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1.
Food Funct ; 12(20): 9719-9738, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34664590

RESUMO

Obesity is a global chronic disease epidemic that is attributed to the abnormal accumulation of lipids in adipose tissue. Astaxanthin (AST) from Haematococcus pluvialis, a natural carotenoid, exhibits antioxidant, anti-lipogenic, anti-diabetic and other potent effects. Herein, we evaluated the effect of AST to illuminate its efficacy and mechanisms in high-fat diet-fed mice. AST supplementation not only significantly decreased body weight and lipid droplet accumulation in the liver but also modulated liver function and serum lipid levels. Lipidomic analysis revealed that 13 lipids might be potential biomarkers responsible for the effects of AST in lipid reduction, such as total free fatty acids (FFAs), triacylglycerols (TGs) and cholesterol esters (CEs). The gut microbiota sequencing results indicated that AST alleviated HFD-induced gut microbiota dysbiosis by optimizing the ratio of Firmicutes to Bacteroides and inhibiting the abundance of obesity-related pathogenic microbiota while promoting the abundance of probiotics related to glucose and lipid metabolism. In addition, qRT-PCR demonstrated that AST could regulate the gene expressions of the AMPK/SREBP1c pathway by downregulating lipogenesis correlated-genes and upregulating the lipid oxidant related-gene. The present study revealed the new function of AST in regulating lipid metabolism, which provided a theoretical basis for the development of high-quality AST functional food and the application of diet active substances in obesity, as demonstrated in mice.

2.
Sheng Wu Gong Cheng Xue Bao ; 37(8): 2845-2855, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472302

RESUMO

Production of biofuels such as ethanol from non-grain crops may contribute to alleviating the global energy crisis and reducing the potential threat to food security. Tobacco (Nicotiana tabacum) is a commercial crop with high biomass yield. Breeding of starch-rich tobacco plants may provide alternative raw materials for the production of fuel ethanol. We cloned the small subunit gene NtSSU of ADP-glucose pyrophosphorylase (NtAGPase), which controls starch biosynthesis in tobacco, and constructed a plant expression vector pCAMBIA1303-NtSSU. The NtSSU gene was overexpressed in tobacco upon Agrobacterium-mediated leaf disc transformation. Phenotypic analysis showed that overexpression of NtSSU gene promoted the accumulation of starch in tobacco leaves, and the content of starch in tobacco leaves increased from 17.5% to 41.7%. The growth rate and biomass yield of the transgenic tobacco with NtSSU gene were also significantly increased. The results revealed that overexpression of NtSSU gene could effectively redirect more photosynthesis carbon flux into starch biosynthesis pathway, which led to an increased biomass yield but did not generate negative effects on other agronomic traits. Therefore, NtSSU gene can be used as an excellent target gene in plant breeding to enrich starch accumulation in vegetative organs to develop new germplasm dedicated to fuel ethanol production.


Assuntos
Amido , Tabaco , Biomassa , Regulação da Expressão Gênica de Plantas , Melhoramento Vegetal , Folhas de Planta/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Tabaco/genética , Tabaco/metabolismo
3.
J Med Chem ; 64(11): 7468-7482, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043359

RESUMO

Nowadays, simultaneous inhibition of multiple targets through drug combination is an important anticancer strategy owing to the complex mechanism behind tumorigenesis. Recent studies have demonstrated that the inhibition of histone deacetylases (HDACs) will lead to compensated activation of a notorious cancer-related drug target, signal transducer and activator of transcription 3 (STAT3), in breast cancer through a cascade, which probably limits the anti-proliferation effect of HDAC inhibitors in solid tumors. By incorporating the pharmacophore of the HDAC inhibitor SAHA (vorinostat) into the STAT3 inhibitor pterostilbene, a series of potent pterostilbene hydroxamic acid derivatives with dual-target inhibition activity were synthesized. An excellent hydroxamate derivate, compound 14, inhibited STAT3 (KD = 33 nM) and HDAC (IC50 = 23.15 nM) with robust potency in vitro. Compound 14 also showed potent anti-proliferation ability in vivo and in vitro. Our study provides the first STAT3 and HDAC dual-target inhibitor for further exploration.


Assuntos
Antineoplásicos/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Meia-Vida , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/antagonistas & inibidores , Estilbenos/química , Estilbenos/metabolismo , Relação Estrutura-Atividade , Vorinostat/química , Vorinostat/metabolismo
5.
Eur J Med Chem ; 199: 112375, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32388278

RESUMO

Deregulation of GP130 in signal transduction is involved in multiple types of human diseases, especially in cancers, indicating that GP130 is an attractive target for cancer therapy. However, GP130 was conventionally considered as an undruggable target thus the discovery of GP130 PPI inhibitors is extremely challenging. By the aid of structure-based drug design, in this study, two series of bazedoxifene based analogues were designed to target GP130 D1 domain and block the IL-6/GP130/STAT3 signaling pathway for antitumor treatment. Most of these designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 10a was demonstrated to directly bind to GP130 protein with an affinity (KD) value of 3.8 µM via both SPR and DARTS methods. Subsequently, molecular docking study predicted that 10a targeted D1 domain of GP130 and co-IP assay demonstrated that 10a did not inhibit IL-6R/GP130 interaction, which meant 10a did not bind to the D2 and D3 domains of GP130. Moreover, 10a selectively inhibited JAK2 and STAT3 phosphorylation as well as IL-6 induced STAT3 phosphorylation. 10a effectively inhibited tumor cell viability, migration and promoted apoptosis. Furthermore, 10a effectively suppressed xenograft model tumor growth in vivo. Taken together, this study described a new class of bazedoxifene derived GP130 inhibitors as antitumor agents.


Assuntos
Antineoplásicos/farmacologia , Receptor gp130 de Citocina/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptor gp130 de Citocina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
6.
J Mater Chem B ; 7(47): 7548-7557, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31720667

RESUMO

Etoposide is one of the most used first-line chemotherapeutic drugs. However, its application is still limited by its side effects. Herein, we designed a novel H2O2 sensitive prodrug 6YT for selectively releasing the anti-cancer drug etoposide in cancer cells. In this paper, etoposide and a hydrogen peroxide (H2O2) sensitive aryl borate ester group were linked by a fluorescent coumarin and finally the prodrug 6YT was generated. The fluorescence of coumarin was quenched before the connected aryl borate ester group was cleaved by H2O2. However, in the high level H2O2 environment of the tumor, the fluorescence could be activated simultaneously with the release of etoposide, and the drug release state of the prodrug was monitored real-time. With the support of 6YT, we obtained direct and visual evidence of etoposide release in a high H2O2 environment both in cells and zebrafish. The prodrug 6YT was also verified with comparable activity and improved safety with etoposide both in cells and in a mouse model. As a safe and effective prodrug, 6YT is expected to be one of the promising candidates in chemotherapy against cancer.


Assuntos
Antineoplásicos Fitogênicos/química , Etoposídeo/química , Peróxido de Hidrogênio/química , Pró-Fármacos/química , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Liberação Controlada de Fármacos , Etoposídeo/metabolismo , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Neoplasias/patologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Taxa de Sobrevida , Transplante Heterólogo , Peixe-Zebra
7.
Eur J Med Chem ; 174: 236-251, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048139

RESUMO

STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Tiofenos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Descoberta de Drogas , Fluorescência , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/química , Serina/química , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia , Tirosina/química
8.
Cell Death Dis ; 9(11): 1098, 2018 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-30368518

RESUMO

Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22-24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Transcrição STAT3/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína X Associada a bcl-2/genética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fenantrenos/síntese química , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
9.
Eur J Med Chem ; 151: 752-764, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29674294

RESUMO

Persistent activated STAT3 has a striking correlation with cancer development and inhibition of STAT3 signaling pathway is a novel therapeutic way for human cancers. Among STAT family, STAT1 and STAT3 play opposite roles in tumorigenesis. However, the discovery of selective STAT3 inhibitors is still challenging to date. In this study, a series of small-molecular (MW < 500) benzensulfanilamide derivatives were designed to selectively suppress STAT3 activation for anti-cancer treatment. The most potent compound 11 inhibited both overexpressed and IL-6 induced STAT3 phosphorylation, whereas 11 displayed little effect on the phosphorylation of other STAT isoforms STAT1, STAT5, demonstrating 11 was a selective STAT3 inhibitor. Meanwhile, 11 dismissed STAT3 DNA binding activity and colony formation. In addition, 11 elevated the ROS level and induced apoptosis of cancer cells. Furthermore, 11 effectively suppressed tumor growth in an in vivo mouse-xenograft model.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Derivados de Benzeno/química , Derivados de Benzeno/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Desenho de Fármacos , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
10.
Artigo em Chinês | MEDLINE | ID: mdl-17723192

RESUMO

OBJECTIVE: To study the diagnostic value of CT/HRCT for the coal workers' pneumoconiosis (CWP) with large opacities. METHODS: Sixty-two patients with CWP were examined with both chest radiograph and CT/HRCT scan. Comparison was done. RESULTS: Large opacities were found in 19 patients in the chest radiograph of 62 patients with CWP. The detection rate was 30.6%. Thirty large opacities were found using chest radiograph. Forty-three patients with large opacities were found using the CT/HRCT. The detection rate was 69.4%. One hundred and twenty-three large opacities were found using CT/HRCT. Ninety-three more large opacities were found by CT/HRCT than by chest radiograph. The total detection rate of large opacities by CT was 4.1 times than by chest radiograph. Both differences were statistically significant (chi2 = 18.58, P < 0.01). CT/HRCT found all patients with large opacities detected in the chest radiograph. Seventeen patients with Stage III large opacities (>or= 1.0 cm x 2.0 cm) were found by the chest radiograph. The detection rate was 27.4% (17/62). Twenty-seven large opacities were found using chest radiograph. Thirty-four patients with Stage III large opacities were found using the CT/HRCT. The detection rate was 54.8%. The found Stage III large opacities added up to 67. The found Stage III large opacities by CT/HRCT were 40 more than using chest radiograph. Both differences were statistically significant (chi2 = 9.63, P < 0.01). CT/HRCT was reliable to show the morphology, the inside structure, the tiny lesion and the special location of the large opacities of CWP. It could provide more important information for differential diagnosis. CONCLUSION: CT/HRCT is significantly better than the chest radiograph in the diagnosis of complicated CWP. It can find the large opacities that the chest radiograph can not. It has a great diagnostic and practical value as an assistant examination method. CT/HRCT could be considered as the reference and evidence for staging progression in diagnosis of pneumoconiosis.


Assuntos
Antracose/diagnóstico por imagem , Minas de Carvão , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade
11.
Artigo em Chinês | MEDLINE | ID: mdl-15033017

RESUMO

OBJECTIVE: To analyse CT and high resolution computerized tomography (HRCT) diagnostic value and morphologic manifestation in coal miner's pneumoconiosis with pleural pathological changes. METHODS: One hundred and thirty-one cases of coal miner patients with pneumoconiosis (0(+) type: 14 cases, type I: 46 cases, type II: 58 cases, type III: 13 cases) and 20 normal people as control group were first examined by routine CT scan at 4 fixed slices, followed by HRCT examination at the region of interest (ROI). Meanwhile, all of them had high-kV chest radiography. RESULTS: According to the national standard of the People's Republic of China in the diagnosis of coal miner's pneumoconiosis with pleural plaque, 68 cases of pleural disease making up 51.91% (68/131) were found (type I accounted for 17.65%, type II 63.24%, type III 19.12%). The morphologic manifestation of pleural pathology by HRCT could be classified into four types: (1) nodular type: 73.38%, (2) flat type: 18.71%, (3) irregular type: 7.91%, (4) mixed type. The pleural pathological changes were found in thoracic wall pleura (65.02%), surface of mediastinum (22.16%), and pericardium (12.80%), but not found in the top of lung and costo-phrenic angles. The thickness of pleura was often about 5 approximately 10 mm (88.17%). CONCLUSION: Pleural pathological changes were not seldom seen in coal miner's pneumoconiosis. HRCT is a reliable examination method aiding routine CT to show pleural pathological changes, thus it has a great diagnostic and practical value. It is necessary to make a further comparison study between pathology and imagology.


Assuntos
Minas de Carvão , Pleura/patologia , Pneumoconiose/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pleura/diagnóstico por imagem , Doenças Pleurais/diagnóstico
12.
Artigo em Chinês | MEDLINE | ID: mdl-14694625

RESUMO

OBJECTIVE: To study the value of CT quantitativeness in the diagnosis of coal miner's pneumoconiosis. METHODS: 104 cases were examined by HRCT scan at top of aortic arc, carina of trachea, 3 cm below the bifurcation of bronchi, among them there were 87 patients with different stages of coal miner's pneumoconiosis, 17 cases of normal males as the control group. All images were determined by CT density histogram at specific region (- 1,024-0 HU). Calculated the percentage of each pixel included a varying number of CT value, and the ratio of density values in the specific region. RESULTS: The ratio of density values in the region of -983 (-) -778 HU was 87.31% in normal control group, and 80.51%, 75.27% and 72.99% respectively in the I, II, III stages of coal miner's pneumoconiosis. There were statistically significant differences among the groups (P < 0.01). CONCLUSION: CT quantitative histogram information was able to observe the fibrosis and its degree of coal miner's pneumoconiosis. It has a good diagnostic value for its reliability and objectiveness.


Assuntos
Minas de Carvão , Pneumoconiose/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Humanos , Fibrose Pulmonar/diagnóstico por imagem
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