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1.
Life Sci ; 232: 116637, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31288014

RESUMO

Keloid is characterized by overactive fibroblasts. Forkhead box M1 (FOXM1) is transcription factor that plays important roles in the progression of fibrosis. However, the role of FOXM1 in keloid has not been elucidated. In the present study, we examined the expression levels of FOXM1 in clinical keloid tissue specimens and primary keloid fibroblasts (KFs). The results showed that FOXM1 levels were significantly increased in both keloid tissues and KFs. To further investigate the biological functions of FOXM1, FOXM1 was knocked down in KFs by transfection with small interfering RNA targeting FOXM1 (si-FOXM1). Knockdown of FOXM1 inhibited transforming growth factor-ß1 (TGF-ß1)-induced cell proliferation and migration of KFs. Besides, the increased expressions of collagen (coll I), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) in TGF-ß1-induced KFs were suppressed by si-FOXM1 transfection. Furthermore, TGF-ß1-induced increase in p-Smad2 and p-Smad3 expressions was attenuated by FOXM1 knockdown. These data indicated that knockdown of FOXM1 inhibited TGF-ß1-induced KFs activation and extracellular matrix (ECM) accumulation, which was attributed to the inhibition of TGF-ß1/Smad pathway.


Assuntos
Proteína Forkhead Box M1/deficiência , Queloide/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Técnicas de Silenciamento de Genes/métodos , Humanos , Queloide/genética , Masculino , Fosforilação , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteína Smad2/antagonistas & inibidores , Proteína Smad2/metabolismo , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/metabolismo
2.
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
3.
Cell Physiol Biochem ; 53(2): 301-322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343125

RESUMO

BACKGROUND/AIMS: Propolis is one of the most promising natural products, exhibiting not only therapeutic but also prophylactic actions. Propolis has several biological and pharmacological properties, including hepatoprotective activities. The present study aimed to investigate the underlying molecular mechanisms of propolis against CCl4-mediated liver fibrosis. METHODS: Three groups of male BALB/c mice (n=15/ group) were used: group 1 comprised control mice; groups 2 and 3 were injected with CCl4 for the induction of liver fibrosis. Group 3 was then orally supplemented with propolis (100 mg/kg body weight) for four weeks. Different techniques were used to monitor the antifibrotic effects of propolis, including histopathological investigations using H&E, Masson's trichrome and Sirius red staining; Western blotting; flow cytometry; and ELISA. RESULTS: We found that the induction of liver fibrosis by CCl4 was associated with a significant increase in hepatic collagen and α-smooth muscle actin (α-SMA) expression. Moreover, CCl4-treated mice also exhibited histopathological alterations in the liver architecture. Additionally, the liver of CCl4-treated mice exhibited a marked increase in proinflammatory signals, such as increased expression of HSP70 and increased levels of proinflammatory cytokines and ROS. Mechanistically, the liver of CCl4-treated mice exhibited a significant increase in the phosphorylation of AKT and mTOR; upregulation of the expression of BAX and cytochrome C; downregulation of the expression of Bcl2; a significant elevation in the levels of TGF-ß followed by increased phosphorylation of SMAD2; and a marked increase in the expression of P53 and iNOS. Interestingly, oral supplementation of CCl4-treated mice with propolis significantly abolished hepatic collagen deposition, abrogated inflammatory signals and oxidative stress, restored CCl4-mediated alterations in the signaling cascades, and hence repaired the hepatic architecture nearly to the normal architecture observed in the control mice. CONCLUSION: Our findings revealed the therapeutic potential and the underlying mechanisms of propolis against liver fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Cirrose Hepática Experimental/patologia , Própole/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Citocinas/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
4.
Life Sci ; 232: 116609, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254585

RESUMO

Pioglitazone has been demonstrated to exert anti-fibrotic and renoprotective effects. But the detailed pharmacological mechanisms have not been clearly revealed. The present study aimed to investigate the possible mechanisms of pioglitazone in these two effects. TGF-ß1-stimulated HK-2 cells and unilateral ureteral obstruction (UUO) mice were used as in vitro and in vivo models. The results showed that pioglitazone inhibited Smad-2/3 phosphorylation, upregulated Smad-7 expression and downregulated miR-21-5p expression in TGF-ß1-exposed HK-2 cells. In addition, miR-21-5p inhibitors replicated the anti-fibrotic effects of pioglitazone, and miR-21-5p mimics inhibited these effects. In in vivo study, pioglitazone attenuated UUO-induced renal fibrosis and significantly decreased the expressions of pro-fibrotic proteins. Whereas, agomir of miR-21-5p inhibited the renoprotective function of pioglitazone in UUO mice. In conclusion, the present data suggest that modulation of miR-21-5p/Smad-7 signal may be involved in the anti-fibrotic effect of pioglitazone in the kidney of UUO mice.


Assuntos
Rim/efeitos dos fármacos , Rim/patologia , MicroRNAs/metabolismo , Pioglitazona/farmacologia , Animais , Linhagem Celular , Fibrose/induzido quimicamente , Fibrose/genética , Células HEK293 , Humanos , Rim/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/patologia
5.
Cancer Sci ; 110(8): 2507-2519, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215741

RESUMO

Abnormal tumor microenvironment and the epithelial-mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor-associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)-362-3p. In this study, we found that by releasing TGF-ß, M2 macrophages mediate binding of Smad2/3 to miR-362-3p promoter, leading to overexpression of miR-362-3p. MicroRNA-362-3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR-362-3p can serve as a core factor mediating cross-talk between the TGF-ß pathway in tumor-associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/fisiologia , Proteína Kangai-1/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Camundongos , Camundongos Nus , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Tetraspaninas/metabolismo
6.
Mol Immunol ; 112: 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202101

RESUMO

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.


Assuntos
Fibrose/tratamento farmacológico , Limoninas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo
7.
BMC Cancer ; 19(1): 439, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088527

RESUMO

BACKGROUND: Dendritic cells (DCs) alter their role from being immunostimulatory to immunosuppressive at advanced stages of tumor progression, but the influence of cancer stem cells (CSCs) and their secreted factors on generation and phenotypic change of DCs is unknown. Retinoic acid-inducible gene I (RIG-I) plays a role in regulation of other cellular processes including leukemic stemness besides its antiviral function. METHODS: Short hairpin RNA-mediated gene silencing was employed to generate stable RIG-I-knocked-down human hepatocellular carcinoma (HCC) cell lines. Expression levels of genes and proteins in spheres of those HCC cells were determined by quantitative real-time PCR and Western bot, respectively. Levels of secreted cytokines were measured by ELISA. The surface molecule expression levels of DCs were analyzed using flow cytometry. The ability of DCs to induce proliferation of T cells was assessed by a mixed lymphocyte reaction (MLR) assay. RESULTS: RIG-I-knocked-down HCC cells showed upregulated expression of stem cell marker genes, enhanced secretion of factors suppressing in vitro generation of DCs into the conditioned medium (CM), and induction of a phenotype of tumor-infiltrating DCs (TIDCs) with low levels of DC markers in their tumors in nude mice. Those DCs and TIDCs showed reduced MLR, indicating RIG-I deficiency-induced immunotolerance. The RIG-I-deficient HCC cells secreted more TGF-ß1 than did reference cells. The tumors formed after injection of RIG-I-deficient HCC cells had higher TGF-ß1 contents than did tumors derived from control cells. DC generation and MLR suppressed by the CM of RIG-I-deficient HCC cells were restored by an anti-TGF-ß1 antibody. TGF-ß1-induced phosphorylation of Smad2 and Akt was enhanced in RIG-I-deficient HCC spheres, knockdown of AKT gene expression abolishing the augmentation of TGF-ß1-induced Smad2 phosphorylation. Akt and p-Akt were co-immunoprecipitated with Smad2 in cytoplasmic proteins of RIG-I-deficient spheres but not in those of control spheres, the amounts of co-immunoprecipitated Akt and p-Akt being increased by TGF-ß stimulation. CONCLUSIONS: Our results demonstrate that RIG-I deficiency in HCC cells induced their stemness, enhanced secretion and signaling of TGF-ß1, tolerogenic TIDCs and less generation of DCs, and the results suggest involvement of TGF-ß1 in those RIG-I deficiency-induced tolerogenic changes and involvement of CSCs in DC-mediated immunotolerance.


Assuntos
Carcinoma Hepatocelular/patologia , Proteína DEAD-box 58/deficiência , Células Dendríticas/citologia , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Microambiente Tumoral , Regulação para Cima
8.
Mol Med Rep ; 19(6): 5203-5210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059039

RESUMO

The aim of the current study was to investigate the expression and role of microRNA­486­5p (miR­486­5p) in hypertrophic scar (HS) formation, and to examine the associated mechanisms. First, miR­486­5p expression was detected in HS tissues and human hypertrophic scar fibroblasts (hHSFs) by reverse transcription­quantitative polymerase chain reaction. Target genes of miR­486­5p were predicted using TargetScan and verified by dual­luciferase reporter assays. To investigate the role of miR­486­5p in HS formation, miR­486­5p was overexpressed in hHSFs through transfection with miR­486­5p mimics. MTT, cell apoptosis and cell cycle assays were preformed to investigate the proliferation, cell apoptosis and cell cycle distribution of hHSFs, respectively. Additionally, protein expression was measured by western blot analysis. The results demonstrated that miR­486­5p expression was significantly decreased in HS tissues and cells. Mothers against decapentaplegic homolog (Smad)2 was a target gene of miR­486­5p, and it was negatively regulated by miR­486­5p. It was also found that Smad2 expression was significantly increased in HS tissues and cells. Further analysis indicated that miR­486­5p mimic transfection inhibited the proliferation, induced cell apoptosis and increased G1/S phase arrest in hHSFs. Furthermore, the expression of cyclin­dependent kinase (CDK)2, CDK4 and apoptosis regulator Bcl­2 was repressed, while apoptosis regulator BAX expression was enhanced by miR­486­5p mimic transfection. Notably, the effects of miR­486­5p mimic on hHSFs were significantly eliminated by Smad2 plasmid transfection. Taken together, these results demonstrated that miR­486­5p inhibited the proliferation, induced apoptosis and increased G1/S phase arrest of hHSFs by targeting Smad2. miR­486­5p may be a promising therapeutic target for HS management.


Assuntos
Cicatriz Hipertrófica/patologia , MicroRNAs/metabolismo , Proteína Smad2/metabolismo , Regiões 3' não Traduzidas , Adulto , Antagomirs/metabolismo , Apoptose , Proliferação de Células , Cicatriz Hipertrófica/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Smad2/química , Proteína Smad2/genética , Proteína X Associada a bcl-2/metabolismo
9.
BMC Cancer ; 19(1): 405, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035970

RESUMO

BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action. METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified. RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p. CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Transdução de Sinais/genética , Tumor de Wilms/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Criança , Progressão da Doença , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia
10.
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
11.
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
12.
Mol Cell Biochem ; 458(1-2): 143-157, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31004309

RESUMO

MicroRNAs (miRNAs) regulate osteogenic differentiation of bone cells, which has applications in orthodontics. Here we evaluated the miRNA expression profile of MC3T3-E1 osteoblasts under cyclic tensile stress with chip technology and found that miR-132-3p was up-regulated by 12% cyclic tensile stress. Alkaline phosphatase activity and osteocalcin expression in MC3T3-E1 cells were decreased under these conditions. Smad2 and Smad5 were identified as potential target genes of miR-132-3p. Native and phosphorylated Smad2 and Smad5 expression was negatively correlated with miR-132-3p levels in the cells under cyclic stretch; however, only Smad5 protein level was reduced upon miR-132-3p overexpression. The luciferase reporter assay confirmed a direct interaction between miR-132-3p and Smad5. Thus, miR-132-3p maybe regulates osteoblast differentiation via Smad5 in response to cyclic tensile stress.


Assuntos
Diferenciação Celular , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Proteína Smad5/metabolismo , Estresse Mecânico , Resistência à Tração , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Linhagem Celular , Camundongos , MicroRNAs/genética , Osteoblastos/citologia , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad5/genética
13.
Int J Mol Sci ; 20(7)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959909

RESUMO

Culturing articular chondrocytes under physiological oxygen tension exerts positive effects on their extracellular matrix synthesis. The underlying molecular mechanisms which enhance the chondrocytic phenotype are, however, still insufficiently elucidated. The TGF-ß superfamily of growth factors, and the prototypic TGF-ß isoforms in particular, are crucial in maintaining matrix homeostasis of these cells. We employed a feedback-controlled table-top bioreactor to investigate the role of TGF-ß in microtissues of human chondrocytes over a wider range of physiological oxygen tensions (i.e., physoxia). We compared 1%, 2.5%, and 5% of partial oxygen pressure (pO2) to the 'normoxic' 20%. We confirmed physoxic conditions through the induction of marker genes (PHD3, VEGF) and oxygen tension-dependent chondrocytic markers (SOX9, COL2A1). We identified 2.5% pO2 as an oxygen tension optimally improving chondrocytic marker expression (ACAN, COL2A1), while suppressing de-differentiation markers (COL1A1, COL3A1). Expression of TGF-ß isoform 2 (TGFB2) was, relatively, most responsive to 2.5% pO2, while all three isoforms were induced by physoxia. We found TGF-ß receptors ALK1 and ALK5 to be regulated by oxygen tension on the mRNA and protein level. In addition, expression of type III co-receptors betaglycan and endoglin appeared to be regulated by oxygen tension as well. R-Smad signaling confirmed that physoxia divergently regulated phosphorylation of Smad1/5/8 and Smad2/3. Pharmacological inhibition of canonical ALK5-mediated signaling abrogated physoxia-induced COL2A1 and PAI-1 expression. Physoxia altered expression of hypertrophy markers and that of matrix metalloproteases and their activity, as well as expression ratios of specific proteins (Sp)/Krüppel-like transcription factor family members SP1 and SP3, proving a molecular concept of ECM marker regulation. Keeping oxygen levels tightly balanced within a physiological range is important for optimal chondrocytic marker expression. Our study provides novel insights into transcriptional regulations in chondrocytes under physoxic in vitro conditions and may contribute to improving future cell-based articular cartilage repair strategies.


Assuntos
Reatores Biológicos/microbiologia , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Transdução de Sinais/fisiologia , Agrecanas/metabolismo , Colágeno Tipo II/metabolismo , Colágeno Tipo III/metabolismo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isoformas de Proteínas/metabolismo , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais/genética , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
BMC Cancer ; 19(1): 308, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943930

RESUMO

BACKGROUND: Expression of Nodal, a member of the TGF-ß superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy. However, little is known about its involvement in ovarian tumorigenesis. Herein, we focused on the functional roles of Nodal in ovarian endometriosis-carcinoma lesions. METHODS: Regulation and function of Nodal and its associated molecules, including Smad2, GSK-3ß, and several cell kinetics-related molecules, were assessed using clinical samples consisting of 108 ovarian carcinomas and 33 endometriotic lesions, as well as ES-2 (ovarian clear cell carcinoma; OCCCa) and Ishikawa (endometrial carcinoma) cell lines. RESULTS: Nodal expression was significantly higher in endometriosis and OCCCa lesions as compared to that of non-OCCCas, with positive correlations to phosphorylated forms of both Smad2 (pSmad2) and GSK-3ß. When compared to endometriotic lesions, the expression of Nodal and pSmad2 was significantly decreased in OCCCa. Treatment of Ishikawa cells with TGF-ß1 resulted in transcriptional upregulation of Nodal, along with increased pSmad2 expression, while inhibition of GSK-3ß also induced an increase in Nodal expression at the posttranslational level. Both ES-2 and Ishikawa cells stably overexpressing Nodal had increased susceptibility to apoptosis in response to treatment with cisplatin and doxorubicin, respectively, together with higher cleaved caspase-3 expression and decreased Bcl2/Bax ratio. Moreover, the stable Nodal-overexpressing cells showed reduced cell proliferation, along with increased expression of p27kip1 and p21waf1. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in Nodal-positive as compared to Nodal-negative OCCCa. CONCLUSIONS: These findings suggest that Nodal is a multifunctional cytokine involved in the modulation of cell kinetics in ovarian endometriosis-OCCCa lesions.


Assuntos
Adenocarcinoma de Células Claras/metabolismo , Endometriose/metabolismo , Proteína Nodal/metabolismo , Neoplasias Ovarianas/metabolismo , Regulação para Cima , Adenocarcinoma de Células Claras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Proliferação de Células , Endometriose/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteína Nodal/genética , Neoplasias Ovarianas/genética , Fosforilação , Transdução de Sinais , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo
15.
Nat Commun ; 10(1): 1665, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971692

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-ß2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-ß signaling provides a potential way for the treatment of GATA4-deficient lung cancer.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Proteínas Wnt/metabolismo , Células A549 , Animais , Senescência Celular/genética , Regulação para Baixo , Feminino , Fator de Transcrição GATA4/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Regulação para Cima , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Life Sci ; 225: 20-28, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928408

RESUMO

AIMS: Increasing nicotinamide adenine dinucleotide (NAD+) by Nicotinamide riboside (NR) provides protective benefits in multiple disorders. However, the role of NR on liver fibrosis is unclear. We performed in vivo and in vitro experiments to test the hepatic protective effects of NR against liver fibrosis and the underlying mechanisms. MATERIALS AND METHODS: Mice were injected with CCl4 to establish liver fibrosis model. NR was given by gavage to explore the hepatic protection of NR. LX-2 cells were given a TGF-ß stimulation ±â€¯NR, the activation of LX-2 cells and the acetylation of Smads were analyzed. To further confirm the role of Sirt1 on the protective pathway of NR, we knockdown Sirt1 in LX-2 cells. KEY FINDINGS: We found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-ß, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway. SIGNIFICANCE: NR protected mice against liver fibrosis induced by CCl4. NR suppressed activation of hepatic stellate cells induced by TGF-ß. NR protects liver fibrosis via increasing the activity of Sirt1 and decreasing the expression of P300, resulting in the deacetylation of Smads in stellate cells.


Assuntos
Tetracloreto de Carbono/toxicidade , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Niacinamida/análogos & derivados , Substâncias Protetoras/farmacologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Acetilação , Animais , Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/farmacologia , Sirtuína 1/metabolismo , Fator de Crescimento Transformador beta/metabolismo
17.
Oxid Med Cell Longev ; 2019: 8639791, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931081

RESUMO

Background: As a key step in enhancing cancer cell invasion and metastasis, epithelial-mesenchymal transition (EMT) plays an important role in colorectal cancer progression. EMT is triggered by a variety of signaling pathways, among which the transforming growth factor ß (TGF-ß) signaling pathway has been implicated as a primary inducer. Accumulating evidence demonstrates that MnTE-2-PyP (chemical name: manganese(III) meso-tetrakis-(N-ethylpyridinium-2-yl), a superoxide dismutase (SOD) mimetic, inhibits TGF-ß signaling; however, its ability to inhibit TGF-ß-induced EMT in colorectal cancer has not yet been explored. Methods: To verify our hypothesis that MnTE-2-PyP attenuates TGF-ß-induced EMT, human colorectal cancer cells were treated with TGF-ß in the presence or absence of MnTE-2-PyP. Cells were analyzed by several techniques including western blotting, real-time quantitative PCR, transwell assay, and wound healing assay. Results: MnTE-2-PyP reverses cell phenotypes induced by TGF-ß in colon cancer cells. MnTE-2-PyP treatment significantly reduced the expression of mesenchymal markers but maintained epithelial marker expression. Mechanistically, MnTE-2-PyP suppressed the phosphorylated Smad2/3 protein levels induced by TGF-ß in SW480 cells, but MnTE-2-PyP failed to suppress TGF-ß-induced Slug and Snail expression in colorectal cells. Furthermore, MnTE-2-PyP effectively suppressed TGF-ß-mediated cell migration and invasion and the expression of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in colorectal cells. Conclusion: Taken together, we provide an in-depth mechanism by which MnTE-2-PyP inhibits colorectal cancer progression, supporting an important role for MnTE-2-PyP as an effective and innovative antitumor agent to enhance treatment outcomes in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Metaloporfirinas/metabolismo , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
18.
J Pharm Pharmacol ; 71(6): 1017-1028, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847938

RESUMO

OBJECTIVES: Investigating the antipulmonary fibrosis effect of mangiferin from Mangifera indica and the possible molecular mechanism. METHODS: In vivo, bleomycin (BLM)-induced pulmonary fibrosis experimental model was used for evaluating antipulmonary fibrosis effect of mangiferin. Histopathologic examination and collagen deposition were investigated by HE and Masson staining as well as detecting the content of hydroxyproline. The expression of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), TLR4 and p-P65 in lung tissue was analysed through immunofluorescence. Leucocytes and inflammatory cytokines including IL-1ß, IL-6, TNF-α and MCP-1 in bronchoalveolar lavage fluid were detected by cell counting and enzyme-linked immunosorbent assay. In vitro, TGF-ß1-induced A549 epithelial-mesenchymal transition (EMT) cell model was used for investigating the possible molecular mechanism. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay. Expression of all proteins was examined by Western blot. KEY FINDINGS: Oral administration of mangiferin could attenuate the severity of BLM-induced pulmonary fibrosis through increasing the survival rate, improving histopathological lesion and body weight loss as well as decreasing pulmonary index visibly. Pulmonary hydroxyproline content, TGF-ß1, and α-SMA levels were reduced significantly. The molecular mechanism of mangiferin for inhibiting pulmonary fibrosis is that it could obviously inhibit the occurrence of inflammation and the secretion of inflammatory cytokine through inhibiting activation of TLR4 and phosphorylation of p65. Meanwhile, EMT process was suppressed obviously by mangiferin through blocking the phosphorylation of Smad2/3 and reducing MMP-9 expression. Besides, mangiferin could significantly inhibit the process of oxidant stress through downregulating the intracellular ROS generation. CONCLUSIONS: Mangiferin attenuates BLM-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-ß1/Smad2/3 pathway.


Assuntos
Mangifera/classificação , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Xantonas/farmacologia , Células A549 , Animais , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Xantonas/isolamento & purificação
19.
J Ethnopharmacol ; 236: 258-262, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30836175

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Yi-Shen-Hua-Shi (YSHS) granule is a modern Chinese patent drug for treating chronic glomerulonephritis (CGN). It is derived from a traditional Chinese medicine formula Sheng-Yang-Yi-Wei decoction that is used to treat CGN in ancient China. Pharmacological activities of YSHS granule have not been reported. In this work, we investigated the anti-CGN effects and TGFß signaling-related mechanism of action of this herbal drug. MATERIALS AND METHODS: The rat model of CGN was established by injection of cationization-bovine serum albumin (C-BSA) for five weeks. After finishing C-BSA injection, drugs were intragastrically administered to the rats once daily for four weeks. Clinical signs were recorded daily. Serum and urine biochemical parameters were analyzed by respective kits. Protein levels were examined by Western blotting. Pathological changes of renal tissues were evaluated by HE and Masson's trichrome staining. RESULTS AND CONCLUSIONS: No significant differences in clinical signs and body weights were found among normal, model and drug treatment groups. Proteinuria; albuminuria; increased urine volume; elevated urea nitrogen, creatinine, total cholesterol and triglyceride levels in sera; decreased serum total protein and albumin; as well as renal pathological damage and fibrosis were observed in CGN model rats. YSHS granule ameliorated all the abnormal behavioral and biochemical changes in the model rats. Mechanical investigations showed that YSHS granule down-regulated proteins levels of TGFß1, phospho-Smad2/3 (Thr 8) and Smad4 in rat renal tissues. In conclusion, YSHS granule demonstrates therapeutic effects in a rat model of CGN, and inhibition of the TGFß/Smad signaling pathway is involved in the mechanism of action of the granule. This study provides a pharmacological basis for the use of modern YSHS granule and ancient Sheng-Yang-Yi-Wei decoction in treating CGN.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glomerulonefrite/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Animais , Doença Crônica/tratamento farmacológico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Medicina Tradicional Chinesa , Patentes como Assunto , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Soroalbumina Bovina/toxicidade , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Resultado do Tratamento
20.
Mol Immunol ; 109: 51-57, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852246

RESUMO

BACKGROUND: Asthma is a chronic disease involving inflamed airways, which were previously demonstrated, can be modulated by the mesenchymal stem cells derived from induced pluripotent stem cells (iPSC-MSCs). However, the long-term effects of iPSC-MSCs in inflamed airways are still unidentified. This study investigated the long-term effects and potential mechanisms involved in the immunomodulatory effects of iPSC-MSCs in the chronic mouse asthma model. METHODS: Both human iPSC-MSCs and bone marrow (BM)-MSCs were transplanted into the long-term ovalbumin-induced mice before sensitization phase or during the challenge phase. Airway hyper-respnsiveness measurement, immunohistochemistry and ELISA were employed to assess the effects of MSCs. In addition, Smad2/3 levels were assessed by western blot analysis to investigate the possible mechanism involved. RESULTS: The systemic administration of human iPSC-MSCs before the challenge protected the mice from the characters of the chronic allergic airway inflammation, in particular improving the airway remodeling and preventing fibrosis. In addition, the TGF-ß1/Smad pathway was identified involved in the immunomodulatory effects of iPSC-MSCs on chronic allergic airway inflammation. CONCLUSIONS: The study demonstrated that iPSC-MSCs are capable of preventing chronic allergic airway inflammation over a prolonged period, which further proved the iPSC-MSC therapeutic potential for allergic airway inflammation in a clinical scenario.


Assuntos
Hipersensibilidade/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pneumonia/terapia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/patologia , Camundongos Endogâmicos BALB C , Ovalbumina , Pneumonia/complicações , Pneumonia/patologia , Transdução de Sinais
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