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1.
Sci Rep ; 10(1): 2044, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029792

RESUMO

GPNCA is a long non-coding RNA with unknown functions. In this study, using data from 9 cancers obtained from The Cancer Genome Atlas (TCGA), GPNCA was identified as overexpressed in cancer vs. normal tissues. The upregulation of GPNCA was associated with poor overall prognosis in colon, liver, renal clear cell and breast cancers. The upregulation of GPNCA was partly due to enhanced H3K27ac occupancy on its promoter region via EP300 and KAT2A/GCN5. The overexpression of GPNCA was positively related to tumor metastasis in colon cancer and poor disease-free and recurrence-free survival in colon and liver cancer. Both gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis indicated that GPNCA was closely linked to regulation of gene transcription and post-transcriptional modifications, which was further supported by in vitro cell cytoplasmic and nuclear RNA purification assessments. Furthermore, GPNCA was associated with cell growth. Our in vitro experiments demonstrated that GPNCA silencing inhibited tumor growth via inhibiting its nearby gene GSK3B. Taken together, these findings highlight GPNCA as a biomarker for cancer diagnosis and a potential target for future cancer drug development.

2.
Biochem Pharmacol ; : 113856, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32061772

RESUMO

Cancer easily induces resistance to most chemotherapy drugs. In this study, we investigated the combination cytotoxic and antitumor effects of canagliflozin (CAN) and doxorubicin (DOX) in vitro and in vivo. CAN significantly increased the cytotoxicity of DOX in HepG2, HepG2-ADR (adriamycin or doxorubicin-resistant) and MCF7 cells. CAN significantly promoted the intracellular uptake of DOX in HepG2 cells. CAN also reduced the p-gp level in HepG2 cells. The function of p-gp required ATP, but CAN significantly reduced the intracellular ATP level. CAN might inhibit the function of p-gp, increase the intracellular DOX concentration and contribute to an enhanced cytotoxic activity. Autophagy plays a protective role in chemotherapy-induced cell survival. However, CAN significantly inhibited DOX-induced autophagy in HepG2 cells, and the mechanism appeared to be mediated by promoting ULK1 phosphorylation. The downregulation of P-glycoprotein (P-gp) may be associated with protein degradation but is independent of the autophagy pathway. Furthermore, in HepG2-xenograft BALB/c naked mice, CAN significantly increased the antitumor effect of DOX. This study is the first to report that a classical antidiabetic drug, CAN improved the sensitivity to the antitumor effect of DOX, and the potential molecular mechanisms of CAN may involve the inhibition of P-gp function and the autophagy pathway.

3.
Mol Ther Nucleic Acids ; 18: 518-532, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31671345

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment.

4.
Cell Death Dis ; 10(10): 688, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534127

RESUMO

CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific alternative splicing and contributes to the pathogenesis of myotonic dystrophy (DM), however the role of CELF6 in cancer cell proliferation is less appreciated. Here, we show that the expression of CELF6 is cell cycle regulated. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-ß-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. Overexpression or depletion of CELF6 modulates p21 gene expression. CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. The effect of CELF6 on cell proliferation is p53 and/or p21 dependent. Collectively, these data demonstrate that CELF6 might be a potential tumor suppressor, CELF6 regulates cell proliferation and cell cycle progression via modulating p21 stability.

5.
Cell Mol Life Sci ; 76(15): 3005-3018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006037

RESUMO

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Caveolina 2/antagonistas & inibidores , Caveolina 2/genética , Caveolina 2/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
6.
Drug Deliv ; 26(1): 168-178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30822166

RESUMO

The present study aims at designing a thermosensitive gel prepared from w1/o/w2 multiple microemulsions (MMEs) for the vaginal delivery of siRNA. The w1/o/w2 MMEs were prepared by two-step emulsifications: the first step was to prepare primary emulsions (w1/o) by low energy emulsification (LEE); the second step was to obtain stable w1/o/w2 MMEs by self-emulsifying. An extensive formulation optimization process was undertaken. The final w1/o/w2 MMEs could be formed in ddH2O, phosphate buffer solution (PBS, pH 7.4) and 1640 culture media with diameter size about 166.5 ± 13.1, 271.0 ± 11.1 and 278.7 ± 12.1 nm respectively. The release rates of siRNA from solutions, MMEs and MMEs-gels were completed within 2 h, 6 h and13 h respectively. The transfection efficiency of MMEs was confirmed both in vitro and in vivo. The relative target gene expressions of MMEs were 0.07 ± 0.05% vs. 0.37 ± 0.06% in Hela cells against Lipofectamine2000® and 1.88% ± 0.00% vs. 9.65% ± 0.02% in mouse vaginal mucosa against PEI. Good biocompatibility of MMEs was verified by cytotoxicity and pathological studies. Overall, our results indicated the potential of the MMEs-gel system for the vaginal delivery of siRNA.


Assuntos
Administração Intravaginal , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Microesferas , Ácidos Nucleicos/administração & dosagem , Tensoativos/administração & dosagem , Animais , Emulsões/síntese química , Emulsões/metabolismo , Feminino , Géis , Células HeLa , Humanos , Camundongos , Ácidos Nucleicos/síntese química , Ácidos Nucleicos/metabolismo , Distribuição Aleatória , Tensoativos/síntese química , Tensoativos/metabolismo , Água/administração & dosagem , Água/química , Água/metabolismo
7.
EBioMedicine ; 41: 200-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30796006

RESUMO

BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.


Assuntos
Núcleo Celular/metabolismo , Glicólise , Histona Desacetilase 2/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , Transporte Ativo do Núcleo Celular , Animais , Glutaminase/metabolismo , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Longo não Codificante/metabolismo
8.
Molecules ; 23(11)2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30423891

RESUMO

Insulin injection relies on strict blood glucose monitoring. However, existing techniques and algorithms for blood glucose monitoring cannot be completed in a timely way. In this study, we have developed a new intelligent glucose-sensitive insulin delivery system to stabilize blood glucose levels in the body. This system does not require real-time detection of blood glucose. First, we successfully synthesized a nanoscale material called PAM-PAspPBA-b-PEG by using chemical methods. We then conducted TEM, DLS, and ¹H-NMR analyses to characterize the physicochemical properties, such as size, molecular composition, and configuration of the nanomaterial. We verified the glucose responsibility of the insulin loading nanoscale material in vitro and evaluated its safety and effect on mice in vivo. Results showed that insulin-loaded PAM-PAspPBA-b-PEG is glucose-sensitive, safer and more effective than regular insulin injection. This study provides a basis for future development of smart insulin delivery systems.


Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Insulina/administração & dosagem , Nanopartículas , Glicemia/efeitos dos fármacos , Ácidos Borônicos/química , Dendrímeros , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Insulina/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Peptídeos/química , Poliaminas/química
9.
Cancer Sci ; 109(12): 4033-4044, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30290038

RESUMO

Long noncoding RNAs (lncRNA) are reported to be potential cancer biomarkers. This study aims to find new lncRNA biomarker relevant to lung adenocarcinoma. Gene expression profile and clinical data of lung adenocarcinoma and lung squamous cell carcinoma patients were downloaded from the UCSC Xena database. These data were analyzed to identify potential lncRNA prognostic biomarkers, and the candidate lncRNAs were analyzed and verified with association analysis, meta-analysis, survival analysis, gene ontology analysis, gene set enrichment analysis, and other statistical methods. A group of 5 lncRNAs was identified from the 1965 differentially expressed (fold-change >2) genes. Four of these 5 lncRNAs were expressed at a lower level in lung adenocarcinoma tissues and the other one at a higher level (P < .0001). A risk score model was constructed using a linear combination of the expression levels of these lncRNAs. High-risk patients showed poorer overall survival (hazard ratio [HR] = 2.14; 95% confidence interval [CI], 1.67-3.06, P < .0001), disease-free survival (HR = 1.84; 95% CI, 1.26-2.35, P = .0007), and recurrence-free survival (HR = 1.51; 95% CI, 1.02-2.40, P = .04). The 5-fold cross-validation and subsequent meta-analysis further verified that patients in the low-risk group had better survival (95% CI, 0.74-1.79, Z = 4.72, P < .00001). Furthermore, both univariate and multivariate Cox regression analyses revealed that the prognostic value of these 5 lncRNAs was independent of other clinical prognostic factors. Further analysis indicated that these 5 lncRNAs might be associated with tumor metastasis. Taken together, our study suggests new prognostic lncRNA biomarkers for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Mineração de Dados/métodos , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Prognóstico , Análise de Regressão , Análise de Sobrevida
10.
Molecules ; 23(8)2018 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-30060618

RESUMO

Obesity and nonalcoholic fatty liver disease (NAFLD) are highly prevalent and cause numerous metabolic diseases. However, drugs for the prevention and treatment of obesity and NAFLD remain unavailable. In this study, we investigated the effects of mogrosides (luo han guo, LH) in Siraitia grosvenorii saponins on high-fat-diet-induced obesity and NAFLD in mice. We found that compared with the negative control, LH reduced body and liver weight. LH also decreased fat accumulation and increased AMP-activated protein kinase (AMPK) phosphorylation (pAMPK) levels in mouse livers. We also found that high-purity mogroside V upregulated pAMPK expression in HepG2 cells. In addition, high-purity mogroside V inhibited reactive oxygen species production and upregulated sequestosome-1 (SQSTM1, p62) expression in THP-1 cells. These results suggest that LH may affect obesity and NAFLD by enhancing fat metabolism and antioxidative defenses. Mogroside V may be a main component of LH. However, the exact molecular mechanisms and active components responsible for the inhibitory effects of LH on obesity and NAFLD require further investigation.


Assuntos
Fármacos Antiobesidade/farmacologia , Anticolesterolemiantes/farmacologia , Momordica/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Anticolesterolemiantes/química , Anticolesterolemiantes/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Tamanho do Órgão/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Saponinas/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Proteína Sequestossoma-1/agonistas , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Células THP-1 , Triterpenos/química , Triterpenos/isolamento & purificação
11.
Oncogene ; 37(44): 5829-5842, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29973691

RESUMO

Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research.


Assuntos
Autofagia/genética , Neoplasias da Mama/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , RNA/fisiologia , Transporte Ativo do Núcleo Celular , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Senescência Celular/genética , Senescência Celular/fisiologia , Progressão da Doença , Feminino , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Humanos , Camundongos , Camundongos Nus , RNA/genética , RNA/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Biochim Biophys Acta Mol Cell Res ; 1865(10): 1385-1396, 2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-30049645

RESUMO

Autophagy dysregulation has emerged in age-related neurological diseases (Ulland et al.; Matheoud et al.; Ashkenazi et al.). Alzheimer Disease (AD), the most common progressive neurodegenerative disorder, is characterized by the accumulation of amyloid-ß (Aß) plaques caused by aberrant Aß metabolism (Qiang et al.; Sevigny et al.; Ittner et al.). Glia constitute the brain immune system and ingest extracellular Aß for degradation via the autophagy-lysosome machinery (Ries and Sastre; Cho et al.). Here, we model the molecular rationale for this clearance process in glioma cells by showing that miR34a inhibits autophagy-mediated disposal of Aß fibrils and identifying two novel direct targets of miR34a, endophilin-3 and cathepsin B (CTSB, a previously reported enzyme for Aß degrading (Sun et al.)). Bioinformatics analyses revealed that endophilin-3 expresses at a significantly lower level in neurodegenerative diseases. Its gain-of-function substantially promotes both uptake and degradation of Aß while small interfering RNA (siRNA)-mediated endophilin-3 knockdown slowed down Aß clearance and blocked autolysosome formation. Mechanistically, gene ontology (GO) analysis of the endophilin-3 interactome identified by mass spectrometry uncovered enriched components involved in actin binding (with the highest score). Importantly, we validated that the actin-binding protein phostensin interacted with endophilin-3. Phostensin knockdown restored endophilin-3-mediated up-regulation of Aß clearance. Thus, our findings indicate that miR34a inhibits Aß clearance by targeting endophilin-3 and CTSB at multiple steps including uptake and autophagy-mediated degradation.

13.
J Assist Reprod Genet ; 35(8): 1437-1442, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29785531

RESUMO

OBJECTIVE: To evaluate the association of two common methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with recurrent miscarriage (RM) and repeated implantation failure (RIF) METHODS: The study comprised of 521 patients, with a history of RM (n = 370) or RIF (n = 151). One hundred forty-four women with fallopian tube blockages who had successfully conceived after the first in vitro fertilization embryo transfer treatment served as the control group. The MTHFR alleles, genotypes, and haplotypes were assessed in different groups. RESULTS: There was no difference in allele frequency and distribution of MTHFR polymorphisms between case and control patients. The 1298AA genotype was represented in a higher frequency, and 1298AC genotype was significantly lower in subfertile group when compared to the control group. A significant relationship was found between the 1298AC genotype and the RIF subgroup. The haplotype 677CC/1298AA was overrepresented in the RM subgroup (> 2 times) and haplotype 677CC/1298AC was underrepresented in the RIF subgroup (P < 0.05). Nevertheless, these two haplotypes were not connected to fertilization and embryo cleavage rates. CONCLUSION: Our findings indicate that the MTHFR gene polymorphism might play a role in the etiology of patients with RM or RIF. No adverse effects of different MTHFR haplotypes on embryo development were detected. Further studies on the biological role are needed to better understand the susceptibility to pregnancy complications.


Assuntos
Aborto Habitual/genética , Implantação Tardia do Embrião/genética , Implantação do Embrião/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Aborto Habitual/fisiopatologia , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez
14.
Molecules ; 23(3)2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29495390

RESUMO

Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.


Assuntos
Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Emodina/análogos & derivados , Inflamação/etiologia , Inflamação/metabolismo , NF-kappa B/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Emodina/farmacologia , Inflamação/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Modelos Biológicos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Transporte Proteico , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
15.
Biochem Pharmacol ; 152: 45-59, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29551587

RESUMO

Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.


Assuntos
Autofagia/efeitos dos fármacos , Canagliflozina/farmacologia , Glucose/metabolismo , Inflamação/induzido quimicamente , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Canagliflozina/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio , Células THP-1
16.
Gene ; 636: 17-22, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28912064

RESUMO

Genetic defect is a major cause of early miscarriage, but still in many cases the etiology are not fully understood. Recent studies have shown that dysregulation of genes in placenta tissue are participated in the pathogenesis of unexplained early miscarriage. The aim of our study is to explore mRNA expression profile in placental chorionic villi and to reveal the underlying mechanism of unexplained early miscarriage. Chorionic villous were isolated and extracted from early miscarriage (n=3) and control pregnancy (n=3) placenta with normal chromosome karyotype using MLPA assay, and then mRNA expression profiles were determined by microarray. For verification the reproducibility of the microarray, three up-regulated genes and six down-regulated genes were chosen and examined by real-time PCR (n=30). A total of 81 genes were up-regulated and 231 genes were down-regulated when compared to the control group, and the differences were reached statistically significances (P<0.05). After Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we found that almost down-regulation genes are associated with cell cycle and histone modification, and these genes are participated in several important physiological processes, such as cell proliferation, nuclear division, chromatic assembly, DNA packing and modification. These results indicated that cell cycle and histone modification genes, and related signaling pathway maybe contribute to the genesis and development of unexplained early miscarriage. Further studies and validations are necessary to elucidate the exact roles of these genes in miscarriage pathogenesis, which can develop tools for early detection and management.


Assuntos
Aborto Espontâneo/genética , Genes cdc , Código das Histonas/genética , Placenta/metabolismo , Aborto Espontâneo/metabolismo , Vilosidades Coriônicas/metabolismo , Feminino , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Gravidez , Mapas de Interação de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
17.
Sci Rep ; 7(1): 5270, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28706254

RESUMO

Diabetes is an inflammatory disease. Inflammation plays an important role in islet functions. However, the exact mechanisms by which inflammation affects islet functions remain unclear. In this study, we investigated the regulatory effects of miR-30a on inflammation and islet functions. The results indicate that miR-30a serves as an inflammation-resolving buffer factor by targeting interleukin 1a (IL-1α) in immune cells and in islet cells, which might play an important role in inflammation homeostasis. miR-30a ameliorates islet functions in an inflammatory micro-environment by targeting the IL-1α/nuclear factor kappa B (NFKB) p65 subunit (p65)/p62 (SQSTM1)/insulin axis, which can be developed into a novel antidiabetic approach. miR-30a serves as a promising inflammation-response biomarker in inflammatory diseases and is possibly activated by the toll-like receptor 4 (TLR4)/IL-1α/NFKB pathways. However, the exact molecular mechanisms by which miR-30a regulates inflammation and islet functions as well as the potential applications in transitional medicine require further elucidation.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Inflamação/patologia , Células Secretoras de Insulina/patologia , Interleucina-1alfa/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Animais , Células Cultivadas , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Interleucina-1alfa/genética , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais
18.
PLoS One ; 12(5): e0177964, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28562667

RESUMO

Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene. However, efficient delivery of small interfering RNA (siRNA) in vivo remains a significant hurdle for its successful therapeutic application. In this study, we first identified, on a cell-based experiment, applying a 1:1 mixture of two PTN specific siRNA engenders a higher silencing efficiency on both mRNA and protein level than using any of them discretely at the same dose. As a consequence, slower melanoma cells growth was also observed for using two specific siRNA combinatorially. To establish a robust way for siRNA delivery in vivo and further investigate how silence of PTN affects tumor growth, we tested three different methods to deliver siRNA in vivo: first non-targeted in-vivo delivery of siRNA via jetPEI; second lung targeted delivery of siRNA via microbubble coated jetPEI; third tumor cell targeted delivery of siRNA via transferrin-polyethylenimine (Tf-PEI). As a result, we found that all three in-vivo siRNAs delivery methods led to an evident inhibition of melanoma growth in non-immune deficiency C57BL/6 mice without a measureable change of ALT and AST activities. Both targeted delivery methods showed more significant curative effect than jetPEI. The lung targeted delivery by microbubble coated jetPEI revealed a comparable therapeutic effect with Tf-PEI, indicating its potential application for target delivery of siRNA in vivo.


Assuntos
Proteínas de Transporte/genética , Proliferação de Células/genética , Citocinas/genética , Inativação Gênica , Metástase Neoplásica/genética , Neoplasias/patologia , RNA Interferente Pequeno/administração & dosagem , Animais , Humanos , Melanoma Experimental/patologia , Camundongos
19.
Oncotarget ; 8(9): 15283-15293, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28146429

RESUMO

LINC00341 is a novel long intergenic non-protein coding RNA with unknown functions. In our report, we investigated LINC00341 expression and its prognostic value in cancer patients. DNA over-methylation triggered low expression of LINC00341 and that was associated with poor prognosis in cancers. A meta-analysis further confirmed that high expression of LINC00341 was associated with a better prognosis in cancer patients. Both gene set enrichment analysis and meta-analysis showed that LINC00341 inhibited cancer metastasis. Finally, a large-scale multicentre analysis supported a prognostic value of LINC00341 in cancers.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias da Mama/patologia , Humanos , Metástase Linfática , Metanálise como Assunto , Estudos Multicêntricos como Assunto , Prognóstico
20.
Reprod Health ; 14(1): 5, 2017 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-28086915

RESUMO

BACKGROUND: Chlamydia, caused by the bacterium Chlamydia trachomatis(C. trachomatis), is the most common sexually transmitted disease. The incidence is not clear due to the asymptomatic nature of early stage of infections. The incidence of Chlamydia has not been fully investigated in the Chinese Han population. Since chronic infection with can C. trachomatis can lead to infertility in males and females, it is important to determine the impact of infection on clinical outcomes. The aim of this study is to explore the epidemiology of C. trachomatis in subfertile couples and to determine whether infections will adversely affect clinical outcomes after assisted reproduction technique (ART) treatment. METHODS: Subfertile patients (n = 30760) were screened in the research for C. trachomatis in our center from January 2010 to December 2014. C. trachomatis-specific DNA was detected by Taq-man PCR from semen or swabs from the urethral, endocervix or vaginal. The control group consisted of 1140 subfertile patients without C. trachomatis infection. The prevalence and characteristics of C. trachomatis were identified for subfertile couples and clinical outcomes were collected and analyzed. A retrospective study was performed. RESULTS: Nine hundred and seventy patients were diagnosed with C. trachomatis infection, and the overall prevalence was 3.15% in the most recent five years, with a yearly increasing. The incidence was a higher in the second half of the year (3.40%) compared to the first half (2.69%). The age group with the highest-risk of infection with C. trachomatis was between 26 to 35 years old, and in about one third of the couples, both partners were infected. The basic parameters and clinical outcomes were not statistically significant between different the groups (P > 0.05), even though some minor data were different (P < 0.05). CONCLUSIONS: C. trachomatis is a common infection in subfertile people and it is essential to test for this organism in ART couples' screening. This study identified no adverse on clinical outcomes after successful treatment of C. trachomatis infection, regardless of gender, age and number of C. trachomatis copies.


Assuntos
Infecções por Chlamydia/epidemiologia , Chlamydia trachomatis/isolamento & purificação , Infertilidade Feminina/epidemiologia , Infertilidade Masculina/epidemiologia , Adulto , China/epidemiologia , Infecções por Chlamydia/microbiologia , Feminino , Humanos , Infertilidade Feminina/microbiologia , Infertilidade Masculina/microbiologia , Masculino , Prevalência , Estudos Retrospectivos , Parceiros Sexuais , Adulto Jovem
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