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1.
Korean J Radiol ; 21(6): 670-683, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32410406

RESUMO

OBJECTIVE: The presence of coagulative necrosis (CN) in clear cell renal cell carcinoma (ccRCC) indicates a poor prognosis, while the absence of CN indicates a good prognosis. The purpose of this study was to build and validate a radiomics signature based on preoperative CT imaging data to estimate CN status in ccRCC. MATERIALS AND METHODS: Altogether, 105 patients with pathologically confirmed ccRCC were retrospectively enrolled in this study and then divided into training (n = 72) and validation (n = 33) sets. Thereafter, 385 radiomics features were extracted from the three-dimensional volumes of interest of each tumor, and 10 traditional features were assessed by two experienced radiologists using triple-phase CT-enhanced images. A multivariate logistic regression algorithm was used to build the radiomics score and traditional predictors in the training set, and their performance was assessed and then tested in the validation set. The radiomics signature to distinguish CN status was then developed by incorporating the radiomics score and the selected traditional predictors. The receiver operating characteristic (ROC) curve was plotted to evaluate the predictive performance. RESULTS: The area under the ROC curve (AUC) of the radiomics score, which consisted of 7 radiomics features, was 0.855 in the training set and 0.885 in the validation set. The AUC of the traditional predictor, which consisted of 2 traditional features, was 0.843 in the training set and 0.858 in the validation set. The radiomics signature showed the best performance with an AUC of 0.942 in the training set, which was then confirmed with an AUC of 0.969 in the validation set. CONCLUSION: The CT-based radiomics signature that incorporated radiomics and traditional features has the potential to be used as a non-invasive tool for preoperative prediction of CN in ccRCC.

2.
Environ Monit Assess ; 191(11): 704, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673801

RESUMO

In light of ongoing changes in how humans interact with the environment, it is of great importance to quantitatively assess the impact of land use and cover change (LUCC) on ecosystems. Using a variety of methods, we analyzed land-use patterns and ecosystem service values (ESV) in 1990, 2000, and 2010; normalized difference vegetation index (NDVI) from 1982 to 2010 in the arid region of Northwest China; and quantitatively assessed the effects of LUCC on changes in NDVI and ESV. The results indicate the following: (1) From 1990 to 2010, the rate of increase in the amount of cropland and urban land was highest at 19.13% and 18.25%, respectively, followed by the rate for water cover (5.10%) and forest land (3.55%), while grassland experienced a reduction of 2.25%. (2) From 1990 to 2010, the total ESV increased by 1.82%. Changes in the amount of water cover and cropland were responsible for an increase in ESV of 1.42% and 1.10%, respectively, while the change in the amount of grassland was responsible for a decrease of 1.09%. Based on this, it seems likely that climate variability is a substantial cause of change in ESV. (3) From 1982 to 2010, NDVI showed an overall increase, first increasing significantly between 1982 and 2002 and then decreasing somewhat from 2002 to 2010. From 1990 to 2010, the contribution rate of LUCC to change in total NDVI was 26.74%, indicating that the contribution rate of climate variability to NDVI change was up to 73.26%. Therefore, over those 20 years, climate warming and humidification had an important impact on the development of ecosystems in the arid region of Northwest China.


Assuntos
Conservação dos Recursos Naturais/tendências , Produtos Agrícolas/crescimento & desenvolvimento , Monitoramento Ambiental/métodos , Poaceae/crescimento & desenvolvimento , Urbanização/tendências , China , Mudança Climática , Ecossistema , Florestas , Humanos
3.
Cell Tissue Bank ; 20(4): 557-568, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31583486

RESUMO

The purpose of this paper is to analyze the properties of porcine cartilage type II collagen scaffolds crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy-succinamide (EDC/NHS) under different conditions. The porous EDC/NHS-crosslinked scaffolds were obtained through a two-step freeze-drying process. To determine the optimal crosslinking condition, we used different solvents and various crosslinking temperatures to prepare the scaffolds. Three crosslinking solutions were prepared with different solvents, photographs were taken with a flash in the darkroom, and light transmission was observed. Type II collagen was crosslinked on a horizontal shaker at a speed of 60 r/min according to the above grouping conditions, and then the structural change of the scaffold in each group was observed. To investigate the swelling ratio and the in vitro degradation of the collagen scaffold, tests were also carried out by immersion of the scaffolds in a PBS solution and digestion in type II collagenase, respectively. The influence of the scaffolds on the proliferation of chondrocytes was assessed by the methyl thiazolyl tetrazolium colorimetric assay. The morphology of the crosslinked scaffolds cocultured with chondrocytes was characterized by a scanning electron microscope. The results proved that 75% alcohol and a crosslinking temperature of 37 °C are recommended. Collagen fibrils are more densely packed after crosslinking with EDC/NHS and have a more uniform structure than that of noncrosslinked ones. The EDC-crosslinked scaffolds possessed excellent mechanical property and biocompatibility.

4.
Colloids Surf B Biointerfaces ; 183: 110445, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31446324

RESUMO

Thermoset polymers synthesized from the polycondensation of glycerol with biocompatible diacids represent a promising class of absorbable materials for biomedical applications. However, the utility of these polymers for bone fixation devices is hampered due to the lack of mechanical strength. Herein we synthesized a high-strength thermoset polymer, poly(glycerol-succinate) (PGS), via a catalyst-free and solvent-free reaction. The bending strength of PGS reaches 122.01 ±â€¯8.82 MPa, signifying its great potential for fixation devices. The degradation property of the polymer can be tuned by adjusting the monomer ratio and reaction time. Bone screws based on the PGS polymer were successfully manufactured using a lathe. In vitro evaluation showed the PGS polymer was able to well support cell adhesion and proliferation. In vivo evaluation using a rat subcutaneous implantation model showed that the inflammatory response to the polymer was mild. After the PGS screws were implanted in the rabbit femoral condyle for 12 weeks, micro-computed tomography (micro-CT) and histological analysis revealed that the screws achieved good osseointegration. Consequently, the polymer developed in current study can serve as internal fixation devices due to the proper mechanical strength, excellent biocompatibility, and feasibility of manufacturing screws.

5.
Sci Total Environ ; 693: 133538, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31362222

RESUMO

To investigate the occurrence, gas-particle partitioning, and potential sources of polybrominated diphenyl ethers (PBDEs) in the atmosphere over the Yangtze River Estuary, gas and particle samples were collected at the remote Huaniao Island, East China Sea, during a whole year from 2013 to 2014. Nine PBDEs, with total atmospheric concentration of Σ9BDEs of 20.3 ±â€¯26.5 pg/m3, were found in both the gas and particle phases in most samples. BDE-209 dominated both the gas and particle phases, which is consistent with the PBDE usage record in China. Seasonal variation of particle-phase Σ9BDEs was observed, with the highest concentration in winter and the lowest in summer; however, a reversed seasonal trend was observed in the gas phase. Correlation analysis between log Kp and log KOA suggested that the gas-particle (G/P) partitioning was in a non-equilibrium state, particularly for BDE-209 throughout the year. The KOA-based adsorption model prediction performed relatively well for the particle-phase fraction of Br<10-BDEs, but largely overestimated BDE-209. A steady-state model could be superior to predict G/P partitioning of BDE-209 based on annual values, though with the exception of summer samples. A relatively higher gas-phase distribution for BDE-209 than high-brominated BDEs was observed, especially in summer, when it reached 73%, implying a sustained input of gas-phase BDE-209. The potential source contribution function showed that the possible source regions for BDE-209 included Shandong and Jiangsu Provinces (the main BDE-209 production regions in China), the Yangtze River Delta region, and the southeastern coastal areas (which hosts intensive electronic waste recycling activities).

6.
Cancer Imaging ; 19(1): 34, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174617

RESUMO

OBJECTIVE: To identify imaging markers that reflect the epidermal growth factor receptor (EGFR) mutation status by comparing computed tomography (CT) imaging-based histogram features between bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma. MATERIALS AND METHODS: This retrospective study included 57 patients, with pathologically confirmed bone metastasis of primary lung adenocarcinoma. EGFR mutation status of bone metastases was confirmed by gene detection. The CT imaging of the metastatic bone lesions which were obtained between June 2014 and December 2017 were collected and analyzed. A total of 42 CT imaging-based histogram features were automatically extracted. Feature selection was conducted using Student's t-test, Mann-Whitney U test, single-factor logistic regression analysis and Spearman correlation analysis. A receiver operating characteristic (ROC) curve was plotted to compare the effectiveness of features in distinguishing between EGFR(+) and EGFR(-) groups. DeLong's test was used to analyze the differences between the area under the curve (AUC) values. RESULTS: Three histogram features, namely range, skewness, and quantile 0.975 were significantly associated with EGFR mutation status. After combining these three features and combining range and skewness, we obtained the same AUC values, sensitivity and specificity. Meanwhile, the highest AUC value was achieved (AUC 0.783), which also had a higher sensitivity (0.708) and specificity (0.788). The differences between AUC values of the three features and their various combinations were statistically insignificant. CONCLUSION: CT imaging-based histogram features of bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma were identified, and they may contribute to diagnosis and prediction of EGFR mutation status.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Mutação , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
7.
Medicine (Baltimore) ; 98(14): e15022, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946334

RESUMO

BACKGROUND: To explore whether radiomics combined with computed tomography (CT) images can be used to establish a model for differentiating high grade (International Society of Urological Pathology [ISUP] grade III-IV) from low-grade (ISUP I-II) clear cell renal cell carcinoma (ccRCC). METHODS: For this retrospective study, 3-phase contrast-enhanced CT images were collected from 227 patients with pathologically confirmed ISUP-grade ccRCC (155 cases in the low-grade group and 72 cases in the high-grade group). First, we delineated the largest dimension of the tumor in the corticomedullary and nephrographic CT images to obtain the region of interest. Second, variance selection, single variable selection, and the least absolute shrinkage and selection operator were used to select features in the corticomedullary phase, nephrographic phase, and 2-phase union samples, respectively. Finally, a model was constructed using the optimal features, and the receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the predictive performance of the features in the training and validation queues. A Z test was employed to compare the differences in AUC values. RESULTS: The support vector machine (SVM) model constructed using the screening features for the 2-stage joint samples can effectively distinguish between high- and low-grade ccRCC, and obtained the highest prediction accuracy. Its AUC values in the training queue and the validation queue were 0.88 and 0.91, respectively. The results of the Z test showed that the differences between the 3 groups were not statistically significant. CONCLUSION: The SVM model constructed by CT-based radiomic features can effectively identify the ISUP grades of ccRCC.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Gradação de Tumores/métodos , Máquina de Vetores de Suporte/estatística & dados numéricos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Área Sob a Curva , Carcinoma de Células Renais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos
8.
J Pain Res ; 12: 879-890, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881098

RESUMO

Background: Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is one of the essential signaling pathways for the development and maintenance of neuropathic pain. Objective: To investigate the effect of resveratrol (RES) on paclitaxel-induced neuropathic pain in rats and elucidate the underlying molecular mechanisms. Method: Male Sprague Dawley rats were randomly divided into seven groups (n=10/group): Group C, Group P, Group R, Group R+P, Group LY + R+P, Group LY (the specific inhibitor of PI3K), Group E (the specific inhibitor of sirtuin 1 [SIRT1]). Paw withdrawal mechanical threshold (PWT) and thermal withdrawal latency (TWL) were recorded. Mitochondrial histomorphology was performed by transmission electron microscope. PI3K, p-Akt, and t-Akt expressions were tested using immunohistochemistry. Western blot was used to detect p-Akt, t-Akt, SIRT1, and PGC1α expressions. The apoptosis in the striatum, spinal dorsal horns (SDH), and dorsal root ganglions (DRG) tissues was assayed by TUNEL. ELISA was used to detect the contents of IL-ß, IL-10, malondialdehyde (MDA), and superoxide dismutase (SOD) in striatum, SDH, and DRG tissues. Results: Compared to the control group, PWT and TWL in the P and LY +R+P groups were significantly decreased on 8th and 14th day after paclitaxel administration (P<0.05). The expressions of p-Akt, SIRT1, and PGC1α were decreased in paclitaxel-induced neuropathic rats; however, the expressions of p-Akt, SIRT1, and PGC1α were significantly increased after RES treatment (P<0.05). Furthermore, the expression of p-Akt was decreased by LY294002 (P<0.05), and amount of SIRT1 and PGC1α expression was inhibited by EX-527 (P<0.05). The t-Akt level was not significantly changed in all groups. RES prevented paclitaxel-induced mitochondrial damage by PI3K/Akt. RES improves the pain symptoms of paclitaxel neuralgia rats by increasing the IL-10 and decreasing the expression of IL-1ß. RES increases the SOD and reduces the MDA. RES reduces apoptosis by SIRT1/PGC1α signal pathway. Conclusion: Our results suggest that RES may inhibit paclitaxel-induced neuropathic pain via PI3K/Akt and SIRT1/PGC1α pathways.

9.
Food Chem ; 285: 296-304, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30797348

RESUMO

Dried egg white powders are used in many segments of the food industry in place of traditional liquid egg materials. Dry heating during the processing of these products plays an essential role in obtaining their excellent functionalities, which are associated with protein aggregation. The objective of this study was to understand the aggregation behaviour of ovalbumin (OVA), the major component of egg-white proteins, during dry heating at 75 °C for 21 days. The results indicated that OVA aggregation increased from 28.7 ±â€¯1.23% to 57.5 ±â€¯2.45% as the reaction time increased, resulting in the generation of insoluble aggregates that were often 1-100 nm in diameter. However, a few soluble OVA aggregates became insoluble precipitates as their morphology changed from long strands to denser networks after 15 days of heat treatment. Moreover, covalent bonds, hydrophobic interactions and electrostatic repulsion played important roles in the formation of the small aggregates.


Assuntos
Ovalbumina/química , Calefação , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Eletricidade Estática
10.
J Cell Biochem ; 120(3): 3401-3414, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30368870

RESUMO

Ligamentum flavum (LF)-derived mesenchymal stem cells (MSCs) have been implicated in the pathogenesis of calcification of the ligamentum flavum (CLF) leading to the increased presence of chondrocyte-like cells and calcium deposition in CLF; however, the mechanisms of LF-MSCs in differentiation are not defined. In this study, we investigated the role of antidifferentiation noncoding RNA (ANCR) in the differentiation of LF-MSCs. We found that ANCR was downregulated in human CLF tissues. In cultured LF-MSCs, ANCR downregulation led to decreased cell proliferation but enhanced chondrogenic differentiation and calcification. In contract, ANCR overexpression increased cell proliferation but inhibited differentiation and calcification. Mechanistically, we detected a positive correlation between ANCR and enhancer of zeste homolog 2 (EZH2) in human CLF tissues. In cultured LF-MSCs, ANCR knockdown decreased while ANCR overexpression increased EZH2 expression. In addition, physical association between ANCR and EZH2 was revealed by an RNA pull-down assay. Functionally, EZH2 overexpression prevented chondrogenic differentiation and calcification enhanced by ANCR knockdown. These findings indicated that ANCR upregulates EZH2 expression and physically binds to EZH2 in LF-MSCs to suppress chondrogenic differentiation and calcification. Therefore, downregulated ANCR contributes to increasing of chondrocyte-like cells and calcium deposition in CLF. ANCR may serve as a therapeutic target for CLF.

11.
EBioMedicine ; 40: 210-223, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30587459

RESUMO

BACKGROUND: Osteosarcoma (OS) is a malignant tumor mainly occurring in young people. Due to the limited effective therapeutic strategies, OS patients cannot achieve further survival improvement. G-protein-coupled receptors (GPCRs) constitute the largest family of cell membrane receptors and consequently hold the significant promise for tumor imaging and targeted therapy. We aimed to explore the biological functions of Sphingosine 1-phosphate receptor 3 (S1PR3), one of the members of GPCRs family, in OS and the possibility of S1PR3 as an effective target for the treatment of osteosarcoma. METHODS: The quantitative real time PCR (qRT-PCR) and western blotting were used to analyze the mRNA and protein expressions. Cell counting kit-8 (CCK8), colony formation assay and cell apoptosis assay were performed to test the cellular proliferation in vitro. Subcutaneous xenograft mouse model was generated to evaluate the functions of S1PR3 in vivo. RNA sequencing was used to compare gene expression patterns between S1PR3-knockdown and control MNNG-HOS cells. In addition, metabolic alternations in OS cells were monitored by XF96 metabolic flux analyzer. Co-immunoprecipitation (Co-IP) assay was used to explore the interaction between Yes-associated protein (YAP) and c-MYC. Chromatin immunoprecipitation was used to investigate the binding capability of PGAM1 and YAP or c-MYC. Moreover, the activities of promoter were determined by the luciferase reporter assay. FINDINGS: S1PR3 and its specific ligand Sphingosine 1-phosphate (S1P) were found elevated in OS, and the higher expression of S1PR3 was correlated with the poor survival rate. Moreover, our study has proved that the S1P/S1PR3 axis play roles in proliferation promotion, apoptosis inhibition, and aerobic glycolysis promotion of osteosarcoma cells. Mechanistically, the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted the nuclear translocation of YAP, which contributed to the formation of the YAP-c-MYC complex and enhanced transcription of the important glycolysis enzyme PGAM1. Moreover, the S1PR3 antagonist TY52156 exhibited in vitro and in vivo synergistic inhibitory effects with methotrexate on OS cell growth. INTERPRETATION: Our study unveiled a role of S1P, a bioactive phospholipid, in glucose metabolism reprogram through interaction with its receptor S1PR3. Targeting S1P/S1PR3 axis might serve as a potential therapeutic target for patients with OS. FUND: This research was supported by National Natural Science Foundation of China (81472445 and 81672587).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Ósseas/metabolismo , Lisofosfolipídeos/metabolismo , Osteossarcoma/metabolismo , Fosfoglicerato Mutase/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Animais , Apoptose/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicólise , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Complexos Multiproteicos/metabolismo , Osteossarcoma/genética , Osteossarcoma/patologia , Fosforilação Oxidativa , Ligação Proteica , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais , Esfingosina/metabolismo , Fatores de Transcrição
12.
Medicine (Baltimore) ; 97(47): e13263, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30461632

RESUMO

BACKGROUND: The genetic factor is importantly enrolled in the pathogenesis of ankylosing spondylitis (AS) and haplotype leukocyte antigen (HLA)-B27 is the most well-known. However, only 1% to 5% of B27-positive individuals will develop AS, and it confers only 20% to 30% of the overall genetic risks, indicating more genes other than HLA-B27 may play important roles in AS pathologies. The present study aims to investigate whether the polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) is associated with increased risk of AS susceptibility. METHODS: The Cochrane library, Pubmed, and Embase databases were carefully searched for potential researches published before May 30, 2018. The title, abstract, and full text were assessed to determine whether the paper was suitable for inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were presented to assess the associations between ERAP1 polymorphisms and AS susceptibility. RESULTS: The study finally enrolled 10 papers, 4 matched single nucleotide polymorphisms (SNPs) of ERAP1 (rs27044, rs27434, rs30187, and rs27037), and a total of 30552 patients (12492 with AS and 18060 for control). No significant difference was found between the AS susceptibility and polymorphisms of rs27044 and rs27434. However, there was a significant association between ERAP1 polymorphisms rs30187 and rs27037 (T vs C, OR, 1.322, 95% CI = 1.240-10410, P <.05; T vs G, OR, 1.247, 95% CI = 1.149-1.353; P <.05; respectively) and AS susceptibility. CONCLUSION: There was a significant association between ERAP1 polymorphisms (rs30187 and rs27037) and increased risk of AS susceptibility.


Assuntos
Aminopeptidases/genética , Antígenos de Histocompatibilidade Menor/genética , Espondilite Anquilosante , Extremo Oriente/epidemiologia , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/genética
13.
Cell Physiol Biochem ; 50(4): 1510-1521, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30359987

RESUMO

BACKGROUND/AIMS: Periodic mechanical stress has been shown to promote extracellular matrix (ECM) synthesis and cell migration of nucleus pulposus (NP) cells, however, the mechanisms need to be fully elucidated. The present study aimed to investigate the signal transduction pathway in the regulation of NP cells under periodic mechanical stress. METHODS: Primary rat NP cells were isolated and seeded on glass slides, and then treated in our self-developed periodic stress field culture system. To further explore the mechanisms, data were analyzed by scratch-healing assay, quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis, western blotting, and co-immunoprecipitation assay. RESULTS: Under periodic mechanical stress, the mRNA expression of ECM collagen 2A1 (Col2A1) and aggrecan, and migration of NP cells were significantly increased (P < 0.05 for each), associating with increases in the phosphorylation of Src, GIT1, and ERK1/2 (P < 0.05 for each). Pretreatment with the Src inhibitor PP2 reduced periodic mechanical stress-induced ECM synthesis and cell migration of NP cells (P < 0.05 for each), while the phosphorylation of GIT1 and ERK1/2 were inhibited. ECM synthesis, cell migration, and phosphorylation of ERK1/2 were inhibited after pretreatment with the small interfering RNA for GIT1 in NP cells under periodic mechanical stress (P < 0.05 for each), whereas the phosphorylation of Src was not affected. Pretreatment with the ERK1/2 inhibitor PD98059 reduced periodic mechanical stress-induced ECM synthesis and cell migration of NP cells (P < 0.05 for each). Co-immunoprecipitation assay showed that there was a direct interaction between Src and GIT1 and between GIT1 and ERK1/2. CONCLUSION: In conclusion, periodic mechanical stress induced ECM expression and migration of NP cells via Src-GIT1-ERK1/2 signaling pathway, playing an important role in regulation of NP cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfoproteínas/metabolismo , Estresse Mecânico , Quinases da Família src/metabolismo , Agrecanas/metabolismo , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo II/metabolismo , Matriz Extracelular/metabolismo , Flavonoides/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Núcleo Pulposo/citologia , Núcleo Pulposo/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosforilação/efeitos dos fármacos , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores
14.
Biochem Biophys Res Commun ; 503(4): 2749-2757, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30093112

RESUMO

Blocking aerobic glycolysis has been proposed as an attractive therapeutic strategy for impairing the proliferation of cancer cells. However, the underlying mechanisms are poorly understood. Here, we show that miR-15b-5p was downregulated in osteosarcoma (OS) and that lower expression of miR-15b-5p promoted proliferation and contributed to the Warburg effect in OS cells. Mechanistically, miR-15b-5p acted as a tumor suppressor in OS by directly targeting pyruvate dehydrogenase kinase-4 and inhibiting its expression. These results reveal a previously unknown function of miR-15b-5p in OS, which is associated with metabolic alterations that promote cancer progression. miR-15b-5p may play an essential role in the molecular therapy of patients with OS.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteoblastos/metabolismo , Osteossarcoma/genética , Proteínas Serina-Treonina Quinases/genética , Regiões 3' não Traduzidas , Animais , Apoptose , Sequência de Bases , Sítios de Ligação , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Glicólise/genética , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Osteoblastos/patologia , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncol Rep ; 40(2): 793-802, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901170

RESUMO

Toll-like receptor 4 (TLR4) families are receptors for ligands that initiate extracellular or intracellular signaling, such as lipopolysaccharides (LPS). It has been reported that TLR4 activation resulted in the upregulation of a coordinated set of proinflammatory mediators and inhibition of matrix expression in the intervertebral disc (IVD). miR-140-5p (miR-140) is reported to participate in cellular anti-inflammatory processes and target TLR4. In the present study, we investigated the relationship between TLR4 and miR-140 in IVD degeneration. The expression of TLR4, interleukin (IL)-6, IL-I, L-1ß and tumor necrosis factor (TNF)-α was higher, in high-grade IVD degeneration tissues than in low-grade tissues. In contrast, the expression of miR-140, aggrecan and collagen type II was lower in high-grade IVD degeneration tissues than in low-grade IVD degeneration tissues. LPS stimulation resulted in significant increases in TLR4 expression and decreases in miR-140 expression in nucleus pulposus (NP) cells and TLR4 was identified as a target of miR-140 by dual-luciferase reporter assay. The overexpression of miR-140 inhibited the upregulation of the expression of TLR4, TNF-α, IL-1ß and IL-6 inflammation cytokines, and the activation of NF-κB and reversed the downregulation of the expression of aggrecan and collagen type II induced by LPS stimulation. In conclusion, the present study may lead to a greater understanding of IVD degeneration and provide new insights into the treatment of this disease.


Assuntos
Regulação para Baixo/genética , Inflamação/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Disco Intervertebral/metabolismo , MicroRNAs/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Idoso , Colágeno Tipo II/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Disco Intervertebral/efeitos dos fármacos , Degeneração do Disco Intervertebral/induzido quimicamente , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
Cell Death Dis ; 9(3): 390, 2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523788

RESUMO

Cellular metabolic reprogramming is the main characteristic of cancer cells and identification of targets using this metabolic pattern is extremely important to treat cancers, such as osteosarcoma (OS). In this study, SLIT2 and ROBO1 were upregulated in OS, and higher expression of ROBO1 was associated with worse overall survival rate. Furthermore, in vitro and in vivo experiments demonstrated that the SLIT2/ROBO1 axis promotes proliferation, inhibits apoptosis, and contributes to the Warburg effect in OS cells. Mechanistically, the SLIT2/ROBO1 axis exerted cancer-promoting effects on OS via activation of the SRC/ERK/c-MYC/PFKFB2 pathway. Taken together, the findings reveal a previously unappreciated function of SLIT2/ROBO1 signaling in OS, which is intertwined with metabolic alterations that promote cancer progression. Targeting the SLIT2/ROBO1 axis may be a potential therapeutic approach for patients with OS.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteossarcoma/metabolismo , Fosfofrutoquinase-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Imunológicos/metabolismo , Quinases da Família src/metabolismo , Animais , Glicólise , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas do Tecido Nervoso/genética , Osteossarcoma/genética , Fosforilação Oxidativa , Fosfofrutoquinase-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Imunológicos/genética , Transdução de Sinais , Quinases da Família src/genética
17.
Exp Cell Res ; 367(2): 119-131, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29601800

RESUMO

Ossification of the ligamentum flavum (OLF) is a debilitating disease resulting from the development of ectopic bone formation, which leads to the compression of the spinal cord. Nicotinamide phosphoribosyltransferase (NAMPT) was found to be upregulated and microRNA-182 (miR-182) was downregulated in OLF tissue. We investigated the effects of NAMPT and miR-182 expression in OLF cells and the influence on proteins associated with osteogenic differentiation. MiR-182 overexpression inhibited NAMPT, RUNX2, OCN and OPN mRNA and protein expression in OLF cells. Alkaline phosphatase (ALP) assay and Alizarin red staining confirmed reduced levels of osteogenic differentiation and mineralized nodule formation. Knockdown of NAMPT and the NAMPT inhibitor FK866 also inhibits RUNX2, OCN and OPN mRNA expression and protein levels, whereas overexpression of NAMPT promotes the expression of RUNX2, OCN and OPN and the generation of bone nodules. Dual-luciferase reporter assays revealed that miR-182 directly targets NAMPT and downregulates its expression. Transfection of OLF cells with miR-182 downregulated NAMPT and suppressed the regulation of RUNX2, OCN, and OPN by NAMPT overexpression. Overall, these data demonstrate that miR-182 suppresses OLF by downregulating NAMPT.


Assuntos
Citocinas/genética , Ligamento Amarelo/patologia , MicroRNAs/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Ossificação Heterotópica/genética , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia
18.
FASEB J ; 32(7): 3832-3843, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29447005

RESUMO

Acid-sensing ion channels (ASICs) are the major proton receptor in the brain and a key mediator of acidosis-induced neuronal injuries in disease. Most of published data on ASIC function came from studies performed in mice, and relatively little is known about potential differences between human and mouse ASICs (hASIC and mASIC, respectively). This information is critical for us to better interpret the functional importance of ASICs in human disease. Here, we examined the expression of ASICs in acutely resected human cortical tissue. Compared with mouse cortex, human cortical tissue showed a similar ratio of ASIC1a:ASIC2a expression, had reduced ASIC2b level, and exhibited a higher membrane:total ratio of ASIC1a. We further investigated the mechanism for higher surface trafficking of hASIC1a in heterologous cells. A single amino acid at position 285 was critical for increased N-glycosylation and surface expression of hASIC1a. Consistent with the changes in trafficking and current, cells expressing hASIC1a or mASIC1a S285P mutant had a higher acid-activated calcium increase and exhibited worsened acidotoxicity. These data suggest that ASICs are likely to have a larger impact on acidosis-induced neuronal injuries in humans than mice, and this effect is, at least in part, a result of more efficient trafficking of hASIC1a.-Xu, Y., Jiang, Y.-Q., Li, C., He, M., Rusyniak, W. G., Annamdevula, N., Ochoa, J., Leavesley, S. J., Xu, J., Rich, T. C., Lin, M. T., Zha, X.-M. Human ASIC1a mediates stronger acid-induced responses as compared with mouse ASIC1a.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Prótons , Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/genética , Potenciais de Ação , Adolescente , Adulto , Animais , Células CHO , Cálcio/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Cricetinae , Cricetulus , Feminino , Humanos , Ativação do Canal Iônico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação , Especificidade da Espécie
19.
Exp Biol Med (Maywood) ; 243(4): 344-349, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29350066

RESUMO

It has been previously suggested that cytokeratins (CKs) are important diagnostic and prognostic biomarkers for urothelial lesions. Hence it is imperative to understand the expression pattern of cytokeratins during formation of papillary bladder cancer, which was the objective of the current study. Expression pattern of CK14 and CK18 were examined using immunohistochemical staining in a mice model of papillary bladder cancer. Twenty female mice were divided into two groups-group 1 (NT) and group 2, which received N-butyl- N-(4-hydroxybutyl) nitrosamine (BBN) for 20 weeks plus one week without treatment. Following histological classification of bladder lesions, CK14 and CK18 immunostaining was assessed according to its distribution and intensity. In NT animals, both basal cells and umbrella cells showed sporadic positive staining for CK14 and CK18, respectively. In BBN group, hyperplastic lesions showed significantly more CK14 and significantly less CK18 staining ( P < 0.05 in each case). Invasive carcinomas showed increased CK14 immunostaining in all epithelial layers. Cumulatively, our data indicate that altered CK14 (high) and CK18 (low) expression is perhaps an early event in bladder cancer tumorigenesis in females at least and is characteristic of both urothelial superficial pre-neoplastic and neoplastic lesions. Impact statement Studies have shown that expression of cytokeratins (CKs) or their altered distribution affects the bladder cancer pathogenesis and disease outcome, while the underlying mechanisms are not clear. The present study aims to explore the expression pattern of CK14 and CK18 during formation of papillary bladder cancer. The results showed that hyperplastic lesions showed significantly more CK14 and significantly less CK18 staining and invasive carcinomas showed increased CK14 immunostaining in all epithelial layers in N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse model. The results indicate that altered CK14 (high) and CK18 (low) expression is perhaps an early event in bladder cancer tumorigenesis and is characteristic of both urothelial superficial pre-neoplastic and neoplastic lesions, which may provide the early diagnosis index.


Assuntos
Carcinoma Papilar/patologia , Queratina-14/análise , Queratina-18/análise , Lesões Pré-Cancerosas/patologia , Neoplasias da Bexiga Urinária/patologia , Animais , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Camundongos Endogâmicos C57BL
20.
Mediators Inflamm ; 2018: 6016272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30647535

RESUMO

Diabetic neuropathic pain (DNP) is a prevalent complication in diabetes patients. Neuronal inflammation and activation of Toll-like receptor 4 (TLR4) are involved in the occurrence of DNP. However, the underlying mechanisms remain unclear. Downregulation of gamma-aminobutyric acid B (GABAB) receptor contributes to the DNP. GABAB receptor interacts with NF-κB, a downstream signaling factor of TLR4, in a neuropathic pain induced by chemotherapy. In this study, we determined the role of TLR4/Myd88/NF-κB signaling pathways coupled to GABAB receptors in the generation of DNP. Intrathecal injection of baclofen (GABAB receptor agonist), LPS-RS ultrapure (TLR4 antagonist), MIP (MyD88 antagonist), or SN50 (NF-κB inhibitor) significantly increased paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) in DNP rats, while intrathecal injection of saclofen (GABAB receptor blocker) decreased PWT and PWTL in DNP rats. The expression of TLR4, Myd88, NF-κBp65, and their downstream components IL-1 and TNF-α was significantly higher in the spinal cord tissue in DNP rats compared to control rats. Following inhibition of TLR4, Myd88, and NF-κB, the expression of IL-1 and TNF-α decreased. Activation of GABAB receptors downregulated the expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. Blockade of GABAB receptors significantly upregulated expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. These data suggest that activation of the TLR4/Myd88/NF-κB signaling pathway is involved in the occurrence of DNP in rats. Activation of GABAB receptor in the spinal cord may suppress the TLR4/Myd88/NF-κB signaling pathway and alleviate the DNP.


Assuntos
Neuropatias Diabéticas/metabolismo , Receptores de GABA-B/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
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