Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Sci Rep ; 12(1): 2701, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177771

RESUMO

Traumatic brain injury (TBI) is an important cause of death in young adults and children. Till now, the treatment of TBI in the short- and long-term complications is still a challenge. Our previous evidence implied aquaporin 4 (AQP4) and hypoxia inducible factor-1α (HIF-1α) might be potential targets for TBI. In this study, we explored the roles of AQP4 and HIF-1α on brain edema formation, neuronal damage and neurological functional deficits after TBI using the controlled cortical injury (CCI) model. The adult male Sprague Dawley rats were randomly divided into sham and TBI group, the latter group was further divided into neutralized-AQP4 antibody group, 2-methoxyestradiol (2-ME2) group, and their corresponding control, IgG and isotonic saline groups, respectively. Brain edema was examined by water content. Hippocampal neuronal injury was assessed by neuron loss and neuronal skeleton related protein expressions. Spatial learning and memory deficits were evaluated by Morris water maze test and memory-related proteins were detected by western blot. Our data showed that increased AQP4 protein level was closely correlated with severity of brain edema after TBI. Compared with that in the control group, both blockage of AQP4 with neutralized-AQP4 antibody and inhibition of HIF-1α with 2-ME2 for one-time treatment within 30-60 min post TBI significantly ameliorated brain edema on the 1st day post-TBI, and markedly alleviated hippocampal neuron loss and spatial learning and memory deficits on the 21st day post-TBI. In summary, our preliminary study revealed the short-term and long-term benefits of targeting HIF-1α-AQP4 axis after TBI, which may provide new clues for the selection of potential therapeutic targets for TBI in clinical practice.


Assuntos
Aquaporina 4/antagonistas & inibidores , Edema Encefálico/tratamento farmacológico , Edema Encefálico/metabolismo , Córtex Cerebral/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neurônios/metabolismo , 2-Metoxiestradiol/administração & dosagem , Animais , Anticorpos/administração & dosagem , Aquaporina 4/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/lesões , Transtorno Conversivo/tratamento farmacológico , Transtorno Conversivo/etiologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intravenosas , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley
2.
Pharmacol Res ; 169: 105685, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022398

RESUMO

Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.


Assuntos
2-Metoxiestradiol/uso terapêutico , Antineoplásicos/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ligação a DNA/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , 2-Metoxiestradiol/administração & dosagem , 2-Metoxiestradiol/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Transplante de Neoplasias
3.
Pharm Dev Technol ; 26(1): 1-10, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32985928

RESUMO

The use of chemotherapeutic drug paclitaxel (PTX) for the treatment of tumors has several limitations, including multidrug resistance (MDR) and serious adverse reactions. This research aims to co-encapsulate PTX and the chemosensitizer 2-methoxyestradiol (2-ME) into folate-conjugated human serum albumin nanoparticles (FA-HSANPs) to reduce multiple drug resistance and improve antitumor efficiency. The results show PTX/2-ME@FA-HSANPs had uniform particle size (180 ± 12.31 nm) and high encapsulation efficacy. It also exhibited highly potent cytotoxicity and apoptosis-inducing activities in the G2/M phase of PTX-resistant EC109/Taxol cells. Moreover, PTX/2-ME@FA-HSANPs not only displayed better inhibition of tumor growth in S-180 tumor-bearing mice than PTX alone but also reduced pathological damage to normal tissues. In summary, PTX/2-ME@FA-HSANPs could be a promising vehicle for tumor therapy and reducing drug resistance. This research will also provide references for other MDR treatment.


Assuntos
2-Metoxiestradiol/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Albumina Sérica Humana/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Humanos , Camundongos , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
J Ovarian Res ; 12(1): 49, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31128594

RESUMO

BACKGROUND: We have previously shown that a whole flaxseed supplemented diet decreased the onset and severity of ovarian cancer in the laying hen, the only known animal model of spontaneous ovarian cancer. Flaxseed is rich in omega-3 fatty acids (OM3FA), mostly α-Linoleic acid (ALA), which gets converted to Docosahexaenoic acid (DHA) by the action of delta-6 desaturase enzyme. Ingestion of flaxseed also causes an increase in production of 2-methoxyestradiol (2MeOE2) via the induction of the CYP1A1 pathway of estrogen metabolism. We have previously reported that the flaxseed diet induces apoptosis via p38-MAPK pathway in chicken tumors. The objective of this study was to investigate the effect of the flaxseed diet on ovarian cancer in chickens, focusing on two hallmarks of cancer, apoptosis and angiogenesis. RESULTS: The anti-cancer effects of two active biologically derived compounds of flax diet, 2MeOE2 and DHA, were individually tested on human ovarian cancer cells and in vivo by the Chick Chorioallantoic Membrane (CAM) assay. Our results indicate that a flaxseed-supplemented diet promotes apoptosis and inhibits angiogenesis in chicken tumors but not in normal ovaries. 2MeOE2 promotes apoptosis in human ovarian cancer cells, inhibits angiogenesis on CAM and its actions are dependent on the p38-MAPK pathway. DHA does not have any pro-apoptotic effect on human ovarian cancer cells but has strong anti-angiogenic effects as seen on CAM, but not dependent on the p38-MAPK pathway. CONCLUSIONS: Dietary flaxseed supplementation promotes a pro-apoptotic and anti-angiogenic effect in ovarian tumors, not in normal ovaries. The biologically derived active compounds from flaxseed diet act through different pathways to elicit their respective anti-cancer effects. A flaxseed-supplemented diet is a promising approach for prevention of ovarian cancer as well as having a significant potential as an adjuvant treatment to supplement chemotherapeutic agents for treatment of advanced stages of ovarian cancer.


Assuntos
2-Metoxiestradiol/farmacologia , Apoptose/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Linho , Neoplasias Ovarianas/prevenção & controle , 2-Metoxiestradiol/administração & dosagem , Animais , Linhagem Celular Tumoral , Galinhas , Membrana Corioalantoide , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/administração & dosagem , Feminino , Linho/química , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário , Sementes/química
5.
Future Microbiol ; 13: 785-798, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29848058

RESUMO

AIM: Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary tuberculosis (TB). METHODS & RESULTS: A model of progressive pulmonary TB in BALB/c mice, immunohistochemistry and digital pathology were used. High HIF-1α expression was observed during early TB in activated macrophages. During late TB, even higher HIF-1α expression was observed in foamy macrophages, which are resistant to apoptosis. Blocking HIF-1α during early infection with 2-methoxyestradiol worsened the disease, while during late TB, it induced macrophage apoptosis and decreased bacillary loads. CONCLUSION: HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Tuberculose Pulmonar/metabolismo , 2-Metoxiestradiol/administração & dosagem , Animais , Antituberculosos/administração & dosagem , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/fisiopatologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA