Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.501
Filtrar
1.
Bioengineered ; 10(1): 282-291, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31311401

RESUMO

Transforming growth factor (TGF)-ß1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in many cancer types and in thyroid cancers. Epigallocatechin-3-gallate (EGCG), the most important ingredient in the green tea, has been reported to possess antioxidant and anticancer activities. However, the cellular and molecular mechanisms explaining its action have not been completely understood. In this study, we found that EGCG significantly suppresses EMT, invasion and migration in anaplastic thyroid carcinoma (ATC) 8505C cells in vitro by regulating the TGF-ß/Smad signaling pathways. EGCG significantly inhibited TGF-ß1-induced expression of EMT markers (E-cadherin reduction and vimentin induction) in 8505C cells in vitro. Treatment with EGCG completely blocked the phosphorylation of Smad2/3, translocation of Smad4. Taken together, these results suggest that EGCG suppresses EMT and invasion and migration by blocking TGFß/Smad signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Catequina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Células Epiteliais da Tireoide/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Antígenos CD/genética , Antígenos CD/metabolismo , Caderinas/antagonistas & inibidores , Caderinas/genética , Caderinas/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Células Epiteliais da Tireoide/metabolismo , Células Epiteliais da Tireoide/patologia , Fator de Crescimento Transformador beta1/farmacologia , Vimentina/agonistas , Vimentina/genética , Vimentina/metabolismo
2.
Planta Med ; 85(9-10): 755-765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185503

RESUMO

Antcin-A (ATA) is a steroid-like phytochemical isolated from the fruiting bodies of a precious edible mushroom Antrodia cinnamomea. We previously showed that ATA has strong anti-inflammatory and anti-tumor effects; however, other possible bioactivities of this unique compound remain unexplored. In the present study, we aimed to investigate the modulation of epithelial-to-mesenchymal transition (EMT), anti-migration, and anti-invasive potential of ATA against human breast cancer cells in vitro. Human breast cancer cell lines, MCF-7 and MDA-MB-231, were incubated with ATA for 24 h. Wound healing, trans-well invasion, western blot, q-PCR, F-actin staining, and immunofluorescence assays were performed. We found that treatment with ATA significantly blocked EMT processes, as evidenced by upregulation of epithelial markers (E-cadherin and occludin) and downregulation of mesenchymal markers (N-cadherin and vimentin) via suppression of their transcriptional repressor ZEB1. Next, we found that ATA could induce miR-200c, which is a known player of ZEB1 repression. Further investigations revealed that ATA-mediated induction of miR-200c is associated with transcriptional activation of p53, as confirmed by the fact that ATA failed to induce miR-200c or suppress ZEB1 activity in p53 inhibited cells. Further in vitro wound healing and trans-well invasion assays support that ATA could inhibit migratory and invasive potentials of breast cancer cells, and the effect was likely associated with induced phenotypic modulation. Taken together, the present study suggests that antcin-A could be a lead phyto-agent for the development of anti-metastatic drug for breast cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Esteroides/farmacologia , Proteína Supressora de Tumor p53/genética , Antígenos CD/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , MicroRNAs/genética , Fator de Crescimento Transformador beta1/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
3.
Nat Commun ; 10(1): 2549, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186409

RESUMO

Human adipose tissue (hAT) is constituted of structural units termed lobules, the organization of which remains to be defined. Here we report that lobules are composed of two extracellular matrix compartments, i.e., septa and stroma, delineating niches of CD45-/CD34+/CD31- progenitor subsets characterized by MSCA1 (ALPL) and CD271 (NGFR) expression. MSCA1+ adipogenic subset is enriched in stroma while septa contains mainly MSCA1-/CD271- and MSCA1-/CD271high progenitors. CD271 marks myofibroblast precursors and NGF ligand activation is a molecular relay of TGFß-induced myofibroblast conversion. In human subcutaneous (SC) and visceral (VS) AT, the progenitor subset repartition is different, modulated by obesity and in favor of adipocyte and myofibroblast fate, respectively. Lobules exhibit depot-specific architecture with marked fibrous septa containing mesothelial-like progenitor cells in VSAT. Thus, the human AT lobule organization in specific progenitor subset domains defines the fat depot intrinsic capacity to remodel and may contribute to obesity-associated cardiometabolic risks.


Assuntos
Tecido Adiposo/anatomia & histologia , Tecido Adiposo/citologia , Nicho de Células-Tronco , Células-Tronco/citologia , Adipócitos/metabolismo , Adipogenia , Fosfatase Alcalina , Diferenciação Celular , Matriz Extracelular , Humanos , Gordura Intra-Abdominal/citologia , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Obesidade , Receptores de Fator de Crescimento Neural/metabolismo , Células-Tronco/metabolismo , Gordura Subcutânea/citologia , Fator de Crescimento Transformador beta1/farmacologia
4.
Biomed Res Int ; 2019: 1321973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119150

RESUMO

Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults. Despite continuous improvements in diagnosis and therapeutic method, the prognosis is still far away from expectations. The invasive phenotype of GBM is the main reason for the poor prognosis. Epithelial-mesenchymal transition (EMT) is recognized as a participator in this invasive phenotype. Resveratrol, a natural plant-derived compound, is reported to be able to regulate EMT. In the present study, we used TGF-ß1 to induce EMT and aimed to evaluate the effect of resveratrol on EMT and to explore the underline mechanism in GBM. Western blotting was used to detect the expression of EMT-related markers, stemness markers, and Smad-dependent signaling. Wound healing assay and transwell invasion assay were performed to evaluate the migratory and invasive ability of GBM cells. Gliosphere formation assay was used to investigate the effect of resveratrol on the ability of self-renewal. Xenograft experiment was conducted to examine the effect of resveratrol on EMT and Smad-dependent signaling in vivo. Our data validated that resveratrol suppressed EMT and EMT-associated migratory and invasive ability via Smad-dependent signaling in GBM cells. We also confirmed that resveratrol obviously inhibited EMT-induced self-renewal ability of glioma stem cells (GSCs) and inhibited EMT-induced cancer stem cell markers Bmi1 and Sox2, suggesting that resveratrol is able to suppress EMT-generated stem cell-like properties in GBM cells. Furthermore, we also showed the inhibitory effect of resveratrol on EMT in xenograft experiments in vivo. Overall, our study reveals that resveratrol suppresses EMT and EMT-generated stem cell-like properties in GBM by regulating Smad-dependent signaling and provides experimental evidence of resveratrol for GBM treatment.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Resveratrol/farmacologia , Proteínas Smad/genética , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Xenoenxertos , Humanos , Camundongos , Proteína Quinase 7 Ativada por Mitógeno/genética , Fatores de Transcrição SOXB1/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia
5.
Chem Biol Interact ; 307: 158-166, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31059706

RESUMO

Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-ß1 (TGF-ß1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-ß-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-ß1-induced EMT by inhibiting TGF-ß1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.


Assuntos
Diterpenos de Caurano/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos de Caurano/química , Diterpenos de Caurano/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosforilação/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Vimentina/metabolismo
6.
Invest Ophthalmol Vis Sci ; 60(5): 1431-1441, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30947333

RESUMO

Purpose: Hyaluronan (HA) is a potential regulator of TGFß1-induced differentiation in perimysial orbital fibroblasts (pOFs). Our study aimed to explore the effects of PH20 (a hyaluronidase) and HA on TGFß1-induced differentiation in pOFs cultured from thyroid-associated ophthalmopathy (TAO) and control subjects. Methods: TAO and control pOFs (passages 3-6) were incubated with TGFß1 ± PH20 or TGFß1 ± HA for 72 hours and processed for various analyses, including HA electrophoresis; αSMA immunofluorescence; and quantification of αSMA (encoded by ACTA2), CD44 (a cell surface HA receptor), and SMAD2/3 (signaling molecule in the TGFß1 pathway). Results: TGFß1 induced myogenic differentiation (marked by αSMA upregulation) of pOFs. After TGFß1 treatment, more HA accumulated in the TAO group than in the control group. PH20 mainly digested medium to small HA and increased the percentage of high molecular weight HA (HMW-HA) in total HA. Both PH20 and HMW-HA inhibited TGFß1-induced differentiation in the TAO group, but neither showed significant effects in the control group. CD44 level negatively correlated with ACTA2 level in the TAO group, but no correlation was detected in the control group. Both PH20 and HMW-HA upregulated CD44 expression and inhibited SMAD2/3 expression in the TAO group, and the inhibitory effects were partially reversed by CD44 blockage. CD44 level in the control group was not affected by PH20 or HMW-HA treatment, and CD44 blockage showed no significant effects on control pOF differentiation. Conclusions: PH20 inhibits TGFß1-induced differentiation of TAO pOFs via HA-CD44-SMAD2/3 signaling, and the HA-CD44 signaling plays a divergent role in TAO and control pOFs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Oftalmopatia de Graves/tratamento farmacológico , Ácido Hialurônico/farmacologia , Hialuronoglucosaminidase/farmacologia , Órbita/citologia , Fator de Crescimento Transformador beta1/farmacologia , Análise de Variância , Estudos de Casos e Controles , Células Cultivadas , Oftalmopatia de Graves/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(2): 121-127, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30975276

RESUMO

Objective To investigate the role of transforming growth factor ß1/nicinamide adenine dinucleotide phosphate oxidase/reactive oxygen species (TGF-ß1/NOX4/ROS) signaling pathway in the invasion and migration of cervical cancer cells. Methods The cultured SiHa, CaSki, HeLa, C4-I and C33A cervical cancer cells were treated with 5 ng/mL TGF-ß1 for 4 hours or 8 hours. ROS levels in these cervical cancer cells were detected using 2', 7'-dichlorofluorescein diacetate (DCFH-DA) staining combined with flow cytometry. After the transfection of NOX4 small interfering RNA (NOX4-siRNA) into HeLa cells or using of NOX4 signaling pathway inhibitor diphenylidene iodine chloride (DPI), NOX4 protein expression was measured by Western blotting, and the effect of TGF-ß1 on migration and invasion ability of cervical cancer cells were analyzed by TranswellTM assay. Results TGF-ß1 significantly up-regulated NOX4 protein expression, increased ROS production in HPV-positive cervical cancer cells (SiHa, CaSki, HeLa and C4-I) and promoted the migration and invasion abilities of cervical cancer cells. Silencing the NADPH oxidase gene or using the NOX4 pathway inhibitor DPI could reverse this effect. Conclusion TGF-ß1 can activate NOX4/ROS signaling pathway to enhance the invasion and migration abilities of cervical cancer cells.


Assuntos
NADPH Oxidase 4 , Espécies Reativas de Oxigênio , Fator de Crescimento Transformador beta1 , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Movimento Celular , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HeLa , Humanos , NADPH Oxidase 4/metabolismo , Invasividade Neoplásica/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
8.
ACS Appl Mater Interfaces ; 11(16): 14608-14618, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30938503

RESUMO

Continuous delivery of growth factors to the injury site is crucial to creating a favorable microenvironment for cartilage injury repair. In the present study, we fabricated a novel sustained-release scaffold, stromal-derived factor-1α (SDF-1α)/transforming growth factor-ß1 (TGF-ß1)-loaded silk fibroin-porous gelatin scaffold (GSTS). GSTS persistently releases SDF-1α and TGF-ß1, which enhance cartilage repair by facilitating cell homing and chondrogenic differentiation. Scanning electron microscopy showed that GSTS is a porous microstructure and the protein release assay demonstrated the sustainable release of SDF-1α and TGF-ß1 from GSTS. Bone marrow-derived mesenchymal stem cells (MSCs) maintain high in vitro cell activity and excellent cell distribution and phenotype after seeding into GSTS. Furthermore, MSCs acquired enhanced chondrogenic differentiation capability in the TGF-ß1-loaded scaffolds (GSTS or GST: loading TGF-ß1 only) and the conditioned medium from SDF-1α-loaded scaffolds (GSTS or GSS: loading SDF-1α only) effectively promoted MSCs migration. GSTS was transplanted into the osteochondral defects in the knee joint of rats, and it could promote cartilage regeneration and repair the cartilage defects at 12 weeks after transplantation. Our study shows that GSTS can facilitate in vitro MSCs homing, migration, chondrogenic differentiation and SDF-1α and TGF-ß1 have a synergistic effect on the promotion of in vivo cartilage forming. This SDF-1α and TGF-ß1 releasing GSTS have promising therapeutic potential in cartilage repair.


Assuntos
Cartilagem , Quimiocina CXCL12 , Condrogênese/efeitos dos fármacos , Fibroínas , Gelatina , Fator de Crescimento Transformador beta1 , Animais , Cartilagem/lesões , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/química , Quimiocina CXCL12/farmacocinética , Quimiocina CXCL12/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Fibroínas/química , Fibroínas/farmacocinética , Fibroínas/farmacologia , Gelatina/química , Gelatina/farmacocinética , Gelatina/farmacologia , Masculino , Porosidade , Ratos , Fator de Crescimento Transformador beta1/química , Fator de Crescimento Transformador beta1/farmacocinética , Fator de Crescimento Transformador beta1/farmacologia
9.
Int J Biol Macromol ; 132: 541-549, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951775

RESUMO

Transforming growth factor-beta1 (TGF-ß1) is a pleiotropic and ubiquitous cytokine involved in bone development and bone remodeling. Matrix metalloproteinase-13 (MMP13) plays a role in the degradation of the extracellular matrix (ECM), and the regulation of this gene is critical in bone remodeling. We previously reported that TGF-ß1 stimulates MMP13 expression in rat osteoblasts. Recently, studies have examined the regulation of bone metabolism by microRNAs (miRNAs) to determine their therapeutic potential in osteogenesis. Here, we assessed the effect of TGF-ß1 on down-regulation of miRNAs that target MMP13 and stimulation of MMP13 expression in osteoblasts. We used in silico analysis and identified 11 specific miRNAs which directly target rat MMP13. Among these miRNAs, miR-203a-5p expression was significantly decreased by TGF-ß1-treatment in rat osteoblasts. Transient transfection of a miR-203a-5p mimic into rat osteoblasts reduced MMP13 expression. A luciferase reporter assay confirmed a direct targeting of miR-miR-203a-5p with the 3' untranslated regions of the MMP13 gene. Hence, we suggest that TGF-ß1 stimulated down-regulation of miR-203a-5p, resulting in the stimulation of MMP13 expression in rat osteoblasts. Thus, identification of the role of miR-203a-5p via TGF-ß1 and MMP13 in bone remodeling indicated its potential as a biomarker or therapeutic agent for treating bone and bone-related diseases.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , MicroRNAs/genética , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Linhagem Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ratos
10.
ACS Appl Mater Interfaces ; 11(16): 14660-14671, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30973698

RESUMO

Cancer progression is regulated by multiple factors of extracellular matrix (ECM). Understanding how cancer cells integrate multiple signaling pathways to achieve specific behaviors remains a challenge because of the lack of appropriate models to copresent and modulate ECM properties. Here we proposed a strategy to build a thin biomaterial matrix by poly(l-lysine) and hyaluronan as an artificial stiffness-tunable ECM. Transforming growth factor-beta 1 (TGF-ß1) was used as a biochemical cue to present in an immobilized and spatially controlled manner, with a high loading efficiency of 90%. Either soft matrix with immobilized TGF-ß1 (i-TGF) or bare stiff matrix could only promote HCC cells to form the epithelial phenotype, whereas stiff matrix with i-TGF was the only condition to induce the mesenchymal phenotype. Further investigation revealed that i-TGF increased the specific TGF-ß1 receptor (TßRI) expression to activate PI3K pathway. i-TGF-TßRI interactions also promoted HCC cell adhesion to enlarge contact area for stiffness sensing, resulting in the raising expression of the mechano-sensor (ß1 integrin). Mechanotransduction would then be enhanced by the ß1 integrin/vinculin/p-FAK pathway, leading to a noble PI3K activation. Using our model, a novel mechanism was discovered to elucidate regulation of cell fates by coupling mechanotransduction and biochemical signaling.


Assuntos
Carcinoma Hepatocelular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/química , Neoplasias Hepáticas , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Transformador beta1/química , Fator de Crescimento Transformador beta1/farmacologia
11.
Cell Physiol Biochem ; 52(4): 822-837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946557

RESUMO

BACKGROUND/AIMS: Lung fibrosis is associated with lung tissue contraction due to abnormal accumulation of myofibroblasts, which aggressively promote the fibrotic process. Transforming growth factor (TGF)-ß signaling in fibroblasts promotes extracellular matrix (ECM) synthesis and fibroblast migration and differentiation into myofibroblasts. Inhibition of extracellular signal-regulated kinase (ERK)5 blocks lung fibroblast activation by suppressing TGF-ß signaling. Here, we examined the effects of an ERK5 inhibitor on TGF-ß1-induced fibrosis in lung fibroblasts. METHODS: The effects of ERK5 inhibition following TGF-ß1 exposure were evaluated in lung fibroblasts isolated from fibrotic human lung tissues. Fibroblast-mediated collagen gel contraction and fibroblast migration towards fibronectin were assessed. Phenotypic differences in fibrotic fibroblasts were examined using the cap analysis gene expression method for genome-wide quantification of promoter activity. RESULTS: TGF-ß1stimulated contraction of collagen gels, fibroblast migration, and α-smooth muscle actin and fibronectin expression, and Smad3 phosphorylation were increased in fibrotic fibroblasts as compared to normal lung fibroblasts. Treatment with the ERK5 inhibitor blocked these responses to a greater extent in fibroblasts from patients with usual interstitial pneumonia as compared to nonspecific interstitial pneumonia, independent of bone morphogenetic protein/Smad1 regulation. Moreover, 223 genes including fibulin-5 -which is involved in the TGF-ß1-ERK5 signaling network- were upregulated in fibrotic fibroblasts, and ECM regulation was found to be enriched in the Reactome analysis. CONCLUSION: ERK5 inhibition attenuated the high sensitivity of fibrotic fibroblasts to TGF-ß1/Smad3 signaling. Thus, the ERK5 pathway components and fibulin-5 are potential therapeutic targets to prevent lung fibrosis progression.


Assuntos
Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Fibrose Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Actinas/metabolismo , Idoso , Compostos de Anilina/farmacologia , Biomarcadores/metabolismo , Movimento Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Indóis/farmacologia , Masculino , Pessoa de Meia-Idade , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 7 Ativada por Mitógeno/genética , Fibrose Pulmonar/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteína Smad3/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Cancer Sci ; 110(6): 1959-1973, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004547

RESUMO

Activation of transforming growth factor ß (TGF-ß) combined with persistent hypoxia often affects the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIF), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF-1α expression by protein phosphatase activity on dissociation of the E-cadherin/ß-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGF-ß. By using lung cancer cells treated with HIF-1α stabilizers or carrying doxycycline-dependent HIF-1α deletion or point mutants, we investigated the role of stabilized HIF-1α expression on TGF-ß-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGF-ß and hypoxia induced EMT phenotypes in H358 cells in which stabilized HIF-1α expression was inhibited. Stabilized HIF-1α protein expression inhibited the TGF-ß-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase 2A activity abrogated the HIF-1α-induced repression of the TGF-ß-stimulated appearance of EMT phenotypes. This is the first study to show a direct role of stabilized HIF-1α expression on inhibition of TGF-ß-induced EMT phenotypes in lung cancer cells, in part, through protein phosphatase activity.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fator de Crescimento Transformador beta1/farmacologia , Animais , Hipóxia Celular , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estabilidade Proteica , Interferência de RNA , Ratos
13.
Invest Ophthalmol Vis Sci ; 60(4): 1156-1164, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30908581

RESUMO

Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown antifibrotic effects on several diseases. The aims of the present in vitro study were to investigate the antifibrotic effects of bromfenac (a kind of NSAID) on primary human pterygium fibroblasts (HPFs) and primary human conjunctival fibroblasts (HConFs), as well as to explore the possible mechanisms of these effects. Methods: The cells used in this study were primary HPFs and HConFs, and profibrotic activation was induced by transforming growth factor-beta1 (TGF-ß1). Western blot, quantitative real-time PCR, and immunofluorescence (IF) assays were used to detect the effects of TGF-ß1 and bromfenac on the synthesis of fibronectin (FN), type III collagen (COL3), and alpha-smooth muscle actin (α-SMA) in HPFs and HConFs; the changes of signaling pathways were detected by Western blot; cell migration ability was detected by wound healing assay; cell proliferation ability was detected by CCK-8 assay; and pharmaceutical inhibitions of the downstream signaling pathways of TGF-ß1 were used to assess their possible associations with the effects of bromfenac. Results: Bromfenac suppressed the TGF-ß1-induced protein expression of FN (0.59 ± 0.07 folds, P = 0.008), COL3 (0.48 ± 0.08 folds, P = 0.001), and α-SMA (0.61 ± 0.03 folds, P = 0.008) in HPFs. Bromfenac also attenuated TGF-ß1-induced cell migration (0.30 ± 0.07 folds, P < 0.001), cell proliferation (0.64 ± 0.03 folds, P = 0.002) and the expression levels of p-AKT (0.66 ± 0.08 folds, P = 0.032), p-ERK1/2 (0.69 ± 0.11 folds, P = 0.003), and p-GSK-3ß-S9 (0.65 ± 0.10 folds, P = 0.002) in HPFs. PI3K/AKT inhibitor (wortmannin) and MEK/ERK inhibitor (U0126) reduced the TGF-ß1-induced synthesis of FN, COL3, and α-SMA in HPFs. All the results were similar in HConFs. Conclusions: Bromfenac protects against TGF-ß1-induced synthesis of FN, α-SMA, and COL3 in HPFs and HConFs at least in part by inactivating the AKT and ERK pathways.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzofenonas/farmacologia , Bromobenzenos/farmacologia , Túnica Conjuntiva/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pterígio/patologia , Pterígio/prevenção & controle , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Actinas/genética , Actinas/metabolismo , Idoso , Western Blotting , Diferenciação Celular/fisiologia , Proliferação de Células , Células Cultivadas , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Túnica Conjuntiva/metabolismo , Fibroblastos/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt , Pterígio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , Sincalida/farmacologia , Fator de Crescimento Transformador beta1/farmacologia
14.
Int J Biol Macromol ; 131: 886-895, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30857966

RESUMO

In this study, we purified a water-soluble polysaccharide, SBPW3, from the whole plant of Scutellaria barbata D. Don through ethanol precipitation, deproteinization, lyophilization, dialysis and separation using a DEAE cellulose column and a Superdex 200 gel filtration chromatography column. SBPW3 is a homogeneous polysaccharide with a molecular weight of 10.2 kDa and is composed of rhamnose (2.51%), arabinose (25.68%), xylose (10.94%), mannose (12.56%), glucose (20.59%) and galactose (27.72%). FT-IR spectrum analysis of the polysaccharide showed that SBPW3 contained a pyranose ring. The effects of SBPW3 on TGF-ß1-induced epithelial-mesenchymal transition (EMT) were tested in colon cancer cells. These results suggested that SBPW3 significantly suppressed TGF-ß1-induced migration and invasion. Additionally, SBPW3 reduced EMT by increasing the expression of epithelial markers and by decreasing the expression of mesenchymal markers by blocking the Smad2/3 signalling pathway in colon cancer cells. Furthermore, to explore the anti-metastatic effect of SBPW3, we established a mouse model of colon cancer metastasis and found that SBPW3 significantly inhibited the metastatic dissemination of the primary tumour to the liver. These findings provide us with a potential chemotherapeutic strategy for the treatment of human colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Movimento Celular/efeitos dos fármacos , Polissacarídeos/farmacologia , Scutellaria/química , Fator de Crescimento Transformador beta1/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Células HT29 , Humanos , Camundongos , Peso Molecular , Monossacarídeos/química , Polissacarídeos/química , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 156-161, 2019 02 28.
Artigo em Chinês | MEDLINE | ID: mdl-30890502

RESUMO

OBJECTIVE: To explore the effect of telmisartan on the expression of metadherin in the kidney of mice with unilateral ureter obstruction. METHODS: Eighteen male C57 mice were randomized into sham-operated group, model group and telmisartan treatment group. In the latter two groups, renal interstitial fibrosis as the result of unilateral ureter obstruction (UUO) was induced by unilateral ureteral ligation with or without telmisartan intervention. Renal pathological changes of the mice were assessed using Masson staining, and immunohistochemistry and Western blotting were used to detect the expression of extracellular matrix proteins and metadherin in the kidney of the mice. In the in vitro experiment, cultured mouse renal tubular epithelial cells (mTECs) were stimulated with transforming growth factor-ß1 (TGF-ß1) and transfected with a siRNA targeting metadherin, and the changes in the expressions of extracellular matrix proteins and metadherin were detected using Western blotting. RESULTS: The expressions of extracellular matrix proteins and metadherin increased significantly in the kidney of mice with UUO (P < 0.05). Intervention with telmisartan significantly lowered the expressions of extracellular matrix proteins and metadherin and alleviated the pathology of renal fibrosis in mice with UUO (P < 0.05). In cultured mTECs, siRNA-mediated knockdown of metadherin obviously reversed TGF-ß1-induced increase in the expressions of extracellular matrix proteins and metadherin. CONCLUSIONS: Telmisartan can suppress the production of extracellular matrix proteins and the expression of metadhein to attenuate UUO-induced renal fibrosis in mice.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Rim/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Telmisartan/farmacologia , Obstrução Ureteral/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Anti-Hipertensivos , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno , Distribuição Aleatória , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/complicações
16.
Pharm Biol ; 57(1): 169-175, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30905239

RESUMO

CONTEXT: Ursolic acid (UA; 3ß-hydroxy-urs-12-en-28-oic acid), one of the pentacyclic triterpenoids found in various plants and herbs, possesses some beneficial effects under pathological conditions, including combating hepatic fibrosis. OBJECTIVE: This study investigates the effects of UA on renal tubulointerstitial fibrosis in vivo and in vitro. MATERIALS AND METHODS: In vivo, 24 male C57BL6 mice were divided into four groups. Eighteen mice were subjected to unilateral ureteral obstruction (UUO) and the remaining six sham-operated mice served as control. UUO mice received either vehicle or UA (50 or 100 mg/kg) by gastric gavage for 6 days. In vitro, HK-2 cells were treated with 10 or 50 µM UA and 10 ng/mL recombinant human transforming growth factor-ß1 (TGF-ß1). The molecular mechanisms of fibrosis were investigated. RESULTS: UUO induced marked interstitial collagen I and fibronectin deposition and epithelial-mesenchymal transition (EMT), as evidenced by increased α-smooth muscle actin (α-SMA) and decreased E-cadherin. However, UA treatment significantly reduced collagen I and fibronectin accumulation in the fibrotic kidney. UA treatment also decreased α-SMA and preserved E-cadherin in vivo. In vitro, TGF-ß1-treated HK-2 cells demonstrated elevated α-SMA, snail1, slug, TGF-ß1, and p-smad3, as well as diminished E-cadherin. UA pretreatment prevented E-cadherin loss and diminished α-SMA expression in HK-2 cells. UA downregulated mRNA expression of snail1 and slug. UA also lowered TGF-ß1 protein expression and p-Smad3 in HK-2 cells. CONCLUSIONS: UA attenuated renal tubulointerstitial fibrosis by inhibiting EMT, and such inhibition may be achieved by decreasing profibrotic factors. UA may be a novel therapeutic agent for renal fibrosis.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Nefropatias/tratamento farmacológico , Triterpenos/farmacologia , Actinas/metabolismo , Animais , Caderinas/metabolismo , Linhagem Celular , Colágeno/metabolismo , Fibronectinas/metabolismo , Fibrose/patologia , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
17.
Eur Cell Mater ; 37: 214-232, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30900738

RESUMO

Nasal chondrocytes (NCs) have gained increased recognition for cartilage tissue regeneration. To assess NCs as a source for cell therapy treatment of intervertebral disc (IVD) degeneration, tissue-forming properties of NCs under physiological conditions mimicking the degenerated IVD were compared to those of mesenchymal stromal cells (MSCs) and articular chondrocytes (ACs), two cell sources presently used in clinical trials. Cells were cultured in a combination of low glucose, hypoxia, acidity and inflammation for 28 d. Depending on the conditions, cells were either cultured in the absence of instructive growth factors or underwent chondrogenic instructional priming by addition of transforming growth factor ß1 (TGFß1) for the first 7 d. Histology, immunohistochemistry, biochemistry, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses demonstrated limited cell maintenance and accumulation of cartilaginous extracellular matrix for MSCs in IVD conditions. ACs maintained a steady accumulation of glycosaminoglycans (GAGs) throughout all non-acidic conditions, with and without priming, but could not synthesise type II collagen (Col2). NCs accumulated both GAGs and Col2 in all non-acidic conditions, independent of priming, whereas MSCs strongly diminished their GAG and Col2 accumulation in an inflamed environment. Supplementation with inflammatory cytokines or an acidic environment affected NCs to a lower extent than ACs or MSCs. The data, overall indicating that in an inflamed IVD environment NCs were superior to ACs and MSCs, encourage further assessment of NCs for treatment of degenerative disc disease.


Assuntos
Condrócitos/patologia , Degeneração do Disco Intervertebral/patologia , Nariz/patologia , Adolescente , Adulto , Biomarcadores/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Condrócitos/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , DNA/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Glucose/farmacologia , Glicosaminoglicanos/metabolismo , Humanos , Inflamação/patologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Núcleo Pulposo/patologia , Oxigênio/farmacologia , Receptores de Citocinas/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Adulto Jovem
18.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897818

RESUMO

A total of 18 matrine derivatives were designed, synthesized, and evaluated for their inhibitory effect against TGF-ß1-induced total collagen accumulation in human fetal lung fibroblast MRC-5 cell lines. Among them, compound 3f displayed the most potent anti-fibrotic activity (IC50 = 3.3 ± 0.3 µM) which was 266-fold more potent than matrine. 3f significantly inhibited the fibroblast-to-myofibroblast transition and extracellular matrix production of MRC-5 cells. The TGF-ß/small mothers against decapentaplegic homologs (Smad) signaling was also inhibited by 3f, as evidenced by inhibition of cytoplasm-to-nuclear translocation of Smad2/3 and suppression of TGF-ß1-induced upregulation of TGF-ß receptor type I (TGFßRI). Additionally, 3f exhibited potent inhibitory effects against TGF-ß1-induced fibroblasts migration. These data suggested that 3f might be a potential agent for the treatment of idiopathic pulmonary fibrosis via repression of the TGFß/Smad signaling pathway.


Assuntos
Alcaloides/química , Alcaloides/síntese química , Quinolizinas/química , Quinolizinas/síntese química , Alcaloides/farmacologia , Linhagem Celular , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Imuno-Histoquímica , Indóis/química , Espectroscopia de Ressonância Magnética , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Quinolizinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/farmacologia
19.
Molecules ; 24(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901941

RESUMO

Metastasis is a major cause of death in patients with breast cancer. In the process of cancer development, epithelial-mesenchymal transition (EMT) is crucial to promoting the invasion and migration of tumor cells. In a previous study, the role of resveratrol in migration and metastasis was investigated in MDA-MB-231 (MDA231) human breast cancer cells and a xenograft-bearing mouse model. Additionally, the related mechanism was explored. In the present study, in vitro Transwell assays showed that resveratrol can inhibit the migration of transforming growth factor (TGF)-ß1-induced MDA231 cells in a concentration-dependent manner. An enzyme-linked immunosorbent assay (ELISA) showed that resveratrol can reduce the secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Immunofluorescence was performed to confirm the expression of EMT-related markers. Immunofluorescence assays confirmed that resveratrol changed the expression of the EMT-related markers E-cadherin and vimentin. Western blot analysis demonstrated that resveratrol decreased the expression levels of MMP-2, MMP-9, Fibronectin, α-SMA, P-PI3K, P-AKT, Smad2, Smad3, P-Smad2, P-Smad3, vimentin, Snail1, and Slug, as well as increased the expression levels of E-cadherin in MDA231 cells. In vivo, resveratrol inhibited lung metastasis in a mouse model bearing MDA231 human breast cancer xenografts without marked changes in body weight or liver and kidney function. These results indicate that resveratrol inhibits the migration of MDA231 cells by reversing TGF-ß1-induced EMT and inhibits the lung metastasis of MDA231 human breast cancer in a xenograft-bearing mouse model.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Resveratrol/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cell Tissue Bank ; 20(1): 61-75, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729369

RESUMO

To investigate the impact of different anticoagulants and coagulants with autologous platelet-rich plasma (PRP) in order to evaluate the clinical application of PRP standardization. Bone marrow stem cells (BMSCs) were seeded into autologous PRP gel scaffolds with different anticoagulants (EDTA, heparin sodium HS, and sodium citrate SC) as well as control group (the whole blood group). Quality of PRP was evaluated and flow cytometric assay was used to detect the activity of the platelet (CD62p, PAC-1). BMSCs were also seeded into PRP with different coagulants (Thrombin, Collagen-I, ADP) as well as PRP un-activated (negative group) and L-DMEM complete culture without PRP (control group). The effects of different coagulants with PRP on proliferation, osteogenic differentiation of BMSCs were analyzed by methyl thiazolyl tetrazolium assay (MTT), ALP staining, Von Kossa staining, Confocal microscopic observation, RT-PCR and Western Blot at the morphological, cellular and molecular levels. Different anticoagulants (EDTA, HS, and SC) could affect the quality of PRP. EDTA group revealed the best quality and activity (CD62p, PAC-1). With different coagulants (Thrombin, Collagen-I and ADP) in the proliferation of BMSCs, the MTT assay showed that the proliferation of BMSCs was increased in all groups with time. On the sixth day of culture, the cell number of each PRP group was significantly higher than that in the control group (P < 0.05), while the most rapidly increasing was found in Collagen-I group. The cumulative release of growth factor (TGF-ß1, PDGF) at each time point in the PRP gel of the four groups was higher than that in the control group (P < 0.05). Collagen-I was considered as the best PRP coagulant. When thrombin was used as a platelet coagulant, the release of growth factor in PRP was rapid and direct, while the release of growth factor in Collagen-I-activated PRP was sustained and slow, and the total release of ADP-activated PRP growth factors was the lowest. The study demonstrated the similar outcome in osteogenic differentiation. In terms of gene expression and western bolt, the PCR results showed that the expression levels of OCN gene and RUNX2 protein in each PRP group were higher than that in the control group (P < 0.05). Different anticoagulants caused different degrees of lysis and spontaneous activation of platelets, which lead to different quality of PRP. Compared with HS and SC, EDTA could maintain the structural integrity of platelets, reduce their spontaneous activation, and increase the release of PRP growth factors for a longer period of time, thus ensuring the biomass of PRP. In addition, different coagulants also showed different results in the proliferation as well as osteogenic differentiation of BMSCs. Compared with Thrombin and ADP, Collagen-I may be a better choice.


Assuntos
Anticoagulantes/farmacologia , Coagulantes/farmacologia , Plasma Rico em Plaquetas/metabolismo , Animais , Bioensaio , Plaquetas/citologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fosfatase 2 de Especificidade Dupla/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Selectina-P/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Coelhos , Padrões de Referência , Fator de Crescimento Transformador beta1/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA