Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Curr Med Sci ; 39(5): 694-701, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612385

RESUMO

Long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) has been reported to be highly expressed in many kinds of cancers. This meta-analysis summarized its potential prognostic value in digestive system malignancies. A meta-analysis was performed through a comprehensive search in PubMed, EMBASE, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI) for suitable articles on the prognostic impact of UCA1 in digestive system malignancies from inception to June 27, 2019. Pooled hazard ratios (HRs) with 95% confidence interval (95%CI) were calculated to summarize the effect. Sixteen studies were included in the study, with a total of 1504 patients. A significant association was observed between UCA1 abundance and poor overall survival (OS), and shorter disease-free survival (DFS) for patients with digestive system malignancies, with pooled HR of 2.07 (95%CI: 1.74-2.47), and of 2.50 (95%CI: 1.62-3.86). Subgroup analysis and sensitivity analysis suggested the reliability of our findings. It is suggested that UCA1 abundance may serve as a reliable predictive factor for poor prognosis in patients with digestive system malignancies.

2.
World J Gastroenterol ; 25(24): 3044-3055, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31293340

RESUMO

BACKGROUND: The formation of liver fibrosis is mainly caused by the activation of hepatic stellate cells (HSCs) and the imbalance of extracellular matrix (ECM) production and degradation. The treatment of liver fibrosis mainly includes removing the cause, inhibiting the activation of HSCs, and inhibiting inflammation. NOD-like receptor (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5/NOD27/CLR16.1 (NLRC5) is a highly conserved member of the NLR family and is involved in inflammation and immune responses by regulating various signaling pathways such as nuclear factor-κB (NF-κB) signaling. It has been found that NLRC5 plays an important role in liver fibrosis, but its specific effect and possible mechanism remain to be fully elucidated. AIM: To investigate the role of NLRC5 in the activation and reversion of HSCs induced with transforming growth factor-ß (TGF-ß) and MDI, and to explore its relationship with liver fibrosis. METHODS: A total of 24 male C57BL/6 mice were randomly divided into three groups, including normal, fibrosis, and recovery groups. Twenty-four hours after a liver fibrosis and spontaneous reversion model was established, the mice were sacrificed and pathological examination of liver tissue was performed to observe the degree of liver fibrosis in each group. LX-2 cells were cultured in vitro and treated with TGF-ß1 and MDI. Real-time quantitative PCR (qPCR) and Western blot were used to analyze the expression levels of NLRC5, α-smooth muscle actin (α-SMA), and collagen type I alpha1 (Col1a1) in each group. The activity of NF-κB in each group of cells transfected with NLRC5-siRNA was detected. RESULTS: Compared with the normal mice, the expression level of NLRC5 increased significantly (P < 0.01) in the fibrosis group, but decreased significantly in the recovery group (P < 0.01). In in vitro experiments, the content of NLRC5 was enhanced after TGF-ß1 stimulation and decreased to a lower level when treated with MDI (P < 0.01). The expression of α-SMA and Col1a1 proteins and mRNAs in TGF-ß1-mediated cells was suppressed by transfection with NLRC5-siRNA (P < 0.01). Western blot analysis showed that the expression of NF-κB p65 protein and phosphorylated IκBα (p-IκBα) was increased in the liver of mice in the fibrosis group but decreased in the recovery group (P < 0.01), and the protein level of nuclear p65 and p-IκBα was significantly increased after treatment with NLRC5-siRNA (P < 0.01). CONCLUSION: NLRC5 may play a key role in the development and reversal of hepatic fibrosis through the NF-κB signaling pathway, and it is expected to be one of the clinical therapeutic targets.

3.
Invest New Drugs ; 37(6): 1300-1308, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30929157

RESUMO

Background Gastric cancer (GC) is the second most common cause of cancer-related death worldwide. Novel anticancer drugs against gastric cancer are urgently needed. Methods Compound 10 was designed and synthesized via a molecular hybridization strategy based on the natural product formononetin. It was evaluated for their antiproliferative activity against three gastric cancer cell lines (SGC7901, MKN45 and MGC803). Results Derivative 10 displayed potently antiproliferative activity with an IC50 value of 1.07 µM against SGC7901 cells. Derivative 10 could inhibit the growth and migration against gastric cancer SGC7901 cells through the Wnt/ß-Catenin and AKT/mTOR pathways. From the in vivo expremints, it could effectively inhibited SGC7901 xenograft tumor growth in vivo without significant loss of the body weight. Conclusion Derivative 10 is an novel antitumor agent with potential for further clinical applications to treat gastric cancer. Graphical abstract.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30302853

RESUMO

INTRODUCTION: Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on If current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. METHODS AND RESULTS: We investigated both the If current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the If current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the If current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V1/2 : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform If loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01). CONCLUSION: IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating If gain-of-function.

5.
Biol Chem ; 399(11): 1285-1295, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-29924724

RESUMO

The paxillin and M2 macrophage are all involved in cell proliferation and tumor progression, and this study aims to explore the interaction between them in colon cancer and the role of paxillin in cancer progression. Expression of mRNAs and proteins was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, separately. Endogenous expression of genes was modulated by recombinant plasmids and cell transfection. The levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The cell viability, invasion and migration were detected using the MTT assay, the transwell assay and the wound-healing cell migration assay, respectively. A nude mouse model for human colon cancer was constructed for tumor orthotopic expression. Paxillin was up-regulated in tumor-associated macrophages (TAMs). Paxillin was up-regulated in process of M2 macrophage polarization. M2 macrophage polarization was inhibited with paxillin suppressed. Down-regulated paxillin inhibited cell proliferation and invasion in colon cancer through suppressing M2 macrophage polarization. PI3k/Akt inhibitor repressed M2 macrophage polarization through down-regulating paxillin. PI3k/Akt inhibitor inhibited the function of the macrophage in promoting cell proliferation and invasion of colon cancer through down-regulating paxillin. Down-regulated paxillin in macrophages inhibited tumor growth of colon cancer. With the PI3K/AKT pathway inhibited, down-regulated paxillin suppressed colon cancer cell proliferation and invasion by inhibiting the M2 macrophage polarization, thereby restraining the tumor progression.

6.
Oncol Rep ; 39(6): 2595-2603, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29658590

RESUMO

Cucurbitacin D (CuD), isolated from plants from the Cucurbitaceae family, is a potential antitumour agent since it inhibits proliferation, migration and metastasis of cancer cells. Despite CuD antitumour activity in cancer cells, the effects of CuD on gastric cancer cell lines remain unclear. The present study aimed to investigate the effects of CuD on gastric cancer cell growth and death. Human gastric cancer cell lines (AGS, SNU1 and Hs746T) were cultured and treated with different concentrations of CuD (0, 0.25, 0.5, 1 and 2 µM). Cell proliferation was assessed using Cell Counting Kit­8 assay. Oxidative stress was evaluated by generation of reactive oxygen species (ROS). Cell apoptosis was assessed by terminal deoxynucleotidyl transferase 2'­deoxyuridine­5'­triphosphate nick­end labelling (TUNEL) staining. Levels of intracellular Ca2+ and adenosine triphosphate (ATP) were also assessed. In the present study, CuD effectively inhibited cell proliferation, triggered ROS generation and induced apoptosis in gastric cancer cells (AGS, SNU1 and Hs746T). Treatment with CuD increased intracellular Ca2+ and ATP levels. CuD also stimulated the expression of inducible nitric oxide synthase (iNOS), which augmented nitric oxide production. In addition, CuD activated the mitochondrial apoptosis pathway, which increased the expression of Bax and the release of cleaved caspace­9 (C­caspase­9) and cytochrome c, decreased the expression of B­cell lymphoma 2 (Bcl­2). The mechanism of action of CuD involved the regulation of the protein kinase B/mechanistic target of rapamycin (Akt/mTOR) pathway. We confirmed the effects of CuD on gastric tumours via an in vivo xenograft gastric tumour model. In conclusion, CuD inhibited Akt and activated the iNOS pathway, leading to higher ROS and nitric oxide production, which accelerated gastric cancer cell apoptosis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Triterpenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biomed Pharmacother ; 101: 257-263, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29494963

RESUMO

OBJECTIVE: To identify the molecular mechanism that modulates the killing effect of natural killer (NK) cells to colorectal cancer cells. MATERIALS AND METHODS: Expressions of miR-24 and Paxillin were detected by qRT-PCR and Western blot. Secretions of IFN-γ and TNF-α were measured by ELISA. The killing effect of NK cells was detected by CytoTox 96 non-radioactive cytotoxicity assay. Luciferase reporter assay was conducted to confirm the regulation of miR-24 on Paxillin. RESULTS: miR-24 was overexpressed in NK cells from patients with colorectal cancer than healthy volunteers. Secretions of IFN-γ and TNF-α in activated NK cells were significantly increased, indicating the enhancement of the killing effect of NK cells. Paxillin expression was overexpressed in activated NK cells. Interference of Paxillin significantly decreased Paxillin expression, secretions of IFN-γ and TNF-α, and the killing effect of NK cells to colorectal cancer cells. In addition, we confirmed that Paxillin was a direct target of miR-24, and miR-24 was negatively correlated with Paxillin. Moreover, overexpression of miR-24 inhibited secretions of IFN-γ and TNF-α, and decreased cytotoxicity by downregulating Paxillin expression. Finally, we observed that overexpression of Paxillin significantly decreased tumor volume of colorectal cancer. CONCLUSION: Overexpression of miR-24 supressed the killing effect of NK cells to colorectal cancer cells by downregulating Paxillin expression.


Assuntos
Neoplasias Colorretais/genética , Células Matadoras Naturais/metabolismo , MicroRNAs/genética , Paxilina/genética , Animais , Estudos de Casos e Controles , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/metabolismo
8.
Oncotarget ; 8(59): 99284-99295, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245901

RESUMO

Voltage-gated sodium channels beta 2 (Navß2, encoded by SCN2B) is a substrate of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and regulates cell surface expression of channels in neurons. Previous studies reported enhanced Navß2 processing by BACE1 in Alzheimer's disease (AD) model and patients. We investigated whether changes in Navß2 expression affect neuronal seizure and amyloid precursor protein (APP) processing in an AD mouse model. Our study used eight-month-old APP/presenilin 1 (PS1) mice and transgenic Navß2 knockdown [by 61% vs. wild type (WT)] APP/PS1 mice (APP/PS1/Navß2-kd), with age-matched WT and Navß2 knockdown (Navß2-kd) mice as controls. We found that Navß2 knockdown in APP/PS1 mice partially reversed the abnormal Navß2 cleavage and the changes in intracellular and total Nav1.1α expression. It also restored sodium currents density in hippocampal neurons and neuronal activity, as indicated by EEG tracing; improved Morris water maze performance; and shifted APP amyloidogenic metabolism towards non-amyloidogenic processing. There were no differences in these indicators between WT and Navß2-kd mice. These results suggest Navß2 knockdown may be a promising strategy for treating AD.

10.
Oncol Rep ; 38(4): 2123-2131, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28849234

RESUMO

Sanggenon C is a well-known, major active agent of the flavonoid derivative of benzopyrone with valuable biological properties, including anticancer, anti-inflammatory, antimicrobial, antiviral, antithrombotic, and immune-modulatory activities. In this study, we investigated the molecular mechanisms by which sanggenon C mediated the induction of cell death in colorectal cancer cells (CRC). Treatment of colorectal cancer cells (LoVo, HT-29 and SW480) with sanggenon C (0, 5, 10, 20, 40 and 80 µM) resulted in inhibited proliferation of colon cancer cells. In addition, Sanggenon C (10, 20, 40 µM) induces apoptosis of HT-29 colon cancer cells as well as the increased ROS generation. Furthermore, treatment with sanggenon C increased the level of intracellular Ca2+ and ATP, while inhibited the nitric oxide production via inhibiting inducible nitric oxide synthase expression. This resulted in the activation of mitochondrial apoptosis pathway as evidenced by the decrease in Bcl-2 protein expression. Consistently, the anti-growth and pro-apoptosis effects of sanggenon C on xenograft colon tumor were further confirmed in vivo. Collectively, our results demonstrated sanggenon C induced apoptosis of colon cancer cells by increased reactive oxygen species generation and decreased nitric oxide production, which is associated with inhibition of inducible nitric oxide synthase expression and activation of mitochondrial apoptosis pathway.


Assuntos
Benzofuranos/administração & dosagem , Cromonas/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico/genética , Animais , Apoptose/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Chin Med J (Engl) ; 130(11): 1333-1341, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28524834

RESUMO

BACKGROUND: Myocardial infarction (MI) is a major disease burden. Wild-type p53-induced phosphatase 1 (Wip1) has been studied extensively in the context of cancer and the regulation of different types of stem cells, but the role of Wip1 in cardiac adaptation to MI is unknown. We investigated the significance of Wip1 in a mouse model of MI. METHODS: The study began in June 2014 and was completed in July 2016. We compared Wip1-knockout (Wip1-KO) mice and wild-type (WT) mice to determine changes in cardiac function and survival in response to MI. The heart weight/body weight (HW/BW) ratio and cardiac function were measured before MI. Mouse MI was established by ligating the left anterior descending (LAD) coronary artery under 1.5% isoflurane anesthesia. After MI, survival of the mice was observed for 4 weeks. Cardiac function was examined by echocardiography. The HW/BW ratio was analyzed, and cardiac hypertrophy was measured by wheat germ agglutinin staining. Hematoxylin and eosin (H&E) staining was used to determine the infarct size. Gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) was assessed by quantitative real-time polymerase chain reaction (qPCR), and the levels of signal transducers and activators of transcription 3 (stat3) and phosphor-stat3 (p-stat3) were also analyzed by Western blotting. Kaplan-Meier survival analysis, log-rank test, unpaired t-test, and one-way analysis of variance (ANOVA) were used for statistical analyses. RESULTS: Wip1-KO mice had a marginally increased HW/BW ratio and slightly impaired cardiac function before LAD ligation. After MI, Wip1-deficient mice exhibited increased mortality (57.14% vs. 29.17%; n = 24 [WT], n = 35 [Wip1-KO], P< 0.05), increased cardiac hypertrophy (HW/BW ratio: 7 days: 7.25 ± 0.36 vs. 5.84 ± 0.18, n = 10, P< 0.01, and 4 weeks: 6.05 ± 0.17 vs. 5.87 ± 0.24, n = 10, P > 0.05; cross-sectional area: 7 days: 311.80 ± 8.29 vs. 268.90 ± 11.15, n = 6, P< 0.05, and 4 weeks: 308.80 ± 11.26 vs. 317.00 ± 13.55, n = 6, P > 0.05), and reduced cardiac function (ejection fraction: 7 days: 29.37 ± 1.38 vs. 34.72 ± 1.81, P< 0.05, and 4 weeks: 19.06 ± 2.07 vs. 26.37 ± 2.95, P< 0.05; fractional shortening: 7 days: 13.72 ± 0.71 vs. 16.50 ± 0.94, P< 0.05, and 4 weeks: 8.79 ± 1.00 vs. 12.48 ± 1.48, P< 0.05; n = 10 [WT], n = 15 [Wip1-KO]). H&E staining revealed a larger infarct size in Wip1-KO mice than in WT mice (34.79% ± 2.44% vs. 19.55% ± 1.48%, n = 6, P< 0.01). The expression of IL-6 and p-stat3 was downregulated in Wip1-KO mice (IL-6: 1.71 ± 0.27 vs. 4.46 ± 0.79, n = 6, P< 0.01; and p-stat3/stat3: 1.15 ± 0.15 vs. 1.97 ± 0.23, n = 6, P< 0.05). CONCLUSION: The results suggest that Wip1 could protect the heart from MI-induced ischemic injury.


Assuntos
Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Proteína Fosfatase 2C/metabolismo , Animais , Ecocardiografia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Knockout , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Proteína Fosfatase 2C/deficiência , Proteína Fosfatase 2C/genética , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo , Remodelação Ventricular
12.
Biosens Bioelectron ; 81: 460-464, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27015149

RESUMO

A novel fluorescence turn-on strategy for the alkaline phosphatase (ALP) assay is developed based on the preferential binding of graphene oxide (GO) to single-stranded DNA (ssDNA) over double-stranded DNA (dsDNA) coupled with λ exonuclease (λ exo) cleavage. Specifically, in the absence of ALP, the substrate-dsDNA constructed by one oligonucleotide with a fluorophore at the 3'-end (F-DNA) and its complementary sequence modified with a 5'-phosphoryl termini (p-DNA), is promptly cleaved by λ exo, and the resulting F-DNA is adsorbed on GO surface, allowing fluorescence quenching. Whereas the introduction of ALP leads to the hydrolysis of the P-DNA, and the yielding 5'-hydroxyl end product hampers the λ exo cleavage, inducing significant fluorescence enhancement due to the weak binding of dsDNA with GO. Under the optimized conditions, the approach exhibits high sensitivity and specificity to ALP with a detection limit of 0.19 U/L, and the determination of ALP in spiked human serum samples has also been realized. Notably, this new approach not only provides a novel and sensitive platform for the ALP activity detection but also promotes the exploitation of the GO-based biosensing for the detection of the protein with no specific binding element, and thus extending the GO-based sensing applications into a new field.


Assuntos
Fosfatase Alcalina/sangue , Técnicas Biossensoriais/métodos , Ensaios Enzimáticos/métodos , Fosfatase Alcalina/metabolismo , DNA/metabolismo , DNA de Cadeia Simples/metabolismo , Exonucleases/metabolismo , Grafite/metabolismo , Humanos , Limite de Detecção , Óxidos/metabolismo , Espectrometria de Fluorescência/métodos
13.
Mol Neurobiol ; 53(2): 955-67, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25575679

RESUMO

The role of sodium channel voltage-gated beta 2 (SCN2B) in brain aging is largely unknown. The present study was therefore designed to determine the role of SCN2B in brain aging by using the senescence-accelerated mice prone 8 (SAMP8), a brain senescence-accelerated animal model, together with the SCN2B transgenic mice. The results showed that SAMP8 exhibited impaired learning and memory functions, assessed by the Morris water maze test, as early as 8 months of age. The messenger RNA (mRNA) and protein expressions of SCN2B were also upregulated in the prefrontal cortex at this age. Treatment with traditional Chinese anti-aging medicine Xueshuangtong (Panax notoginseng saponins, PNS) significantly reversed the SCN2B expressions in the prefrontal cortex, resulting in improved learning and memory. Moreover, SCN2B knockdown transgenic mice were generated and bred to determine the roles of SCN2B in brain senescence. A reduction in the SCN2B level by 60.68% resulted in improvement in the hippocampus-dependent spatial recognition memory and long-term potential (LTP) slope of field excitatory postsynaptic potential (fEPSP), followed by an upregulation of COX5A mRNA levels and downregulation of fibroblast growth factor-2 (FGF-2) mRNA expression. Together, the present findings indicated that SCN2B could play an important role in the aging-related cognitive deterioration, which is associated with the regulations of COX5A and FGF-2. These findings could provide the potential strategy of candidate target to develop antisenescence drugs for the treatment of brain aging.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Plasticidade Neuronal , Subunidade beta-2 do Canal de Sódio Disparado por Voltagem/metabolismo , Animais , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Masculino , Aprendizagem em Labirinto , Memória , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais
14.
Dis Model Mech ; 8(8): 795-804, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26092120

RESUMO

Cardiac hypertrophy is associated with many forms of heart disease, and identifying important modifier genes involved in the pathogenesis of cardiac hypertrophy could lead to the development of new therapeutic strategies. Tomoregulin-1 is a growth factor that is primarily involved in embryonic development and adult central nervous system (CNS) function, and it is expressed abnormally in a variety of CNS pathologies. Tomoregulin-1 is also expressed in the myocardium. However, the effects of tomoregulin-1 on the heart, particularly on cardiac hypertrophy, remains unknown. The aim of the study is to examine whether and by what mechanism tomoregulin-1 regulates the development of cardiac hypertrophy induced by pressure overload. In this study, we found that tomoregulin-1 was significantly upregulated in two cardiac hypertrophy models: cTnT(R92Q) transgenic mice and thoracic aorta constriction (TAC)-induced cardiac hypertrophy mice. The transgenic overexpression of tomoregulin-1 increased the survival rate, improved the cardiac geometry and functional parameters of echocardiography, and decreased the degree of cardiac hypertrophy of the TAC mice, whereas knockdown of tomoregulin-1 expression resulted in an opposite phenotype and exacerbated phenotypes of cardiac hypertrophy induced by TAC. A possible mechanism by which tomoregulin-1 regulates the development of cardiac hypertrophy in TAC-induced cardiac hypertrophy is through inhibiting TGFß non-canonical (TAK1-JNK) pathways in the myocardium. Tomoregulin-1 plays a protective role in the modulation of adverse cardiac remodeling from pressure overload in mice. Tomoregulin-1 could be a therapeutic target to control the development of cardiac hypertrophy.


Assuntos
Cardiomegalia/enzimologia , Cardiomegalia/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Pressão , Animais , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Técnicas de Silenciamento de Genes , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Especificidade de Órgãos , Análise de Sobrevida , Fator de Crescimento Transformador beta/metabolismo , Ultrassonografia
15.
World J Surg Oncol ; 13: 111, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25888731

RESUMO

BACKGROUND: The purpose of this study is to investigate whether (18)F-fluorodeoxyglucose (FDG) micro-positron emission tomography-computed tomography (microPET-CT) can be used to monitor a metabolic response to gefitinib in nude mouse tumor xenografts. METHODS: Sixteen nude mice were implanted with human A431 epidermoid carcinoma cells and ten with human A549 lung adenocarcinoma cells, and the tumors were allowed to grow to an approximate size of 150 mm(3). Ten and five of these mice, respectively, received intragastric gefitinib (100 mg/kg) once daily for 14 days, whereas six and five, respectively, received sterile water. Tumor metabolic activity was assessed by (18)F-FDG microPET imaging before treatment (day 0) and on days 2, 7, and 14. Tumor uptake of (18)F-FDG was determined from a region-of-interest drawn around the tumor, and the maximum percentage injected dose per gram (%ID/gmax) was calculated. Tumor volume measured on day 14 by microCT was used to categorize tumors as sensitive, stable, or resistant to gefitinib, and pathologic changes in these tumors were analyzed. RESULTS: On day 2, the average changes in (18)F-FDG uptake by A431 tumors sensitive, stable, and resistant to gefitinib were -30.92% ± 6.66%, -5.68% ± 6.95%, and 7.72% ± 3.85%, respectively (P < 0.05 each), with no significant differences in the sizes of tumors sensitive and stable to gefitinib (P = 0.169). On day 7, sensitive tumors were significantly smaller than stable tumors (P = 0.034). On day 14, areas of necrosis were observed in gefitinib-sensitive tumors, with tumor necrosis ratios differing significantly among the sensitive, stable, and control groups (P < 0.05 each). In mice implanted with A549 cells, however, tumor (18)F-FDG uptake, volume, and percent necrosis did not differ significantly between gefitinib-treated and untreated mice on days 0, 2, 7, and 14 (P > 0.05 each). CONCLUSIONS: F-FDG uptake is a sensitive method of detecting metabolic changes in tumors associated with therapy in vivo.


Assuntos
Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares/patologia , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/tratamento farmacológico , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Curva ROC , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Exp Biol Med (Maywood) ; 239(3): 320-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24535836

RESUMO

Transforming growth factor ß1 (TGF-ß1) is a multi-functional cytokine implicated in many aspects of mammalian wound healing and scar tissue formation. However, few experiments have so far addressed the potential biological effects of TGF-ß1 in the nervous system after injury, in addition to the immune system. In the present study, expressional silencing TGF-ß1 was achieved by selecting predesigning hairpins targeting mouse TGF-ß1 genes. Four homozygous transgenic offspring were generated and designed as Founder 90, Founder 12, Founder 41 and Founder 46. The down-regulated rates of TGF-ß1 in different transgenic mice were also determined. To investigate the potential roles of TGF-ß1, we observed changes in the neurological behavior of TGF-ß1-knockdown (TGF-ß1-kd) mice after spinal cord transection (SCT). Moreover, mRNA levels of inflammatory cytokines, including IL-1, IL-6, IL-10, NF-κB and TNF, were also detected in nucleate cells from blood by real-time PCR. Consequently, different TGF-ß1 expressions were detected in multiple tissues, and protein levels of TGF-ß1 decreased at different rates relative to that of wild type (WT) ones. The levels of TGF-ß1 proteins in TGF-ß1-kd mice decreased at most by 57% in Founder 90, which showed a significant recovery in Basso, Beattie, Bresnahan (BBB) scores after SCT compared with that of WT. However, expressions of immune relative genes showed no dramatic difference compared with WT ones. This study is the first to generate TGF-ß1 down regulated mice and determine the possible roles of TGF-ß1 in vivo in different conditions.


Assuntos
Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização/genética , Animais , Genótipo , Inflamação/genética , Interleucina-1/genética , Interleucina-10/genética , Interleucina-6/genética , Camundongos , Camundongos Knockout , NF-kappa B/genética , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Medula Espinal/cirurgia , Cicatrização/fisiologia
17.
BMC Biochem ; 14: 21, 2013 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-23914775

RESUMO

BACKGROUND: Transforming growth factor-betas (TGF-ßs), including beta2 (TGF-ß2), constitute a superfamily of multifunctional cytokines with important implications in morphogenesis, cell differentiation and tissue remodeling. TGF-ß2 is thought to play important roles in multiple developmental processes and neuron survival. However, before we carried out these investigations, a TGF-ß2 gene down-regulated transgenic animal model was needed. In the present study, expressional silencing TGF-ß2 was achieved by select predesigning interference short hairpin RNAs (shRNAs) targeting mouse TGF-ß2 genes. RESULTS: Four homozygous transgenic offspring were generated by genetic manipulation and the protein expressions of TGF-ß2 were detected in different tissues of these mice. The transgenic mice were designated as Founder 66, Founder 16, Founder 53 and Founder 41. The rates of TGF-ß2 down-expression in different transgenic mice were evaluated. The present study showed that different TGF-ß2 expressions were detected in multiple tissues and protein levels of TGF-ß2 decreased at different rates relative to that of wild type mice. The expressions of TGF-ß2 proteins in transgenic mice (Founder 66) reduced most by 52%. CONCLUSIONS: The present study generated transgenic mice with TGF-ß2 down-regulated, which established mice model for systemic exploring the possible roles of TGF-ß2 in vivo in different pathology conditions.


Assuntos
Fator de Crescimento Transformador beta2/metabolismo , Animais , Regulação da Expressão Gênica , Genótipo , Homozigoto , Camundongos , Camundongos Transgênicos , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética
18.
Virol J ; 10: 215, 2013 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-23809248

RESUMO

BACKGROUND: Enterovirus 71 (EV71) infections are associated with a high prevalence of hand, foot and mouth disease (HFMD) in children and occasionally cause lethal complications. Most infections are self-limiting. However, resulting complications, including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, and neurological pulmonary edema or hemorrhage, are responsible for the lethal symptoms of EV71 infection, the pathogenesis of which remain to be clarified. RESULTS: In the present study, 2-week-old Institute of Cancer Research (ICR) mice were infected with a mouse-adapted EV71 strain. These infected mice demonstrated progressive paralysis and died within 12 days post infection (d.p.i.). EV71, which mainly replicates in skeletal muscle tissues, caused severe necrotizing myositis. Lesions in the central nervous system (CNS) and other tissues were not observed. CONCLUSIONS: Necrotizing myositis of respiratory-related muscles caused severe restrictive hypoventilation and subsequent hypoxia, which could explain the fatality of EV71-infected mice. This finding suggests that, in addition to CNS injury, necrotic myositis may also be responsible for the paralysis and death observed in EV71-infected mice.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/patologia , Interações Hospedeiro-Patógeno , Hipoventilação , Miosite/patologia , Miosite/virologia , Animais , Morte , Modelos Animais de Doenças , Infecções por Enterovirus/complicações , Infecções por Enterovirus/virologia , Hipóxia , Camundongos Endogâmicos ICR , Miosite/complicações , Paralisia
19.
World J Gastroenterol ; 19(15): 2419-24, 2013 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-23613638

RESUMO

AIM: To determine the effects of gastric juice on the development of esophageal adenocarcinoma (EAC). METHODS: A animal model of duodenogastroesophageal reflux was established in Sprague-Dawley rats undergoing esophagoduodenostomy. The development of EAC and forestomach adenocarcinoma was investigated 40 wk after the treatment. Intraluminal pH and bile of the forestomach were measured. RESULTS: There were no significant differences in pH (t = 0.117, P = 0.925) or bile (χ² = 0.036, P = 0.85) in the forestomach before and 40 wk after esophagoduodenostomy. There were also no significant differences between the model and controls during esophagoduodenostomy or 40 wk after esophagoduodenostomy. The incidence of intestinal metaplasia (88%) and intestinal metaplasia with dysplasia and adenocarcinoma (28%) in the esophagus in the model was higher than in the controls 40 wk after surgery (χ² = 43.06, P < 0.001 and χ² = 9.33, P = 0.002, respectively) and in the forestomach in the model (χ² = 32.05, P < 0.001 and χ² = 8.14, P = 0.004, respectively). The incidence rates of inflammation in the esophagus and forestomach were 100% and 96%, respectively (χ² = 1.02, P = 0.31) in the model, which was higher than in the esophageal control (6.8%) (χ² = 42.70, P < 0.001). CONCLUSION: Gastric juice exposure may not cause intestinal metaplasia with dysplasia or adenocarcinoma of the forestomach and may not be related to EAC.


Assuntos
Adenocarcinoma/etiologia , Neoplasias Esofágicas/etiologia , Suco Gástrico/metabolismo , Adenocarcinoma/patologia , Animais , Esôfago de Barrett/etiologia , Esôfago de Barrett/patologia , Bile/metabolismo , Modelos Animais de Doenças , Neoplasias Esofágicas/patologia , Esôfago/cirurgia , Feminino , Refluxo Gastroesofágico , Concentração de Íons de Hidrogênio , Inflamação , Intestinos/patologia , Masculino , Metaplasia , Ratos , Ratos Sprague-Dawley , Estômago/patologia , Fatores de Tempo
20.
Int J Mol Sci ; 14(3): 5576-86, 2013 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-23478434

RESUMO

The Amyloid-ß (Aß)-induced impairment of hippocampal synaptic plasticity is an underlying mechanism of memory loss in the early stages of Alzheimer's disease (AD) in human and mouse models. The inhibition of the calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation plays an important role in long-term memory. In this study, we isolated naringin from Pomelo peel (a Citrus species) and studied its effect on long-term memory in the APPswe/PS1dE9 transgenic mouse model of AD. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two naringin (either 50 or 100 mg/kg body weight/day) groups, or an Aricept (2 mg/kg body weight/day) group. After 16 weeks of treatment, we observed that treatment with naringin (100 mg/kg body weight/day) enhanced the autophosphorylation of CaMKII, increased the phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor at a CaMKII-dependent site and improved long-term learning and memory ability. These findings suggest that the increase in CaMKII activity may be one of the mechanisms by which naringin improves long-term cognitive function in the APPswe/PS1dE9 transgenic mouse model of AD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA