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1.
J Biol Chem ; 297(3): 100954, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34270958

RESUMO

Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of the AMPK/PPARδ pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, whereas the PPARδ/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.

2.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Med Sci Monit ; 26: e925452, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33041321

RESUMO

BACKGROUND The complex anatomy of the trochanter and the diversity in mechanisms of injury to it complicate intertrochanteric fracture patterns. Using digital technology, we created three-dimensional (3D) computed tomography (CT) mapping to show the relevant characteristics of intertrochanteric fractures in elderly patients. MATERIAL AND METHODS This was a retrospective analysis of a case series of closed intertrochanteric fractures in patients older than age 60 years who had sustained single-sided injuries less than 1 week previously. High-quality CT scans of the cases were used to create a 3D reconstruction fracture model, and fracture maps of the proximal femur were created by overlapping the fracture lines. RESULTS A total of 115 patients were enrolled in this study, with mean age of 78 years (SD 7.98 years; range, 60 to 96 years). The essential features of the fracture lines were recorded in each case. Fracture maps revealed that the fracture lines were mainly concentrated in the area of the lesser and greater trochanter, intertrochanteric line, and intertrochanteric crest. As for fracture subtypes, results between patients were similar for Types A1 and A2 fractures, and differed for Type A3 fractures. CONCLUSIONS Detailed analysis of essential features of fracture lines revealed fracture fragments, some of which may be difficult to see using traditional imaging methods. Fracture maps composed of interindividual fracture lines revealed the relevant characteristics of intertrochanteric fractures in elderly patients. The resulting information about characteristics of distribution of fracture lines may be helpful in clinical practice.


Assuntos
Fixação Intramedular de Fraturas , Fraturas do Quadril/diagnóstico por imagem , Fraturas do Quadril/cirurgia , Imageamento Tridimensional , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Eur J Pharmacol ; 857: 172425, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150647

RESUMO

As a nuclear receptor, ligand binding and activated PPARδ (peroxisome-proliferator-activated receptor δ) plays an important role in regulation of inflammation, metabolism and cancer, while it is unclear the effect of metformin on PPARδ-mediated cancer cell metabolism. Here we found that PPARδ agonist GW501516 significantly increased Glut1 (Glucose transporter 1) and SLC1A5 (solutecarrier family 1 member 5) gene and protein expressions in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines, while metformin inhibited this event, which was associated with metformin-mediated inhibition of PPARδ activity in response to GW501516. Importantly, GW501516 inhibited the binding of PPARδ to AMPK, while metformin reversed this process. Metformin inhibited Glut1 and SLC1A5 expressions leading to reduced influx of glucose and glutamine in cancer cells, which is associated with reduced tumor growth. These findings suggest that metformin inhibited PPARδ agonist GW501516-induced cancer cell metabolism and tumor growth.


Assuntos
Sistema ASC de Transporte de Aminoácidos/genética , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Metformina/farmacologia , Antígenos de Histocompatibilidade Menor/genética , PPAR delta/agonistas , Tiazóis/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Camundongos , Tiazóis/farmacologia , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(1): 87-90, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30707875

RESUMO

OBJECTIVE: To investigate the clinical significance of children bronchial asthma detection by using negative expiratory pressure (NEP) technique. METHODS: The children with bronchial asthma admitted to Department of Pediatrics of Zhejiang Provincial Integrated Traditional Chinese and Western Medicine Hospital from March 2016 to March 2018 were enrolled. They were divided into mild group (0-4 scores) and severe group (5-12 scores) according to asthma clinical scoring criteria. The children undergoing physical examination at the same period were served as healthy control group. NEP technique and tidal volume (VT) were detected by the pulmonary function instrument. Respiratory flow-volume curves (F-V curves) without NEP were compared with tidal F-V curves after NEP application to assess expiratory flow limitation (EFL). EFL index was calculated according to the percentage of expiratory VT after EFL and expiratory VT when NEP was not used. Pearson correlation method was used to analyze the relationship between EFL index and severity of bronchial asthma. Receiver operating characteristic (ROC) curve was plotted to analyze the value of EFL index in evaluating the severity of bronchial asthma in children. RESULTS: A total of 86 children with bronchial asthma were enrolled in the study, and 84 patients completed the test and 2 children withdrew due to other diseases. Finally, 84 patients were included in the final analysis, including 41 mild and 43 severe children. Forty-two healthy children in the same period were served as healthy control group. There was no significant difference in gender or age among the groups, and no adverse reactions occurred during the test. The EFL index of children with bronchial asthma was significantly higher than that of the healthy control group, and it was increased with the severity of the disease [mild group compared with healthy control group: (30.60±6.03)% vs. (6.64±2.37)%, severe group compared with healthy control group: (33.70±5.41)% vs. (6.64±2.37)%, both P < 0.05]. There was no significant difference in respiratory rate (RR) or VT between mild group or severe group and healthy control group [RR (times/min): 31.45±4.18, 32.81±4.07 vs. 31.97±4.01, VT (mL/kg): 6.29±1.14, 5.96±0.90 vs. 6.30±1.20, all P > 0.05]. It was shown by the correlation analysis that EFL index was positively correlated with the severity of asthma (r = 0.836, P = 0.000). It was shown by ROC curve analysis that the area under ROC curve (AUC) of EFL index for predicting the severity of bronchial asthma in children was 0.801 [95% confidence interval (95%CI) = 0.725-0.878]; when the best cut-off value of EFL index was 29.21%, the sensitivity was 85.7%, the specificity was 69.2%, the positive predictive value was 75.1%, and the negative predictive value was 60.2%. CONCLUSIONS: The EFL index measured by NEP technology was closely related to the severity of bronchial asthma. The higher the EFL index, the more serious of the condition. The severity of bronchial asthma could be early judged by EFL index, which provided a basis for the evaluation and treatment of bronchial asthma.


Assuntos
Asma/diagnóstico , Expiração/fisiologia , Pressão , Asma/fisiopatologia , Criança , Humanos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Volume de Ventilação Pulmonar
6.
Crit Rev Eukaryot Gene Expr ; 27(2): 173-181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845766

RESUMO

The association between ATP-binding cassette subfamily B member 1 (ABCB1) C3435T and C1236T polymorphisms and the risk for childhood acute lymphoblastic leukemia (ALL) is inconclusive. We conducted a meta-analysis of all published studies to determine the association of ABCB1 C3435T and C1236T polymorphisms and pediatric ALL risk. A systematic retrieval of relevant publications from the PubMed and Web of Science databases was performed. Data were calculated and statistical analysis was performed using STATA version 12.0 software. Metaanalysis results showed no significant association between C3435T polymorphism and pediatric ALL risk (TT vs. CC: odds ratio [OR] = 1.20, 95% confidence interval [CI] = 0.95-1.52; CT vs. CC: OR = 1.00, 95% CI = 0.82-1.23; the dominant model: OR = 1.07, 95% CI = 0.89-1.29; the recessive model: OR = 1.17, 95% CI = 0.84-1.62). Similarly, there was no association found for the C1236T polymorphism (TT vs. CC: OR = 1.18, 95% CI= 0.82-1.70; CT vs. CC: OR = 1.08, 95% CI = 0.80-1.45; the dominant model: OR = 1.10, 95% CI= 0.83-1.46; the recessive model: OR = 0.98, 95% CI = 0.61-1.58). Similar results were observed in the subgroup analyses on ethnicity and Hardy-Weinberg equilibrium. The present meta-analysis found no evidence for ABCB1 C3435T and C1236T polymorphisms as risk factors for pediatric ALL.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
7.
J Nanosci Nanotechnol ; 15(7): 5434-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26373154

RESUMO

Novel red light-emitting nanophosphors of SrMoO4:Eu3+, Sm3+ were synthesized by a facile sol-gel method. Particles have sizes in the range of 50-80 nm. The structures, morphologies and optical properties of as-prepared products were characterized by means of X-ray diffraction (XRD), transmission electron microscope (TEM) and photo luminescent (PL). The results indicate that the red emission intensity was enhanced significantly with the increase of Sm3+ doping concentrations. When the mole fraction of Sm3+ is 2%, the emission intensity of red light is the strongest. It has been found that the incorporation of R+(Li+, Na+) into SrMoO4:Eu3+, Sm3+ phosphor could lead to a remarkable increase of photoluminescence. Thus, it is considered to be efficient red-emitting phosphors.


Assuntos
Európio/química , Luminescência , Molibdênio/química , Nanopartículas/química , Samário/química , Estrôncio/química , Medições Luminescentes
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