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1.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
2.
Int J Nanomedicine ; 15: 5825-5838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821104

RESUMO

Background and Purpose: The extracellular matrix (ECM) derived from bone marrow mesenchymal stem cells (BMSCs) has been used in regenerative medicine because of its good biological activity; however, its poor mechanical properties limit its application in bone regeneration. The purpose of this study is to construct a three dimensional-printed hydroxyapatite (3D-HA)/BMSC-ECM composite scaffold that not only has biological activity but also sufficient mechanical strength and reasonably distributed spatial structure. Methods: A BMSC-ECM was first extracted and formed into micron-sized particles, and then the ECM particles were modified onto the surface of 3D-HA scaffolds using an innovative linking method to generate composite 3D-HA/BMSC-ECM scaffolds. The 3D-HA scaffolds were used as the control group. The basic properties, biocompatibility and osteogenesis ability of both scaffolds were tested in vitro. Finally, a critical skull defect rat model was created and the osteogenesis effect of the scaffolds was evaluated in vivo. Results: The compressive modulus of the composite scaffolds reached 9.45±0.32 MPa, which was similar to that of the 3D-HA scaffolds (p>0.05). The pore size of the two scaffolds was 305±47 um and 315±34 um (p>0.05), respectively. A CCK-8 assay indicated that the scaffolds did not have cytotoxicity. The composite scaffolds had good cell adhesion ability, with a cell adhesion rate of up to 76.00±6.17% after culturing for 7 hours, while that of the 3D-HA scaffolds was 51.85±4.77% (p<0.01). In addition, the composite scaffold displayed higher alkaline phosphatase (ALP) activity, osteogenesis-related mRNA expression, and calcium nodule formation, thus confirming that the composite scaffolds had good osteogenic activity. The composite scaffolds exhibited good bone repair in vivo and were superior to the 3D-HA scaffolds. Conclusion: We conclude that BMSC-ECM is a good osteogenic material and that the composite scaffolds have good osteogenic ability, which provides a new method and concept for the repair of bone defects.


Assuntos
Durapatita/farmacologia , Matriz Extracelular/metabolismo , Células-Tronco Mesenquimais/citologia , Tecidos Suporte/química , Animais , Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Hidrodinâmica , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/ultraestrutura , Osteogênese/efeitos dos fármacos , Osteogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Cicatrização/efeitos dos fármacos
3.
Int J Nanomedicine ; 15: 4943-4956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764927

RESUMO

Background: Hydroxyapatite (HA) [Ca5(PO4)3(OH)] is a naturally occurring calcium phosphate which makes up 60-70% of the dry weight of human bones. Nano-scale HA particles are increasingly being used as carriers for controlled and targeted delivery of bioactive agents like drugs, proteins, and nucleic acids due to their high porosity, negative charge, and biodegradability. Purpose: Although much effort has been devoted to understanding the delivery kinetics and effects of the payloads in such carriers, a thorough understanding of the influence of the carriers themselves is lacking. Methods: HA particles (300 µg/mL) were administered to primary human dermal fibroblasts (HDFs). The uptake and intracellular localization of the particles were determined by flow cytometry, confocal imaging, and transmission electron microscopy (TEM). Immunological assays and PCR were performed to determine the levels of pro-inflammatory cytokines and collagens in cell lysates and media supernatant. Results: The current study explores the effects of poly-dispersed HA particles on primary HDFs as a model system. The majority of the particles were determined to range between 150 and 200 nm in diameter. Upon exposure to HA suspensions, primary HDFs internalized the particles by endocytosis within 6 hours of exposure, showing maximum uptake at 72 hours following which the particles were exocytosed by 168 hours. This correlated to reduced secretion of various pro-inflammatory and pro-collagenic cytokines. Biochemical analysis further revealed a reduction in Type I collagen expression and secretion. Conclusion: HA particles have an immune-modulatory effect on dermal fibroblasts and reduce collagen production, which may impact the integrity of the extracellular matrix (ECM). This study demonstrates the need to consider the secondary effects of particulate carriers like HA, beyond basic cytotoxicity, in the specific tissue environment where the intended function is to be realized.


Assuntos
Colágeno/metabolismo , Durapatita/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Pele/citologia , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Durapatita/química , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Humanos
4.
An Acad Bras Cienc ; 92(2): e20190107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32556049

RESUMO

The Hancornia speciosa latex reveals angiogenic, osteogenic, and anti-inflammatory properties, which present its potential for developing of wound healing drugs; however, the latex compounds responsible for angiogenesis remain unknown. One strategy to screen these active compounds is evaluation of latex fractions. This study aimed to obtain different fractions of latex and evaluate its angiogenic activity separately using the chick chorioallantoic membrane (CAM) assay. The serum (SE) fraction was responsible for angiogenesis, which was subject to biochemical characterization and computational simulations in order to understand the contribution of H. speciosa latex in wound healing process. Our results revealed weak antioxidant potential and absence of antimicrobial activity in the SE fraction. Phytochemical analysis identified chlorogenic acids (CGA) as the main compound of SE fraction. CGA bioactivity predictions identify different molecules associated with extracellular matrix (ECM) remodeling, such as metalloproteinases, which also are overexpressed in our CAM assay experiment. Docking simulations revealed the interactions between CGA and matrix metalloproteinase 2. In conclusion, SE latex fraction stimulates angiogenesis and may influence ECM remodeling. These properties may contribute to the wound healing process, and also confirm the widespread use of this plant.


Assuntos
Indutores da Angiogênese/farmacologia , Apocynaceae/química , Membrana Corioalantoide/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Látex/farmacologia , Extratos Vegetais/farmacocinética , Indutores da Angiogênese/isolamento & purificação , Animais , Apocynaceae/classificação , Embrião de Galinha , Cromatografia Líquida de Alta Pressão , Látex/isolamento & purificação
5.
PLoS One ; 15(6): e0234641, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574164

RESUMO

Chondrocytes, comparable to many cells from the connective tissue, dedifferentiate and end up in a similar fibroblastoid cell type, marked by the loss of the specific expression pattern. Here, chondrocytes isolated from osteoarthritic (OA) patients were investigated. The OA chondrocytes used in this work were not affected by the loss of specific gene expression upon cell culture. The mRNA levels of known cartilage markers, such as SOX5, SOX6, SOX9, aggrecan and proteoglycan 4, remained unchanged. Since chondrocytes from OA and healthy tissue show different DNA methylation patterns, the underlying mechanisms of cartilage marker maintenance were investigated with a focus on the epigenetic modification by DNA methylation. The treatment of dedifferentiated chondrocytes with the DNA methyltransferase inhibitor 5-aza-2´-deoxycytidine (5-aza-dC) displayed no considerable impact on the maintenance of marker gene expression observed in the dedifferentiated state, while the chondrogenic differentiation capacity was compromised. On the other hand, the pre-cultivation with 5-aza-dC improved the osteogenesis and adipogenesis of OA chondrocytes. Contradictory to these effects, the DNA methylation levels were not reduced after treatment for four weeks with 1 µM 5-aza-dC. In conclusion, 5-aza-dC affects the differentiation capacity of OA chondrocytes, while the global DNA methylation level remains stable. Furthermore, dedifferentiated chondrocytes isolated from late-stage OA patients represent a reliable cell source for in vitro studies and disease models without the need for additional alterations.


Assuntos
Condrócitos/patologia , Decitabina/farmacologia , Osteoartrite/patologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Biomarcadores/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Forma Celular/efeitos dos fármacos , Forma Celular/genética , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Osteoartrite/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética
6.
Life Sci ; 256: 117909, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512009

RESUMO

Hepatic fibrosis (HF) is a wound-healing response that occurs during chronic liver injury and features by an excessive accumulation of extracellular matrix (ECM) components. Activation of hepatic stellate cell (HSC), the leading effector in HF, is responsible for overproduction of ECM. It has been documented that transforming growth factor-ß1 (TGF-ß1) stimulates superfluous accumulation of ECM and triggers HSCs activation mainly via canonical Smad-dependent pathway. Also, the pro-fibrogenic TGF-ß1 is correlated with generation of reactive oxygen species (ROS) and inhibition of antioxidant mechanisms. Moreover, involvement of oxidative stress (OS) can be clearly elucidated as a fundamental event in liver fibrogenesis. Nuclear factor erythroid 2-related factor 2-antioxidant response elements (Nrf2-AREs) pathway, a group of OS-mediated transcription factors with diverse downstream targets, is associated with the induction of diverse detoxifying enzymes and the most pivotal endogenous antioxidative system. More specifically, Nrf2-AREs pathway has recently assigned as a new therapeutic target for cure of HF. The overall goal of this review will focus on recent findings about activation of Nrf2-AREs-mediated antioxidant and suppression of profibrotic TGF-ß1/Smad3 pathway in the liver, providing an overview of recent advances in transcriptional repressors that dislocated during HF formation, and highlighting possible novel therapeutic targets for liver fibrosis.


Assuntos
Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antioxidantes/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
7.
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
8.
J Vis Exp ; (159)2020 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-32449715

RESUMO

A biomimetic NM was developed to serve as a tissue-engineering biological scaffold, which can enhance stem cell anchorage. The biomimetic NM is formed from JBNTs and FN through self-assembly in an aqueous solution. JBNTs measure 200-300 µm in length with inner hydrophobic hollow channels and outer hydrophilic surfaces. JBNTs are positively charged and FNs are negatively charged. Therefore, when injected into a neutral aqueous solution, they are bonded together via noncovalent bonding to form the NM bundles. The self-assembly process is completed within a few seconds without any chemical initiators, heat source, or UV light. When the pH of the NM solution is lower than the isoelectric point of FNs (pI 5.5-6.0), the NM bundles will self-release due to the presence of positively charged FN. NM is known to mimic the extracellular matrix (ECM) morphologically and hence, can be used as an injectable scaffold, which provides an excellent platform to enhance hMSC adhesion. Cell density analysis and fluorescence imaging experiments indicated that the NMs significantly increased the anchorage of hMSCs compared to the negative control.


Assuntos
Biomimética/métodos , Matriz Extracelular/metabolismo , Fibronectinas/farmacologia , Células-Tronco Mesenquimais/citologia , Nanotubos/química , Adesão Celular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/ultraestrutura , Fluorescência , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/ultraestrutura , Nanotubos/ultraestrutura
9.
J Infect Chemother ; 26(8): 831-837, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32414689

RESUMO

Biofilm is a complex structure consisting of microorganisms such as bacteria, fungi and an extracellular matrix (ECM). Biofilms are involved in most microbial infections and show persistent resistance to antibiotic treatment and immune response. Both Aspergillus fumigatus and Streptococcus pneumoniae are colonizers that can form biofilms in the respiratory tract. These pathogens have been simultaneously isolated from the same patient, but their interaction is poorly understood. We observed morphological changes in single- and mixed-species biofilms prepared for confocal laser scanning microscopy and scanning electron microscopy (SEM). Pneumococci suppressed the development of a fungal biofilm, and it even disrupted a preformed fungal biofilm. When a preformed fungal biofilm was treated with pneumococci, the mycelial network was fragmented, and only bacteria could develop. SEM revealed that the fragmented mycelium was further disrupted into fine filaments as treatment time progressed, and that the ECM of the preformed fungal biofilm had disappeared. The pneumococcal culture supernatant contained mycelial fragmentation activity that was heat-sensitive. The culture supernatant of a mutant pneumococcal strain deficient in pneumolysin (Δply) also exhibited the mycelial fragmentation activity. Enolase and lactate oxidase, which are involved in glycolysis and hydrogen peroxide production, were identified in the culture supernatant of the Δply mutant. Neither the wild type nor the mutant strain could fragment the mycelium in the presence of catalase. These data suggest that hydrogen peroxide could fragment the mycelium and would terminate the co-existence of A. fumigatus and S. pneumoniae in biofilm.


Assuntos
Aspergillus fumigatus/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Streptococcus pneumoniae/metabolismo , Aspergilose/microbiologia , Aspergillus fumigatus/fisiologia , Proteínas de Bactérias/metabolismo , Biofilmes/crescimento & desenvolvimento , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Microscopia Eletrônica de Varredura , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/fisiologia , Estreptolisinas/metabolismo
10.
Breast Cancer Res ; 22(1): 41, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370801

RESUMO

BACKGROUND: In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. METHODS: We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. RESULTS: We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. CONCLUSIONS: As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.


Assuntos
Disruptores Endócrinos/toxicidade , Matriz Extracelular/patologia , Glândulas Mamárias Animais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Células Estromais/patologia , Animais , Compostos Benzidrílicos/toxicidade , Estrogênios não Esteroides/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Fenóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Transcriptoma
11.
PLoS One ; 15(4): e0231734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294140

RESUMO

Osteoarthritis is a degenerative disease that causes substantial changes in joint tissues, such as cartilage degeneration and subchondral bone sclerosis. Chondroitin sulfate and glucosamine are commonly used products for the symptomatic treatment of osteoarthritis. The aim of the present study was to investigate the effects of these products when used as structure-modifying drugs on the progression of osteoarthritis in the rabbit temporomandibular joint. Thirty-six New Zealand rabbits were divided into 3 groups (n = 12/group): control (no disease); osteoarthritis (disease induction); and treatment (disease induction and administration of chondroitin sulfate and glucosamine). Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate. Animals were killed at 30 and 90 days after initiation of therapy. The treatment was effective in reducing disease severity, with late effects and changes in the concentration of glycosaminoglycans in the articular disc. The results indicate that chondroitin sulfate and glucosamine may have a structure-modifying effect on the tissues of rabbit temporomandibular joints altered by osteoarthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Sulfatos de Condroitina/administração & dosagem , Glucosamina/administração & dosagem , Osteoartrite/tratamento farmacológico , Articulação Temporomandibular/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/diagnóstico , Artrite Experimental/patologia , Cartilagem Articular/citologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Humanos , Injeções Intra-Articulares , Injeções Subcutâneas , Ácido Iodoacético/administração & dosagem , Ácido Iodoacético/toxicidade , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/diagnóstico , Osteoartrite/patologia , Coelhos , Índice de Gravidade de Doença , Articulação Temporomandibular/patologia
12.
PLoS One ; 15(3): e0227784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160196

RESUMO

Pleural empyema is an inflammatory condition characterized by accumulation of pus inside the pleural cavity, which is usually followed by bacterial pneumonia. During the disease process, the pro-inflammatory and pro-fibrotic cytokines in the purulent pleural effusion cause proliferation of fibroblasts and deposition of extracellular matrix, which lead to fibrin deposition and fibrothorax. Urokinase instillation therapy through a chest drainage tube is frequently used for fibrinolysis in patients with empyema. However, urokinase treatment requires multiple instillation (2-3 times per day, for 4-8 days) and easily flows out from the chest drainage tube due to its high water solubility. In this in vitro study, we developed a thermo-responsive hydrogel based on poloxamer 407 (P407) combined with hyaluronic acid (HA) for optimal loading and release of urokinase. Our results show that the addition of HA to poloxamer gels provides a significantly more compact microstructure, with smaller pore sizes (**p < 0.001). The differential scanning calorimetry (DSC) profile revealed no influence on the micellization intensity of poloxamer gel by HA. The 25% poloxamer-based gel was significantly superior to the 23% poloxamer-based gel, with slower gel erosion when comparing the 16th hour residual gel weight of both gels (*p < 0.05; **p < 0.001). The 25% poloxamer-HA gel also exhibited a superior urokinase release profile and longer release time. A Fourier-transform infrared spectroscopy (FT-IR) study of the P407/HA hydrogel showed no chemical interactions between P407 and HA in the hydrogel system. The thermoresponsive P407/HA hydrogel may have a promising potential in the loading and delivery of hydrophilic drugs. On top of that, in vitro toxicity test of this combination demonstrates a lower toxicity.


Assuntos
Portadores de Fármacos/química , Empiema Pleural/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Ativador de Plasminogênio Tipo Uroquinase/administração & dosagem , Linhagem Celular , Preparações de Ação Retardada/administração & dosagem , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Empiema Pleural/patologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrina/metabolismo , Fibrinolíticos/farmacocinética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/toxicidade , Hidrogéis/química , Hidrogéis/toxicidade , Poloxâmero/química , Poloxâmero/toxicidade , Temperatura , Fatores de Tempo , Testes de Toxicidade , Ativador de Plasminogênio Tipo Uroquinase/farmacocinética
13.
Nat Commun ; 11(1): 1571, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218432

RESUMO

Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membrane-specific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation.


Assuntos
Proteínas ADAMTS/metabolismo , Hormônios/farmacologia , Glândulas Mamárias Animais/citologia , Nicho de Células-Tronco , Células-Tronco/metabolismo , Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Animais , Antígenos CD/metabolismo , Linhagem Celular , Autorrenovação Celular/efeitos dos fármacos , Epitélio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Glicoproteínas/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Progesterona/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
14.
PLoS One ; 15(3): e0227165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218565

RESUMO

AIM: Abdominal aortic aneurysms (AAA) is a life-threatening weakening and expansion of the abdominal aorta due to inflammatory cell infiltration and gradual degeneration of extracellular matrix (ECM). There are no pharmacological therapies to treat AAA. We tested the hypothesis that nanoparticle (NP) therapy that targets degraded elastin and delivers anti-inflammatory, anti-oxidative, and ECM stabilizing agent, pentagalloyl glucose (PGG) will reverse advance stage aneurysm in an elastase-induced mouse model of AAA. METHOD AND RESULTS: Porcine pancreatic elastase (PPE) was applied periadventitially to the infrarenal aorta in mice and AAA was allowed to develop for 14 days. Nanoparticles loaded with PGG (EL-PGG-NPs) were then delivered via IV route at 14-day and 21-day (10 mg/kg of body weight). A control group of mice received no therapy. The targeting of NPs to the AAA site was confirmed with fluorescent dye marked NPs and gold NPs. Animals were sacrificed at 28-d. We found that targeted PGG therapy reversed the AAA by decreasing matrix metalloproteinases MMP-9 and MMP-2, and the infiltration of macrophages in the medial layer. The increase in diameter of the aorta was reversed to healthy controls. Moreover, PGG treatment restored degraded elastic lamina and increased the circumferential strain of aneurysmal aorta to the healthy levels. CONCLUSION: Our results support that site-specific delivery of PGG with targeted nanoparticles can be used to treat already developed AAA. Such therapy can reverse inflammatory markers and restore arterial homeostasis.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/tratamento farmacológico , Portadores de Fármacos/química , Taninos Hidrolisáveis/administração & dosagem , Imunoconjugados/administração & dosagem , Animais , Anticorpos/administração & dosagem , Anticorpos/imunologia , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Modelos Animais de Doenças , Elastina/antagonistas & inibidores , Elastina/imunologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Ouro , Humanos , Imunoconjugados/imunologia , Injeções Intravenosas , Masculino , Nanopartículas Metálicas/química , Camundongos , Elastase Pancreática/administração & dosagem , Elastase Pancreática/toxicidade , Soroalbumina Bovina/química , Ultrassonografia
15.
Phytother Res ; 34(8): 2044-2052, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32155298

RESUMO

Oxidative stress plays an important role in diabetic nephropathy (DN), which is a diabetic complication. Ampelopsin (AMP) is a natural flavonoid that has been found to possess antidiabetic and antioxidative activities. However, the effect of AMP on DN remains unclear. In this study, we aimed to evaluate the protective effect of AMP on glomerular mesangial cells (MCs) exposed to high glucose (HG). We found that AMP improved HG-caused cell viability reduction in MCs. AMP significantly suppressed the intracellular ROS production and expression levels of ROS producing enzymes NADPH oxidase 2 (NOX2) and NOX4. Increased of NOX activity in HG-stimulated MCs was suppressed by AMP. Pretreatment with AMP inhibited extracellular matrix (ECM) accumulation in HG-stimulated MCs with decreased expression levels of fibronectin (FN) and collagen type IV (Col IV). Furthermore, AMP elevated the expression levels of nuclear Nrf2 and heme oxygenase-1 (HO-1), as well as increased the mRNA levels of Nrf2-driven genes NAD(P)H dehydrogenase quinone-1 (NQO-1) and HO-1 in HG-treated MCs. Knockdown of Nrf2 reversed the protective effects of AMP against HG-induced oxidative stress and EMC accumulation in MCs. In conclusion, these findings indicated that AMP protected MCs from HG-induced oxidative damage and ECM accumulation, which might be mediated by Nrf2/HO-1 pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Matriz Extracelular/efeitos dos fármacos , Flavonoides/uso terapêutico , Glucose/metabolismo , Células Mesangiais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nefropatias Diabéticas/patologia , Flavonoides/farmacologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo
16.
J Pathol ; 251(1): 49-62, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32083318

RESUMO

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Ferro/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Bleomicina/farmacologia , Proliferação de Células , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Knockout
17.
Arthritis Rheumatol ; 72(7): 1123-1133, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32067417

RESUMO

OBJECTIVE: To investigate the effects of a young systemic environment and growth differentiation factor 11 (GDF-11) on aging cartilage. METHODS: A heterochronic parabiosis model (2-month-old mouse and 12-month-old mouse [Y/O]), an isochronic parabiosis model (12-month-old mouse and 12-month-old mouse [O/O]), and 12-month-old mice alone (O) were evaluated. Knee joints and chondrocytes from old mice were examined by radiography, histology, cell proliferation assays, immunohistochemistry, Western blotting, and quantitative reverse transcriptase-polymerase chain reaction 16 weeks after parabiosis surgery. GDF-11 was injected into 12-month-old mouse joints daily for 16 weeks. Cartilage degeneration, cell proliferation, and osteoarthritis-related gene expression were evaluated. RESULTS: Osteoarthritis Research Society International scores in old mice were significantly lower in the Y/O group than in the O/O and O groups (both P < 0.05). The percentage of 5-ethynyl-2'-deoxyuridine-positive chondrocytes in old mice was significantly higher in the Y/O group than in the other groups (P < 0.05). Type II collagen (CII) and SOX9 messenger RNA levels differed in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). RUNX-2, CX, and matrix metalloproteinase 13 levels were significantly lower in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). Similar results were obtained for protein expression levels and after GDF-11 treatment in vitro and in vivo. Phosphorylated Smad2/3 (pSmad2/3) levels were higher in the recombinant GDF-11-treated group than in the control group. CONCLUSION: A young systemic environment promotes chondrocyte proliferation and cartilage matrix synthesis in old mice. GDF-11, a "young factor," contributes to these effects through the up-regulation of pSmad2/3.


Assuntos
Envelhecimento/genética , Proteínas Morfogenéticas Ósseas/farmacologia , Cartilagem Articular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fatores de Diferenciação de Crescimento/farmacologia , Osteoartrite do Joelho/genética , Parabiose , Adolescente , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Artroplastia do Joelho , Proteínas Morfogenéticas Ósseas/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Colágeno Tipo II/efeitos dos fármacos , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Colágeno Tipo X/efeitos dos fármacos , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Fatores de Diferenciação de Crescimento/metabolismo , Humanos , Técnicas In Vitro , Articulação do Joelho , Masculino , Metaloproteinase 13 da Matriz/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Osteoartrite do Joelho/metabolismo , Fosforilação , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição SOX9/efeitos dos fármacos , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteína Smad2/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/efeitos dos fármacos , Proteína Smad3/metabolismo , Joelho de Quadrúpedes , Adulto Jovem
18.
PLoS One ; 15(1): e0220019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945053

RESUMO

The migration of cancer cells is highly regulated by the biomechanical properties of their local microenvironment. Using 3D scaffolds of simple composition, several aspects of cancer cell mechanosensing (signal transduction, EMC remodeling, traction forces) have been separately analyzed in the context of cell migration. However, a combined study of these factors in 3D scaffolds that more closely resemble the complex microenvironment of the cancer ECM is still missing. Here, we present a comprehensive, quantitative analysis of the role of cell-ECM interactions in cancer cell migration within a highly physiological environment consisting of mixed Matrigel-collagen hydrogel scaffolds of increasing complexity that mimic the tumor microenvironment at the leading edge of cancer invasion. We quantitatively show that the presence of Matrigel increases hydrogel stiffness, which promotes ß1 integrin expression and metalloproteinase activity in H1299 lung cancer cells. Then, we show that ECM remodeling activity causes matrix alignment and compaction that favors higher tractions exerted by the cells. However, these traction forces do not linearly translate into increased motility due to a biphasic role of cell adhesions in cell migration: at low concentration Matrigel promotes migration-effective tractions exerted through a high number of small sized focal adhesions. However, at high Matrigel concentration, traction forces are exerted through fewer, but larger focal adhesions that favor attachment yielding lower cell motility.


Assuntos
Colágeno/farmacologia , Células Epiteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Adesões Focais/efeitos dos fármacos , Laminina/farmacologia , Mecanotransdução Celular , Proteoglicanas/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colágeno/química , Combinação de Medicamentos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Adesões Focais/ultraestrutura , Expressão Gênica , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Laminina/química , Modelos Biológicos , Proteoglicanas/química , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Propriedades de Superfície , Microambiente Tumoral/efeitos dos fármacos
19.
Life Sci ; 243: 117301, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953160

RESUMO

AIM: Pancreatic stellate cells (PSCs) are the main functional cells leading to pancreatic fibrosis. Nicotine is widely considered as an independent risk factor of pancreatic fibrosis, but the mechanism is still unclear. Our study was aimed to explore the effects of nicotine on human pancreatic stellate cells (hPSCs) and involved pathways. MATERIALS AND METHODS: Primary human PSCs were cultured and treated with nicotine (0.1 µM and 1 µM). The proliferation, apoptosis, α-SMA expression, extracellular matrix metabolism and autophagy of hPSCs were detected by CCK-8 assay, flow cytometry, real-time PCR and Western blotting analysis. The α7nAChR-mediated JAK2/STAT3 signaling pathway was also examined, and an α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. KEY FINDINGS: The proliferation, α-SMA expression and autophagy of hPSCs were significantly promoted by 1 µM nicotine. Meanwhile, the apoptosis of hPSCs was significantly reduced. The extracellular matrix metabolism of hPSCs was also regulated by nicotine. Moreover, the α7nAChR-mediated JAK2/STAT3 signaling pathway was activated by nicotine, this pathway and effects of nicotine can be blocked by α-BTX. SIGNIFICANCE: Our finding suggests that nicotine can promote activation of human pancreatic stellate cells (hPSCs) through inducing autophagy via α7nAChR-mediated JAK2/STAT3 signaling pathway, providing a new insight into the mechanisms by which nicotine affects pancreatic fibrosis.


Assuntos
Autofagia/efeitos dos fármacos , Janus Quinase 2/metabolismo , Nicotina/farmacologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Actinas/metabolismo , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Células Estreladas do Pâncreas/metabolismo
20.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G504-G517, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928221

RESUMO

Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A's expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis.NEW & NOTEWORTHY Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.


Assuntos
Citoesqueleto de Actina/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/patologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Cirrose Hepática Experimental/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Ácidos Nipecóticos/farmacologia , Proteínas Nucleares/genética , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad Reguladas por Receptor/metabolismo , Fatores de Tempo , Transativadores/genética , Fatores de Transcrição/genética , Regulação para Cima
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