RESUMEN
As a common anticancer drug, cisplatin has been widely used for treating tumors in the clinic. However, its side effects, especially its nephrotoxicity, noticeably restrict the application of cisplatin. Therefore, it is imperative to investigate the mechanism of renal injury and explore the corresponding remedies. In this study, we showed the phenotypes of the renal tubules and epithelial cell death as well as elevated cleaved-caspase3- and TUNEL-positive cells in rats intraperitoneally injected with cisplatin. Similar cisplatin-induced cell apoptosis was found in HK-2 and NRK-52E cells exposed to cisplatin as well. In both models of cisplatin-induced apoptosis in vivo and in vitro, quantitative PCR data displayed reductions in miR-30a-e expression levels, indicating that miR-30 might be involved in regulating cisplatin-induced cell apoptosis. This was further confirmed when the effects of cisplatin-induced cell apoptosis were found to be closely correlated with alterations in miR-30c expression, which were manipulated by transfection of either the miR-30c mimic or miR-30c inhibitor in HK-2 and NRK-52E cells. Using bioinformatics tools, including TargetScan and a gene expression database (Gene Expression Omnibus), Adrb1, Bnip3L, Hspa5 and MAP3K12 were predicted to be putative target genes of miR-30c in cisplatin-induced apoptosis. Subsequently, Bnip3L and Hspa5 were confirmed to be the target genes after determining the expression of these putative genes following manipulation of miR-30c expression levels in HK-2 cells. Taken together, our current experiments reveal that miR-30c is certainly involved in regulating the renal tubular cell apoptosis induced by cisplatin, which might supply a new strategy to minimize cisplatin-induced nephrotoxicity.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de la Membrana/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Línea Celular , Chaperón BiP del Retículo Endoplásmico , Femenino , Proteínas de Choque Térmico/genética , Humanos , Etiquetado Corte-Fin in Situ , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Proteínas de la Membrana/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Supresoras de Tumor/genéticaRESUMEN
As a neonicotinoid pesticide, imidacloprid is widely used to control insects in agriculture and fleas on domestic animals. However, it is not known whether imidacloprid exposure negatively affects neurogenesis during embryonic development. In this study, using a chick embryo model, we investigated the effects of imidacloprid exposure on neurogenesis at the earliest stage and during late-stage embryo development. Exposing HH0 chick embryos to imidacloprid in EC culture caused neural tube defects (NTDs) and neuronal differentiation dysplasia as determined by NF/Tuj1 labeling. Furthermore, we found that F-actin accumulation on the apical side of the neural tube was suppressed by exposure to imidacloprid, and the expression of BMP4 and Shh on the dorsal and ventral sides of the neural tubes, respectively, were also reduced, which in turn affects the dorsolateral hinge points during bending of the neural plate. In addition, exposure to imidacloprid reduced cell proliferation and increased cell apoptosis, as determined by pHIS3 labeling and TUNEL staining, respectively, also contributing to the malformation. We obtained similar results in late-stage embryos exposed to imidacloprid. Finally, a bioinformatics analysis was employed to determine which genes identified in this study were involved in NTDs. The experimental evidence and bioinformatics analysis suggested that imidacloprid exposure during chick embryo development could increase the risk of NTDs and neural dysplasia.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Insecticidas/toxicidad , Neonicotinoides/toxicidad , Tubo Neural/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Nitrocompuestos/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Gastrulación/efectos de los fármacos , Hibridación in Situ , Etiquetado Corte-Fin in Situ , Tubo Neural/citología , Defectos del Tubo Neural/inducido químicamente , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Although biomedical ontologies have standardized the representation of gene products across species and databases, a method for determining the functional similarities of gene products has not yet been developed. METHODS: We proposed a new semantic similarity measure based on Gene Ontology that considers the semantic influences from all of the ancestor terms in a graph. Our measure was compared with Resnik's measure in two applications, which were based on the association of the measure used with the gene co-expression and the protein-protein interactions. RESULTS: The results showed a considerable association between the semantic similarity and the expression correlation and between the semantic similarity and the protein-protein interactions, and our measure performed the best overall. CONCLUSION: These results revealed the potential value of our newly proposed semantic similarity measure in studying the functional relevance of gene products.
Asunto(s)
Ontología de Genes , Unión ProteicaRESUMEN
Biomaterials and neurotrophic factors represent promising guidance for neural repair. In this study, we combined poly-(lactic acid-co-glycolic acid) (PLGA) conduits and neurotrophin-3 (NT-3) to generate NT-3-loaded PLGA carriers in vitro. Bioactive NT-3 was released stably and constantly from PLGA conduits for up to 4 weeks. Neural stem cells (NSCs) and Schwann cells (SCs) were coseeded into an NT-releasing scaffold system and cultured for 14 days. Immunoreactivity against Map2 showed that most of the grafted cells (>80%) were differentiated toward neurons. Double-immunostaining for synaptogenesis and myelination revealed the formation of synaptic structures and myelin sheaths in the coculture, which was also observed under electron microscope. Furthermore, under depolarizing conditions, these synapses were excitable and capable of releasing synaptic vesicles labeled with FM1-43 or FM4-64. Taken together, coseeding NSCs and SCs into NT-3-loaded PLGA carriers increased the differentiation of NSCs into neurons, developed synaptic connections, exhibited synaptic activities, and myelination of neurites by the accompanying SCs. These results provide an experimental basis that supports transplantation of functional neural construction in spinal cord injury.
Asunto(s)
Células-Madre Neurales/citología , Células-Madre Neurales/fisiología , Neurotrofina 3/administración & dosificación , Células de Schwann/citología , Células de Schwann/fisiología , Animales , Comunicación Celular , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Portadores de Fármacos , Ácido Láctico , Microscopía Electrónica de Transmisión , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/fisiología , Nanomedicina , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/fisiología , Fibras Nerviosas Mielínicas/ultraestructura , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Células-Madre Neurales/efectos de los fármacos , Neuritas/efectos de los fármacos , Neuritas/fisiología , Neuritas/ultraestructura , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ratas , Células de Schwann/efectos de los fármacos , Sinapsis/efectos de los fármacos , Sinapsis/ultraestructura , Andamios del Tejido/químicaRESUMEN
AIM: To study the correlation between high metastasis-associated protein 1 (MTA1) expression and lymphangiogenesis in colorectal cancer (CRC) and its role in production of vascular endothelial growth factor-C(VEGF-C). METHODS: Impact of high MTA1 and VEGF-C expression levels on disease progression and lymphovascular density (LVD, D2-40-immunolabeled) in 81 cases of human CRC was evaluated by immunohistochemistry. VEGF-C mRNA and protein expressions in human LoVo and HCT116 cell lines were detected by real-time polymerase chain reaction and Western blotting, respectively, with a stable expression vector or siRNA. RESULTS: The elevated MTA1 and VEGF-C expression levels were correlated with lymph node metastasis and Dukes stages (P < 0.05). Additionally, high MTA1 expression level was correlated with a large tumor size (P < 0.05). A significant correlation was found between MTA1 and VEGF-C protein expressions in tumor cells (r = 0.371, P < 0.05). Similar to the VEGF-C expression level, high MTA1 expression level was correlated with high LVD in CRC (P < 0.05). Furthermore, over-expression of MTA1 significantly enhanced the VEGF-C mRNA and protein expression levels, whereas siRNAs - knocked down MTA1 decreased the VEGF-C expression level. CONCLUSION: MTA1, as a regulator of tumor-associated lymphangiogenesis, promotes lymphangiogenesis in CRC by mediating the VEGF-C expression.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Histona Desacetilasas/metabolismo , Linfangiogénesis/fisiología , Proteínas Represoras/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Progresión de la Enfermedad , Femenino , Histona Desacetilasas/genética , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Interferencia de ARN , Proteínas Represoras/genética , TransactivadoresRESUMEN
OBJECTIVE: To determine the value of concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma from the mainland of China. METHODS: Data were extracted from randomized trials comparing chemotherapy plus radiotherapy with radiotherapy alone in locally advanced nasopharyngeal carcinoma. Actuarial rates of survival and distant metastases were calculated. The followed electronic databases were searched the Chinese Biomedicine database, Pubmed, Medline, Embase and Cochrane library; Data were extracted by tow reviewers and Review manager 4.1 software was applied for statistical analysis. RESULTS: Eighteen trials with 1993 patients were include according to the including criterion. The 3-year overall survival rate of the chemoradiotherapy group and the radiotherapy group were 68.47% and 56.38% respectively, and the 5-year overall survival rate of the two groups above were 51.91% and 41.09% respectively, while the distant metastases rate of the chemoradiotherapy group and the radiotherapy group were 26.19% and 38.71% respectively. The result demonstrated that chemoradiotherapy increased overall survival by 12% at 3 years, and 11% at 5 years after treatment. After chemoradiotherapy, the rate of distant metastasis was reduce by 12%. CONCLUSIONS: In patients with locoregionally advanced nasopharyngeal carcinoma, chemoradiotherapy significantly improves overall survival at 3 years, and 5 years compared with radiotherapy alone.