RESUMO
Survival for patients with advanced gastric cancer (GC) remains poor. Systemic chemotherapy which has reached a plateau stays the standard first-line (1L) treatment for advanced human epidermal growth-factor receptor 2 (HER2)-negative GC. To maximize the benefit of 1L treatment, the concept of maintenance treatment is constantly being explored. In advanced HER2-negative GC, current clinical guidelines do not recommend a standard maintenance therapy strategy. In addition to the monotherapy maintenance with fluorouracil after 4-6 cycles of 1L chemotherapy, some agents that are active against novel targets have been evaluated in clinical trials for maintenance treatment. Whereas most of these trials do not reach their primary endpoints, they open new horizons for the 1L treatment of advanced HER2-negative GC. Therefore, we reviewed the clinical trials in the field of maintenance treatment in advanced HER2-negative GC and discussed some of the problems in clinical trials.
Assuntos
Quimioterapia de Manutenção , Receptor ErbB-2 , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Ensaios Clínicos como Assunto , Ensaios Clínicos Fase III como Assunto , Fluoruracila/uso terapêutico , Humanos , Oxaliplatina/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/química , Neoplasias Gástricas/patologia , RamucirumabRESUMO
The peel of mango (Mangifera indica L.) is a special plant tissue that contains many compounds that interfere with protein extraction. A successful separation with Two-dimensional electrophoresis (2-DE) is the key step for proteomic analysis. To evaluate the efficiencies of mango peel protein extraction for 2-DE, four extraction methods were tested: 1) 2-D clean-up kit, 2) trichloroacetic acid/acetone precipitation, 3) phenol extraction, 4) phenol with methanol/ammonium acetate precipitation. The results showed that the phenol with methanol/ammonium acetate precipitation produced the best quality protein extraction and separation. Proteins were separated in 30-70 and >70 kDa ranges better than with the other methods. Acidic proteins had better resolution with fewer horizontal and vertical streaks. Sixteen proteins were identified by maxtrix-assisted laser desorption/ ionisation time-of-flight tandem mass spectrometry (MALDI-TOF/ TOF-MS/MS). The result demonstrated that each of these four methods can be used to prepare mango peel proteins. The phenol with methanol/ ammonium acetate precipitation was the best choice for proteomic analysis of mango peel.
Assuntos
Frutas/química , Mangifera/química , Proteínas de Plantas/isolamento & purificação , Proteoma/isolamento & purificação , Acetatos/química , Precipitação Química , Metanol/química , Fenol/química , Proteínas de Plantas/química , Proteoma/química , Proteômica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em TandemRESUMO
Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/farmacologia , Imunoglobulina G/farmacologia , Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Animais , Células CHO , Linhagem Celular , Clonagem Molecular/métodos , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/genética , Imunoglobulina G/química , Imunoglobulina G/genética , Resistência à Insulina , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Engenharia de Proteínas , Estrutura Terciária de Proteína , Receptor de Insulina/metabolismo , Receptores Fc/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais/efeitos dos fármacos , Tirosina/metabolismoRESUMO
The objective of the present study was to determine if the combination of alkaloids from Sophora moorcroftiana seeds and albendazole might be effective in the treatment of experimental echinococcosisin female NIH mice (6 weeks old and weighing 18-20 g, N = 8 in each group) infected withprotoscolices of Echinococcus granulosus. Viable protoscolices (N = 6 x 103) were cultured in vitro in 1640 medium and mortality was calculated daily. To determine the in vivo efficacy, mice were inoculated intraperitoneally with viable protoscolices and then treated once daily by gavage for three months with the alkaloids (50 mg kg-1 day-1) and albendazole (50 mg kg-1 day-1), separately and in combination (both alkaloids at 25 mg kg-1 day-1 and albendazole at 25 mg kg-1 day-1). Next, the hydatid cysts collected from the peritoneal cavity of the animals were weighed and serum IL-4, IL-2, and IgE levels were analyzed. Administration of alkaloids to cultured protoscolices showed significant dose- and time-dependent killing effects. The weight of hydatid cysts was significantly decreased upon treatment with each drug (P < 0.01), but the decrease was more prominent and the rate of hydatid cyst growth inhibition was much higher (76.1 percent) in the group receiving the combined treatments (18.3 ± 4.6 mg). IL-4 and total IgE were decreased (939 ± 447 pg/mL and 2.03 ± 0.42 IU/mL, respectively) in serum from mice treated with alkaloids and albendazole compared with the untreated control (1481 ± 619 pg/mL and 3.31 ± 0.37 IU/mL; P < 0.01). These results indicate that S. moorcroftiana alkaloids have protoscolicidal effects and the combination of alkaloids and albendazole has significant additive effects.
Assuntos
Animais , Feminino , Camundongos , Albendazol/administração & dosagem , Alcaloides/administração & dosagem , Anticestoides/administração & dosagem , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Sophora/química , Modelos Animais de Doenças , Quimioterapia Combinada , Equinococose/imunologia , Equinococose/patologia , Imunoglobulina E/sangue , /sangue , /sangue , Camundongos Endogâmicos , Sementes/química , Fatores de TempoRESUMO
The objective of the present study was to determine if the combination of alkaloids from Sophora moorcroftiana seeds and albendazole might be effective in the treatment of experimental echinococcosisin female NIH mice (6 weeks old and weighing 18-20 g, N = 8 in each group) infected withprotoscolices of Echinococcus granulosus. Viable protoscolices (N = 6 x 10(3)) were cultured in vitro in 1640 medium and mortality was calculated daily. To determine the in vivo efficacy, mice were inoculated intraperitoneally with viable protoscolices and then treated once daily by gavage for three months with the alkaloids (50 mg kg-1 day-1) and albendazole (50 mg kg-1 day-1), separately and in combination (both alkaloids at 25 mg kg-1 day-1 and albendazole at 25 mg kg-1 day-1). Next, the hydatid cysts collected from the peritoneal cavity of the animals were weighed and serum IL-4, IL-2, and IgE levels were analyzed. Administration of alkaloids to cultured protoscolices showed significant dose- and time-dependent killing effects. The weight of hydatid cysts was significantly decreased upon treatment with each drug (P < 0.01), but the decrease was more prominent and the rate of hydatid cyst growth inhibition was much higher (76.1%) in the group receiving the combined treatments (18.3 +/- 4.6 mg). IL-4 and total IgE were decreased (939 +/- 447 pg/mL and 2.03 +/- 0.42 IU/mL, respectively) in serum from mice treated with alkaloids and albendazole compared with the untreated control (1481 +/- 619 pg/mL and 3.31 +/- 0.37 IU/mL; P < 0.01). These results indicate that S. moorcroftiana alkaloids have protoscolicidal effects and the combination of alkaloids and albendazole has significant additive effects.