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2.
J Cancer ; 10(10): 2299-2311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258733

RESUMO

Background: Lymphocytes were reported to play a significant part in host anticancer immune responses and influence tumour prognosis. Few studies have focused on the prognostic values of aspartate aminotransferase (AST) to lymphocyte ratio (ALRI), aspartate aminotransferase to platelet count ratio index (APRI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) treated with palliative treatments. Methods: Five hundred and ninety-eight HCC patients treated with palliative therapies were retrospectively analysed. We randomly assigned patients into the training cohort (429 patients) and the validation cohort I (169 patients). Receiver operating characteristic (ROC) curves were used to identify the best cut-off values for the ALRI, APRI and SII in the training cohort and the values were further validated in the validation cohort I. Correlations between ALRI and other clinicopathological factors were also analysed. A prognostic nomogram including ALRI was established. We validated the prognostic value of the ALRI, SII and APRI with two independent cohorts, the validation cohort II of 82 HCC patients treated with TACE and the validation cohort III of 150 HCC patients treated with curative resection. In the training cohort and all the validation cohorts, univariate analyses by the method of Kaplan-Meier and multivariate analysis by Cox proportional hazards regression model were carried out to identify the independent prognostic factors. Results: The threshold values of ALRI, APRI and SII were 86.3, 1.37 and 376.4 respectively identified by ROC curve analysis in the training cohort. Correlation analysis showed that ALRI>86.3 was greatly associated with higher rates of Child-Pugh B&C, portal vein tumor thrombosis (PVTT) and ascites (P < 0.05). Correspondingly, ALRI level of HCC patients with Child-Pugh B&C, PVTT and ascites was evidently higher than that of HCC patients with Child-Pugh A, without PVTT and without ascites (P < 0.001). In the training cohort and the validation cohort I, II, III, the OS of patients with ALRI >86.3 was obviously shorter than patients with ALRI ≤86.3 (P <0.001). We identified ALRI as an independent prognostic factor by univariate and multivariate analyses both in training Cohort (HR=1.481, P=0.004), validation cohort I (HR=1.511, P=0.032), validation cohort II (HR=3.166, P=0.005) and validation cohort III (HR=3.921, P=0.010). The SII was identified as an independent prognostic factor in training cohort (HR=1.356, P=0.020) and the validation cohort II (HR=2.678, P=0.002). The prognostic nomogram including ALRI was the best in predicting 3-month, 6-month, 1-year, 2-year survival And OS among TNM, ALRI, ALRI-TNM and nomogram. Conclusions: The ALRI was a novel independent prognostic index for the HCC patients treated with palliative treatments.

3.
J Exp Clin Cancer Res ; 38(1): 196, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088567

RESUMO

BACKGROUND: Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). METHODS: Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. RESULTS: EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. CONCLUSIONS: EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Iniciação 4A em Eucariotos/metabolismo , Oxaliplatina/farmacologia , Adulto , Idoso , Animais , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Asian Nat Prod Res ; 21(2): 93-102, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29595067

RESUMO

Three new compounds, periplanamides A (1) and B (2), periplanpyrazine A (3), a new naturally occurring compound salicyluric acid methyl ester (6), and seventeen known compounds were isolated from the medicinal insect Periplaneta americana. The structures of the new compounds were elucidated on the basis of spectroscopic methods. The absolute configurations of 2 were assigned by computational methods. Biological activities of these isolates except 1, 9, 11, and 13 toward nitric oxide (NO) production, cell proliferation in HDFs, cell migration and angiogenesis in HUVECs were evaluated.


Assuntos
Amidas/farmacologia , Periplaneta/química , Pirazinas/farmacologia , Cicatrização/efeitos dos fármacos , Amidas/química , Amidas/isolamento & purificação , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hidrocarbonetos Cíclicos , Estrutura Molecular , Pirazinas/química , Pirazinas/isolamento & purificação
5.
Molecules ; 23(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544580

RESUMO

A novel sesquiterpene dimer, spirocommiphorfuran A (1); two new cadinane sesquiterpenoids, commiphorenes A (2) and B (3); along with three known terpenoids (4⁻6), were isolated from Resina Commiphora. The structures of these new compounds were characterized by NMR, HRESIMS, quantum chemical computation, and X-ray diffraction analysis. Compound 1 features a 7-oxabicyclo[2.2.1]heptane-2-ene core, representing the first example of germacrane-type sesquiterpene dimer fused via a spiro ring system. Compound 2 is a novel sesquiterpene with a completely new carbon skeleton, which is characteristic of an additional carbon attaching to the cadinane backbone via a carbon⁻carbon bond. Additionally, compounds 2 and 4 exert acceptable cytotoxicity toward normal cells and high selectivity in cancer cells, especially in HepG2 cells.


Assuntos
Burseraceae/química , Terpenos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Terpenos/química
6.
Molecules ; 23(2)2018 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-29401662

RESUMO

A novel flavonoid glucoside, ruthenicunoid A (1), together with eight known substances, were isolated from the fruits of Lycium ruthenicun Murr. Their structures were elucidated by extensive spectroscopic data and chemical methods. Especially, the absolute configuration of glucose residue in 1 was assigned by acid hydrolysis followed by derivatization and GC analysis. Biological evaluation towards Sirtuin 1 (SIRT1) found that compounds 1 and 2 exhibit inhibitory activity against SIRT1 in a concentration-dependent manner, indicating its potential on SIRT1-associated disorders.


Assuntos
Flavonoides/química , Frutas/química , Glucosídeos/química , Inibidores de Histona Desacetilases/química , Lycium/química , Sirtuína 1/antagonistas & inibidores , Ensaios Enzimáticos , Flavonoides/isolamento & purificação , Glucosídeos/isolamento & purificação , Inibidores de Histona Desacetilases/isolamento & purificação , Humanos , Hidrólise , Extração Líquido-Líquido/métodos , Estrutura Molecular , Sirtuína 1/química
7.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 4): o1111, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22589968

RESUMO

The asymmetric unit of the title compound, C(12)H(12)N(2)O(3), contains two mol-ecules in which the benzene and isoxazole rings are almost coplanar, the dihedral angles between their mean planes being 1.76 (9) and 5.85 (8)°. The two mol-ecules inter-act with each other via N-H⋯N and N-H⋯O hydrogen bonds, which link the mol-ecules into layers parallel to the ac plane. The layers stack in a parallel mode with an inter-layer distance of 3.36 (7) Å.

8.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 25(2): 164-7, 2003 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-12905712

RESUMO

OBJECTIVE: To investigate the dual effects by the delta opioid receptor agonists DPDPE on the delayed rectified potassium channels in NG108-15 cells. METHODS: A series of outward currents were evoked in NG108-15 cells by depolarizing voltage from -50 mV to +80 mV at holding potential of -90 mV. These currents were delayed rectified potassium currents. Relatively selected delta opioid receptor agonists DPDPE of higher and lower concentrations were used to modulate the delayed rectified K+ current in NG108-15 cells. Opioid receptor antagonist Naloxone (NAL) and relatively selected delta opioid receptor antagonist Naltrindole (NTI) were used in the present experiments for the characterization of the actions of opioid receptors. RESULTS: The relatively higher concentrations of delta opioid receptor agonist DPDPE (> or = 10(-6) mol/L) significantly increased the amplitude of the delayed rectified K+ current. On the contrary, the relatively lower concentrations of DPDPE (< or = 10(-12) mol/L) decreased the amplitude of the delayed rectified K+ current (P < 0.05). Furthermore both the increase and decrease were time-dependent. CONCLUSIONS: delta opioid receptor agonist has dual regulatory effects on the delayed rectified potassium channels in NG108-15 cells.


Assuntos
D-Penicilina (2,5)-Encefalina/farmacologia , Naltrexona/análogos & derivados , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Receptores Opioides delta/agonistas , Animais , Membrana Celular/metabolismo , Glioma/metabolismo , Glioma/patologia , Células Híbridas/metabolismo , Camundongos , Naloxona/farmacologia , Naltrexona/farmacologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos , Células Tumorais Cultivadas
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 25(3): 297-300, 2003 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-12905743

RESUMO

OBJECTIVE: To observe the role of G protein in the dual regulation of opioid receptor agonist on the delayed rectified potassium channels. METHODS: Using whole-cell patch-clamp techniques applied to NG108-15 cells, investigate the effect of opioid receptor agonist on the delayed rectified potassium channels by administration of Guanosine-5'-0'-2-thiociphosphate (GDP beta S), Pertusis Toxin (PTX), Tetroacetic acid nueleoside diphosphate kinase (NDPK) and Adenosine-3' 5' cyclic monophosphate cAMP in the pipette solution. RESULTS: (1) GDP beta S could block the changes induced by both high and low concentration of (D-Pen2.5)-enkephalin (DPDPE) (P < 0.05). (2) PTX could inhibit the excitative regulation on K+ channel by high concentration of DPDPE (P < 0.05). But CTX had no effect on K+ channel caused by DPDPE. (3) UDP could block the excitative effect of K+ channel by high concentration of NDPK, while have no changes on the inhibitory effect caused by low concentration of opioid agonists. (4) cAMP took part in the regulation in high concentration of agonist administration (P < 0.05), while no changes for low concentration of agonists. CONCLUSIONS: Dual changes were observed on delayed rectifier potassium channel by agonist treatment on NG108-15 cells. The excitative effect was Gi/o coupled in high concentration of agonist incubation, related to cAMP. While the inhibitory effect was possibly induced by G protein beta gamma subunit directly.


Assuntos
Proteínas de Ligação ao GTP/fisiologia , Guanosina Monofosfato/análogos & derivados , Células Híbridas/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores Opioides/agonistas , Animais , D-Penicilina (2,5)-Encefalina/farmacologia , Glioma/metabolismo , Glioma/patologia , Guanosina Monofosfato/farmacocinética , Células Híbridas/patologia , Camundongos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Técnicas de Patch-Clamp , Toxina Pertussis/farmacologia , Ratos , Tionucleotídeos/farmacocinética
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