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Glutamine synthetase (GS) is a key enzyme involved in nitrogen metabolism. GS can be divided into cytosolic and plastidic subtypes and has been reported to respond to various biotic and abiotic stresses. However, little research has been reported on the function of GS in mulberry. In this study, the full length of MaGS2 was cloned, resulting in 1302 bp encoding 433 amino acid residues. MaGS2 carried the typical GS2 motifs and clustered with plastidic-subtype GSs in the phylogenetic analysis. MaGS2 localized in chloroplasts, demonstrating that MaGS2 is a plastidic GS. The expression profile showed that MaGS2 is highly expressed in sclerotiniose pathogen-infected fruit and sclerotiniose-resistant fruit, demonstrating that MaGS2 is associated with the response to sclerotiniose in mulberry. Furthermore, the overexpression of MaGS2 in tobacco decreased the resistance against Ciboria shiraiana, and the knockdown of MaGS2 in mulberry by VIGS increased the resistance against C. shiraiana, demonstrating the role of MaGS2 as a negative regulator of mulberry resistance to C. shiraiana infection.
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Herein, we present toxicological assessments of carbon nanomaterials in HL-7702 cells, and it was found that reactive oxygen species (ROS) levels were elevated. Mass spectrometry results indicated that cysteine sulfhydryl of glutaredoxin-1 (GLRX1) was oxidized to sulfenic acids and sulfonic acids by excessive ROS, which broke the binding of GLRX1 to apoptosis signal-regulating kinase 1, causing the activation of the JNK/p38 signaling pathway and ultimately hepatocyte apoptosis. However, a lower level of ROS upregulated GLRX1 instead of sulfonation modification of its active sites. Highly expressed GLRX1 in turn enabled the removal of intracellular ROS, thereby exerting inconspicuous toxic effects on cells. Taken together, these findings emphasized that CNM-induced hepatotoxicity is attributable to oxidative modifications of GLRX1 arising from redox imbalance.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Glutarredoxinas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Glutarredoxinas/farmacologia , Oxirredução , Apoptose , Estresse OxidativoRESUMO
Helicobacter pylori (H. pylori) infection is considered to be an important factor in gastric cancer (GC). Long noncoding RNA (lncRNA) and m6A modification are involved in the occurrence and development of GC, but the role of lncRNA m6A modification in the development of GC mediated by H. pylori is still unclear. Here, we found that H. pylori infection downregulated the expression of lnc-PLCB1 through METTL14-mediated m6A modification and IRF2-mediated transcriptional regulation. Overexpression of lnc-PLCB1 inhibited the proliferation and migration of GC cells, while downregulation of lnc-PLCB1 promoted the proliferation and migration ability of GC cells. In addition, clinical analysis showed that lnc-PLCB1 is lower in GC tissues than in normal tissues. Further study found that lnc-PLCB1 reduced the protein stability of its binding protein DEAD-box helicase 21 (DDX21) and then downregulated the expression of CCND1 and Slug, thereby playing tumour suppressing role in the occurrence and development of GC. In conclusion, the METTL14/lnc-PLCB1/DDX21 axis plays an important role in H. pylori-mediated GC, and lnc-PLCB1 can be used as a new target for GC treatment.
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Adenina , Infecções por Helicobacter , Helicobacter pylori , RNA Longo não Codificante , Neoplasias Gástricas , Humanos , Helicobacter pylori/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/patologia , Regulação para Baixo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Proliferação de Células , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Fosfolipase C beta/genética , Fosfolipase C beta/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismoRESUMO
Disulfiram (DSF) has proven to be a promising anti-tumor drug in preclinical studies. However, its anti-cancer mechanism has not yet been elucidated. As an activator in tumor metastasis, N-myc downstream regulated gene-1 (NDRG1) is involved in multiple oncogenic signaling pathways and is upregulated by cell differentiation signals in various cancer cell lines. DSF treatment results in a significant reduction in NDRG1, while down-regulated NDRG1 has a pronounced effect on invading cancer cells, as shown in our previous work. Here, in vitro and in vivo experiments confirm that DSF contributes to regulating tumor growth, EMT, and the migration and invasion of cervical cancer. Furthermore, our results show DSF binds to the ATP-binding pocket in the N-terminal domain of HSP90A, thereby affecting the expression of its client protein NDRG1. To our knowledge, this is the first report of DSF binding to HSP90A. In conclusion, this study sheds light on the molecular mechanism by which DSF inhibits tumor growth and metastasis through the HSP90A/NDRG1/ß-catenin pathway in cervical cancer cells. These findings provide novel insights into the mechanism underlying DSF function in cancer cells.
Assuntos
Dissulfiram , Neoplasias do Colo do Útero , Feminino , Humanos , Dissulfiram/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Electrical stimulation is a promising method to modulate gastrointestinal disorders. However, conventional stimulators need invasive implantation and removal surgeries associated with risks of infection and secondary injuries. Here, we report a battery-free and deformable electronic esophageal stent for wireless stimulation of the lower esophageal sphincter in a noninvasive fashion. The stent consists of an elastic receiver antenna infilled with liquid metal (eutectic gallium-indium), a superelastic nitinol stent skeleton, and a stretchable pulse generator that jointly enables 150% axial elongation and 50% radial compression for transoral delivery through the narrow esophagus. The compliant stent adaptive to the dynamic environment of the esophagus can wirelessly harvest energy through deep tissue. Continuous electrical stimulations delivered by the stent in vivo using pig models significantly increase the pressure of the lower esophageal sphincter. The electronic stent provides a noninvasive platform for bioelectronic therapies in the gastrointestinal tract without the need for open surgery.
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Esfíncter Esofágico Inferior , Trato Gastrointestinal , Animais , Suínos , Stents , Pressão , Estimulação ElétricaRESUMO
Due to the ecotoxicity of 17ß-estradiol (E2), residual E2 in the environment poses potential risks to human and animal health and ecosystems. Biodegradation is considered one of the most effective strategies to remove E2 from the environment. Here, a novel, efficient E2-degrading bacterial strain Microbacterium resistens MZT7 was isolated from activated sludge and characterized. The genome of strain MZT7 contained 4,011,347 bp nucleotides with 71.26% G + C content and 3785 coding genes. There was 86.7% transformation efficiency of 10 mg/L E2 by strain MZT7 after incubation for 5 d at optimal temperature (30 °C) and pH (7.0). This strain was highly tolerant to ranges in pH (5.0-11.0), temperature (20-40 °C), and salinity (2-8%). Adding sources of carbon (glucose, maltose, sucrose, or lactose) or nitrogen sources (urea, peptone, or beef extract) promoted the degradation of E2 by strain MZT7. However, when yeast extract was added as a nitrogen source, the degradation efficiency of E2 was inhibited. Metabolites were analyzed by LC-MS and three metabolic pathways of E2 degradation were proposed. Further, the intermediates dehydroepiandrosterone and androsta-1,4-diene-3,17-dione were detected, as well as identification of kshB and fadD3 genes by KEGG, confirming one E2 degradation pathway. This study provided some insights into E2 biodegradation.
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Ecossistema , Estradiol , Animais , Bactérias/metabolismo , Biodegradação Ambiental , Bovinos , Estradiol/metabolismo , Humanos , Microbacterium , NitrogênioRESUMO
This case report describes a 58-year-old, never-smoking housewife with chief complaints of progressively worsening cough, dyspnea, and intermittent fever, who was initially misdiagnosed with community-acquired pneumonia (CAP). However, her pulse oximetry oxygen saturation continued to decline, and eventually, she underwent an endotracheal intubation. Fortunately, transbronchial cryobiopsy (TBCB) assisted by extracorporeal membrane oxygenation (ECMO) was performed in the most critical situation, and it revealed an organizing pneumonia (OP) pattern. OP describes a histological pattern of acute or subacute pulmonary damage, which may be idiopathic or associated with a known or unknown underlying disease. A definitive diagnosis of OP usually obtained from pathology, and surgical lung biopsy with large lung tissue is recommended. However, since the surgical lung biopsy was not convenient for this patient after mechanical ventilation, bedside TBCB supported by ECMO was selected. To our knowledge, we are the first to report the pathological diagnosis of ECMO assisted TBCB in acute respiratory failure. When oxygenation cannot be maintained after endotracheal intubation and surgical lung biopsy is not feasible, ECMO-supported TBCB may be a good choice to obtain lung tissue for histopathological diagnosis in patients with acute lung injury of unknown etiology.
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Mulberry (Morus spp., Moraceae) is an important economic crop plant and is rich in flavonoids and anthocyanidins in ripe fruits. Anthocyanins are glycosides of anthocyanidins. Flavanone 3-hydroxylase (F3H) catalyzes the conversion of naringenin into dihydroflavonols and is responsible for the biosynthesis of flavonols and anthocyanidins. In this study, MazsF3H was cloned and characterized from Morus atropurpurea var. Zhongshen 1. Conserved motif analysis based on alignment and phylogenetic analysis indicated that MazsF3H belonged to 2-oxoglutarate-dependent dioxygenase and MazsF3H clustered with F3Hs from other plants. MazsF3H was located in both nucleus and cytosol. MazsF3H was expressed in stems, leaves, stigmas and ovaries, except buds. F3H expression levels showed a positive and close relationship with anthocyanin content during the anthocyanin-rich fruit ripening process, while it showed a negative correlation with anthocyanin content in LvShenZi, whose fruits are white and would not experience anthocyanin accumulation during fruit ripening. Significantly different F3H expression levels were also found in different mulberry varieties that have quite different anthocyanin contents in ripe fruits. Overexpression MazsF3H in tobacco showed unexpected results, including decreased anthocyanin content. Down-regulation of F3H expression levels resulted in co-expression of the genes involved in anthocyanin biosynthesis and a significant decrease in anthocyanin content, but the change in total flavonoid content was subtle. Our results indicated that F3H may play quite different roles in different varieties that have quite different fruit colors. In addition, possible complex regulation of flavonoid biosynthesis should be further explored in some of the featured plant species.
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Antocianinas , Morus , Antocianinas/metabolismo , Flavonoides/metabolismo , Frutas/genética , Frutas/metabolismo , Oxigenases de Função Mista , Morus/genética , Morus/metabolismo , FilogeniaRESUMO
A time-lapse system (TLS) with a well-of-the-well (WOW) dish, which allows individual identification and the possibility of autocrine and paracrine signaling between group-cultured embryos, has been widely used in clinic. However, there is a need to re-think the inclusion principles of human embryos in WOW-based TLS, especially for grade IV (G4) embryos, which are considered to potentially have detrimental effects on surrounding embryos. Here, we carried out a single-center, large-cohort, retrospective study, comprising 303 patients undergoing IVF (148 cases) and ICSI (155 cases), with a total of 3282 embryos, to compare embryonic development until the blastocyst stage in the group culture system with or without G4 embryos. Further, LC-MS/MS was used to analyze the G1-G4 embryo secretome to understand the influence of G4 embryos on the group culture microenvironment. We proved that polypronuclear (PPN) embryos positively contribute to the development of the neighboring embryos through secretion of ILIAP, ITI-H4, and keratin. Existence of more than one G4 embryo had a negative effect on the other embryos (p < 0.05). Moreover, G4 embryos were found to secrete KLKB1 and VTDB, which might harm the neighboring embryos. Thus, our study clarified that when embryos are subjected to group culture in WOW-based TLS, the PPN-derived embryos need not be removed, and it is important to ensure that no more than one G4 embryo is present to avoid negative effects on the neighboring embryos.
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Fertilização in vitro/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Imagem com Lapso de Tempo/métodos , Adulto , Blastocisto/efeitos dos fármacos , Cromatografia Líquida , Técnicas de Cocultura , Meios de Cultura/metabolismo , Técnicas de Cultura Embrionária , Feminino , Humanos , Queratinas/metabolismo , Análise Multivariada , Recuperação de Oócitos , Ovulação , Estudos Retrospectivos , Secretoma , Espectrometria de Massas em Tandem , Zigoto/metabolismoRESUMO
Background: We performed a meta-analysis to systematically review the risk factors of mortality from non-HIV-related Pneumocystis pneumonia (PcP) and provide the theoretical basis for managing non-HIV-related PcP. Methods: PubMed, Embase, Web of Science, the Cochrane Library and CNKI databases were searched. A meta-analysis of the risk factors of mortality from non-HIV-related PcP was conducted. Results: A total of 19 studies and 1,310 subjects were retrieved and included in the meta-analysis, including 485 and 825 patients in the non-survivor and survivor groups, respectively. In the primary analysis, age, concomitant with other pulmonary diseases at diagnosis of PcP, solid tumors, cytomegalovirus(CMV) co-infection, lactate dehydrogenase (LDH), lymphocyte count, invasive ventilation during hospitalization, and pneumothorax were associated with mortality from non-HIV-related PcP, whereas sex, albumin, PcP prophylaxis, use of corticosteroids after admission, and time from onset of symptoms to treatment were not associated with mortality from non-HIV-related PcP. Conclusions: The mortality rate of non-HIV-infected patients with PcP was still high. Age, concomitant with other pulmonary diseases at diagnosis of PcP, solid tumors, CMV co-infection, LDH, lymphocyte count, invasive ventilation during hospitalization, and pneumothorax were risk factors of mortality from non-HIV-related PcP. Improved knowledge of prognostic factors is crucial to guide early treatment.
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Coinfecção , Infecções por Citomegalovirus , Pneumocystis , Pneumonia por Pneumocystis , Infecções por Citomegalovirus/epidemiologia , Humanos , Fatores de RiscoRESUMO
It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.
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BACKGROUND: There are many progesterone (P) elevation-related indicators for predicting pregnancy outcomes, including the serum P, P-to-oestradiol ratio (P/E2), P-to-follicle index (PFI), and P-to-mature oocyte index (PMOI); however, due to inconsistencies in study populations and controlled ovarian hyperstimulation (COH) protocols among studies, these indicators are controversial. Moreover, no researchers have included these four commonly used indicators in one study to compare their predictive efficacies. The objective of this study was to compare the predictive value of P-related indicators for pregnancy outcomes of women undergoing the short-acting GnRH agonist long protocol. METHODS: A total of 612 infertile women undergoing IVF/ICSI were recruited for this study. Serum samples were obtained on the morning of HCG injection for serum P and E2 measurements. Transvaginal ultrasound was performed to determine the follicle count (≥ 14 mm in diameter). The number of mature oocytes was observed in the embryo laboratory after oocyte retrieval. RESULTS: In cases of P < 2.5 ng/ml, there was no significant difference in the serum P level or P/E2 between the pregnant group and the non-pregnant group. The PFI and PMOI of the pregnant group were significantly lower than those of the non-pregnant group. According to the stratified analysis of the ovarian response, only the PMI and PMOI of the pregnant women in the normal ovarian response group were lower than those of the non-pregnant women. To compare the predictive value of the PFI and PMOI in IVF/ICSI outcomes, the patients were divided into four groups. The good-quality embryo rate and clinical pregnancy rate were highest in Group A (low PFI and low PMOI) and lowest in Group D (high PFI and high PMOI). In the two groups with discordant PFI and PMOI, namely Group B (low PFI and high PMOI) and Group C (high PFI and low PMOI), the good-quality embryo rate and clinical pregnancy rate were not significantly different. CONCLUSIONS: The PFI and PMOI had equal value in predicting clinical pregnancy outcomes in the normal ovarian response group undergoing the short-acting GnRH agonist long protocol. Each clinical centre can choose one of the indicators according to their actual situation in clinical practice and establish individual cut-off values for PFI and PMOI based on their own hormonal measurements.
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Hormônio Liberador de Gonadotropina/uso terapêutico , Progesterona/metabolismo , Adulto , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Gravidez , Estudos RetrospectivosRESUMO
Pseudogenes have long been considered as nonfunctional genomic sequences. Recent studies have shown that they can potentially regulate the expression of protein-coding genes and are dysregulated in diseases including cancer. However, the potential roles of pseudogenes in ovarian cancer have not been well studied. Here we characterized the pseudogene expression profile in HGSOC (high-grade serous ovarian carcinoma) by microarray. We identified 577 dysregulated pseudogenes and most of them were up-regulated (538 of 577). HMGA1P6 (High mobility group AT-hook 1 pseudogene 6) was one of the overexpressed pseudogenes and its expression was inversely correlated with patient survival. Mechanistically, HMGA1P6 promoted ovarian cancer cell malignancy by acting as a ceRNA (competitive endogenous RNA) that led to enhanced HMGA1 and HMGA2 expression. Importantly, HMGA1P6 was transcriptionally activated by oncogene MYC in ovarian cancer. Our findings reveal that MYC may contribute to oncogenesis through transcriptional regulation of pseudogene HMGA1P6 in ovarian cancer.
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Proteína HMGA1a/genética , Proteína HMGA2/genética , Neoplasias Ovarianas/genética , Pseudogenes/genética , Carcinogênese/genética , Carcinoma Epitelial do Ovário/genética , Cistadenocarcinoma Seroso/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes myc/genética , Genes myc/fisiologia , Proteína HMGA1a/metabolismo , Proteína HMGA2/metabolismo , Humanos , Oncogenes/genética , Pseudogenes/fisiologiaRESUMO
Endometrial cancer (EC) is the most common gynaecologic malignancy in western countries and has been reported to account for about 7% of female malignant tumours and 20% to 30% of female genital system malignant tumours. Accumulating evidence showed the expression of human trophoblast cell surface antigen 2 (Trop2) was abnormal in many cancers; however, the expression and role of Trop2 in EC are not clear. The Trop-2 protein expression was detected by western blot in EC cells. Cell proliferation, apoptosis, and migration were measured by CCK-8, flow cytometry, and Transwell assay, respectively. The epithelial mesenchymal transition (EMT) and AKT/ß-catenin signalling pathway-related proteins in EC cell lines were detected by western blot assay following Trop2 gene silencing. The present study revealed that the Trop2 protein was highly expressed in EC cell lines compared with human endometrial epithelial cells. The Trop2 mRNA and protein were obviously decreased following transfection with Trop2-siRNA sequence in KLE and Ishikawa cells. Meanwhile, Trop2 gene silencing in KLE and Ishikawa cells strongly inhibited cell proliferation and migration and increased cell apoptosis. Investigation into the molecular mechanism indicated that the Trop2 gene silencing suppressed EMT and AKT/ß-catenin signalling pathway activation. SIGNIFICANCE OF THE STUDY: These findings suggested that Trop2 silencing inhibited EC cell proliferation and migration and promoted cell apoptosis. The mechanism might be related to the inhibition of the AKT/ß-catenin signalling pathway in EC cells. Therefore, Trop2 may be a potential therapeutic target for the treatment of EC.
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Antígenos de Neoplasias/metabolismo , Apoptose , Moléculas de Adesão Celular/metabolismo , Neoplasias do Endométrio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Neoplasias do Endométrio/genética , Transição Epitelial-Mesenquimal , Feminino , Inativação Gênica , Humanos , Metástase Neoplásica , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Trofoblastos/metabolismoRESUMO
Iodine125 (125I) seed radiation applied around the celiac ganglion can relieve the refractory pain in pancreatic cancer. In an in vitro cell radiation model of human neuroblastoma cell lines, the impact of 125I radiation on the expression of transient receptor potential vanilloid1 (TRPV1) was investigated. The results indicated that the radiation delivering doses <2.13 Gy did not significantly affect cell growth, whereas the doses >3.12 Gy significantly reduced cell viability. The reduced TRPV1 mRNA level was dependent on the doses, while the reduced protein level occurred at lower doses (2.63 and 4.27 Gy), then returned to normal at an intermediate dose of 5.09 Gy, and decreased again at higher doses (5.91 and 6.73 Gy). The miRNA profiling at the dose of 2.63 Gy revealed 32 and 22 miRNAs that were significantly upregulated and downregulated, respectively. In addition, the upregulated miR1246 target, regulated the expression of TRPV1, indicating that miR1246 may be a new therapeutic target for pancreatic pain.
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Regulação para Baixo , Radioisótopos do Iodo/farmacologia , MicroRNAs/genética , Neuroblastoma/genética , Canais de Cátion TRPV/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/radioterapia , Análise de Sequência com Séries de Oligonucleotídeos , Canais de Cátion TRPV/metabolismoRESUMO
The role of microRNA-132 in human pancreatic ductal adenocarcinomas is still ambiguous. We explored the association between microRNA-132 and pancreatic ductal adenocarcinoma prognosis. The expression of microRNA-132 in 50 pancreatic ductal adenocarcinoma tissue samples and pancreatic ductal adenocarcinoma cell lines was examined, and the association between its expression and pancreatic ductal adenocarcinoma prognosis was assessed. Functional analysis and factors downstream of microRNA-132 were investigated. Kaplan-Meier survival curves showed that high expression of microRNA-132 was a significant prognostic factor for 1-year survival of patients with pancreatic ductal adenocarcinoma ( P = .028). Multivariate analysis for overall survival indicated that high expression of microRNA-132 was an independent prognostic factor for patients with pancreatic ductal adenocarcinoma ( P = .044). Low expression of microRNA-132 was associated with poor prognosis in pancreatic ductal adenocarcinoma. Ectopic expression of microRNA-132 significantly inhibited proliferation and promoted apoptosis of 2 pancreatic ductal adenocarcinoma cell lines. Bioinformatic analysis revealed that microRNA-132 may exert its effects on pancreatic ductal adenocarcinoma through downregulating mitogen-activated protein kinase 3 and nuclear transcription factor Y subunit α. The results of this study further our understanding of the relationship between microRNA-132 and pancreatic ductal adenocarcinoma by showing that microRNA-132 might inhibit the progression of pancreatic ductal adenocarcinoma by regulating mitogen-activated protein kinase and nuclear transcription factor Y subunit alpha.
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Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/patologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , MicroRNAs/genética , Neoplasias Pancreáticas/patologia , Adenocarcinoma/genética , Adenocarcinoma/terapia , Apoptose , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Ciclo Celular , Proliferação de Células , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Prognóstico , Taxa de SobrevidaRESUMO
High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecologic malignancies. Currently, anti-angiogenesis therapy is the most promising strategy for the successful treatment of HGSOC. In this study, we found Neferine could inhibit the angiogenesis of ovarian cancer cells both in vitro and in vivo. Further analysis revealed that its suppressive effect on human umbilical vein endothelial cell (HUVEC) proliferation correlated with promoting cell cycle arrest and autophagy. The cell cycle genes were dose-dependently reduced and the level of LC3II/LC3I (microtubule associated protein 1 light chain 3) was increased. Using a specific marker for macrophages (CD206 and Mrc1), we indicated that Neferine could inhibit M2-macrophage in vivo. Finally, CD206 was stained in 150 HGSOC samples and its high expression predicted inferior overall survival. Our current study is the first to demonstrate the anti-angiogenesis mechanism of Neferine by inducing autophagy via mTOR/p70S6K pathway inhibition and suppressing M2-macrophage polarization. Our findings suggest that Neferine is an attractive reagent with great potential in HGSOC therapy, especially in standard-therapy resistant cases.
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Inibidores da Angiogênese/farmacologia , Autofagia , Benzilisoquinolinas/farmacologia , Cistadenocarcinoma Seroso/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Neoplasias Ovarianas/tratamento farmacológico , Animais , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Cistadenocarcinoma Seroso/irrigação sanguínea , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Macrófagos/patologia , Camundongos , Gradação de Tumores , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells. miR-130a could also attenuate rapamycin/starvation-induced autophagy. Ectopic TSC1 expression could block the effects of miR-130a on cell proliferation, migration and autophagy. Finally, we found that miR-130a expression could be upregulated by inflammatory factors and was transactivated by NF-κB. Therefore, our findings establish a crosstalk between inflammation and mTOR signaling that is mediated by miR-130a, which might have a pivotal role in the initiation and progression of HGSOC.
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Cistadenocarcinoma Seroso/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neoplasias Ovarianas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , NF-kappa B/genética , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Transfecção , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. CD47 is overexpressed in various human malignancies. However, the expression and functional significance of CD47 in high-grade serous ovarian carcinoma (HGSOC) has not been completely understood. In this study, we reported that CD47 was commonly overexpressed in HGSOC. Higher CD47 expression was significantly correlated with poor prognosis of HGSOC patients. Functional investigations revealed that CD47 overexpression in ovarian cancer cells significantly promoted migration and invasion. Moreover, CD47 induced epithelial-mesenchymal transition (EMT) through modulating E-cadherin and N-cadherin. Our findings suggest that up-regulation of CD47 is correlated with ovarian cancer progression and it might be a potential biomarker for predicting clinical outcomes.
RESUMO
BACKGROUND: Association between exogenous estrogen intake and cholelithiasis risk has been reported in several epidemiological studies, including oral contraceptive (OC) and hormone replacement therapy (HRT), while the results were controversial. This study aimed to perform a comprehensive meta-analysis of this issue. METHODS: PUBMED, EMBASE, and Cochrane library database were searched up to October 2016. Two reviewers independently extracted data from eligible studies, relative risks (RRs), and/or odds ratios (ORs) with 95% confidence intervals (95% CIs) for the highest versus lowest categories of intake were adopted. Either a fixed- or a random-effects model was adopted to estimate overall RRs or ORs. Besides, subgroup and publication bias analyses were applied to explain the heterogeneity. An original study was also conducted to verify our conclusion. RESULTS: A total of 19 studies with approximately 556,620 participants were included in this meta-analysis. The pooled RR of cholelithiasis for the highest versus the lowest categories was 1.59 (95% CI: 1.44-1.75), indicating that exogenous estrogen was positive associated with the intake of exogenous estrogen. However, the pooled RR of OC intake and cholelithiasis risk was 1.19 (95% CI: 0.97-1.45), and the RR for HRT was 1.79 (95% CI: 1.61-2.00). CONCLUSION: The HRT was positively associated with the cholelithiasis risk, and the OC will not increase the risk of cholelithiasis.