, surpassing the inhibitory effect of EH by a factor of 1-2 and reaching significantly lower concentrations (8-15 times lower) than EH. The cumulative inhibitory effect of GAGQPFPI, FFPGAG, and FPGIG reached 91.5%. Further analysis revealed that FFPGAG and FPGIG exhibited mixed inhibition, whereas GAGQPFPI displayed non-competitive inhibition. Molecular simulations showed that these peptides interacted effectively with the elastase active site through hydrogen bonding and hydrophobic interactions. Furthermore, GAGQPFPI, FFPGAG, and FPGIG demonstrated high stability in gastrointestinal digestion, demonstrated transcellular permeability across Caco-2 cell monolayers, and exhibited remarkable photoprotective properties against UVB-irradiated HaCaT cells. CONCLUSION: GAGQPFPI showed the most promising potential as a functional food with photoprotective effects against UVB damage and inhibitory properties against elastase. © 2023 Society of Chemical Industry.


Assuntos
Elastase Pancreática , Dermatopatias , Humanos , Animais , Bovinos , Células CACO-2 , Peptídeos/farmacologia , Peptídeos/química , Elastina
4.
Brief Bioinform ; 22(6)2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34058751

RESUMO

Genetic and epigenetic contributions to various diseases and biological processes have been well-recognized. However, simultaneous identification of single-nucleotide variants (SNVs) and DNA methylation levels from traditional bisulfite sequencing data is still challenging. Here, we develop double strand bisulfite sequencing (DSBS) for genome-wide accurate identification of SNVs and DNA methylation simultaneously at a single-base resolution by using one dataset. Locking Watson and Crick strand together by hairpin adapter followed by bisulfite treatment and massive parallel sequencing, DSBS simultaneously sequences the bisulfite-converted Watson and Crick strand in one paired-end read, eliminating the strand bias of bisulfite sequencing data. Mutual correction of read1 and read2 can estimate the amplification and sequencing errors, and enables our developed computational pipeline, DSBS Analyzer (https://github.com/tianguolangzi/DSBS), to accurately identify SNV and DNA methylation. Additionally, using DSBS, we provide a genome-wide hemimethylation landscape in the human cells, and reveal that the density of DNA hemimethylation sites in promoter region and CpG island is lower than that in other genomic regions. The cost-effective new approach, which decodes DNA methylome and genomic variants simultaneously, will facilitate more comprehensive studies on numerous diseases and biological processes driven by both genetic and epigenetic variations.


Assuntos
Biologia Computacional/métodos , Metilação de DNA , Epigenômica/métodos , Análise de Sequência de DNA , Software , Sulfitos , Ilhas de CpG , Epigênese Genética , Patrimônio Genético , Genética Populacional , Genômica , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
5.
Hepatology ; 73(5): 1797-1815, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33058300

RESUMO

BACKGROUND AND AIMS: Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain-containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor. APPROACH AND RESULTS: Here, using a liver-specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine-induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. Setd2 deficiency down-regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High-fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2-deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c-Jun/activator protein 1 (AP-1) activation in the liver, which was trigged by accumulated lipid. c-Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2-deficient cells. CONCLUSIONS: We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c-Jun/AP-1 signaling.


Assuntos
Carcinoma Hepatocelular/etiologia , Histona-Lisina N-Metiltransferase/deficiência , Metabolismo dos Lipídeos , Neoplasias Hepáticas/etiologia , Fígado/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Colesterol/sangue , Imunoprecipitação da Cromatina , Edição de Genes , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células Hep G2 , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/sangue
6.
Exp Eye Res ; 219: 109023, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35276183

RESUMO

High myopia has been continually increasing globally until now and often results in visual impairment. Scleral extracellular matrix (ECM) remodeling is considered a common factor contributing to progression of myopia. However, the role of microRNAs (miRNAs) in regulating scleral ECM organization is not well understood. We aimed to explore the effect and regulatory mechanism of hsa-miR-142-3p on collagen I in human scleral fibroblasts in high myopia. First, next-generation sequencing was conducted to identify 37 miRNAs differentially expressed in the aqueous humor of high myopia samples and control samples. Furthermore, hsa-miR-142-3p in the aqueous humor was found to positively relate to the ocular axial length. Besides, the results of immunofluorescence and Western blot assay indicated that hsa-miR-142-3p overexpression decreased collagen I expression in the human fetal scleral fibroblasts (HFSFs); while hsa-miR-142-3p downregulation increased collagen I. Moreover, hsa-miR-142-3p targets TGFß-1 gene expression. Quantitative polymerase chain reaction (qPCR) and Western blot analysis showed that miRNA 142-3p reduced TGFß-1 expression while an inhibitor had an opposite effect. Therefore, there is an inverse relationship between changes in miR-142-3p expression levels and those of collagen1a1 in human scleral fibroblasts. Such a dependence suggests that miR-142-3p may be a target to improve therapeutic management of this condition.


Assuntos
MicroRNAs , Miopia , Colágeno/metabolismo , Fibroblastos/metabolismo , Humanos , MicroRNAs/metabolismo , Miopia/genética , Miopia/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
7.
Nucleic Acids Res ; 48(3): 1192-1205, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31950163

RESUMO

Somatic synonymous mutations are one of the most frequent genetic variants occurring in the coding region of cancer genomes, while their contributions to cancer development remain largely unknown. To assess whether synonymous mutations involved in post-transcriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types. By employing our developed algorithm, PIVar, we identified a total of 22,948 posttranscriptionally impaired synonymous SNVs (pisSNVs) spanning 2,042 genes. In addition, 35 RNA binding proteins impacted by these identified pisSNVs were significantly enriched. Remarkably, we discovered markedly elevated ratio of somatic pisSNVs across all 22 cancer types, and a high pisSNV ratio was associated with worse patient survival in five cancer types. Intriguing, several well-established cancer genes, including PTEN, RB1 and PIK3CA, appeared to contribute to tumorigenesis at both protein function and posttranscriptional regulation levels, whereas some pisSNV-hosted genes, including UBR4, EP400 and INTS1, exerted their function during carcinogenesis mainly via posttranscriptional mechanisms. Moreover, we predicted three drugs associated with two pisSNVs, and numerous compounds associated with expression signature of pisSNV-hosted genes. Our study reveals the prevalence and clinical relevance of pisSNVs in cancers, and emphasizes the importance of considering posttranscriptional impaired synonymous mutations in cancer biology.


Assuntos
Carcinogênese/genética , Genoma Humano/genética , Neoplasias/genética , Mutação Silenciosa/genética , Adulto , Idoso , Proteínas de Ligação a Calmodulina/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Exoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/classificação , Neoplasias/patologia , PTEN Fosfo-Hidrolase/genética , Intervalo Livre de Progressão , Processamento de Proteína Pós-Traducional/genética , Locos de Características Quantitativas/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Proteína Wnt1/genética
8.
Proc Natl Acad Sci U S A ; 116(21): 10447-10452, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31061131

RESUMO

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.


Assuntos
Carcinogênese/metabolismo , Colite/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17 , Animais , Diferenciação Celular , Colite/complicações , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Camundongos
9.
Biochem Biophys Res Commun ; 571: 46-52, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34303195

RESUMO

Asthma remains a severe public health problem. Long non-coding RNAs (lncRNAs) are potent regulators in various diseases including asthma. This study investigated the mechanism of lncRNA NF-κB interacting lncRNA (NKILA) in asthma. The model of asthma in mice was induced by ovalbum (OVA). LncRNA NKILA expression, serum total IgE level and expressions of inflammatory cytokines (IL-4, IL-5, IL-13, and TNF-α) in OVA-induced asthmatic mice were detected. NKILA was overexpressed to evaluate the airway inflammation and airway hyperresponsiveness (AHR) in asthmatic mice. Macrophage abundance, M1/M2-polarized macrophage numbers, and expressions of macrophage polarization-related genes were detected. Levels of the NF-κB pathway-related proteins were determined. Downregulated NKILA and upregulated total IgE level and expressions of inflammatory cytokines were observed in asthmatic mice. NKILA overexpression alleviated AHR and airway inflammation in asthmatic mice. NKILA reduced macrophage abundance and promoted M2 macrophage polarization in asthmatic mice. NKILA inhibited the NF-κB pathway in asthmatic mice. We highlighted that lncRNA NKILA limited the asthmatic airway inflammation via promoting M2 macrophage polarization and inhibiting the NF-κB pathway.


Assuntos
Asma/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Asma/patologia , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Camundongos , Camundongos Endogâmicos BALB C , RNA Longo não Codificante/genética
10.
Analyst ; 147(1): 55-65, 2021 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-34821249

RESUMO

As a neglected member of the platinum group elements, osmium, the metal with the highest density in the earth, is very suitable for the preparation of a peroxidase with high catalytic activity and stability, and can also be associated with the development of a sensor. In this study, we accessed Os nano-hydrangeas (OsNHs) with one-pot synthesis and utilized them in a bifunctional immunosensor that can present both catalytic chromogenic and tinctorial signal for nanozyme-linked immunosorbent assay (NLISA) and lateral flow immunoassay (LFIA) for use in folic acid (FA) detection. In the OsNHs-NLISA, the linear range is from 9.42 to 167.53 ng mL-1. The limit of detection (LOD) is 4.03 ng mL-1 and the IC50 value is 39.73 ng mL-1. In OsNHs-LFIA, the visual cut-off value and limit of detection (v-LOD) are 100 ng mL-1 and 0.01 ng mL-1, respectively. Additionally, the outcome from the specificity and spiked sample analysis offered recovery from the spiked milk powder sample ranging from 93.9 to 103.6% with a coefficient of variation under 4.9%, compared with UPLC-MS/MS for a correlation of R2 = 0.999 and admirable validation. The promising application of the OsNHs can also be used in other bioprobes, and this bifunctional immunosensor analysis mode is suitable for diversified analytes.


Assuntos
Técnicas Biossensoriais , Hydrangea , Cromatografia Líquida , Ácido Fólico , Imunoensaio , Osmio , Espectrometria de Massas em Tandem
11.
Nanotechnology ; 32(19): 195709, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33535190

RESUMO

Achieving a balanced strength-toughness in polymer composites is a challenge largely because of poor interfacial interaction between the fillers and matrix. Here, we report that terpolymer grafted multi-wall carbon nanotubes (Ter-CNT) imparted good dispersion of CNT in matrix and strong CNT-matrix interaction. With the addition of 2 vol% filler into polymethyl methacrylate (PMMA) matrix, the composite exhibited simultaneously a balanced strength-toughness property with flexural strength of 72.3 MPa, toughness of 10.1 MJ m-3, which increased by 40.1% and 578% compared with those of pure PMMA. In addition, the composite also shows a high static contact angle (110.3°), and thermal conductivity (0.50 Wm K-1), which endow the composite with good self-cleaning and thermal management capabilities. Thus, this preparation process shows guidance for the design of polymer composite with integrated high strength-toughness, thermal conductivity and good self-cleaning.

12.
Nucleic Acids Res ; 47(5): 2349-2364, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30649550

RESUMO

Hippo pathway is involved in tumorigenesis, and its regulation in cytosol has been extensively studied, but its regulatory mechanisms in the nuclear are not clear. In the current study, using a FBS-inducing model following serum starvation, we identified KDM3A, a demethylase of histone H3K9me1/2, as a positive regulator for hippo target genes. KDM3A promotes gene expression through two mechanisms, one is to upregulate YAP1 expression, and the other is to facilitate H3K27ac on the enhancers of hippo target genes. H3K27ac upregulation is more relevant with gene activation, but not H3K4me3; and KDM3A depletion caused H3K9me2 upregulation mainly on TEAD1-binding enhancers rather than gene bodies, further resulting in H3K27ac decrease, less TEAD1 binding on enhancers and impaired transcription. Moreover, KDM3A is associated with p300 and required for p300 recruitment to enhancers. KDM3A deficiency delayed cancer cell growth and migration, which was rescued by YAP1 expression. KDM3A expression is correlated with YAP1 and hippo target genes in colorectal cancer patient tissues, and may serve as a potential prognosis mark. Taken together, our study reveals novel mechanisms for hippo signaling and enhancer activation, which is critical for tumorigenesis of colorectal cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Histona Desmetilases com o Domínio Jumonji/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Histona-Lisina N-Metiltransferase/genética , Humanos , Proteínas Nucleares/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
13.
Mikrochim Acta ; 187(12): 675, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33241461

RESUMO

A highly sensitive colorimetric sensing strategy based on enzyme@metal-organic framework (GAA@Cu-MOF) and IrO2/MnO2 nanocomposite was exploited innovatively for screening of α-glucosidase (GAA) inhibitors. IrO2/MnO2 nanocomposite exhibits excellent oxidase-mimicking activity which can directly catalyze the oxidation of 3,3,5,5,-tetramethylbenzidine (TMB) into a blue product with an absorption maximum at 652 nm. And GAA@Cu-MOF can decompose L-ascorbic acid-2-O-α-D-glucopyranosyl (AAG) to ascorbic acid (AA). The produced AA can destroy the IrO2/MnO2 nanocomposite and reduce its oxidase-like activity. However, the generation of AA is restricted when GAA inhibitors are added to the system, which allows the oxidase-like activity of the IrO2/MnO2 nanocomposite to be maintained. In view of this, a method for screening of GAA inhibitors was developed. In addition to enhancing the stability of GAA, the method can also effectively avoid the potential interference of H2O2 in the screening process of GAA inhibitors, which helps to improve the sensitivity of the method. Therefore, highly sensitive determination for acarbose and ascorbic acid are achieved with detection limits of 6.27 nM and 1.23 µM, respectively. The proposed method was successfully applied to screen potential GAA inhibitors from oleanolic acid derivatives. Graphical abstract.


Assuntos
Colorimetria/métodos , Inibidores de Glicosídeo Hidrolases/análise , Estruturas Metalorgânicas/química , Nanocompostos/química , alfa-Glucosidases/metabolismo , Acarbose/análise , Ácido Ascórbico/análise , Catálise , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Irídio/química , Limite de Detecção , Compostos de Manganês/química , Óxidos/química , alfa-Glucosidases/química
14.
Biochim Biophys Acta Mol Cell Res ; 1865(7): 970-980, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29655804

RESUMO

ERAD is an important process of protein quality control that eliminates misfolded or unassembled proteins from ER. Before undergoing proteasome degradation, the misfolded proteins are dislocated from ER membrane into cytosol, which requires the AAA ATPase p97/VCP and its cofactor, the NPL4-UFD1 dimer. Here, we performed a CRISPR-based screen and identify many candidates for ERAD regulation. We further confirmed four proteins, FBOX2, TRIM6, UFL1 and WDR20, are novel regulators for ERAD. Then the molecular mechanism for WDR20 in ERAD is further characterized. Depletion of WDR20 inhibits the degradation of TCRα, a typical ERAD substrate, while WDR20 overexpression reduces TCRα protein level. WDR20 associates with TCRα and central regulators of the ERAD system, p97, GP78 and HRD1. A portion of WDR20 localizes to the ER-containing microsomal membrane. WDR20 expression increases TCRα ubiquitination, and HRD1 E3 ligase is essential for the process. WDR20 seems to serve as an adaptor protein to mediate the interaction between p97 and TCRα. Our study provides novel candidates and reveals an unexpected role of WDR20 in ERAD regulation.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Degradação Associada com o Retículo Endoplasmático , Adenosina Trifosfatases/metabolismo , Sistemas CRISPR-Cas , Proteínas de Transporte/química , Linhagem Celular Tumoral , Células HEK293 , Humanos , Microssomos/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Ubiquitinação
15.
J Immunol ; 198(3): 1274-1284, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011935

RESUMO

Upon virus infection, host cells use retinoic-acid-inducible geneI I (RIG-I)-like receptors to recognize viral RNA and activate type I IFN expression. To investigate the role of protein methylation in the antiviral signaling pathway, we screened all the SET domain-containing proteins and identified TTLL12 as a negative regulator of RIG-I signaling. TTLL12 contains SET and TTL domains, which are predicted to have lysine methyltransferase and tubulin tyrosine ligase activities, respectively. Exogenous expression of TTLL12 represses IFN-ß expression induced by Sendai virus. TTLL12 deficiency by RNA interference and CRISPR-gRNA techniques increases the induced IFN-ß expression and inhibits virus replication in the cell. The global gene expression profiling indicated that TTLL12 specifically inhibits the expression of the downstream genes of innate immunity pathways. Cell fractionation and fluorescent staining indicated that TTLL12 is localized in the cytosol. The mutagenesis study suggested that TTLL12's ability to repress the RIG-I pathway is probably not dependent on protein modifications. Instead, TTLL12 directly interacts with virus-induced signaling adaptor (VISA), TBK1, and IKKε, and inhibits the interactions of VISA with other signaling molecules. Taken together, our findings demonstrate TTLL12 as a negative regulator of RNA-virus-induced type I IFN expression by inhibiting the interaction of VISA with other proteins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Transporte/fisiologia , Interferon Tipo I/fisiologia , Transdução de Sinais/fisiologia , Proteínas de Transporte/análise , Linhagem Celular , Citosol/química , Proteína DEAD-box 58/fisiologia , Humanos , Quinase I-kappa B/fisiologia , Imunidade Inata , Proteínas Serina-Treonina Quinases/fisiologia , Receptores Imunológicos , Replicação Viral
16.
Mol Carcinog ; 57(3): 419-428, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29144562

RESUMO

Cisplatin-based chemotherapy is the most commonly used treatment regimen for lung cancer. Cancer stem cells (CSCs) are postulated to be important promoters of drug resistance. We previously found that miR-5100 is overexpressed in lung cancer, but it is unknown whether and how miR-5100 regulates cisplatin resistance. Here, we demonstrated that miR-5100 was significantly up-regulated in CD44+ CD133+ lung cancer stem cells (LCSCs) compared with non-CSCs. Additionally, over-expression of miR-5100 increased CSC properties, cell growth, and tumor sphere formation in lung cancer cell line A549 or H1299, and that miR-5100 inhibitor significantly increased sensitivity of LCSCs to cisplatin in vitro. Surprisingly, the combination with miR-5100 inhibitor significantly decreased the IC50 of LCSCs to cisplatin. Furthermore, miR-5100 increased CSC properties and cisplatin resistance by inhibiting Rab6, a direct target gene of miR-5100. We demonstrated that miR-5100 overexpression increases the cisplatin resistance of the LCSCs through the mitochondrial apoptosis pathway. In conclusion, our results suggest that miR-5100 increases the cisplatin resistance of the LCSCs by inhibiting the Rab6. This study provides novel insight into the regulation of LCSCs by miRNA.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas rab de Ligação ao GTP/genética , Células A549 , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
17.
Chemistry ; 20(11): 2998-3004, 2014 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-24585543

RESUMO

Acetylcholine (ACh), a neurotransmitter located in cholinergic synapses, can trigger cargo release from mesoporous silica nanoparticles equipped with calixarene- or pillarene-based nanovalves by removing macrocycles from the stalk components. The amount and speed of cargo release can be controlled by varying the concentration of ACh in solution or changing the type of gating macrocycle. Although this proof-of-concept study is far from a real-life application, it provides a possible route to treat diseases related to the central nervous system.


Assuntos
Acetilcolina/química , Acetilcolina/farmacologia , Materiais Biocompatíveis/química , Calixarenos/química , Sistema Nervoso Central/química , Sistema Nervoso Central/efeitos dos fármacos , Compostos Macrocíclicos/química , Nanopartículas/química
18.
Medicine (Baltimore) ; 103(12): e37455, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38518007

RESUMO

RATIONALE: Cryptococcosis presenting as endobronchial obstruction and lung collapse is an extremely rare occurrence. While these patients were treated with antifungal agents, unfortunately, half of them showed a suboptimal response. PATIENT CONCERNS: A 45-year-old immunocompetent male was admitted to the hospital due to a cough, yellow phlegm, and dyspnea persisting for 5 months. Chest computer tomography revealed a mass in the right main bronchus accompanied by right lower lobe atelectasis. DIAGNOSES: Endobronchial cryptococcosis presenting as endobronchial obstruction and lung collapse. INTERVENTIONS: Early rigid bronchoscopic therapy was performed to resect endobronchial obstruction, which combined with antifungal agent. OUTCOMES: The patient recovered well with completely clinical and radiologic resolution at 1 year follow-up. LESSONS: This case provides a good example of successful utilization of the early respiratory interventional therapy combined with antifungal agent in obstructive endobronchial cryptococcosis.


Assuntos
Obstrução das Vias Respiratórias , Broncopatias , Criptococose , Atelectasia Pulmonar , Humanos , Masculino , Pessoa de Meia-Idade , Antifúngicos/uso terapêutico , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Brônquios/diagnóstico por imagem , Brônquios/microbiologia , Pulmão/microbiologia , Broncopatias/tratamento farmacológico , Broncopatias/complicações , Obstrução das Vias Respiratórias/etiologia
19.
J Colloid Interface Sci ; 673: 893-900, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38908288

RESUMO

Cervical cancer is one of the most common gynecological malignancies, with the vast majority of which being caused by persistent infection with Human Papillomavirus (HPV) 16 and 18. The current available HPV detection methods are sensitive and genotyped but are restricted by expensive instruments and skilled personnel. The development of an easy-to-use, rapid, and cost-friendly analysis method for HPV is of great need. Herein, hollow palladium-ruthenium nanocages modified with two oligonucleotides (PdRu capture probes) were constructed for genotyping and simultaneous detection of target nucleic acids HPV16 and HPV18 by dual lateral flow assay (DLFA). PdRu capture probes were endowed with bi-functions for the first time, which could be used to output signals and hybridize target nucleic acids. Under optimized conditions, the PdRu based-DLFA with detection limits of 0.93 nM and 0.19 nM, respectively, exhibited convenient operation, and high sensitivity. Meanwhile, the DLFA achieved excellent rapid detection within 20 min, which was attributed to capture probes that can be directly bound to amplification-free target nucleic acids. Therefore, the development of PdRu-based DLFA can be utilized for rapid, sensitive, and simultaneous genotyping detection of HPV16 and HPV18, showing great application for nucleic acid detection.

20.
Front Public Health ; 12: 1296714, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716251

RESUMO

The forest experience is good for people's physical and mental health. However, few studies on the effects of pure forest based on the duration and way of experience on people's physical and mental recovery. In this study, we took 180 first-year college students as research objects and conducted experiments in Pinus sylvestris and Betula platyphylla and the control group of grass plot. The changes of physiological and psychological indexes of the subjects were compared by two perception methods (onsite perception, video perception) and three perception duration (10 min, 20 min, 30 min). The results indicated that: (1) Differences between the two pure forests were mainly reflected in short-term recovery of diastolic blood pressure (DBP) and long-term recovery of total mood disorder (TMD). (2) Video perception was more conducive to short-term recovery of systolic blood pressure (SBP) and diastolic blood pressure (DBP). (3) Viewing the Pinus sylvestris for 20 min in different ways was the best way to relieve stress. It is suggested that, Pinus sylvestris can be used as the rehabilitation perception material, and reasonable path length or perception time can be selected for landscape construction in future. These results can provide scientific reference for landscape design based on forest health and environmental perception.


Assuntos
Pressão Sanguínea , Florestas , Humanos , Masculino , Feminino , Adulto Jovem , Pressão Sanguínea/fisiologia , Betula , Percepção , Pinus sylvestris , Adulto , Fatores de Tempo
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