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1.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
2.
PLoS One ; 15(8): e0237479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790806

RESUMO

OBJECTIVE: As native cartilage consists of different phenotypical zones, this study aims to fabricate different types of neocartilage constructs from collagen hydrogels and human mesenchymal stromal cells (MSCs) genetically modified to express different chondrogenic factors. DESIGN: Human MSCs derived from bone-marrow of osteoarthritis (OA) hips were genetically modified using adenoviral vectors encoding sex-determining region Y-type high-mobility-group-box (SOX) 9, transforming growth factor beta (TGFB) 1 or bone morphogenetic protein (BMP) 2 cDNA, placed in type I collagen hydrogels and maintained in serum-free chondrogenic media for three weeks. Control constructs contained unmodified MSCs or MSCs expressing GFP. The respective constructs were analyzed histologically, immunohistochemically, biochemically, and by qRT-PCR for chondrogenesis and hypertrophy. RESULTS: Chondrogenesis in MSCs was consistently and strongly induced in collagen I hydrogels by the transgenes SOX9, TGFB1 and BMP2 as evidenced by positive staining for proteoglycans, chondroitin-4-sulfate (CS4) and collagen (COL) type II, increased levels of glycosaminoglycan (GAG) synthesis, and expression of mRNAs associated with chondrogenesis. The control groups were entirely non-chondrogenic. The levels of hypertrophy, as judged by expression of alkaline phosphatase (ALP) and COL X on both the protein and mRNA levels revealed different stages of hypertrophy within the chondrogenic groups (BMP2>TGFB1>SOX9). CONCLUSIONS: Different types of neocartilage with varying levels of hypertrophy could be generated from human MSCs in collagen hydrogels by transfer of genes encoding the chondrogenic factors SOX9, TGFB1 and BMP2. This technology may be harnessed for regeneration of specific zones of native cartilage upon damage.


Assuntos
Proteína Morfogenética Óssea 2/genética , Hidrogéis/química , Fatores de Transcrição SOX9/genética , Fator de Crescimento Transformador beta1/genética , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Cartilagem/citologia , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Condrogênese/genética , Colágeno Tipo I/química , Colágeno Tipo X/genética , Meios de Cultura Livres de Soro/química , Glicosaminoglicanos/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , RNA Mensageiro/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
3.
PLoS One ; 15(8): e0238076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857768

RESUMO

Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFß signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfß1/ß2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFß1/ß2) and diminishes activity of TGFß signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFß components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFß ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFß signaling pathway. Finally, we show that pharmacological inhibition of TGFß signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.


Assuntos
Subunidade 1 do Complexo Mediador/genética , Regeneração/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Animais , Linhagem da Célula , Movimento Celular , Proliferação de Células , Regulação para Baixo , Epiderme/fisiologia , Queratinócitos/citologia , Queratinócitos/metabolismo , Subunidade 1 do Complexo Mediador/antagonistas & inibidores , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Pele/metabolismo , Pele/patologia , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta2/genética , Regulação para Cima
4.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 40(7): 988-994, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32701245

RESUMO

OBJECTIVE: To study the anti- fibrotic effect of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) and explore the mechanism. METHODS: Twenty-four C57 BL/6 mice were divided into 4 groups (n=6), including the control group treated with intratracheal injection of saline (3 mg/kg); lung fibrosis model group with intratracheal injection of 1.5 mg/mL bleomycin solution (prepared with saline, 3 mg/kg); EXOs1 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 µg/250 µL, given by tail vein injection on the next day after modeling); and EXOs2 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 µg/250 µL, given by tail vein injection on the 10th day after modeling). At 21 days after modeling, pulmonary index, lung tissue pathology and collagen deposition in the mice were assessed using HE staining and Masson staining. The expression level of TGF-ß1 was detected using ELISA, and vimentin, E-cadherin and phosphorylated Smad2/3 (p-Smad2/3) were detected using immunohistochemical staining. CCK8 assay was used to evaluate the effect of hUCMSCEXOs on the viability of A549 cells, and Western blotting was used to detect the expression levels of p-Smad2/3, vimentin, and E-cadherin in the cells. RESULTS: Compared with those in the model group, the mice treated with hUCMSC-EXOs showed significantly reduced the pulmonary index (P < 0.05), collagen deposition, lung tissue pathologies, lowered expressions of TGF-ß1 (P < 0.05), vimentin, and p-Smad2/3 and increased expression of E-cadherin. hUCMSC-EXOs given on the second day produced more pronounced effect than that given on the 11th day (P < 0.05). CCK8 assay results showed that hUCMSC-EXOs had no toxic effects on A549 cells (P > 0.05). Western blotting results showed that hUCMSC-EXOs treatment significantly increased the expression of E-cadherin and decreased the expressions of p-Smad2/3 and vimentin in the cells. CONCLUSIONS: hUCMSC-EXOs can alleviate pulmonary fibrosis in mice by inhibiting epithelialmesenchymal transition activated by the TGF-ß1/Smad2/3 signaling pathway, and the inhibitory effect is more obvious when it is administered on the second day after modeling.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Fibrose Pulmonar , Animais , Transição Epitelial-Mesenquimal , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Fibrose Pulmonar/terapia , Fator de Crescimento Transformador beta1/genética , Cordão Umbilical/citologia
5.
Clin Sci (Lond) ; 134(12): 1433-1448, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32478392

RESUMO

Recent identification of an RNA-binding protein (HuR) that regulates mRNA turnover and translation of numerous transcripts via binding to an ARE in their 3'-UTR involved in inflammation and is abnormally elevated in varied kidney diseases offers a novel target for the treatment of renal inflammation and subsequent fibrosis. Thus, we hypothesized that treatment with a selective inhibition of HuR function with a small molecule, KH-3, would down-regulate HuR-targeted proinflammatory transcripts thereby improving glomerulosclerosis in experimental nephritis, where glomerular cellular HuR is elevated. Three experimental groups included normal and diseased rats treated with or without KH-3. Disease was induced by the monoclonal anti-Thy 1.1 antibody. KH-3 was given via daily intraperitoneal injection from day 1 after disease induction to day 5 at the dose of 50 mg/kg BW/day. At day 6, diseased animals treated with KH-3 showed significant reduction in glomerular HuR levels, proteinuria, podocyte injury determined by ameliorated podocyte loss and podocin expression, glomerular staining for periodic acid-Schiff positive extracellular matrix proteins, fibronectin and collagen IV and mRNA and protein levels of profibrotic markers, compared with untreated disease rats. KH-3 treatment also reduced disease-induced increases in renal TGFß1 and PAI-1 transcripts. Additionally, a marked increase in renal NF-κB-p65, Nox4, and glomerular macrophage cell infiltration observed in disease control group was largely reversed by KH-3 treatment. These results strongly support our hypothesis that down-regulation of HuR function with KH-3 has therapeutic potential for reversing glomerulosclerosis by reducing abundance of pro-inflammatory transcripts and related inflammation.


Assuntos
Proteína Semelhante a ELAV 1/antagonistas & inibidores , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite/metabolismo , Nefrite/patologia , Animais , Biomarcadores/metabolismo , Peso Corporal , Polaridade Celular , Colágeno/genética , Colágeno/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Humanos , Inflamação/patologia , Testes de Função Renal , Glomérulos Renais/fisiopatologia , Macrófagos/metabolismo , Masculino , Monócitos/metabolismo , NADPH Oxidase 4/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Antígenos Thy-1 , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
6.
Cancer Sci ; 111(7): 2310-2324, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32372436

RESUMO

ETS homologous factor (EHF) plays a critical function in epithelial cell differentiation and proliferation. However, the roles of EHF in cancer remain largely unknown. In the present study, we investigated the expression levels, precise function and mechanism of EHF in colorectal carcinoma (CRC). We observed significantly elevated EHF expression in CRC cell lines and tissues. EHF overexpression correlated positively with poor differentiation, advanced T stage, and shorter overall survival of CRC patients. Function experiments revealed that EHF overexpression promoted CRC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EHF could directly upregulate transforming growth factor ß1 (TGF-ß1) expression at the transcription level, thereby activating canonical TGF-ß signaling. Our findings provide novel insights into the mechanisms of EHF in tumorigenesis, invasion, and metastasis of CRC, which may help to provide new therapeutic targets for CRC intervention.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Transporte Proteico , Fatores de Transcrição/genética , Carga Tumoral
7.
Cancer Sci ; 111(7): 2620-2634, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32412154

RESUMO

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.


Assuntos
Linfedema/etiologia , Linfedema/metabolismo , Complicações Pós-Operatórias , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Humanos , Imuno-Histoquímica , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Linfedema/diagnóstico por imagem , Linfedema/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Ratos , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta1/genética
8.
Phytomedicine ; 72: 153232, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32460034

RESUMO

BACKGROUND: In chronic kidney disease, although fibrosis prevention is beneficial, few interventions are available that specifically target fibrogenesis. Poricoic acid A (PAA) isolated from Poria cocos exhibits anti-fibrotic effects in the kidney, however the underlying mechanisms remain obscure. PURPOSE: We isolated PAA and investigated its effects and the underlying mechanisms in renal fibrosis. STUDY DESIGN: Unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (Nx) animal models and TGF-ß1-induced renal fibroblasts (NRK-49F) were used to investigate the anti-fibrotic activity of PAA and its underlying mechanisms. METHODS: Western blots, qRT-PCR, immunofluorescence staining, co-immunoprecipitation and molecular docking methods were used. Knock-down and knock-in of adenosine monophosphate-activated protein kinase (AMPK) in the UUO model and cultured NRK-49F cells were employed to verify the mechanisms of action of PAA. RESULTS: PAA improved renal function and alleviated fibrosis by stimulating AMPK and inhibiting Smad3 specifically in Nx and UUO models. Reduced AMPK activity was associated with Smad3 induction, fibroblast activation, and the accumulation and aberrant remodelling of extracellular matrix (ECM) in human renal puncture samples and cultured NRK-49F cells. PAA stimulated AMPK activity and decreased fibrosis in a dose-dependent manner, thus showing that AMPK was essential for PAA to exert its anti-fibrotic effects. AMPK deficiency reduced the anti-fibrotic effects of PAA, while AMPK overexpression enhanced its effect. CONCLUSION: PAA activated AMPK and further inhibited Smad3 specifically to suppress fibrosis by preventing aberrant ECM accumulation and remodelling and facilitating the deactivation of fibroblasts.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Matriz Extracelular/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Rim/patologia , Triterpenos/farmacologia , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/genética , Animais , Estudos de Casos e Controles , Linhagem Celular , Relação Dose-Resposta a Droga , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
9.
Am J Kidney Dis ; 76(1): 100-108, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32354559

RESUMO

RATIONALE & OBJECTIVE: Recent studies in the human immunodeficiency virus (HIV)-infected population have suggested that there are genetic predispositions to the development of chronic kidney disease (CKD) in this context. We investigated the association of genetic polymorphisms of the genes encoding apolipoprotein L1 (APOL1), transforming growth factor ß1 (TGF-ß1; a profibrotic cytokine), and heme oxygenase 1 (HMOX1) with prevalent CKD among adults with and without HIV infection. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: West African adults including 217 HIV-infected patients with CKD (HIV+/CKD+ group), 595 HIV-infected patients without CKD (HIV+/CKD- group), 269 with CKD and no HIV infection (HIV-/CKD+ group), and 114 with neither CKD nor HIV (HIV-/CKD- group). EXPOSURE: The genetic polymorphisms with reference single-nucleotide polymorphism (rs) identification numbers rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1 G1 risk allele), rs73885319 (APOL1 G1 risk allele), rs71785313 (APOL1 G2 risk allele), and rs743811 (HMOX1); HIV. OUTCOME: CKD. ANALYTICAL APPROACH: Single-nucleotide polymorphism (SNP) genotyping of rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1), rs73885319 (APOL1), rs71785313 (APOL1), and rs743811 (HMOX1) was performed. Hardy-Weinberg equilibrium was evaluated for all SNPs, and minor allele frequencies were reported. A case-control analysis was performed, and multivariable logistic regression was used to control for potential confounders. RESULTS: Minor allele frequencies for TGF-ß1 (rs1800469, rs1800470, and rs1800471), APOL1 (rs60910145, rs73885319, and rs71785313), and HMOX1 (rs743811) were 0.25, 0.46, 0.46, 0.44, 0.45, 0.17, and 0.14, respectively. Among HIV-positive individuals, only TGF-ß1 rs1800470 (GG vs AA), APOL1 (in the recessive model), and hypertension were associated with prevalent CKD (adjusted ORs of 0.44 [95% CI, 0.20-0.97], 2.54 [95% CI, 1.44-4.51], and 2.17 [95% CI, 1.35-3.48], respectively). No SNP polymorphisms were associated with prevalent CKD among HIV-negative individuals. LIMITATIONS: The lack of histopathology data for proper categorization of the type of HIV-related nephropathy. CONCLUSIONS: APOL1 polymorphisms were highly prevalent in this population and among adult patients infected with HIV and were associated with increased CKD risk. The TGF-ß1 (rs1800470) polymorphism was associated with reduced risk, and HMOX1 polymorphisms were unassociated with CKD.


Assuntos
Apolipoproteína L1/genética , Infecções por HIV/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia
10.
J Cancer Res Ther ; 16(1): 144-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362625

RESUMO

Introduction: Laryngeal cancer is the most common head-and-neck malignancies with more than 20% of all cases. The vast majority of tumors are squamous cell carcinoma (SCC). Several genes encoding different cytokines may play crucial roles in host susceptibility to cancer because cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. Materials and Methods: The association between cytokine gene polymorphisms with primary laryngeal SCC was investigated. DNA samples were obtained from a Turkish population of eighty patients with primary cancer and fifty healthy controls. Results: All genotyping (interferon-gamma, transforming growth factor-ß1 [TGF-ß1], tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, and IL-10) experiments were performed using polymerase chain reaction sequence-specific primers. When compared to the healthy controls, the frequencies of TGF-ß1 codon 25 (rs1800471) GC genotype and 25 C allele were significantly more common in the patient group. Conclusions: These results suggest that TGF-ß1 gene polymorphisms may affect host susceptibility to laryngeal cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Citocinas/genética , Predisposição Genética para Doença , Neoplasias Laríngeas/genética , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Citocinas/metabolismo , Humanos , Interleucina-10/genética , Interleucina-6/genética , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Turquia/epidemiologia
11.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G989-G999, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32363890

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. However, NAFLD patients generally do not respond to treatment with testosterone alone. We investigated the innate immune mechanisms underlying the effects of treatment with testosterone alone, estrogen alone, or combined testosterone and estrogen on high-fat diet (HFD)-induced NAFLD due to testosterone deficiency. Orchiectomized (OCX) male Rag2-/- mice were used as a model of testosterone deficiency. To assess NAFLD severity, NAFLD activity score (NAS) is adopted. Moreover, immunological change was analyzed by multicolor flow cytometry. Treatment with both testosterone and estrogen significantly decreased body weight to that of the sham mice/normal diet (ND). NAS and liver fibrosis in OCX-HFD mice were significantly deteriorated, and treatment with testosterone and estrogen improved same as sham-ND mice. HFD increased the ratio of both type 2 and 3 innate lymphoid cells (ILC2s and ILC3s) to CD45-positive cells in the liver. Treatment with testosterone alone decreased the ratio of ILC2 to CD45 but not the ILC3-to-CD45 ratio. Addition of estrogen to the treatment reduced the ratios of ILC2-to-CD45 and ILC3-to-CD45 to the same level observed in sham-HFD mice. Moreover, OCX-HFD mice had a decreased proportion of M2 macrophages compared with sham-ND mice. Treatment with testosterone alone did not restore the proportion of M2 macrophages; however, combination treatment with both estrogen and testosterone increased that to the same level as that in sham-HFD mice. Treatment with both testosterone and estrogen improves liver fibrosis and decreases ILC3 and increases M2 macrophage abundance in the liver.NEW & NOTEWORTHY The progression of nonalcoholic fatty liver disease (NAFLD) is associated with testosterone deficiency. NAFLD patients generally do not respond to treatment with testosterone alone. In animal studies, treatment with testosterone and estrogen reduced the ratios of ILC2:CD45 and ILC3:CD45 and increased M2 macrophages in liver. Our study suggests, based on our immunological data, that a combination of estrogen and testosterone may be clinically relevant for the treatment of NAFLD in patients with male menopause.


Assuntos
Estradiol/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Testosterona/farmacologia , Aminoácidos , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Cromo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação para Baixo , Estradiol/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Cirrose Hepática , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Knockout , Ácidos Nicotínicos , Hepatopatia Gordurosa não Alcoólica/patologia , Orquiectomia , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Testosterona/administração & dosagem , Testosterona/deficiência , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
12.
Gene ; 744: 144633, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32240778

RESUMO

BACKGROUND: Several studies have examined the association between transforming growth factor-ß (TGF-ß) genetic polymorphisms and chronic obstructive pulmonary disease (COPD) risk, but the results remained inconclusive and controversial. AIMS: We aimed to examine the correlation between TGF-ß genetic polymorphisms and COPD risk through a comprehensive meta-analysis. Additionally, changes in circulating TGF-ß concentrations across genotypes of TGF-ß genetic polymorphisms were analyzed. METHODS: Literature search, quality assessment, and data extraction were completed independently and in duplicate. Data are expressed in odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: A total of 12 articles, involving 14 independent studies and 7 170 participants, were meta-analyzed for the correlation of five polymorphisms (rs2241712, rs1800469, rs1982073, rs6957, and rs2241718) in TGF-ß gene with COPD risk. Under the allele model, no statistical significance was observed for all polymorphisms associated with COPD risk. Subsidiary analyses indicated that country, COPD stage, and diagnosis of COPD were potential sources of between-study heterogeneity. Filled full plots revealed no missing studies for all studied polymorphisms, except rs1982073. Genotype-phenotype analyses showed that carriers of rs1800469 CT genotype had significantly higher concentrations of circulating TGF-ß than those with CC genotype in COPD patients (WMD: 0.28 pg/ml, 95% CI: 0.01 to 0.56). CONCLUSION: Our findings failed to support the candidacy of TGF-ß gene in the development of COPD, whereas the contribution of TGF-ß gene to COPD might be ethnicity- and stage-dependent.


Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , Fator de Crescimento Transformador beta1/genética , Correlação de Dados , Genótipo , Humanos , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/sangue , Fatores de Risco , Fator de Crescimento Transformador beta1/sangue
13.
PLoS One ; 15(4): e0232055, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324796

RESUMO

Chronic kidney diseases affect more than 800 million people globally and remain a high unmet need. Various therapeutic targets are currently under evaluation in pre-clinical and clinical studies. Because the growth arrest specific gene 6 (Gas6)/AXL pathway has been implicated in the pathogenesis of kidney diseases, we generated a novel selective and potent AXL inhibitor, CH5451098, and we evaluated its efficacy and elucidated its mechanism in an NEP25 mouse model that follows the clinical course of glomerular nephritis. In this model, CH5451098 significantly ameliorated the excretion of urinary albumin and elevation of serum creatinine. Additionally, it also inhibited tubulointerstitial fibrosis and tubular damage. To elucidate the mechanism behind these changes, we analyzed the effect of CH5451098 against transforming growth factor ß1 (TGFß1) and Gas6, which is a ligand of AXL receptor, in NRK-52E renal tubular epithelial cells. CH5451098 inhibited epithelial-to-mesenchymal transition (EMT) caused by the synergistic effects of TGFß1 and Gas6 in NRK-52E cells. This inhibition was also observed in NEP25 mice. Taken together, these results suggest that CH5451098 could ameliorate kidney dysfunction in glomerular nephritis by inhibiting EMT in tubular cells. These results reveal that AXL strongly contributes to the disease progression of glomerular nephritis.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glomerulonefrite/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Túbulos Renais/citologia , Rim/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Albuminas/análise , Animais , Linhagem Celular , Creatinina/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/fisiopatologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/efeitos dos fármacos , Testes de Função Renal , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Fator de Crescimento Transformador beta1/genética
14.
Am J Physiol Renal Physiol ; 318(5): F1210-F1219, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200666

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-ß1 (TGF-ß1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 µL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated (P < 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-ß1, TGF-ß receptor type I, and TGF-ß receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and -9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration (P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-ß1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-ß1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.


Assuntos
Lesão Renal Aguda/etiologia , Meios de Contraste , Rim/metabolismo , Insuficiência Renal Crônica/complicações , Ácidos Tri-Iodobenzoicos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose , Artérias Carótidas , Hipóxia Celular , Proliferação de Células , Colágeno/genética , Colágeno/metabolismo , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Injeções Intra-Arteriais , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Nefrectomia , Fosforilação , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ácidos Tri-Iodobenzoicos/administração & dosagem
15.
Am J Hum Genet ; 106(4): 559-569, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197075

RESUMO

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- ß1) and anchors it on the cell surface; this anchoring is required for activation of TGF-ß1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-ß1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-ß1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-ß1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-ß1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-ß1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.


Assuntos
Encefalopatias/genética , Calcinose/genética , Variação Genética/genética , Proteínas de Ligação a TGF-beta Latente/genética , Doenças Neurodegenerativas/genética , Fator de Crescimento Transformador beta1/genética , Alelos , Feminino , Células HEK293 , Humanos , Lactente , Macrófagos/patologia , Masculino , Microglia/patologia
16.
Nat Commun ; 11(1): 1539, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210242

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Proteínas de Bactérias/imunologia , Fibrose Pulmonar Idiopática/imunologia , Peptídeos/imunologia , Staphylococcus/imunologia , Idoso , Animais , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/análise , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Bactérias/análise , Proteínas de Bactérias/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Voluntários Saudáveis , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/microbiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Peptídeos/análise , Peptídeos/metabolismo , Staphylococcus/metabolismo , Staphylococcus/patogenicidade , Exacerbação dos Sintomas , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
17.
Nature ; 578(7796): 610-614, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32076265

RESUMO

The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation1,2. The molecular basis of this bi-directional communication remains to be fully determined. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically γδ T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGFß1 in parenchymal cells via the IL-17 receptor C (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGFß1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGFß1 expression. Ablating γδ Τ cells and the IL-17RC signalling pathway also impairs sympathetic innervation in other tissues such as salivary glands. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/inervação , Tecido Adiposo/metabolismo , Interleucina-17/metabolismo , Sistema Nervoso Simpático/fisiologia , Linfócitos T/metabolismo , Termogênese , Tecido Adiposo Marrom/metabolismo , Animais , Interleucina-17/deficiência , Interleucina-17/genética , Masculino , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Tecido Parenquimatoso/citologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
18.
Nat Commun ; 11(1): 722, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024825

RESUMO

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFß1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFß levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.


Assuntos
Queimaduras/patologia , Monócitos/patologia , Ossificação Heterotópica/patologia , Cicatrização/fisiologia , Animais , Antígeno CD47/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Macrófagos/patologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peptídeos/farmacologia , Fagocitose , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
19.
Toxicol Appl Pharmacol ; 391: 114916, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035996

RESUMO

Fibroblast-to-myofibroblast differentiation is one of the most important characteristics of pulmonary fibrosis, and screening natural compounds targeting fibroblast differentiation is always a promising approach to discover drug candidates for treatment of pulmonary fibrosis. Trehalose reportedly has many potential medical applications, especially in treating neurodegeneration diseases. However, it remains unclear whether trehalose suppresses lung fibroblast differentiation. In this work, we found that trehalose decreased the expression levels of α-smooth muscle actin (α-SMA) following the induction of transforming growth factor ß1 (TGF-ß1) in pretreatment, co-treatment, and post-treatment groups. Trehalose also reduced the production of type I collagen, lung fibroblast-containing gel contractility and cell filament formation in TGF-ß1-stimulated MRC-5 cells. Although trehalose is a known autophagy inducer, our results showed that its suppressive effect on fibroblast differentiation was not via trehalose-induced autophagy. And it did not affect canonical TGFß/Smad2/3 pathway. By applying proteomic profiling technology, we demonstrated that the downregulation of ß-catenin was involved in the trehalose-repressive action on fibroblast differentiation. The ß-catenin agonist, SKL2001, reversed the suppressive effect of trehalose on fibroblast differentiation. Overall, these experiments demonstrated that trehalose suppressed fibroblast differentiation via the downregulation of ß-catenin, but not through canonical autophagy and TGFß/Smad2/3 pathway, which is not only a novel understanding of trehalose, but also quite helpful for in vivo research of trehalose on pulmonary fibrosis in future.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pulmão/citologia , Miofibroblastos/efeitos dos fármacos , Proteômica/métodos , Fator de Crescimento Transformador beta1/genética , Trealose/farmacologia , Actinas/biossíntese , Actinas/genética , Autofagia/efeitos dos fármacos , Linhagem Celular , Colágeno Tipo I/biossíntese , Regulação para Baixo , Humanos , Imidazóis/farmacologia , Isoxazóis/farmacologia , Fibrose Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Trealose/antagonistas & inibidores , beta Catenina/agonistas , beta Catenina/antagonistas & inibidores
20.
J Mol Biol ; 432(7): 2030-2041, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32061928

RESUMO

AIMS: Several signaling pathways contribute to endothelial-mesenchymal transitions and vascular calcification, including bone morphogenetic protein (BMP) and transforming growth factor (TGF) ß signaling. The transcription factor homeobox D3 (Hoxd3) is known to regulate an invasive endothelial phenotype, and the aim of the study is to determine if HOXD3 modulates BMP and TGFß signaling in the endothelium. METHODS AND RESEARCH: We report that the endothelium with high BMP activity due to the loss of BMP inhibitor matrix Gla protein (MGP) shows induction of Hoxd3. HOXD3 is part of a BMP-triggered cascade. When activated by BMP9, activin receptor-like kinase (ALK) 1 induces HOXD3 expression. Hoxd3 promoter is a direct target of phosphorylated (p) SMAD1, a mediator of BMP signaling. High BMP activity further results in enhanced TGFß signaling due to induction of TGFß1 and its receptor, ALK5. This is mediated by HOXD3, which directly targets the Tgfb1 promoter. Finally, TGFß1 and BMP9 stimulate the expression of MGP, which limits the enhanced ALK1 induction by counteracting BMP4. The cascade of BMP9-HOXD3-TGFß also affects Notch signaling and angiogenesis through induction of Notch ligand Jagged 2 and suppression of Notch ligand delta-like 4 (Dll4). CONCLUSION: The results suggest that HOXD3 is a novel link between BMP9/ALK1 and TGFß1/ALK5 signaling. TRANSLATIONAL PERSPECTIVE: BMP and TGFß signaling are instrumental in vascular disease such as vascular calcification and atherosclerosis. This study demonstrated a novel type of cross talk between endothelial BMP and TGFß signaling as mediated by HOXD3. The results provide a possible therapeutic approach to control dysfunctional BMP and TGFß signaling by regulating HOXD3.


Assuntos
Receptores de Activinas Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Neovascularização Fisiológica , Proteínas/fisiologia , Receptores Notch/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Receptores de Activinas Tipo II/genética , Animais , Proteínas de Ligação a DNA/genética , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Fator 2 de Diferenciação de Crescimento/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Receptores Notch/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética
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