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Objective: Nucleotide excision repair (NER) plays a vital role in maintaining genome stability, and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation. This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children. Methods: In this five-center case-control study, we enrolled 966 subjects from East China (193 hepatoblastoma patients and 773 healthy controls). The TaqMan method was used to genotype 19 single nucleotide polymorphisms (SNPs) in NER pathway genes, including ERCC1, XPA, XPC, XPD, XPF, and XPG. Then, multivariate logistic regression analysis was performed, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to assess the strength of associations. Results: Three SNPs were related to hepatoblastoma risk. XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07-2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12-2.45, P=0.012, respectively). However, XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model (adjusted OR=0.68, 95% CI=0.49-0.95; P=0.024). Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups. Moreover, there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) analysis. Conclusions: In summary, NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) are significantly associated with hepatoblastoma risk, and further research is required to verify these findings.
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Malignant tumors are one of the fatal diseases that threaten children's physical and mental health and affect their development. Research has shown that the occurrence and development of malignant tumors are associated with the abnormal expression and regulation of genes. Circular RNAs (circRNAs) are noncoding RNAs that have a closed circular structure, with a relatively stable expression, and do not undergo exonuclease-mediated degradation readily. Recent studies have shown that circRNA plays an important role in the occurrence, metastasis, and invasion of solid malignant tumors (SMTs) in children. Thus, circRNA is being considered as a breakthrough in the treatment of SMTs in children. In this review, we describe the functions and mechanisms of circRNAs involved in SMTs in children oncogenesis, and summarize the roles of circRNAs in regulating cell proliferation, cell apoptotic death, the cell cycle, cell migrative and invasive ability, epithelial-mesenchymal transition (EMT), cancer stem cells and drug resistance in SMTs in children. In addition, we also discuss the role of circRNAs in the early diagnosis, pathological grading, targeted therapy, and prognosis evaluation of common SMTs in children. CircRNAs are likely to provide a novel direction in therapy in SMTs of children.
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BACKGROUND: Perioperative complications are common during the surgical treatment of pediatric retroperitoneal teratoma (RPT). Some clinical and radiographic features could be associated with perioperative complications. This study was designed to identify the factors associated with such complications. MATERIALS AND METHODS: We retrospectively analyzed the clinical data of RPT patients who underwent surgical treatment at the Department of Pediatric Surgery of The Affiliated Hospital of Qingdao University between January 2008 and January 2020, including demographics, imaging data, intraoperative findings, perioperative complications, pathological data, and outcomes. RESULTS: A total of 91 patients were included in this study, including 30 boys and 61 girls. Of these, 71 patients (78%) were 1 y old or younger. Thirty-eight patients (41%) had perioperative complications (44 intraoperative and 7 postoperative). Preoperative imaging studies showed that the tumor distorted adjacent arteries, veins, and organs in all patients. More veins and organs were displaced and distorted by the tumor in patients who had perioperative complications. Multivariate analysis showed that the number of organs compressed and distorted by the tumor was significantly related to perioperative complications (odds ratio 1.69, 95% confidence interval 1.19-2.41). CONCLUSIONS: Surgical treatment of RPT is complex and challenging. As majority are benign, a complete excision is usually curative. The number of organs compressed and distorted by the tumor is positively related to perioperative complications.
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Complicações Intraoperatórias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Neoplasias Retroperitoneais/cirurgia , Teratoma/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/prevenção & controle , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Neoplasias Retroperitoneais/irrigação sanguínea , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/patologia , Espaço Retroperitoneal/diagnóstico por imagem , Espaço Retroperitoneal/cirurgia , Estudos Retrospectivos , Fatores de Risco , Teratoma/irrigação sanguínea , Teratoma/diagnóstico , Teratoma/patologia , Resultado do TratamentoRESUMO
BACKGROUND: MicroRNAs (miRNAs or miRs) can participate in the development and progression of neuroblastoma. Many studies have indicated that miR-429 can participate in tumor development. However, the mechanism underlying miR-429-mediated progression of neuroblastoma remains largely unclear. METHODS: Colony formation and apoptosis assays were used to determine the effect of miR-429 on cell proliferation. Its impact on cell migration was determined using the wound-healing and Transwell assays. The target gene of miR-429 was confirmed via western blotting and luciferase reporter assays. A nude mouse xenograft model with miR-429 overexpression was used to assess the effect on tumor growth. RESULTS: Our findings indicate that miR-429 is downregulated in neuroblastoma cell lines. We also found that it can induce apoptosis and inhibit proliferation in cells of those lines. MiR-429 can bind to the 3'-UTR of IKKß mRNA and overexpression of IKKß can reverse cell proliferation, blocking the effect of miR-429. Furthermore, miR-429 overexpression inhibited neuroblastoma growth in our nude mouse xenograft model. CONCLUSION: We provide important insight into miR-429 as a tumor suppressor through interaction with IKKß, which is a catalytic subunit of the IKK complex that activates NF-κB nuclear transport. Our results demonstrate that miR-429 may be a new target for the treatment of neuroblastoma.
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Movimento Celular/genética , Proliferação de Células/genética , Genes Supressores de Tumor , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neuroblastoma/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose/genética , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Neuroblastoma/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To study the variations of the right branch of the hepatic portal vein in children. METHODS: A total of 810 children's abdominal CT images were reconstructed with three-dimensional (3D) simulation software, Variations of the right branch of the hepatic portal vein were analyzed and classified. RESULTS: The most common anatomy (type A) was seen in 355 patients (43.83%). Trifurcation in the right anterior portal vein (type B) variation was seen in 250 cases (30.86%). The right posterior portal vein arched without obvious branching (type C) was seen in 71 cases (8.77%). There were 134 special variants (16.54%) named type D, including 14 cases (1.73%) with the right anterior branch in four sub-branches, 13 cases (1.60%) in one trunk and multiple sub-branches, 92 cases (11.36%) originating from the left trunk of the portal vein, and 15 cases (1.85%) with the VI segment of the portal vein originating from the right anterior branch of the portal vein. CONCLUSION: Variations in the right branch of the hepatic portal vein seems to be very frequent. Recognition of such variations is important in the preoperative evaluation of children with surgery planned, because these variations may have implications for anatomy-guided liver resection and for planning the operative approach.
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Variação Anatômica , Veia Porta/anatomia & histologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imageamento Tridimensional , Lactente , Masculino , Veia Porta/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada EspiralRESUMO
OBJECTIVE: To study the differentially expressed mRNAs between MYCN-amplified neuroblastoma (NB) and non-amplified NB, to screen out the genes which can be used to predict the prognosis of MYCN-amplified NB, and to analyze their value in predicting prognosis. METHODS: NB transcriptome data and the clinical data of children were obtained from the TARGET database. According to the presence or absence of MYCN amplification, the children were divided into two groups: MYCN amplification (n=33) and non-MYCN amplification (n=121). The expression of mRNAs was compared between the two groups to obtain differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis was performed to investigate the main functions of DEGs. The Cox proportional-hazards regression model analysis was used to investigate the genes influencing the prognosis of MYCN-amplified NB. The children were divided into a high-risk group (n=77) and a low-risk group (n=77) based on the median of risk score. A survival analysis was used to compare survival rate between the two groups. The receiver operating characteristic (ROC) curve was used to investigate the value of risk score in predicting the prognosis of children with MYCN-amplified NB. RESULTS: A total of 582 DEGs were screened out, and they were involved in important biological functions such as ribosome composition, expression of cell adhesion molecules, and activity of membrane receptor protein. The multivariate Cox regression model analysis showed that FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes had a marked influence on the prognosis of the children with NB in the MYCN amplification group (P<0.05). The survival analysis showed that the high-risk group had a significantly lower overall survival rate than the low-risk group (P<0.05). The ROC curve analysis showed that risk score had a certain value in predicting the prognosis of the children with NB in the MYCN amplification group (P<0.05), with an area under the ROC curve of 0.729, an optimal cut-off value of 1.316, a sensitivity of 53.2%, and a specificity of 84.4%. CONCLUSIONS: The mRNA expression of FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes can be used as biomarkers to predict the prognosis of MYCN-amplified NB, which can help to refine clinical risk stratification.
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Neuroblastoma , Criança , Amplificação de Genes , Humanos , Proteínas de Membrana Transportadoras , Proteína Proto-Oncogênica N-Myc , Prognóstico , RNA Mensageiro , Receptores ViraisRESUMO
Long noncoding RNAs (lncRNAs) are reported to be involved in the pathology of numerous cancers, including neuroblastoma (NB). lncRNA SNHG7 has been recognized as a carcinogen in several cancers, but its role in NB progression remains unknown. Our study revealed that SNHG7 expression was markedly higher in NB tissues than that in nontumor tissues. Besides, upregulated SNHG7 was greatly correlated with poor overall survival of NB patients. Functionally, the loss-of-function assays demonstrated that knockdown of SNHG7 inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition in NB cells. Mechanically, the bioinformatics analysis predicted that miR-653-5p was the shared partner of SNHG7 and signal transducer and activator of transcription 2 (STAT2). Unsurprisingly, we further confirmed that SNHG7 could interact with miR-653-5p and therefore functioned as the ceRNA of STAT2 so as to regulate STAT2 expression in NB cells. Moreover, STAT2 expression was in inverse proportion to miR-653-5p level but in positive proportion to SNHG7 level in NB tissues. Importantly, the repressed NB progression induced by silenced SNHG7 was reversed by STAT2 overexpression or miR-653-5p inhibitors. Jointly, our findings elucidated SNHG7 facilitated NB progression through the miR-653-5p/STAT2 pathway, providing a novel therapeutic target and prognostic biomarker for this disease.
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MicroRNAs/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , RNA Longo não Codificante/genética , Fator de Transcrição STAT2/metabolismo , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Pré-Escolar , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Retroalimentação Fisiológica , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Neuroblastoma/patologia , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Previous studies have shown beneficial effects of dietary approaches for iron deficiency anemia (IDA) control. This study was design to investigate the effect of dietary intervention treatment on children with iron deficiency anemia. METHODS: We performed a systematic review of published dietary interventions effect on IDA treatment through meta-analysis. CBM, CNKI, Wanfang database, EMBASE, VIP, PubMed and Web of science database were searched to identify studies published between January, 1980 and December, 2016. Statistical analysis was performed by Revmen5.2 software. RESULTS: Initially we retrieved for 373 studies, and then 6 studies with a total of 676 individuals were included in the analysis according to the inclusion and exclusion criteria for meta-analysis. The overall pooled estimate of odds ratio [(OR), 95% confidence intervals (95% CI)] in the dietary intervention on children with iron deficiency anemia was 6.54 (95% CI: 3.48-12.31, Z = 5.82, p<0.001) and funnel plot is symmetric. CONCLUSIONS: Our meta-analysis suggested that dietary interventions are effective in improving the iron deficiency in children with iron deficiency anemia (IDA) and should be considered in the overall strategy of IDA management.
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Anemia Ferropriva/dietoterapia , Anemia Ferropriva/epidemiologia , Dieta/métodos , Suplementos Nutricionais , Adolescente , Anemia Ferropriva/patologia , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , MasculinoRESUMO
Porcine epidemic diarrhea (PED) is a highly contagious swine intestinal disease caused by PED virus (PEDV). Vaccination is a promising strategy to prevent and control PED. Previous studies have confirmed that glycosylation could regulate the immunogenicity of viral antigens. In this study, we constructed three recombinant PEDVs which removed the glycosylation sites in RBD. Viral infection assays revealed that similar replication characteristics between the recombinant viruses and parental PEDV. Although animal challenging study demonstrated that the glycosylation sites in RBD do not affect the pathogenicity of PEDV, we found that removing the glycosylation sites on the RBD regions could promote the IgG and neutralization titer in vivo, suggesting deglycosylation in RBD could enhance the immunogenicity of PEDV. These findings demonstrated that removal of the glycosylation sites in RBD is a promising method to develop PEDV vaccines.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Vírus da Diarreia Epidêmica Suína , Glicoproteína da Espícula de Coronavírus , Doenças dos Suínos , Animais , Vírus da Diarreia Epidêmica Suína/imunologia , Vírus da Diarreia Epidêmica Suína/genética , Glicosilação , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Suínos , Doenças dos Suínos/virologia , Doenças dos Suínos/imunologia , Doenças dos Suínos/prevenção & controle , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Vacinas Virais/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células Vero , Chlorocebus aethiops , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Imunogenicidade da Vacina , CamundongosRESUMO
Stress cardiomyopathy is a major clinical complication after severe burn. Multiple upstream initiators have been identified; however, the downstream targets are not fully understood. This study assessed the role of the plasma membrane in this process and its relationship with the protease µ-calpain and tumor necrosis factor-alpha (TNF-α). Here, third-degree burn injury of approximately 40% of the total body surface area was established in rats. Plasma levels of LDH and cTnI and cardiac cell apoptosis increased at 0.5 h post burn, reached a peak at 6 h, and gradually declined at 24 h. This effect correlated well with not only the disruption of cytoskeletal proteins, including dystrophin and ankyrin-B, but also with the activation of µ-calpain, as indicated by the cleaved fragments of α-spectrin and membrane recruitment of the catalytic subunit CAPN1. More importantly, these alterations were diminished by blocking calpain activity with MDL28170. Burn injury markedly increased the cellular uptake of Evans blue, indicating membrane integrity disruption, and this effect was also reversed by MDL28170. Compared with those in the control group, cardiac cells in the burn plasma-treated group were more prone to damage, as indicated by a marked decrease in cell viability and increases in LDH release and apoptosis. Of note, these alterations were mitigated by CAPN1 siRNA. Moreover, after neutralizing TNF-α with rhTNFR:Fc, calpain activity was blocked, and heart function was improved. In conclusion, we identified µ-calpain as a trigger for severe burn-induced membrane disruption in the heart and provided evidence for the application of rhTNFR:Fc to inhibit calpain for cardioprotection.
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INTRODUCTION: Osteosarcoma is a malignant primary bone tumor. Bone marrow-derived mesenchymal stem cells-derived extracellular vesicles (BMSC-EVs) bear repair function for bone and cartilage. This study investigated the mechanism of BMSC-EVs in osteosarcoma cell proliferation, migration and invasion. METHODS: BMSC-EVs were isolated and identified. The effects of different concentrations of EVs on osteosarcoma cell proliferation, migration and invasion were evaluated. LncRNA MALAT1 expression in osteosarcoma cells was detected. BMSCs were transfected with si-MALAT1 or si-NC. The binding relationships between MALAT1 and miR-143, and miR-143 and NRSN2 were verified. Levels of NRSN2 and Wnt/ß-catenin pathway key proteins were detected. miR-143 mimic was transfected into EVs-treated osteosarcoma cells. Nude mice were injected with MG63 cells to verify the effect of EVs on osteosarcoma growth in vivo. RESULTS: BMSC-EVs facilitated proliferation, invasion and migration of osteosarcoma cells. BMSC-EVs carried MALAT1 into osteosarcoma cells. BMSC-EVs-treated osteosarcoma cells showed increased MALAT1 and NRSN2 expressions, decreased miR-143 expression, and activated Wnt/ß-catenin pathway. miR-143 mimic or si-MALAT1 reversed the effects of BMSC-EVs on osteosarcoma cells. In vivo experiment confirmed that BMSC-EVs promoted tumor growth in nude mice. DISCUSSION: BMSC-EVs promoted proliferation, invasion and migration of osteosarcoma cells via the MALAT1/miR-143/NRSN2/Wnt/ß-catenin axis. This study might offer new insights into osteosarcoma management.
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Neuroblastoma (NB) is considered a highly prevalent extracranial solid tumor in young children, and the upregulation of Nmyc protooncogene (MYCN) is closely associated with the late stages of NB and poor prognostic outcomes. The current study was designed to evaluate the effects of exosomal microRNA (miRNA/miR)175p from MYCNamplified NB cells on the proliferative and migratory potential of nonMYCN amplified NB cells. miR175p was found to activate the PI3K/Akt signaling cascade by targeting PTEN, and the overexpression of miR175p was found to promote cellular migration and proliferation in vitro. Further experimentation revealed that the elevated expression of miR175p in SKNBE(2) cellderived exosomes significantly promoted the proliferative and migratory capacities of SHSY5Y cells by inhibiting PTEN. Collectively, these findings demonstrated that miR175p derived from MYCNamplified NB cell exosomes promoted the migration and proliferation of nonMYCN amplified cells, highlighting an exosomeassociated malignant role for miR175p.
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Movimento Celular , Proliferação de Células , Exossomos/metabolismo , Amplificação de Genes , MicroRNAs/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , RNA Neoplásico/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/patologia , Humanos , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Neuroblastoma/patologia , RNA Neoplásico/genéticaRESUMO
BACKGROUND: Previous studies have revealed that WTAP is related to multiple types of cancer. Recently, WTAP has been reported as an independent prognostic factor in patients with neuroblastoma. METHODS: To explore the association between three WTAP polymorphisms (rs9457712 G>A, rs1853259 A>G and rs7766006 G>T) and neuroblastoma susceptibility in Chinese populations, we performed this case-control study including 898 neuroblastoma cases and 1,734 controls. We genotyped these potentially functional single nucleotide polymorphisms (SNPs) by TaqMan assays. The odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression models were used to assess the relationship between WTAP SNPs and the risk of neuroblastoma. RESULTS: No significant associations were observed in the overall analysis between any of the three WTAP polymorphisms and the risk of neuroblastoma. However, in the age ≤18 months subgroup, we found that the rs1853259 AG/GG genotype exerted protective effects against neuroblastoma (adjusted OR =0.77, 95% CI: 0.59-0.998, P=0.048), whereas the presence of 1-2 combined risk genotypes significantly increased the risk of neuroblastoma (adjusted OR =1.32, 95% CI: 1.02-1.71, P=0.036). CONCLUSIONS: WTAP gene polymorphisms only have a weak impact on the risk of neuroblastoma in the Chinese children. Further case-control studies, preferable on larger sample sizes, are needed to validate our results.
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OBJECTIVE: To establish a tumor-bearing nude mouse model of human neuroblastoma in order to study the mechanisms of neuroblastoma invasion and metastasis, and to investigate potential therapeutic modalities in the experimental animal models. METHODS: A human neuroblastoma cell line was cultured in vitro. 1 x 10(7) cells undergoing exponential growth were collected in 0.1 ml of suspension and subcutaneously inoculated into the right flank next to the forelimb in nude mice. The biological characteristics of the developed tumors were observed, and histopathological and DNA microarray analyses were performed. The expressions of NSE in the subcutaneous tumor, metastatic tumor and the primary neuroblastoma tumor tissues from a pediatric patient were analyzed by immunohistochemistry. RESULTS: Tumors successfully grew in 36 out of 48 injected mice, with a total tumor-formation rate of 75.0%. Metastasis occurred in 10 cases, and the metastatic rate was 20.8%. Tumors in five injected mice grew locally without metastasis. These tumors had large volume and the tumor weight reached up to half of the body weight of the host animal. Four mice exhibited systemic metastasis without tumor growth at the primary inoculation site. There were six mice with locally growing tumor accompanied by metastasis. CONCLUSION: We have successfully established a human neuroblastoma xenograft model in nude mice with high tumor growth and metastatic rates. This model depicting the natural cell growth, local infiltration and distant metastasis characteristics of human neuroblastoma, providing an ideal animal model for in vivo studies of neuroblastoma. In addition, the results of this study indicate the heterogeneous nature of neuroblastoma, it may play an important role in metastasis of this tumor.
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Modelos Animais de Doenças , Perfilação da Expressão Gênica , Neoplasias Hepáticas/secundário , Neuroblastoma/patologia , Fosfopiruvato Hidratase/metabolismo , Animais , Linhagem Celular Tumoral , Pré-Escolar , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Transplante de Neoplasias , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/secundário , Carga TumoralRESUMO
Maslinic acid is an active member of pentacyclic triterpenes predominantly found in dietary plants including hawthorn berries and olive fruit skins. It has been reported to show immense pharmacological and biological importance including anticancer property. This research was initiated to explore the anticancer potential of maslinic acid against human neuroblastoma. The effects of maslinic acid on cellular apoptosis, ROS generation, cell migration and invasion, caspase activation and targeting MAPK/ERK signaling pathway were investigated. The proliferation percentage was calculated by performing of MTT assay. AO/EB and annexin V/PI staining assays along with western blotting were used to monitor the apoptosis and expressions of apoptosis connected proteins. Spectrofluorometry was used for ROS monitoring. To assess the anti-metastatic effects of maslinic acid on neuroblastoma cells, transwell chambers assays for migration as well as invasion were executed. Western blotting was implemented to establish the expressions of MAPK/ERK signaling pathway connected proteins. Results evidenced remarkable anticancer potential of maslinic acid against human neuroblastoma. It induced dose as well as time reliant anti-proliferative effects against SHSY-5Y cells selectively. The underlying mechanism of cancer suppressive effects of maslinic acid was found to mediate via caspase-dependent apoptosis. Further, ROS production amplified terrifically with exposure of SHSY-5Y to higher maslinic acid doses. Cell migration and invasion in SHSY-5Y cells were both reduced remarkably by maslinic acid. Finally, the activity of proteins associated with MAPK/ERK signaling pathway was found to be significantly reduced with increasing maslinic acid doses. In conclusion, it was observed that maslinic acid possesses a great anti-neuroblastoma potential and could be considered for its chemotherapy provided further investigations are recommended.
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Previous studies indicated that Ca2+/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca2+-regulated protease µ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca2+ flux using ryanodine and thapsigargin failed to prevent Ca2+ paradox-induced heart injury. In contrast, the Ca2+ paradox increased CaMKII auto-phosphorylation at Thr287, while the CaMKII inhibitor KN-62 and the Na+/Ca2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of µ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.
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Cálcio/metabolismo , Calpaína/metabolismo , Isquemia/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Isquemia/metabolismo , Masculino , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Tapsigargina/farmacologiaRESUMO
Long non-coding (lncRNA) cancer susceptibility candidate (CASC7) plays a tumor-suppressive role in several malignancies. In this study, the role of CASC7 in neuroblastoma was investigated for the first time. We observed the downregulation of CASC7 in neuroblastoma tissues compared to non-cancer tissues of neuroblastoma patients. Across neuroblastoma tissues, CASC7 was inversely correlated with microRNA-10a (miR-10a) but positively correlated with phosphatase and tensin homolog mRNA. In neuroblastoma cells, CASC7 overexpression led to downregulated miR-10a but upregulated phosphatase and tensin homolog. Furthermore, miR-10a overexpression led to downregulated phosphatase and tensin homolog and reduced effects of CASC7 overexpression. CASC7 overexpression resulted in inhibition, while miR-10a overexpression resulted in increased proliferation rate of neuroblastoma cells. We therefore concluded that lncRNA CASC7 may upregulate phosphatase and tensin homolog by downregulating miR-10a to inhibit neuroblastoma cell proliferation.
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Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Neuroblastoma/genética , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , MicroRNAs/genética , Células-Tronco Neurais/metabolismoRESUMO
Neuroblastoma is the primary cause of cancer death in childhood. METTL14 is tightly linked to cancer. However, whether single-nucleotide polymorphisms (SNPs) in the METTL14 gene could predispose to neuroblastoma susceptibility lacks evidence. With an epidemiology case-control study, associations between METTL14 gene SNPs and overall risk for neuroblastoma were estimated in 898 cases and 1,734 controls. Following that, stratified analysis was performed. Among the five analyzed SNPs, rs298982 G>A and rs62328061 A>G exhibited a significant association with decreased susceptibility to neuroblastoma, whereas the associations with increased neuroblastoma susceptibility were observed for rs9884978 G>A and rs4834698 T>C. Moreover, subjects carrying two to five risk genotypes were more inclined to develop neuroblastoma than those with zero to one risk genotypes. The stratified analysis further demonstrated the protective effect of rs298982 G>A and rs62328061 A>G, as well as the predisposing effect of rs4834698 T>C and two to five risk genotypes, in certain subgroups. Haplotype analysis was performed. Moreover, false-positive report probability analysis validated the reliability of the significant results. The expression quantitative trait locus analysis revealed that rs298982 is correlated with the expression levels of its surrounding genes. Our results suggest that some SNPs in the METTL14 gene are associated with predisposition to neuroblastoma.
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BACKGROUND: Surgical management of giant liver tumors involving the hepatic hilum tends to be very difficult. The present study assessed the feasibility and safety of resection of such liver tumors. METHODS: We evaluated 27 patients with liver tumors involving the hepatic hilum. The patients ranged in age from 3 months to 14 years (mean, 4.2 years). Of the 27 cases, 23 were resected completely during the past 10 years. The other four cases did not undergo operation because of their parents' decisions to discontinue treatment; these cases had multiple space-occupying lesions in addition to tumors involving the hepatic hilum. Before resection, the tumor was fully exposed and an occluding tape was placed around the vena cava when necessary. RESULTS: The hepatectomies were performed under intermittent portal triad clamping; 23 cases were successfully resected without postoperative mortality or morbidity. The mean operation duration was 205 min and mean blood loss was 120 ml. Pathological diagnoses included hepatoblastoma (n = 9), endotheliosarcoma (n = 1), mesenchymal hamartoma (n = 4), teratoma (n = 1), adenoma (n = 3), and hepatocellular carcinoma (n = 4). The nine cases with benign liver tumors were healthy at follow-up at 11 months to 9 years after operation. Of the 14 cases with malignant tumors, six died from recurrence, metastasis, or other complications. The other eight cases were still alive without clinical tumors. CONCLUSIONS: Resecting giant liver tumors involving the main hepatic veins and/or the retrohepatic vena cava, although challenging, is feasible and safe.
Assuntos
Hepatectomia/métodos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Sistema Porta/cirurgia , Adolescente , Biópsia por Agulha , Perda Sanguínea Cirúrgica/prevenção & controle , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Hemostasia Cirúrgica/métodos , Hepatectomia/efeitos adversos , Hepatoblastoma/diagnóstico por imagem , Hepatoblastoma/mortalidade , Hepatoblastoma/patologia , Hepatoblastoma/cirurgia , Humanos , Imageamento Tridimensional/métodos , Imuno-Histoquímica , Lactente , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Sistema Porta/patologia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/patologia , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
BACKGROUND: The molecular pattern of severe burn-induced acute lung injury, characterized by cell structure damage and leukocyte infiltration, remains unknown. This study aimed to determine whether calpain, a protease involved in both processes, mediates severe burn-induced acute lung injury. METHODS: Rats received full-thickness scald burns covering 30% of the total body surface area, followed by instant fluid resuscitation. MDL28170 (Tocris Bioscience), an inhibitor of calpain, was given intravenously 1 h before or after the scald burn. The histological score, wet/dry weight ratio, and caspase-3 activity were examined to evaluate the degree of lung damage. Calpain activity and its source were detected by an assay kit and immunofluorescence staining. The proteolysis of membrane skeleton proteins α-fodrin and ankyrin-B, which are substrates of calpain, was measured by Western blot. RESULTS: Time-course studies showed that tissue damage reached a peak between 1 and 6 h post-scald burn and gradually diminished at 24 h. More importantly, calpain activity reached peak levels at 1 h and was maintained until 24 h, paralleled by lung damage to some extent. Western blot showed that the levels of the proteolyzed forms of α-fodrin and ankyrin-B correlated well with the degree of damage. MDL28170 at a dose of 3 mg/kg b. w. given 1 h before burn injury not only antagonized the increase in calpain activity but also ameliorated scald burn-induced lung injury, including the degradation of α-fodrin and ankyrin-B. Immunofluorescence images revealed calpain 1 and CD45 double-positive cells in the lung tissue of rats exposed to scald burn injury, suggesting that leukocytes were a dominant source of calpain. Furthermore, this change was blocked by MDL28170. Finally, MDL28170 given at 1 h post-scald burn injury significantly ameliorated the wet/dry weight ratio compared with burn injury alone. CONCLUSIONS: Calpain, a product of infiltrating leukocytes, is a mediator of scald burn-induced acute lung injury that involves enhancement of inflammation and proteolysis of membrane skeleton proteins. Its late effects warrant further study.