RESUMEN
Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice.
Asunto(s)
Benzoatos/farmacología , HDL-Colesterol/sangre , HDL-Colesterol/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Lipasa/antagonistas & inhibidores , Pirrolidinas/farmacología , Animales , Benzoatos/síntesis química , Benzoatos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Lipasa/deficiencia , Lipasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
BACKGROUND: Multi-drug resistance to chemotherapeutic agents is a major cause of treatment failure in breast cancer. In this study, we investigated the effects of emodin on reversing the multi-drug resistance, examined the ERCC1 protein expression in breast cancer cell line, and explored the relationship between reversal of multi-drug resistance and ERCC1 protein expression. METHODS: MTT assay was conducted to test the cytotoxicity of adriamycin and cisplatin to MCF-7/Adr cells with and without emodin pretreatment, and Western blot was performed to examine the ERCC1 protein expression. RESULTS: MCF-7/Adr cells had 21-fold and 11-fold baseline resistances to adriamycin and cisplatin, respectively. When emodin was added to the cell culture at the concentration of 10 µg/ml, the drug resistance was reduced from 21 folds to 2.86 folds for adriamycin, and from 11 folds to 1.79 folds for cisplatin. MCF-7/Adr cells treated with two concentrations (10 µg/mL and 20 µg/mL) of emodin, after 2, 4, 6, 10 days, the trend of ERCC1 expression was gradually decreased and the reduction was more obvious comparatively at the concentration of 20 µg/mL. CONCLUSIONS: Emodin could reverse the multi-drug resistance in MCF-7/Adr cells and down-regulate ERCC1 protein expression.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Unión al ADN/metabolismo , Emodina/farmacología , Endonucleasas/metabolismo , Western Blotting , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Doxorrubicina/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Células MCF-7RESUMEN
This study is to find out the induction by sodium nitrite of epithelial-mesenchymal transition (EMT) in human hepatocellular carcinoma cells, SMMC-7721. After treatment of SMMC-7721 with 0.25 - 25 mmol.L-1 sodium nitrite for 48 h, the assays used include enzyme-linked immunosorbent assay (ELISA) for evaluation of TGF-beta1, IL-6 and IL-8 level in the conditioned medium, phase-contrast microscopy for morphology observation, and scratch wound healing as well as transwell migration assays for measurement of migration and metastatic potential. Additionally, the hallmarks of EMT, p-AKT and its downstream signaling molecules were examined by Western blotting. The results showed that TGF-beta1 secreted by SMMC-7721 elevated significantly in a dose-dependent fashion, whereas the increased IL-8 and IL-6 did not show dose-dependent response. The EMT was induced by exposure of SMMC-7721 with 0.25 mmol.L-1 of sodium nitrite, which was characterized by increased level of Vimentin, decreased E-cadherin and elevated activity of migration and metastatic potential. The results suggest that sodium nitrite could induce SMMC-7721 EMT by increased secretion of TGF-beta1 and IL-8.
Asunto(s)
Carcinoma Hepatocelular/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Interleucina-8/metabolismo , Neoplasias Hepáticas/patología , Nitrito de Sodio/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Cadherinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Nitrito de Sodio/administración & dosificación , Proteína 1 Relacionada con Twist/metabolismo , Vimentina/metabolismoRESUMEN
A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).
Asunto(s)
Amidas/química , Compuestos de Bifenilo/química , Amidas/síntesis química , Compuestos de Bifenilo/síntesis química , Catálisis , Ciclización , Fluorenos/síntesis química , Fluorenos/química , Estructura MolecularRESUMEN
OBJECTIVE: To investigate the feasibility of adipogenesis from human hair keratin (HHK) material, so as to provide a new method for fat defect and depression deformity. METHODS: 3 Tibet mini-pigs were used. 8 fat defects (1.5 cm in diameter) were made bilaterally on the back. The ball-shaped HHK material was implanted to repair the defects at one side. The defects at contralateral side were as controls. The absorption of the HHK material and adipogenesis were studied histologically. RESULTS: 2 weeks after implantation, connective tissue and capillary grew into the porous HHK material. 4 weeks after implantation, HHK material was almost totally absorbed, leaving some material debris and foreign body granuloma. Around them, there were clusters of adipocyte. 6 weeks after implantation, the HHK material was totally degraded and the granuloma was disappeared, and then de novo adipose tissue was observed. Its volume was close to the volume of peripheral HHK material that was planted originally. 10 weeks later, the new-formed fat tissue had less fibres and was very similar to the normal fat. CONCLUSIONS: New adipose tissue can be formed after HKK material implantation. It can also be remodeled to be similar to normal fat.
Asunto(s)
Tejido Adiposo/fisiopatología , Queratinas Específicas del Pelo/farmacocinética , Implantes Absorbibles , Tejido Adiposo/lesiones , Animales , Modelos Animales de Enfermedad , Humanos , Porcinos , Porcinos EnanosRESUMEN
OBJECTIVE: To investigate the expressions of vascular endothelial growth factor-C (VEGF-C), C-erbB-2, p53, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer tissue and their clinical significance. METHODS: The expressions of C-erbB-2, p53, ER, and PR in 60 breast cancer tissues were detected using immunohistochemistry, and their clinical significance was analyzed. RESULTS: The positivity rates of VEGF-C, C-erbB-2, p53, ER, and PR in the 60 breast cancer tissues were 56.7%, 38.3%, 46.7%, 48.3% and 53.3%, respectively. The expressions of VEGF-C and C-erbB-2 differed significantly in relation to the lymph node status (P<0.05), but not to the patient's age or tumor volume (P>0.05). The expression of VEGF-C was positively correlated to that of C-erbB-2 (P<0.05). The expression of p53 was positively correlated to the tumor volume (P<0.05). The expressions of ER and PR were not correlated to the patient's age, tumor volume and lymph node status (P>0.05), but were inversely correlated to C-erbB-2 expression (P<0.05) independent of VEGF-C and p53 expressions (P>0.05). CONCLUSIONS: The high expressions of VEGF-C and C-erbB-2 are closely related to lymph node metastasis in breast cancer patients, and may cooperate in promoting lymph node metastasis of breast carcinoma. Combined detection of VEGF-C, C-erbB-2, p53, ER and PR may help clinical treatment and prognostic evaluation of breast cancer patients.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Neoplasias de la Mama/patología , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Progesterona/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
OBJECTIVE: To investigate the expression of ERCC1 gene in breast cancer before and after neo-adjuvant chemotherapy. METHODS: The expression of ERCC1 gene was detected by RT-PCR in 40 breast cancer patients and in 14 patients treated with neoadjuvant chemotherapy. RESULTS: Positive expression of ERCC1 gene was detected by RT-PCR in 35.0% of the breast cancer specimens, and ERCC1 expression was not correlated to the patients' age, tumor size, axillary lymph node metastasis, pathological type, histological grade, ER, PR or HER-2 (P>0.05). ERCC1 gene expression was significantly higher in neo-adjuvant chemotherapy group than in non-chemotherapy group (P<0.05). CONCLUSION: The expression of ERCC1 gene does not affect the clinical and pathological features of breast cancer. Neo-adjuvant chemotherapy can increase the expression of ERCC1 gene, due attention should be given to with in subsequent chemotherapy.