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1.
Phytomedicine ; : 153786, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34785104

RESUMO

BACKGROUND: Lung cancer has become the principal cause of cancer-related deaths. Emodin is a Chinese herb-derived compound extracted from the roots of Rheum officinale that exhibits numerous pharmacological characteristics. Secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in cancers and plays an important role in cancer development. PURPOSE: This study aims to investigate the anti-tumor mechanism of emodin in non-small-cell lung cancer (NSCLC). METHODS: MTT assay was applied to detect the sensitivity of emodin to NSCLC cell line. Flow cytometry was used to examine the effect of emodin on cell cycle distribution and evaluate ROS level and apoptosis. Western blot analysis was utilised to examine the expression levels of sPLA2-IIa, PKM2, and AMPK and its downstream pathways induced by emodin. Enzyme inhibition assay was applied to investigate the inhibitory effect of emodin on sPLA2-IIa. The anticancer effect of emodin was also detected using an in vivo model. RESULTS: Emodin significantly inhibited NSCLC proliferation in vivo and in vitro and was relatively less cytotoxic to normal lung cell lines. Most importantly, emodin inhibited the proliferation of KRAS mutant cell lines by decreasing the expression of sPLA2-IIa and NF-κB pathways. Emodin also inhibited mTOR and AKT and activated the AMPK pathway. Furthermore, emodin induced apoptosis, increased the reactive oxygen species (ROS) level, and arrested the cell cycle. CONCLUSION: Emodin exhibited a novel anti-tumor mechanism of inhibiting the proliferation of KRAS mutant cell lines by decreasing the expression levels of sPLA2-IIa and NF-κB pathways. Hence, emodin can potentially serve as a therapeutic target in NSCLC.

2.
Phytomedicine ; : 153831, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34794861

RESUMO

BACKGROUND: Currently, the identification of accurate biomarkers for the diagnosis of patients with early-stage lung cancer remains difficult. Fortunately, metabolomics technology can be used to improve the detection of plasma metabolic biomarkers for lung cancer. In a previous study, we successfully utilised machine learning methods to identify significant metabolic markers for early-stage lung cancer diagnosis. However, a related research platform for the investigation of tumour metabolism and drug efficacy is still lacking. HYPOTHESIS/PURPOSE: A novel methodology for the comprehensive evaluation of the internal tumour-metabolic profile and drug evaluation needs to be established. METHODS: The optimal location for tumour cell inoculation was identified in mouse chest for the non-traumatic orthotopic lung cancer mouse model. Microcomputed tomography (micro-CT) was applied to monitor lung tumour growth. Proscillaridin A (P.A) and cisplatin (CDDP) were utilised to verify the anti-lung cancer efficacy of the platform. The top five clinically valid biomarkers, including proline, L-kynurenine, spermidine, taurine and palmitoyl-L-carnitine, were selected as the evaluation indices to obtain a suitable lung cancer mouse model for clinical metabolomics research by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: The platform was successfully established, achieving 100% tumour development rate and 0% surgery mortality. P.A and CDDP had significant anti-lung cancer efficacy in the platform. Compared with the control group, four biomarkers in the orthotopic model and two biomarkers in the metastatic model had significantly higher abundance. Principal component analysis (PCA) showed a significant separation between the orthotopic/metastatic model and the control/subcutaneous/KRAS transgenic model. The platform was mainly involved in arginine and proline metabolism, tryptophan metabolism, and taurine and hypotaurine metabolism. CONCLUSION: This study is the first to simulate clinical metabolomics by comparing the metabolic phenotype of plasma in different lung cancer mouse models. We found that the orthotopic model was the most suitable for tumour metabolism. Furthermore, the anti-tumour drug efficacy was verified in the platform. The platform can very well match the clinical reality, providing better lung cancer diagnosis and securing more precise evidence for drug evaluation in the future.

3.
Chem Sci ; 9(6): 1666-1673, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29675214

RESUMO

A DNA logic sensor was constructed for gene mutation analysis based on a novel signal amplification cascade by controllably extending a hairpin-structured flap to bridge two invasive reactions. The detection limit was as low as 0.07 fM, and the analytical specificity is high enough to unambiguously pick up 0.02% mutants from a large amount of wild-type DNA. Gene mutations related to the personalized medicine of gefitinib, a typical tyrosine kinase inhibitor, were analyzed by the DNA logic sensor with only a 15 minute response time. Successful assay of tissue samples and cell-free plasma DNA indicates that the new concept we proposed here could benefit clinicians for straightforward prescription of a mutation-targeted drug.

4.
Epigenetics ; 9(6): 896-909, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24699858

RESUMO

DNA methylation plays a critical role during the development of acquired chemoresistance. The aim of this study was to identify candidate DNA methylation drivers of cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC). The A549/DDP cell line was established by continuous exposure of A549 cells to increasing concentrations of DDP. Gene expression and methylation profiling were determined by high-throughput microarrays. Relationship of methylation status and DDP response was validated in primary tumor cell culture and the Cancer Genome Atlas (TCGA) samples. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo. A total of 372 genes showed hypermethylation and downregulation in A549/DDP cells, and these genes were involved in most fundamental biological processes. Ten candidate genes (S100P, GDA, WISP2, LOXL1, TIMP4, ICAM1, CLMP, HSP8, GAS1, BMP2) were selected, and exhibited varying degrees of association with DDP resistance. Low dose combination of 5-aza-2'-deoxycytidine (5-Aza-dC) and trichostatin A (TSA) reversed drug resistance of A549/DDP cells in vitro and in vivo, along with demethylation and restoration of expression of candidate genes (GAS1, TIMP4, ICAM1 and WISP2). Forced expression of GAS1 in A549/DDP cells by gene transfection contributed to increased sensitivity to DDP, proliferation inhibition, cell cycle arrest, apoptosis enhancement, and in vivo growth retardation. Together, our study demonstrated that a panel of candidate genes downregulated by DNA methylation induced DDP resistance in NSCLC, and showed that epigenetic therapy resensitized cells to DDP.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Cisplatino/farmacologia , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/genética , RNA Mensageiro/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Decitabina , Epigênese Genética , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica/métodos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pulmonares/patologia
5.
Arch Med Res ; 43(5): 383-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22863968

RESUMO

BACKGROUND AND AIMS: Epidemiological studies have investigated the association between STXBP4/COX11 rs6504950 (G>A) polymorphism and breast cancer susceptibility. However, the results are still controversial. Hence, we conducted a meta-analysis of the STXBP4/COX11 polymorphism and risk of breast cancer to obtain the most reliable estimate of the association. METHODS: PubMed, Embase and Web of Science databases were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of the association between STXBP4/COX11 rs6504950 (G>A) polymorphism with breast cancer risk. RESULTS: A total of four eligible studies including 17,960 cases and 22,713 controls based on the search criteria were involved in this meta-analysis. The distributions of genotypes in the controls were all in agreement with Hardy-Weinberg equilibrium. We observed that STXBP4/COX11 rs6504950 polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (the allele contrast model: OR = 0.93, 95% CI = 0.87-0.99; the heterozygote codominant model: OR = 0.87, 95% CI = 0.83-0.90; the dominant model OR = 0.92, 95% CI = 0.88-0.96). CONCLUSION: This meta-analysis indicated that the rs6504950 AA/AG genotypes are associated with a significantly decreased risk of breast carcinogenesis.


Assuntos
Neoplasias da Mama/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Proteínas de Transporte de Cobre , Complexo de Proteínas da Cadeia de Transporte de Elétrons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Proteínas Mitocondriais , Razão de Chances , Proteínas de Transporte Vesicular
6.
World J Gastroenterol ; 16(44): 5642-6, 2010 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-21105200

RESUMO

AIM: To explore the regulator of G-protein signaling 5 (RGS5) expression in gastric carcinoma and its association with differentiation and microvascular density (MVD). METHODS: Expression of RGS5 and CD34 were examined in 76 cases of gastric carcinoma, including 22 cases with lymph node metastasis and 54 cases without lymph node metastasis determined by immunohistochemistry (IHC). MVD was assessed using CD34 monoclonal antibody. The presence of RGS5 and CD34 was analyzed by IHC using the Envision technique. RESULTS: The RGS5 expression in gastric carcinoma was positively correlated with the differentiation of the tumor (r = 0.345, P < 0.001), but not related with age, gender, tumor size, clinical stage and lymph node metastasis (P > 0.05). The average MVD in the group with lymph node metastasis was significantly higher than that in the group without lymph node metastasis (P < 0.05). RGS5 expression was negatively correlated with the average MVD (P < 0.05). CONCLUSION: RGS5 expression level in gastric carcinoma is associated with the differentiation and MVD of the tumor, and may be used as an important parameter for determining the prognosis of gastric carcinoma patients.


Assuntos
Adenocarcinoma/química , Biomarcadores Tumorais/análise , Microvasos/patologia , Neovascularização Patológica/patologia , Proteínas RGS/análise , Neoplasias Gástricas/química , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/patologia , Antígenos CD34/análise , Diferenciação Celular , Distribuição de Qui-Quadrado , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/patologia
7.
Zhonghua Bing Li Xue Za Zhi ; 37(2): 92-8, 2008 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-18681319

RESUMO

OBJECTIVE: To evaluate the relationship between p27Kip1 low expression in breast cancer and its prognostic implication in breast carcinoma patients. Methods All data that were associated with the study of the relationship between p27Kip1 and the prognosis for breast cancer was pooled from Cochrane library, PubMed, Embase and Medlinebase. The outcome was measured using the risk ratio (RR). Data pooling was performed by RevMan 4. 2. Results 6457 patients from 20 studies were included in this meta-analysis. RR estimate of overall survival (OS) for patients with low level p27Kip1 was 2.07 [1.66,2.60] (P<0.01). For disease free survival (DFS), the pooled RR was 1.27 [1.10,1.47] (P<0.05). The combined RR estimate of relapse free survival (RFS) for patients with low level of p27Kip1 was 1.49 [0.92, 2.42] (P >0.05). In patients with lymph node negative breast carcinoma, the combined RR for OS and RFS were 1.98 [1.34,2.91] (P <0.01) and 1.28 [0.45,3.65] (P > 0.05), respectively. Among the patients with lymph node positive breast carcinoma, the combined RR for OS and RFS was 1.92 [1.31, 2.82] (P=0.0009) and 1.35 [0.96,1.89] (P>0.05) respectively. Conclusions Low level of p27Kip1 appears to be an independent prognostic factor to OS and DFS of breast cancer patients but not to RFS. Additional studies with large patient number and widely accepted practical methods are required to derive the precise prognostic significance of p27Kip1 expression in breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Metástase Linfática/diagnóstico , Prognóstico , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma/diagnóstico , Carcinoma/genética , Carcinoma/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática/fisiopatologia , Estadiamento de Neoplasias/métodos
8.
Zhonghua Nan Ke Xue ; 12(11): 1021-5, 2006 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-17146932

RESUMO

Prostate cancer is a most common malignant neoplasm in males. In recent years, its incidence has been rising dramatically in China. Patients with recurrent prostate cancer may be treated with androgen deprivation strategies, but most cases will eventually develop into androgen-independent prostate cancer (AIPC). Until recently, chemotherapy has been shown to be effective in palliating the symptoms of the disease but not in improving survival. Current strategies for the treatment of AIPC have shown significant palliation, but no definitive increase in survival. Molecular mechanisms underlying the development of androgen-independent prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. In this paper, we not only review the molecular mechanism of AIPC, but also present some of the promising management principles and systemic chemotherapy options against AIPC.


Assuntos
Androgênios , Neoplasias da Próstata/terapia , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Genética , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
9.
World J Gastroenterol ; 10(21): 3103-6, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15457552

RESUMO

AIM: To study the cell cycle alterations of human hepatoma cell line HepG(2) in vitro after (60)Co gamma-irradiation and further to examine the mechanisms underlying the enhancement of radiosensitivity to gamma-irradiation in HepG(2) transiently transfected with wild type p27(kip1). METHODS: The proliferation of HepG(2) cells was evaluated with MTT assay, and the cell cycle profile and apoptosis were assessed by cell morphology, DNA fragmentation analysis and flow cytometry. HepG(2) cells were transfected with p27(kip1) wild type by using Lipofectamine (LF2000), and the expression and subcellular localization of p27(kip1) in HepG(2) were detected by immunocytochemistry. RESULTS: (60)Co gamma-irradiation inhibited the growth of HepG(2) cells in a dose-dependent manner. Apoptosis of HepG(2) cells was induced 48 h after gamma ray exposure. Furthermore research was carried out to induce exogenous expression of p27(kip1) in HepG(2). The expression of p27(kip1) induced G(0)/G(1) phase arrest in HepG(2) cells. The overexpression of p27(kip1) enhanced (60)Co gamma-irradiation-induced radiosensitivity in HepG(2) cells. CONCLUSION: Overexpression of p27(kip1) is a rational approach to improve conventional radiotherapy outcomes, which may be a possible strategy for human hepatoma therapy.


Assuntos
Carcinoma Hepatocelular , Proteínas de Ciclo Celular/genética , Radioisótopos de Cobalto/farmacologia , Neoplasias Hepáticas , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos da radiação , Divisão Celular/efeitos da radiação , Linhagem Celular Tumoral/citologia , Linhagem Celular Tumoral/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p27 , Raios gama , Humanos , Tolerância a Radiação , Transfecção
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