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1.
Artigo em Inglês | MEDLINE | ID: mdl-31833556

RESUMO

PURPOSE: Genome-wide association studies (GWASs) have identified hundreds of SNPs associated with osteoporosis. Most of these SNPs are non-coding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs, thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis. METHODS: We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. RESULTS: After functional annotation, a total of 5,081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = 0.028) and NRSF (Padj = 0.038). We also found one SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32×10-4; spine BMD: P = 2.72×10-3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice. CONCLUSIONS: By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis.

2.
J Exp Clin Cancer Res ; 38(1): 417, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623651

RESUMO

BACKGROUND: MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. METHODS: The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. RESULTS: The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/ß-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/ß-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. CONCLUSIONS: Our studies indicate that MEISC/D promote HCC development via Wnt/ß-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , Adulto , Idoso , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Progressão da Doença , Feminino , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Bioresour Technol ; 293: 122081, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31479855

RESUMO

It is very important to utilize associated vegetable products as resources, especially in large-scale vegetable cultivation areas. In this study, pepper straw, a vegetable waste, was pyrolyzed into pepper straw biochars (PBs) to investigate their sorption potential for phthalate acid esters (PAEs). The results showed that PBs have porous structures and abundant surface functional groups. Dibutyl phthalate (DBP) and dimethyl phthalate (DMP) removal by PBs was divided into two stages, fast and slow sorption. The PBs pyrolyzed at 500 °C showed greater DBP and DMP sorption capacity than those pyrolyzed at 400 and 600 °C. Both chemical and physical sorption occurred in the whole sorption process of PAEs to PBs. It is proposed that converting pepper straw into biochars to use as sorbents could be an environmentally friendly way of vegetable waste resource utilization.


Assuntos
Ésteres , Ácidos Ftálicos , Adsorção , Carvão Vegetal , Dibutilftalato , Verduras , Água
4.
Artigo em Inglês | MEDLINE | ID: mdl-31385379

RESUMO

Genetic interaction has been recognized to be an important cause of the missing heritability. The topologically associating domain (TAD) is a self-interacting genomic region, and the DNA sequences within a TAD physically interact with each other more frequently. Sex differences influence cancer susceptibility at the genetic level. Here, we performed both regular and sex-specific genetic interaction analyses within TAD to identify susceptibility genes for lung cancer in 5204 lung cancer patients and 7389 controls. We found that one SNP pair, rs4262299-rs1654701, was associated with lung cancer in women after multiple testing corrections (combined P = 8.52 × 10-9 ). Single-SNP analyses did not detect significant association signals for these two SNPs. Both identified SNPs are located in the intron region of ANGPT1. We further found that 5% of nonsmall cell lung cancer patients have an alteration in ANGPT1, indicated the potential role of ANGPT1 in the neoplastic progression in lung cancer. The expression of ANGPT1 was significantly down-regulated in patients in lung squamous cell carcinoma and lung adenocarcinoma. We checked the interaction effect on the ANGPT1 expression and lung cancer and found that the minor allele "G" of rs1654701 increased ANGPT1 gene expression and decreased lung cancer risk with the increased dosage of "A" of rs4262299, which consistent with the tumor suppressor function of ANGPT1. Survival analyses found that the high expression of ANGPT1 was individually associated with a higher survival probability in lung cancer patients. In summary, our results suggest that ANGPT1 may be a novel tumor suppressor gene for lung cancer.

5.
Sci Total Environ ; 695: 133879, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31425980

RESUMO

It remains unclear whether biochar amendment can mediate changes in soil microbial communities caused by organic contaminants in the rhizosphere. In this study, phenanthrene-contaminated soil was amended with biochar and oxalic acid (OA) alone or in combination and incubated for 21 days. Phospholipid fatty acids (PLFAs) and high-throughput sequencing were used to evaluate shifts in bacterial and fungal community structure. Phenanthrene stress led to significant shifts in both soil bacterial and fungal community structure, in particularly, 82% of microbial phyla decreased in abundance. Biochar and/or OA improved the phenanthrene-polluted soil by positively mediating shifts in soil microbial communities stressed by phenanthrene. Specifically, biochar and/or OA led to the survival of certain microbial taxa that were inhibited by phenanthrene stress. In addition, many functional microbial individuals and genes participating in polycyclic aromatic hydrocarbon (PAH) degradation were positively stimulated by high phenanthrene stress and further stimulated by the simultaneous application of biochar and OA. Based on these findings, tandem biochar and rhizoremediation may be a feasible strategy for relieving PAH toxicity to soil microbial communities.


Assuntos
Carvão Vegetal/química , Recuperação e Remediação Ambiental/métodos , Ácido Oxálico/química , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Microbiologia do Solo , Poluentes do Solo/toxicidade , Biodegradação Ambiental , Microbiota
6.
Pharmacol Res ; 144: 227-234, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31028905

RESUMO

Ischemic stroke is a major cause of mortality and disability worldwide. To date there is no ideal effective treatment. 3, 14, 19-triacetyl andrographolide (CX-10) is a new molecule entity derived from andrographolide. The aim of the present study was to evaluate the neuroprotection of CX-10 against experimental cerebral ischemia. The anti-inflammation of CX-10 was screened using LPS-induced inflammation in vitro and in vivo. Rats were subjected to 1.5 h of middle cerebral occlusion (MCAO) and then reperfusion for 72 h. The infarct size was evaluated by TTC staining, and the behavioral disturbance was evaluated, and inflammatory cytokines and anti-oxidant enzymes in brain tissues were examined. Western blot was used to analyze the expression of proteins. The results showed that CX-10 exerted potent anti-inflammatory and anti-oxidation activities, which significantly inhibited LPS-induced TNF-α and NO release, lowered TNF-α and IL-1ß levels in the brain, meanwhile increased activities of SOD, CAT and GSH-P × . The effect of CX-10 was equivalent to that of dexamethasone, and was obviously superior to that of andrographolide. CX-10 exhibited a neuroprotective effects, manifested as reducing infarct size, improving neurological function and reducing motor impairments. Furthermore, western blot analysis revealed that treatment with CX-10 down-regulated the expression of TLR4, NF-κB, TNF-α and iNOS, induced Nrf2 and HO-1 expression. Overall, CX-10 has a favorable neuroprotection in ischemic brain injury. The mechanism may involve inhibition of TLR4/NF-κB signaling pathway and upregulation of Nrf2/ARE signaling pathway. All these indicated that CX-10 is likely to be a promising agent for ischemic stroke.

7.
Transl Psychiatry ; 9(1): 56, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705251

RESUMO

Nearly 95% of susceptibility SNPs identified by genome-wide association studies (GWASs) are located in non-coding regions, which causes a lot of difficulty in deciphering their biological functions on disease pathogenesis. Here, we aimed to conduct a comprehensive functional annotation for all the schizophrenia susceptibility loci obtained from GWASs. Considering varieties of epigenomic regulatory elements, we annotated all 22,688 acquired susceptibility SNPs according to their genomic positions to obtain functional SNPs. The comprehensive annotation indicated that these functional SNPs are broadly involved in diverse biological processes. Histone modification enrichment showed that H3K27ac, H3K36me3, H3K4me1, and H3K4me3 were related to the development of schizophrenia. Transcription factors (TFs) prediction, methylation quantitative trait loci (meQTL) analyses, expression quantitative trait loci (eQTL) analyses, and proteomic quantitative trait loci analyses (pQTL) identified 447 target protein-coding genes. Subsequently, differential expression analyses between schizophrenia cases and controls, nervous system phenotypes from mouse models, and protein-protein interaction with known schizophrenia-related pathways and genes were carried out with our target genes. We finaly prioritized 10 target genes for schizophrenia (CACNA1C, CLU, CSNK2B, GABBR1, GRIN2A, MAPK3, NOTCH4, SRR, TNF, and SYNGAP1). Our results may serve as an encyclopedia of schizophrenia susceptibility SNPs and offer holistic guides for post-GWAS functional experiments.


Assuntos
Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Metilação de DNA , Epigênese Genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Código das Histonas , Histonas/genética , Humanos , Rombencéfalo/metabolismo , Esquizofrenia/metabolismo
8.
Int J Obes (Lond) ; 43(3): 450-456, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29717274

RESUMO

BACKGROUND: Genome-wide association studies have identified many susceptibility loci for obesity. However, missing heritability problem is still challenging and ignorance of genetic interactions is believed to be an important cause. Current methods for detecting interactions usually do not consider regulatory elements in non-coding regions. Interaction analyses within chromatin regulatory circuitry may identify new susceptibility loci. METHODS: We developed a pipeline named interaction analyses within chromatin regulatory circuitry (IACRC), to identify genetic interactions impacting body mass index (BMI). Potential interacting SNP pairs were obtained based on Hi-C datasets, PreSTIGE (Predicting Specific Tissue Interactions of Genes and Enhancers) algorithm, and super enhancer regions. SNP × SNP analyses were next performed in three GWAS datasets, including 2286 unrelated Caucasians from Kansas City, 3062 healthy Caucasians from the Gene Environment Association Studies initiative, and 3164 Hispanic subjects from the Women's Health Initiative. RESULTS: A total of 16,643,227 SNP × SNP analyses were performed. Meta-analyses showed that two SNP pairs, rs6808450-rs9813534 (combined P = 2.39 × 10-9) and rs6808450-rs3773306 (combined P = 2.89 × 10-9) were associated with BMI after multiple testing corrections. Single-SNP analyses did not detect significant association signals for these three SNPs. In obesity relevant cells, rs6808450 is located in intergenic enhancers, while rs9813534 and rs3773306 are located in the region of strong transcription regions of CAND2 and RPL32, respectively. The expression of CAND2 was significantly downregulated after the differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cells (P = 0.0241). Functional validation in the International Mouse Phenotyping Consortium database showed that CAND2 was associated with increased lean body mass and decreased total body fat amount. CONCLUSIONS: Detecting epistasis within chromatin regulatory circuitry identified CAND2 as a novel obesity susceptibility gene. We hope IACRC could facilitate the interaction analyses for complex diseases and offer new insights into solving the missing heritability problem.


Assuntos
Epistasia Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas Musculares/genética , Obesidade , Fatores de Transcrição/genética , Adulto , Idoso , Índice de Massa Corporal , Cromatina/genética , Humanos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética
9.
Brief Bioinform ; 20(1): 26-32, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28968709

RESUMO

Genome-wide association studies (GWASs) are an effective strategy to identify susceptibility loci for human complex diseases. However, missing heritability is still a big problem. Most GWASs single-nucleotide polymorphisms (SNPs) are located in noncoding regions, which has been considered to be the unexplored territory of the genome. Recently, data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap Epigenomics projects have shown that many GWASs SNPs in the noncoding regions fall within regulatory elements. In this study, we developed a pipeline named functional disease-associated SNPs prediction (FDSP), to identify novel susceptibility loci for complex diseases based on the interpretation of the functional features for known disease-associated variants with machine learning. We applied our pipeline to predict novel susceptibility SNPs for type 2 diabetes (T2D) and hypertension. The predicted SNPs could explain heritability beyond that explained by GWAS-associated SNPs. Functional annotation by expression quantitative trait loci analyses showed that the target genes of the predicted SNPs were significantly enriched in T2D or hypertension-related pathways in multiple tissues. Our results suggest that combining GWASs and regulatory features data could identify additional functional susceptibility SNPs for complex diseases. We hope FDSP could help to identify novel susceptibility loci for complex diseases and solve the missing heritability problem.


Assuntos
Estudo de Associação Genômica Ampla/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Biologia Computacional , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Aprendizado de Máquina , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Locos de Características Quantitativas , Sequências Reguladoras de Ácido Nucleico
10.
Cell Signal ; 53: 390-399, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448346

RESUMO

Actin-like 6A (ACTL6A), a component of BAF chromatin remodeling complexes, is important for cell differentiation. Nevertheless, its role and mechanism in acute promyelocytic leukemia (APL) has not been reported. To identify the genes that may participate in the development of APL, we analyzed data from an APL cDNA microarray (GSE12662) in the NCBI database, and found that ACTL6A was up-regulated in APL patients. Subsequently, we investigated the function and mechanisms of ACTL6A in myeloid cell development. The expression of ACTL6A was gradually decreased during granulocytic differentiation in all-trans retinoic acid-treated NB4 and HL-60 cells, and phorbol myristate acetate-treated HL-60 cells. We also found that knockdown of ACTL6A promoted differentiation in NB4 and HL-60 cells, and decreased the levels of Sox2 and Notch1. Mechanistically, ACTL6A interacted with and was co-localized with Sox2 and p53. Meanwhile, CBL0137, an activator of p53, decreased the expression of ACTL6A and promoted differentiation in NB4 and HL-60 cells. These findings suggest that the inhibition of ACTL6A promotes differentiation via the Sox2 and Notch1 signaling pathways. Furthermore, the differentiation promoted by inhibiting ACTL6A could be regulated by p53 via its physical interaction with ACTL6A.


Assuntos
Actinas/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Células HL-60 , Humanos , Mapas de Interação de Proteínas , Transdução de Sinais
11.
Chem Sci ; 10(45): 10577-10585, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-32110343

RESUMO

Effective conversion of solar energy into chemical energy by visible light represents a potential strategy for sustainable development. Among which, photocatalytic hydrogen evolution reaction (HER) with a relatively small activation energy (1.23 eV, around 1000 nm light irradiation) is especially attractive. In this work, well-distributed platinum nanoparticles (Pt-NPs) with a width of about 3 nm have been successfully immobilized into the confined coordination interspaces of 3.7 nm diameter, which are facilitated by early transition metal Hf(iv)-based clusters of a self-sensitized palladium porphyrin metal-organic framework. Under visible light irradiation, the resultant Pt@Pd-PCN-222(Hf) (which is also denoted as Pt@Pd-PMOF-2(Hf)) displays superb photocatalytic activity, achieving an unprecedented maximum H2 evolution rate of 22 674 µmol g-1 h-1 with a turn-over number (TON) of 4131.2 in 32 h and the highest turn-over frequency (TOF) of 482.5 h-1 based on Pt-NPs. This photocatalyst can be recycled and reused for three successive runs without significant loss of catalytic activity. This effective strategy takes advantage of the synergetic effect between Pd-porphyrin photosensitizers and Pt-NP co-catalysts confined within nanoscale coordination interspaces incorporating hydrophilic Hf(iv)-oxo clusters.

12.
J Cancer ; 9(21): 3858-3866, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410588

RESUMO

Although genome-wide association studies (GWASs) have identified some risk single-nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 × 10-4 - 1.35 × 10-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females.

13.
Huan Jing Ke Xue ; 39(2): 684-690, 2018 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-29964831

RESUMO

Spatio-temporal distribution of PM2.5 and variations in the relationship between PM2.5 and other pollutants are the main components of PM2.5spatio-temporal statistical analysis. Existing methods directly analyze spatio-temporal distribution based on monitoring data; thus, it is difficult to effectively reveal the aggregation structure of PM2.5 concentrations. Geographically weighted regression, commonly used to model the relationships between PM2.5 and other pollutants, cannot accurately describe the spatio-temporal variability of dependency. In this study, the clustering structure of PM2.5 concentrations in Beijing was identified using the spatial clustering algorithm and the seasonal distribution characteristics of PM2.5 were analyzed based on the clustering results. The relationship between PM2.5 and PM10 was modeled by geographically and temporally weighted regression and the spatio-temporal variability of dependency was analyzed according to the regression results. The results showed that PM2.5 pollution levels and spatial variability were lower in spring and summer than those in autumn and winter and the concentration of PM2.5 in each season was characterized by low spatial distribution in the north and high spatial distribution in the south. Geographically and temporally weighted regression showed better performance; the correlations between PM2.5 and PM10 in spring and summer are weaker than those in autumn and winter and the correlation between PM2.5 and PM10 in the northwest is stronger than that in the southeast in each season.

14.
Oncol Rep ; 40(2): 877-886, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29989650

RESUMO

At present, acute promyelocytic leukemia (APL) is the most curable form of acute myeloid leukemia and can be treated using all-trans retinoic acid and arsenic trioxide. However, the current treatment of APL is associated with some issues such as drug toxicity, resistance and relapse. Therefore, other strategies are necessary for APL treatment. In the present study, we investigated the effects of salinomycin (SAL) on APL cell lines NB4 and HL-60 and determined its possible mechanisms. We observed that SAL inhibited cell proliferation, as determined by performing Cell Counting Kit-8 (CCK-8) assay, promoted cell apoptosis, as determined based on morphological changes, and increased Annexin V/propidium iodide (PI)-positive apoptotic cell percentage. Treatment with SAL increased Bax/Bcl-2 and cytochrome c expression and activated caspase-3 and -9, thus leading to poly(ADP-ribose) polymerase (PARP) cleavage and resulting in cell apoptosis. These results revealed that SAL induced cell apoptosis through activation of the intrinsic apoptosis pathway. The present study is the first to show that SAL induced the differentiation of APL cells, as determined based on mature morphological changes, increased NBT-positive cell and CD11b-positive cell percentages and increased CD11b and C/EBPß levels. Furthermore, SAL decreased the expression of ß-catenin and its targets cyclin D1 and C-myc. Results of immunofluorescence analysis revealed that SAL markedly decreased the ß-catenin level in both the nucleus and cytoplasm. Combination treatment with SAL and IWR-1, an inhibitor of Wnt signaling, synergistically triggered SAL-induced differentiation of APL cells. These findings demonstrated that SAL effectively inhibited cell proliferation accompanied by induction of apoptosis and promotion of cell differentiation by inhibiting Wnt/ß-catenin signaling. Collectively, these data revealed that SAL is a potential drug for treatment of APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Piranos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio , Arsenicais/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Imidas/farmacologia , Imidas/uso terapêutico , Leucemia Promielocítica Aguda/patologia , Óxidos/farmacologia , Piranos/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Tretinoína/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
15.
Am J Hum Genet ; 102(5): 776-793, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29706346

RESUMO

Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.


Assuntos
Alelos , Cromossomos Humanos Par 1/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Conformação de Ácido Nucleico , Osteoporose/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Densidade Óssea/genética , Osso e Ossos/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular , Cromatina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Regiões Promotoras Genéticas , Ligação Proteica , Locos de Características Quantitativas/genética , RNA Longo não Codificante/química , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Transcrição/metabolismo
16.
Cell Death Dis ; 9(2): 182, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29416013

RESUMO

Gallbladder cancer (GBC) is the most common malignant tumour of the biliary track system. Angiogenesis plays a pivotal role in the development and progression of malignant tumours. miR-143-3p acts as a tumour suppressor in various cancers. Their role in GBC is however less well defined. Here we show that the expression levels of miR-143-3p were decreased in human GBC tissues compared with the non-tumour adjacent tissue (NAT) counterparts and were closely associated with overall survival. We discovered that miR-143-3p was a novel inhibitor of tumour growth and angiogenesis in vivo and in vitro. Our antibody array, ELISA and PLGF rescue analyses indicated that PLGF played an essential role in the antiangiogenic effect of miR-143-3p. Furthermore, we used miRNA target-prediction software and dual-luciferase assays to confirm that integrin α6 (ITGA6) acted as a direct target of miR-143-3p. Our ELISA and western blot analyses confirmed that the expression of PLGF was decreased via the ITGA6/PI3K/AKT pathway. In conclusion, miR-143-3p suppresses tumour angiogenesis and growth of GBC through the ITGA6/PI3K/AKT/PLGF pathways and may be a novel molecular therapeutic target for GBC.


Assuntos
Neoplasias da Vesícula Biliar/genética , Integrina alfa6/metabolismo , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Placentário/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo , Neoplasias da Vesícula Biliar/irrigação sanguínea , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Xenoenxertos , Humanos , Integrina alfa6/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fator de Crescimento Placentário/genética , Transfecção
17.
Arch Oral Biol ; 84: 169-175, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29024853

RESUMO

OBJECTIVE: Compelling evidence suggests that mitogen-activated protein kinases (Mapks) play an important role in amelogenesis. However, the role of transforming growth factor (TGF)-ß-activating kinase 1 (Tak1, Map3k7), which is a known upstream kinase of Mapks, during amelogenesis remains to be determined. The aim of this study was to investigate the possible involvement of Map3k7 in amelogenesis. DESIGN: We generated transgenic mice that produced constitutively active human MAP3K7 (caMAP3K7) under the control of amelogenin (Amelx) gene promoter. Radiography and micro-computed tomography (µCT) analysis was used to detect the radio-opacity and density of the teeth. The enamel microstructure was observed with a scanning electron microscope. Histological analysis was used to observe the adhesion between ameloblasts and residual organic matrix of the enamel. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of enamel matrix protein. RESULTS: The enamel of mandibular molars in caMAP3K7-overexpressing mice displayed pigmentation and a highly irregular structure compared with the wild type littermates. Teeth of transgenic animals underwent rapid attrition due to the brittleness of the enamel layer. The microstructure of enamel, normally a highly ordered arrangement of hydroxyapatite crystals, was completely disorganized. The gross histological appearances of ameloblasts and supporting cellular structures, as well as the expression of the enamel protein amelotin (Amtn) were altered by the overexpression of caMAP3K7. CONCLUSIONS: Our data demonstrated that protein expression, processing and secretion occurred abnormally in transgenic mice overexpressing caMAP3K7. The overexpression of caMAP3K7 had a profound effect on enamel structure by disrupting the orderly growth of enamel prisms.


Assuntos
Ameloblastos/metabolismo , Amelogênese/genética , Esmalte Dentário/metabolismo , MAP Quinase Quinase Quinases/genética , Animais , Esmalte Dentário/diagnóstico por imagem , Proteínas do Esmalte Dentário/metabolismo , Mandíbula/diagnóstico por imagem , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Dente Molar/diagnóstico por imagem , Dente Molar/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Microtomografia por Raio-X
18.
Int J Med Sci ; 14(10): 1031-1039, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28924376

RESUMO

Background and Aims: Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has recently been proven a suppressor of yes-associated protein (YAP) and has shown potential in anticancer treatment. However, its anti-human leukemia effects in NB4 cells remain unclear. In this study, we investigated the effects of VP on proliferation and apoptosis in human leukemia NB4 cells. Methods: NB4 cells were treated with VP for 24 h. The effects of VP on cell proliferation were determined using a Cell-Counting Kit-8 assay (CCK-8) assay and colony forming assay. Apoptosis and cell cycle were evaluated by flow cytometry (FCM). The protein levels were detected by western blot. Results: We found that VP inhibited the proliferation of NB4 cells in a concentration and time-dependent manner. FCM analysis showed that VP induced apoptosis in a concentration dependent manner and that VP treatment led to cell cycle arrest at G0/G1 phase. Moreover, VP significantly decreased the protein expression of YAP, p-YAP, Survivin, c-Myc, cyclinD1, p-ERK, and p-AKT. In addition, VP increased the protein expression of cleaved caspase3, cleaved PARP, Bax, and p-p38 MAPK. Conclusions: VP inhibited the proliferation and induced apoptosis in NB4 cells.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo , Citometria de Fluxo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/patologia , Luz , Regulação para Cima , Verteporfina
19.
Appl Environ Microbiol ; 83(23)2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28939603

RESUMO

Thiobencarb is a thiocarbamate herbicide used in rice paddies worldwide. Microbial degradation plays a crucial role in the dissipation of thiobencarb in the environment. However, the physiological and genetic mechanisms underlying thiobencarb degradation remain unknown. In this study, a novel thiobencarb degradation pathway was proposed in Acidovorax sp. strain T1. Thiobencarb was oxidized and cleaved at the C-S bond, generating diethylcarbamothioic S-acid and 4-chlorobenzaldehyde (4CDA). 4CDA was then oxidized to 4-chlorobenzoic acid (4CBA) and hydrolytically dechlorinated to 4-hydroxybenzoic acid (4HBA). The identification of catabolic genes suggested further hydroxylation to protocatechuic acid (PCA) and finally degradation through the protocatechuate 4,5-dioxygenase pathway. A novel two-component monooxygenase system identified in the strain, TmoAB, was responsible for the initial catabolic reaction. TmoA shared 28 to 32% identity with the oxygenase components of pyrimidine monooxygenase from Agrobacterium fabrum, alkanesulfonate monooxygenase from Pseudomonas savastanoi, and dibenzothiophene monooxygenase from Rhodococcus sp. TmoB shared 25 to 37% identity with reported flavin reductases and oxidized NADH but not NADPH. TmoAB is a flavin mononucleotide (FMN)-dependent monooxygenase and catalyzed the C-S bond cleavage of thiobencarb. Introduction of tmoAB into cells of the thiobencarb degradation-deficient mutant T1m restored its ability to degrade and utilize thiobencarb. A dehydrogenase gene, tmoC, was located 7,129 bp downstream of tmoAB, and its transcription was clearly induced by thiobencarb. The purified TmoC catalyzed the dehydrogenation of 4CDA to 4CBA using NAD+ as a cofactor. A gene cluster responsible for the complete 4CBA metabolic pathway was also cloned, and its involvement in thiobencarb degradation was preliminarily verified by transcriptional analysis.IMPORTANCE Microbial degradation is the main factor in thiobencarb dissipation in soil. In previous studies, thiobencarb was degraded initially via N-deethylation, sulfoxidation, hydroxylation, and dechlorination. However, enzymes and genes involved in the microbial degradation of thiobencarb have not been studied. This study revealed a new thiobencarb degradation pathway in Acidovorax sp. strain T1 and identified a novel two-component FMN-dependent monooxygenase system, TmoAB. Under TmoAB-mediated catalysis, thiobencarb was cleaved at the C-S bond, producing diethylcarbamothioic S-acid and 4CDA. Furthermore, the downstream degradation pathway of thiobencarb was proposed. Our study provides the physiological, biochemical, and genetic foundation of thiobencarb degradation in this microorganism.


Assuntos
Proteínas de Bactérias/metabolismo , Comamonadaceae/metabolismo , Mononucleotídeo de Flavina/metabolismo , Herbicidas/metabolismo , Oxigenases de Função Mista/metabolismo , Tiocarbamatos/metabolismo , Proteínas de Bactérias/genética , Comamonadaceae/enzimologia , Comamonadaceae/genética , Comamonadaceae/isolamento & purificação , Herbicidas/química , Redes e Vias Metabólicas , Oxigenases de Função Mista/genética , Estrutura Molecular , NAD/metabolismo , NADP/metabolismo , Filogenia , Microbiologia do Solo , Tiocarbamatos/química
20.
Int J Med Sci ; 14(9): 902-910, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28824329

RESUMO

Background: Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a candidate oncoprotein and participates in the progression of various malignancies. However, few reports have examined the effect of YAP inhibition in human leukemia HL-60 cells. Methods: We examined the effects of YAP knockdown or inhibition using short hairpin RNA (shRNA) or verteporfin (VP), respectively. Western blot assays were used to determine the expression levels of YAP, Survivin, cyclinD1, PARP, Bcl-2, and Bax. Cell proliferation was assessed using the cell counting kit (CCK-8) assay. Cell cycle progression and apoptosis were evaluated by flow cytometry, and apoptotic cell morphology was observed by Hoechst 33342 staining. Results: Knockdown or inhibition of YAP led to cell cycle arrest at the G0/G1 phase and increased apoptosis, inhibited cell proliferation, increased levels of Bax and cleaved PARP, and decreased levels of PARP, Bcl-2, Survivin, and cyclinD1. Moreover, Hoechst 33342 staining revealed increased cell nuclear fragmentation. Conclusion: Collectively, these results show that inhibition of YAP inhibits proliferation and induces apoptosis in HL-60 cells. Therefore, a novel treatment regime involving genetic or pharmacological inhibition of YAP could be established for acute promyelocytic leukemia.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proliferação de Células/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Promielocítica Aguda/patologia , Fosfoproteínas/antagonistas & inibidores , Porfirinas/farmacologia , RNA Interferente Pequeno/genética , Fatores de Transcrição , Verteporfina
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