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1.
IUBMB Life ; 71(7): 978-985, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31026379

RESUMO

Osteoarthritis (OA) is a common age-related disorder. Chondrocytes in joint tissue play a critical role in normal articular cartilage function and tissue homeostasis. Local inflammatory cytokine-induced chondrocyte senescence contributes to the development and progression of OA. Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used to treat type 2 diabetes. Here, we report a novel pharmacological role of the DPP-4 inhibitor vildagliptin in chondrocyte senescence. Our data indicate that DPP-4 is an inducible factor responsive to tumor necrosis factor-α (TNF-α) treatment in chondrocytes. The inhibition of DPP-4 by vildagliptin ameliorates TNF-α-induced chondrocyte senescence as determined by cellular senescence-associated ß-galactosidase (SA-ß-Gal) activity. Vildagliptin displayed protective capabilities against TNF-α-induced chondrocyte cell cycle arrest in the G1 phase. Moreover, vildagliptin suppresses the three major TNF-α-induced chondrocyte senescence proteins including p53, p21, and plasminogen activator inhibitor-1 (PAI-1). Vildagliptin also suppresses TNF-α-induced p53 acetylation at K382. Consistently, our findings demonstrate the inhibitory effect of vildagliptin on p53 acetylation, which is mediated by sirtuin 1 (SIRT1) as the inhibition of SIRT1 negated the inhibitory action of vildagliptin on p53 acetylation. Furthermore, we found that the effect of vildagliptin on SIRT1 protection is adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) dependent, and the inhibition of AMPK activity negated the protection of vildagliptin against SIRT1 and chondrocytes senescence. In conclusion, our study explored the molecular mechanism and protective effect of the antidiabetic drug vildagliptin against chondrocyte senescence, and our findings imply that vildagliptin has a therapeutic potential in OA. © 2019 IUBMB Life, 1-2, 2019.

2.
Cell Death Dis ; 10(3): 183, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30796205

RESUMO

SETD3 is a member of SET-domain containing methyltransferase family, which plays critical roles in various biological events. It has been shown that SETD3 could regulate the transcription of myogenic regulatory genes in C2C12 differentiation and promote myoblast determination. However, how SETD3 is regulated during myoblast differentiation is still unknown. Here, we report that two important microRNAs (miRNAs) could repress SETD3 and negatively contribute to myoblast differentiation. Using microRNA (miRNA) prediction engines, we identify and characterize miR-15b and miR-322 as the primary miRNAs that repress the expression of SETD3 through directly targeting the 3'-untranslated region of SETD3 gene. Functionally, overexpression of miR-15b or miR-322 leads to the repression of endogenous SETD3 expression and the inhibition of myoblast differentiation, whereas inhibition of miR-15b or miR-322 derepresses endogenous SETD3 expression and facilitates myoblast differentiation. In addition, knockdown SETD3 in miR-15b or miR-322 repressed myoblasts is able to rescue the facilitated differentiation phenotype. More interestingly, we revealed that transcription factor E2F1 or FAM3B positively or negatively regulates miR-15b or miR-322 expression, respectively, during muscle cell differentiation, which in turn affects SETD3 expression. Therefore, our results establish two parallel cascade regulatory pathways, in which transcription factors regulate microRNAs fates, thereby controlling SETD3 expression and eventually determining skeletal muscle differentiation.

3.
J Cancer Res Ther ; 14(4): 799-806, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29970656

RESUMO

Aims: We have previously demonstrated that brain metastases were more common among patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) remains inconclusive. In this study, we explored the potential association between EGFR mutation and the risk of ECM. Patients and Methods: Between March 2007 and December 2014, 234 patients were analyzed for the potential association between EGFR mutation and ECM. Statistical Analysis Used: Multivariate Cox regression analysis. Results: There were no associations between the EGFR mutation and metastases in different organs, except for bone. The frequency of EGFR mutation was statistically higher for patients with bone metastases (BMs) at the initial diagnosis (P = 0.039) and at the last follow-up (P = 0.018) as compared to those with wild-type EGFR. In multivariate logistic regression analysis, EGFR mutation significantly increased the risk of BM at the initial diagnosis (P = 0.036). Among those patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly higher in patients with EGFR-mutant disease (P = 0.026). EGFR mutation was an independent risk factor for subsequent BM (P < 0.05). In addition, patients with finial BM and EGFR-mutant disease had longer median survival as compared to those with wild-type disease (P = 0.020). Conclusions: Only BM in patients with ECM was significantly correlated with EGFR mutation during their disease course. EGFR mutation was an independent predictive and prognostic factor for developing BM, which was also a positive predictive factor for overall survival of patients who developed BM.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma de Pulmão , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco
4.
Drug Des Devel Ther ; 12: 967-979, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29731604

RESUMO

Purpose: The purpose of this study was to investigate the therapeutic mechanism(s) of Clematis chinensis Osbeck/Notopterygium incisum K.C. Ting ex H.T (CN). Methods: A network pharmacology approach integrating prediction of ingredients, target exploration, network construction, module partition and pathway analysis was used. Results: This approach successfully helped to identify 12 active ingredients of CN, interacting with 13 key targets (Akt1, STAT3, TNFsf13, TP53, EPHB2, IL-10, IL-6, TNF, MAPK8, IL-8, RELA, ROS1 and STAT4). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that CN-regulated pathways were mainly classified into signal transduction and immune system. Conclusion: The present work may help to illustrate the mechanism(s) of action of CN, and it may provide a better understanding of antirheumatic effects.


Assuntos
Antirreumáticos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Febre Reumática/tratamento farmacológico , Antirreumáticos/química , Medicamentos de Ervas Chinesas/química , Humanos , Medicina Tradicional Chinesa , Conformação Molecular
5.
Chin J Nat Med ; 16(12): 926-935, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30595217

RESUMO

Notopterygium incisum (QH) has been used for the treatment of rheumatoid arthritis (RA), and volatile oils may be its mainly bioactive constituents. The present study was designed to analyze the volatile compounds in QH and to determine the anti-arthritic capacity of Notopterygium volatile oils and the potential mechanism of action. The volatile compounds analysis was conducted by GC-MS. The anti-arthritic capacity test of the volatile oils was conducted on adjuvant-induced arthritis (AIA) rats. The anti-inflammatory property was tested in NO release model in RAW 264.7 cells. Endothelial cells were used to evaluate the anti-proliferative and anti-tube formative effects. 70 compounds were analyzed by GC-MS in the volatile oils. Notopterygium volatile oils weakened the rat AIA in a dose-dependent manner (2, 4, and 8 g crude drug/kg). The NO production by RAW 264.7 was decreased by more than 50% in Notopterygium volatile oils (5, 15, and 45 µg·mL-1) pretreated groups. Notopterygium volatile oils also inhibited EAhy926 cell proliferation and further delayed EAhy926 cell capillary tube formation in a concentration-dependent manner. The anti-NO productive, anti-proliferative, and anti-tube formative effects of Notopterygium volatile oils strongly suggested that the therapeutic effect of QH in AIA might be related to the potent anti-inflammatory and anti-angiogenic capacities of the volatile oils.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Apiaceae/química , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Óleos Voláteis/administração & dosagem , Inibidores da Angiogênese/química , Animais , Anti-Inflamatórios/química , Artrite Experimental/imunologia , Artrite Experimental/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Camundongos , Óxido Nítrico/imunologia , Óleos Voláteis/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
6.
Medicine (Baltimore) ; 96(34): e7768, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28834880

RESUMO

RATIONALE: Metastasis to the small intestine from a primary lung cancer is rare, and is associated with a poor prognosis. Early diagnosis of small intestine metastasis is difficult because of the low incidence of clinically apparent symptoms. PATIENT CONCERNS: Clinical data and treatment of a 59-year-old man with small intestine metastasis from primary solid subtype lung adenocarcinoma are summarized. DIAGNOSES: A man who was previously diagnosed with stage IIIA (T3N2M0) lung adenocarcinoma (solid subtype) came to our hospital for postoperative radiotherapy. Laboratory tests indicated anemia and melena. The patient was initially believed to have digestive ulcer and was treated with omeprazole, which proved to be ineffective. We conducted an abdominal computed tomography (CT) contrast scan and discovered a mass in the small intestine mass. Further positron emission tomography-computed tomography (PET-CT) imaging indicated the small intestine mass with fluorodeoxyglucose uptake. INTERVENTIONS: The patient underwent an enterectomy and anastomosis. Pathological analysis confirmed the diagnosis of small intestinal metastasis from lung cancer with concomitant mesenteric lymph node metastasis. OUTCOMES: One month after the operation, hemoglobin levels became normal, and the patient had good quality of life. However, 3 months after the operation, the patient suffered from anemia again. An abdominal CT scan indicated a new small intestine mass. Progression continued rapidly, and the patient died of hemorrhagic shock 5.5 months after the resection of the small intestine mass. LESSONS: Although uncommon, if lung cancer patients present with anemia and melena, enteric metastasis should be part of the differential diagnosis. Abdominal CT scans and PET-CT are effective for early diagnosis. The prognosis of metastatic spread of solid subtype lung adenocarcinoma to the small intestine with mesenteric lymph node metastasis is poor. Subgroups of patients benefitting from metastasectomy and more effective systemic therapy need to be further investigated.


Assuntos
Adenocarcinoma/patologia , Anemia/etiologia , Neoplasias Intestinais/complicações , Neoplasias Intestinais/secundário , Neoplasias Pulmonares/patologia , Melena/etiologia , Adenocarcinoma de Pulmão , Humanos , Pessoa de Meia-Idade
7.
Int J Nanomedicine ; 11: 4919-4929, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27713630

RESUMO

BACKGROUND: Akebia saponin D (ASD) exerts various pharmacological activities but with poor oral bioavailability. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) based on the drug-phospholipid complex technique was developed to improve the oral absorption of ASD. METHODS: ASD-phospholipid complex (APC) was prepared using a solvent-evaporation method and characterized by infrared spectroscopy, differential scanning calorimetry, morphology observation, and solubility test. Oil and cosurfactant were selected according to their ability to dissolve APC, while surfactant was chosen based on its emulsification efficiency in SNEDDS. Pseudoternary phase diagrams were constructed to determine the optimized APC-SNEDDS formulation, which was characterized by droplet size determination, zeta potential determination, and morphology observation. Robustness to dilution and thermodynamic stability of optimized formulation were also evaluated. Subsequently, pharmacokinetic parameters and oral bioavailability of ASD, APC, and APC-SNEDDS were investigated in rats. RESULTS: The liposolubility significantly increased 11.4-fold after formation of APC, which was verified by the solubility test in n-octanol. Peceol (Glyceryl monooleate [type 40]), Cremophor® EL (Polyoxyl 35 castor oil), and Transcutol HP (Diethylene glycol monoethyl ether) were selected as oil, surfactant, and cosurfactant, respectively. The optimal formulation was composed of Glyceryl monooleate (type 40), Polyoxyl 35 castor oil, Diethylene glycol monoethyl ether, and APC (1:4.5:4.5:1.74, w/w/w/w), which showed a particle size of 148.0±2.7 nm and a zeta potential of -13.7±0.92 mV after dilution with distilled water at a ratio of 1:100 (w/w) and good colloidal stability. Pharmacokinetic studies showed that APC-SNEDDS exhibited a significantly greater Cmax1 (733.4±203.8 ng/mL) than ASD (437.2±174.2 ng/mL), and a greater Cmax2 (985.8±366.6 ng/mL) than ASD (180.5±75.1 ng/mL) and APC (549.7±113.5 ng/mL). Compared with ASD, Tmax1 and Tmax2 were both remarkably shortened by APC-SNEDDS. The oral bioavailability in rats was enhanced significantly to 183.8% and 431.8% by APC and APC-SNEDDS, respectively. CONCLUSION: These results indicated that APC-SNEDDS was a promising drug delivery system to enhance the oral bioavailability of ASD.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Fosfolipídeos/química , Saponinas/administração & dosagem , Saponinas/química , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Etilenoglicóis/química , Feminino , Glicerídeos/química , Masculino , Tamanho da Partícula , Polietilenoglicóis/química , Ratos Sprague-Dawley , Saponinas/farmacocinética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/química
8.
Medicine (Baltimore) ; 95(40): e5077, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27749580

RESUMO

INTRODUCTION: Currently, the options are limited for the treatment of patients who have failed 2 lines of chemotherapy for advanced lung squamous cell carcinoma (SCC). Recently, nivolumab, a fully human IgG4 programmed death 1 immune checkpoint inhibitor antibody, was approved to treat patients with advanced stage, relapsed/refractory lung SCC. Although nivolumab has demonstrated antitumor activity with survival benefit in Caucasian patients, its efficacy in Asian patients is unknown. CASE REPORT: In this report, we describe a Chinese patient with relapsed advanced stage lung SCC who had an excellent response to nivolumab after only 2 doses without any adverse effects. Immunohistochemical analysis indicated the tumor was stained positive for programmed death-ligand 1. CONCLUSION: To our knowledge, this is the first report of satisfactory efficacy of short-term nivolumab treatment in a Chinese patient with relapsed advanced-stage lung SCC. Further clinical trials in Asian countries are needed to test whether nivolumab immunotherapy is a safe and effective treatment for Asian patients with lung SCC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/diagnóstico , China , Relação Dose-Resposta a Droga , Evolução Fatal , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Nivolumabe , Fatores de Tempo , Tomografia Computadorizada por Raios X
9.
Oncotarget ; 7(35): 56998-57010, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27486770

RESUMO

Lung adenocarcinomas are more commonly associated with brain metastases (BM). Epidermal growth factor receptor (EGFR) mutations have been demonstrated to be both predictive and prognostic for patients with lung adenocarcinoma. We aimed to explore the potential association between EGFR mutation and the risk of BM in pulmonary adenocarcinoma patients. Data of 234 patients from 2007 to 2014 were retrospectively reviewed. A total of 108 patients had EGFR mutations in the entire cohort. Among them, 76 patients developed BM during their disease course. The incidence of BM was statistically higher in patients with EGFR mutations both at initial diagnosis (P=0.014) and at last follow-up (P<0.001). Multivariate logistic regression analysis revealed that EGFR mutation significantly increased the risk of BM at initial diagnosis (OR=2.515, P=0.022). In patients without BM at initial diagnosis, the accumulative rate of subsequent BM was significantly higher with EGFR mutations (P=0.001). Multivariate Cox regression analysis identified EGFR mutation as the only independent risk factor for subsequent BM (HR=3.036, P=0.001). Patients with EGFR mutations demonstrated longer overall survival (OS) after BM diagnosis than patients with wild-type EGFR (P=0.028). Our data suggest that EGFR mutation is an independent predictive and prognostic risk factor for BM and a positive predictive factor for OS in patients with BM.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Encefálicas/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/metabolismo , Mutação , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Análise Mutacional de DNA , Receptores ErbB/metabolismo , Éxons , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco
10.
Clin Exp Pharmacol Physiol ; 43(11): 1115-1124, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27557877

RESUMO

In non-healing wounds, mesenchymal stem cell (MSC)-based therapies have the potential to activate a series of coordinated cellular processes, including angiogenesis, inflammation, cell migration, proliferation and epidermal terminal differentiation. As pro-inflammatory reactions play indispensable roles in initiating wound repair, sustained and prolonged inflammation exhibit detrimental effects on skin wound closure. We investigated the feasibility of using an antioxidant agent epigallocatechin-3-gallate (EGCG), along with MSCs, to improve wound repair through their immunomodulatory actions. In a rat model of wound healing, a single dose of EGCG at 10 mg/kg increased the efficiency of MSC-induced skin wound closure. Twenty days after the wound induction, MSC treatment significantly enhanced the epidermal thickness, which was further increased by EGCG administration. Consistently, the highest extent of growth factors upregulation for neovascularization induction was seen in the animals treated by both MSCs and EGCG, associated with a potent anti-scarring effect throughout the healing process. Finally, expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6, in the wound area were reduced by MSCs, and this reduction was further potentiated by EGCG co-administration. EGCG, together with MSCs, can promote skin wound healing likely through their combinational effects in modulating chronic inflammation.


Assuntos
Catequina/análogos & derivados , Transplante de Células-Tronco Mesenquimais/métodos , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia , Animais , Antioxidantes/administração & dosagem , Catequina/administração & dosagem , Células Cultivadas , Terapia Combinada/métodos , Mediadores da Inflamação/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Resultado do Tratamento
11.
Pharm Biol ; 54(9): 1857-64, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26760929

RESUMO

Context Eucommiae Cortex and Radix Dipsaci, occurring in a ratio of 1:1 in Du-Zhong-Wan (DZW), a Chinese herbal medicine, is available as a water extract followed by ethanol precipitation for the treatment of osteoporosis, fractures and menopausal syndrome. Objective This study investigates the protective effects of DZW in ovariectomy (OVX)-induced bone loss in a rat osteopenia model. Materials and methods Sixty Sprague-Dawley rats were randomly divided into the sham-operated group (SHAM) and five OVX subgroups: OVX with vehicle (OVX), 17ß-estradiol (E2) and with three graded doses of DZW. Daily oral administration of the different samples started on the fifth week and lasted for 12 weeks, respectively. The body weight, uterus wet weight, serum biochemical parameters, bone mineral density (BMD), bone biomechanical properties, bone microarchitecture and immunohistochemistry were examined. Results Compared with the SHAM group, the DZW treatment significantly reversed the osteoporotic changes in OVX rats. The DZW-H group showed that serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels reduced by 152.25% (p < 0.01) and osteocalein (OCN) levels dose dependently increased by 118.43% (p < 0.01) as compared with the OVX group. Compared with the OVX group, the DZW at different three dosages of DZW evidently increased the right femur BMD by 112.43, 114.56 and 116.45%, and dramatically promoted bone quality and bone strength (p < 0.05). Further, immunohistochemical evaluation also showed that DZW administration increased ER expression in uteri (p < 0.01). Conclusions DZW exhibits an anti-osteoporotic effect, probably mediated via phyto-estrogenic effects. It might be a potential herbal alternative for the management of postmenopausal osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/prevenção & controle , Remodelação Óssea/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fêmur/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia , Absorciometria de Fóton , Animais , Biomarcadores/sangue , Fenômenos Biomecânicos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/fisiopatologia , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/fisiopatologia , Humanos , Imuno-Histoquímica , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/efeitos dos fármacos , Receptores Estrogênicos/metabolismo , Regulação para Cima , Útero/efeitos dos fármacos , Útero/metabolismo , Microtomografia por Raio-X
12.
Int J Clin Exp Pathol ; 8(6): 6070-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26261485

RESUMO

53BP1, an important mediator of DNA damage checkpoint, plays an essential role in maintaining the cell genome stability, and the aberrant expression of 53BP1 was found to contribute to tumor occurrence and development. In this study, we explored the clinical significance of 53BP1 expression in colorectal cancer and investigated the effects of 53BP1 expression on tumor cell proliferation and apoptosis and its possible mechanisms. Immunohistochemical analysis was performed to detect the expression of 53BP1 in 95 cases of tumor tissues. After establishment of shRNA-mediated knockdown stable HCT-116 cell lines, cell proliferation, apoptosis and cell cycle distribution were detected by MTT and flow cytometry, and expression of up-and down-steam related proteins as γ-H2AX, CHK2 and P53 were tested by Western blot. 53BP1 intensity was found to be associated with tumor location (P < 0.05), and the low expression of 53BP1 revealed decreased survival time compared with high expression in subgroups as male, tumor size > 5 cm, tumor located at right side, T stage as T3-T4, N0, clinical stage as I-II (P < 0.05). In vitro, shRNA-mediated loss of 53BP1 obviously inhibited HCT-116 tumor cell apoptosis, promoted cell proliferation and increased accumulation of cells in S phase. Meanwhile, the expression of γ-H2AX, CHK2 and P53 was significantly reduced (P < 0.05). Our findings suggest 53BP1 may serve as a candidate biomarker for predicting prognosis and disease development in colorectal cancer.


Assuntos
Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/metabolismo , Dano ao DNA , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Biomarcadores Tumorais/genética , Quinase do Ponto de Checagem 2/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Histonas/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , Fatores de Risco , Pontos de Checagem da Fase S do Ciclo Celular , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53
13.
Radiat Oncol ; 10: 114, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25986069

RESUMO

BACKGROUND: The objective of this study was to compare the dose distributions of RapidArc (RA), static gantry intensity-modulated radiotherapy (IMRT), and three-dimensional conformal radiotherapy (3DCRT) as adjuvant radiotherapy modalities for the treatment of gastric cancer. METHODS: Fifteen patients with gastric cancer that underwent limited lymphadenectomy of perigastric lymph nodes were included in this study. Dosimetric values for a total dose of 45 Gy (1.8 Gy/day) were calculated for the RapidArc, IMRT, and 3DCRT modalities. The following parameters were compared: D99%, D1%, V95%, V107%, and conformity and homogeneity index values (CI and HI, respectively) for the planned target volume (PTV). Dose volume histogram (DVH) and dose distribution of the organs at risk (OAR), as the maximal dose to the spinal cord, V30 and V40 of the small bowel, and V20, V30 of liver and kidney were also assessed respectively. RESULTS: RA, IMRT, and 3DCRT all achieved desirable PTV coverage. However, RA and IMRT significantly decreased D1% and V107%, and provided better CI and HI values compared with 3DCRT (P <0.05). Moreover, RA also achieved a significantly lower maximum dose for the spinal cord, liver V30, and kidney V20 compared to IMRT and 3DCRT; while the mean dose for these three organ types did not differ for the RA, IMRT, and 3DCRT plans. CONCLUSIONS: Both RA and IMRT achieved favorable PTV coverage compared to 3DCRT. In addition, RA achieved better dosimetry than IMRT and 3DCRT, and provided better protection for the spinal cord, liver, and kidneys.


Assuntos
Imagem Tridimensional/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Adjuvante , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias Gástricas/radioterapia , Humanos , Estadiamento de Neoplasias , Órgãos em Risco/efeitos da radiação , Posicionamento do Paciente , Prognóstico , Radiometria/métodos , Dosagem Radioterapêutica , Estudos Retrospectivos
14.
Oncol Rep ; 33(3): 1161-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25572529

RESUMO

The aim of the present study was to explore the efficacy and mechanism of the radiosensitisation of icotinib hydrochloride (IH), a novel oral epidermal growth factor receptor-tyrosine kinase activity inhibitor, by evaluating the changes in tumour cell double-strand breaks (DSBs) repair, cell cycle and apoptosis following a combination of IH and radiotherapy (RT) in human colorectal adenocarcinoma cell lines. The HT29 and HCT116 human CRC cell lines were treated with IH and/or radiation. Effects on cell viability and cell cycle progression were measured by MTT, a clonogenic survival assay, and flow cytometry. Immunofluorescent staining and western blot analysis were applied to detect the expression of γ-H2AX and 53BP1 in the different treatment groups. Finally, the in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. IH inhibited the proliferation and enhanced the radiosensitivity in HT29 and HCT116 CRC cells lines. IH combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the HT29 cell line (P<0.05). Similarly, cell cycle arrest occurred in the HCT116 cell line, although this increase did not result in significant differences in the RT group (P>0.05). IH combined with radiation significantly inhibited the expression of γ-H2AX and 53BP1 based on results of immunofluorescent staining and western blot analysis. In vivo, IH plus radiation significantly inhibited the tumour growth compared to either agent independently. In conclusion, IH significantly increased the radiosensitivity of HT29 and HCT116 cells in vitro and in vivo. Radiation combined with EGFR blockade inhibited tumour proliferation, increased apoptosis, prolonged G2/M arrest and significantly enhanced DNA injury in colorectal cancer. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Éteres de Coroa/farmacologia , Reparo do DNA/efeitos dos fármacos , Quinazolinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Western Blotting , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Citometria de Fluxo , Imunofluorescência , Células HCT116 , Células HT29 , Xenoenxertos , Humanos , Camundongos , Camundongos Nus
15.
Int J Clin Exp Pathol ; 7(8): 4959-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25197367

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer-related death all over the world. Ribosomal s6 kinase4 (RSK4), an X-linked gene, firstly was found as to be a potential tumor suppressive gene in a variety of cancers and is widely participated in signaling pathway. However its role in CRC is unclear. This study is to explore the correlation between the protein expression of RSK4 and clinical pathologic characteristics in colorectal tumors, which might serve as a prognostic determinant of colorectal cancers. METHODS: Biopsies of 103 colorectal cancer and 46 matched adjacent noncancerous tissues were collected for analysis of RSK4 protein by immunohistochemistry. The correlation between RSK4 protein expression and the clinical pathological features of colorectal cancers were evaluated by Chi-square test and Fisher's exact test. The survival rates were analyzed by the Kaplan-Meier method, and the relationship between prognostic factors and patient survival was analyzed by the Cox proportional hazard models. RESULTS: RSK4 was conversely correlated with some pathological classifications (P<0.05 for N, G and clinical staging), and there were no statistically significant differences in age, CEA expression in blood, CA199 and tumors t-staging (x(2) test, P>0.05 for all categories) respectively. Furthermore, patients with high protein level of RSK4 showed prolonged overall survivals (P<0.05). Moreover, multivariate analysis showed that low expression level of RSK is an independent risk factor for high mortality in colorectal cancer. CONCLUSIONS: Low RSK4 expression is correlated with advanced clinical pathologic classifications and is a poor overall survival in colorectal cancer patients. These findings suggest that RSK4 may serve as a useful marker in prognostic evaluation for patients with colorectal cancer.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Proteínas Quinases S6 Ribossômicas 90-kDa/biossíntese , Idoso , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Quinases S6 Ribossômicas 90-kDa/análise
16.
World J Surg Oncol ; 11: 306, 2013 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-24283603

RESUMO

BACKGROUND: With the wide application of targeted drug therapies, the relevance of prognostic and predictive markers in patient selection has become increasingly important. Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer. However, there are currently no predictive or prognostic biomarkers for bevacizumab. Several clinical studies have evaluated bevacizumab-induced hypertension in patients with metastatic colorectal cancer. This meta-analysis was performed to better determine the association of bevacizumab-induced hypertension with outcome in patients with metastatic colorectal cancer, and to assess whether bevacizumab-induced hypertension can be used as a prognostic factor in these patients. METHODS: We performed a systematic review and meta-analysis on seven published studies to investigate the relationship between hypertension and outcome of patients with metastatic colorectal cancer treated with bevacizumab. Our primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Hazard ratios (HRs) for PFS and OS were extracted from each trial, and the log of the relative risk ratio (RR) was estimated for ORR. RESULTS: The occurrence of bevacizumab-induced hypertension in patients was highly associated with improvements in PFS (HR = 0.57, 95% CI: 0.46-0.72; P <0.001), OS (HR = 0.50; 95% CI: 0.37-0.68; P <0.001), and ORR (RR = 1.57, 95% CI: 1.07-2.30, P <0.05), as compared to patients without hypertension. CONCLUSIONS: Bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Hipertensão/induzido quimicamente , Bevacizumab , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Humanos , Hipertensão/mortalidade , Metanálise como Assunto , Metástase Neoplásica , Prognóstico , Taxa de Sobrevida
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