Isoxazole derivatives were characterized by broad spectrum of biological activities, but the condensed heterocyclic compounds containing isoxazole were scarcely reported. In this paper, we studied the 1,3-dipolar cycl...Isoxazole derivatives were characterized by broad spectrum of biological activities, but the condensed heterocyclic compounds containing isoxazole were scarcely reported. In this paper, we studied the 1,3-dipolar cycloaddition of p-methoxybenzohydroxamoyl chloride with ethyl sodioacetoacetate to obtain a key intermediate 2. Through compound 2, fifteen novel S-triazolo-1,3,4-thiadiazines(5a-5e), imidazolo-1,3,4-thiadiazoles(9a-9e) and imidazolo-1,3,4-oxadiazoles(10a-10e) containing isoxazole, which have potentially useful biological activities, were synthesized. The structures of the products were confirmed by elemental analyses and spectral analysis. And the characteristic data of IR, 1H NMR and MS were explained reasonably.展开更多
BACKGROUND:Non-alcoholic fatty liver disease(NAFLD)is one of the most frequent causes of liver diseases,with markedly increased prevalence.However,its mechanisms are not clear.The present study was undertaken to illus...BACKGROUND:Non-alcoholic fatty liver disease(NAFLD)is one of the most frequent causes of liver diseases,with markedly increased prevalence.However,its mechanisms are not clear.The present study was undertaken to illustrate the role of caveolin-1(cav1)and the scavenger receptor class B type 1(SR-B1)in NAFLD.METHODS:Adult male C57BL/6 mice were fed with a normal diet or high fat and cholesterol(HFC)diet for 14 weeks.The mice were sacrificed to collect plasma and harvest the liver;their plasma lipid concentration was measured.Hepatic cav1and SR-B1 mRNA and protein expression were determined by real-time quantitative polymerase chain reaction(qPCR)and Western blotting,respectively.In order to study cav1 and SR-B1distribution and change in hepatocytes,immunohistochemical analysis was performed.RESULTS:HFC diet increased plasma lipids,induced NAFLD and increased the liver/body weight ratio.Compared to the control mice(n=6),the mRNA and protein levels of cav1 and SR-B1 in liver tissue of the NAFLD mice(n=12)increased significantly(cav1 mRNA:1.536±0.226 vs 0.980±0.272,P【0.05;protein:0.643±0.240 vs 0.100±0.130,P【0.01;SR-B1 mRNA:1.377±0.125 vs 0.956±0.151,P【0.01;protein:2.156±0.507vs 0.211±0.211,P【0.01).Furthermore,both cav1 and SR-B1immunoreactivity increased and their distribution was also changed,mainly in the plasma membrane of hepatocytes,cytoplasm and membrane of lipid droplets and around.CONCLUSION:NAFLD is associated with increased concentration of plasma lipids and upregulation of hepatic cav1 and SR-B1 gene and protein expressions,which indicate that cav1 and SR-B1 might play crucial roles in the pathogenesis of NAFLD.展开更多
BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The r...BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.展开更多
文摘Isoxazole derivatives were characterized by broad spectrum of biological activities, but the condensed heterocyclic compounds containing isoxazole were scarcely reported. In this paper, we studied the 1,3-dipolar cycloaddition of p-methoxybenzohydroxamoyl chloride with ethyl sodioacetoacetate to obtain a key intermediate 2. Through compound 2, fifteen novel S-triazolo-1,3,4-thiadiazines(5a-5e), imidazolo-1,3,4-thiadiazoles(9a-9e) and imidazolo-1,3,4-oxadiazoles(10a-10e) containing isoxazole, which have potentially useful biological activities, were synthesized. The structures of the products were confirmed by elemental analyses and spectral analysis. And the characteristic data of IR, 1H NMR and MS were explained reasonably.
基金supported by a grant from the National Natural Science Foundation of China(491010-N11026)
文摘BACKGROUND:Non-alcoholic fatty liver disease(NAFLD)is one of the most frequent causes of liver diseases,with markedly increased prevalence.However,its mechanisms are not clear.The present study was undertaken to illustrate the role of caveolin-1(cav1)and the scavenger receptor class B type 1(SR-B1)in NAFLD.METHODS:Adult male C57BL/6 mice were fed with a normal diet or high fat and cholesterol(HFC)diet for 14 weeks.The mice were sacrificed to collect plasma and harvest the liver;their plasma lipid concentration was measured.Hepatic cav1and SR-B1 mRNA and protein expression were determined by real-time quantitative polymerase chain reaction(qPCR)and Western blotting,respectively.In order to study cav1 and SR-B1distribution and change in hepatocytes,immunohistochemical analysis was performed.RESULTS:HFC diet increased plasma lipids,induced NAFLD and increased the liver/body weight ratio.Compared to the control mice(n=6),the mRNA and protein levels of cav1 and SR-B1 in liver tissue of the NAFLD mice(n=12)increased significantly(cav1 mRNA:1.536±0.226 vs 0.980±0.272,P【0.05;protein:0.643±0.240 vs 0.100±0.130,P【0.01;SR-B1 mRNA:1.377±0.125 vs 0.956±0.151,P【0.01;protein:2.156±0.507vs 0.211±0.211,P【0.01).Furthermore,both cav1 and SR-B1immunoreactivity increased and their distribution was also changed,mainly in the plasma membrane of hepatocytes,cytoplasm and membrane of lipid droplets and around.CONCLUSION:NAFLD is associated with increased concentration of plasma lipids and upregulation of hepatic cav1 and SR-B1 gene and protein expressions,which indicate that cav1 and SR-B1 might play crucial roles in the pathogenesis of NAFLD.
文摘BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.
