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1.
Chem Biol Interact ; 317: 108945, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935363

RESUMO

Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1ß in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis.


Assuntos
Antioxidantes/farmacologia , Benzoquinonas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Tioacetamida/toxicidade , Actinas/genética , Actinas/metabolismo , Animais , Biomarcadores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
2.
J Ethnopharmacol ; 246: 111768, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30849507

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma wenyujin Y.H. (CW), a variety of Curumae Rhizoma, which documented in China Pharmacopeia, has long been used as plant medicine for its traditional effect on promoting Qi, activating blood stagnation and expelling blood stasis. Nowadays, it is often used in clinic for extraordinary effect on liver diseases. It is worthy to be noted that CW processed with vinegar has been applied in clinic for 1500 years which started in the northern and southern dynasties. AIM OF STUDY: Liver fibrosis is a worldwide clinical issue. It is worth developing a multi-target and multicellular approach which is high efficiency and low side effects for the treatment of hepatic fibrosis. The anti-hepatic fibrosis molecular mechanisms of CW and vinegar Curcuma wenyujin (VCW) need to be explored and elucidated. Furthermore, the study aimed to discuss the efficiency and mechanism differences between CW and VCW in hepatic fibrosis. METHODS AND RESULTS: Biochemical assays and histopathology were adopted to evaluate the anti-hepatic fibrosis effect of CW and VCW. The TGF-ß/Smad signaling involving TGF-ß1, TGF-ßRⅠ, TGF-ßRⅡ and Smad2, Smad3, Smad7 in fibrosis is examined, which is a critical step towards the evaluation of anti-hepatic fibrosis agents. Meanwhile, the MMP/TIMP balance is a potential therapy target by modulating extracellular matrix, which is also examined. Both CW and VCW inhibit the activation and proliferation of hepatic stellate cells and induce apoptosis via blocking TGF-ß/Smad signaling pathways. Additionally, the level of MMP-2/TIMP-1 regulated significantly, which suggest CW and VCW participate in the degradation process, and maintain the formation and production of extracellular matrix. CONCLUSION: Raw and vinegar processed Curcuma wenyujin regulates hepatic fibrosis via bloking TGF-ß/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. And VCW has more exhibition than CW.


Assuntos
Curcuma , Cirrose Hepática/metabolismo , Extratos Vegetais/farmacologia , Ácido Acético/química , Animais , Linhagem Celular , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
3.
Life Sci ; 236: 116899, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614145

RESUMO

AIMS: The aim of our study is to illustrate the role of amphiregulin in trophoblast invasiveness and underlying signal cascades. MAIN METHODS: An immortalized human early extravillous cell line, HTR-8/SVneo, was used for this investigation. Matrigel-transwell invasion assay was used for testing the effects of amphiregulin on cell invasiveness. MMP9 and MMP2 mRNA expression level and activity were measured using Rt-qPCR and zymographic analysis. Cell signals involved in the invasion process were verified using western blot and specific inhibitors. KEY FINDINGS: Our results showed that amphiregulin could promote HTR-8/SVneo cell invasiveness without interfering cell proliferation, and significantly upregulate the expression of MMP9 and TIMP-1 mRNAs as well as the ratio of MMP9/TIMP-1. Using specific inhibitors for MEK and PI3K signaling further indicated that, both ERK1/2 and Akt signal pathways were required for amphiregulin-induced cell invasiveness. The co-ordination between ERK1/2 and Akt signaling pathway was needed for the upregulation of MMP9 mRNA, while ERK1/2 was more essential for the upregulation of TIMP-1 mRNA. Meanwhile, we first put forward that the deficiency of amphiregulin expression in trophoblast might be compensated by the upregulation of epidermal growth factor receptor (EGFR) and heparin-binding EGF (HB-EGF) mRNA. SIGNIFICANCE: ERK1/2 and Akt signaling pathways mediate amphiregulin-induced upregulation of MMP9 mRNA and the MMP9/TIMP-1 ratio, which subsequently contribute to amphiregulin-promotion of HTR-8/SVneo cell invasion.


Assuntos
Anfirregulina/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Humanos , Metaloproteinase 9 da Matriz/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Gravidez , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Inibidor Tecidual de Metaloproteinase-1/genética
4.
Mediators Inflamm ; 2019: 6768504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275058

RESUMO

Dysregulation of multiple microRNAs widely takes place during rheumatoid arthritis (RA) and experimental arthritides. This study is performed to explore the possible mechanism underlying DICER1 deficiency-mediated inflammation in human synoviocytes SW982. Firstly, RNAi of DICER1 led to increased COX2, MMP3, and MMP13 protein production, while DICER1 overexpression could reduce MMP13 expression. Secondly, the increase of IL-8 and decrease of TGF-ß1 and TIMP1 were determined in the supernatant derived from DICER1 siRNA-treated cells, while DICER1 overexpression was found capable to reverse this effect. Ingenuity pathway analysis (IPA) software predicted that the Dicer1 deficiency-induced dysregulated cytokines in synoviocytes could possibly lead to the inflammatory disorders in the synovial tissue. Moreover, DICER1 deficiency could also reduce apoptosis, while DICER1 overexpression was found to decrease the proliferation and enhance apoptosis. In addition, DICER1 deficiency could lower the expression of multiple RA-related miRNAs such as miR-155. Meanwhile, DICER1 overexpression could rescue their low expression levels. And then, gain or loss of miR-155 function could regulate the protein levels of MMP3 and MMP13. These results indicated that DICER1 might play its role through regulating its downstream RA-related miRNAs. Our data demonstrated that DICER1 deficiency could cause multiple proinflammatory events in human synoviocytes SW982. This mechanism study might provide the possible target molecule to modify the inflammatory destruction and overproliferation in synoviocytes.


Assuntos
RNA Helicases DEAD-box/metabolismo , Inflamação/metabolismo , Ribonuclease III/metabolismo , Sinoviócitos/metabolismo , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , RNA Helicases DEAD-box/genética , Humanos , Inflamação/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Interferência de RNA , Ribonuclease III/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
5.
Mol Cell Biol ; 39(18)2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208977

RESUMO

Membrane type 1-matrix metalloproteinase (MT1-MMP) and tumor necrosis factor α (TNF-α)-converting enzyme (TACE) are prominent membrane-anchored metalloproteinases that regulate the turnover of extracellular matrix (ECM) components and bioactive molecules required for cancer proliferation. In this study, we describe a novel approach that would allow tissue inhibitor of metalloproteinase 1 (TIMP-1), the endogenous inhibitor of the matrix metalloproteinases (MMPs), to be translocated to the cell membrane for simultaneous MT1-MMP/TACE inhibition. We achieve this by fusing T1TACE, a designer TIMP-1 with superb affinities for MT1-MMP and TACE, to the glycosyl-phosphatidyl inositol anchor of prions to create a membrane-tethered, broad-spectrum inhibitor, named T1Pr αTACE, that colocalizes with MT1-MMP and TACE on the cell surface. Transduction of T1Pr αTACE in human fibrosarcoma cells results not only in a substantial reduction in gelatinolytic and TNF-α/heparin binding epithelial growth factor shedding activities but also in a loss of tubulogenic capability in three-dimensional matrices. In renal carcinoma, T1Pr αTACE triggers cellular senescence and disrupts MMP-mediated proteolysis of ECM components such as fibronectin and collagen I, leading to an impairment in cell motility and survival under both in vitro and in vivo conditions. Taken together, our findings may provide a new perspective in TIMP targeting that could be exploited to halt metastatic renal carcinoma progression.


Assuntos
Carcinoma de Células Renais/terapia , Glicosilfosfatidilinositóis/metabolismo , Neoplasias Renais/terapia , Príons/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Inibidor Tecidual de Metaloproteinase-1/genética , Células A549 , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Transporte Proteico , Proteínas Recombinantes de Fusão/farmacologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Dis Markers ; 2019: 3136792, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143300

RESUMO

The aim of this study was to assess the expression of MMP-9 and TIMP-1 in cancerous tissue as well as in the serum and plasma concentrations of these proteins in patients with laryngeal cancer and compare the results to the inflammatory reaction in healthy subjects. Twenty-seven patients who were diagnosed with laryngeal carcinoma and selected for total laryngectomy were included in the study group. MMP-9 and TIMP-1 expression in tissues was assessed using immunohistochemical assays. Immunoenzymatic ELISA methods were used to measure MMP-9 and TIMP-1 concentrations in serum and plasma. MMP-9 and TIMP-1 were identified in tumor cells and in the tumor stroma compartment, as well as in macroscopically healthy mucous membrane. MMP-9 expression was more significant in tumor stroma than in the perimatrix of the mucous membrane (p = 0.047). TIMP-1 expression was significantly higher in the matrix and perimatrix of the mucous membrane than in cancer tissue (p = 0.0093) and the tumor stroma compartment (p < 0.0001). Expression of TIMP-1 was observed more frequently in tumors without infiltrated lymph nodes (p = 0.009). Serum concentrations of MMP-9 and TIMP-1 as well as plasma TIMP-1 concentration were significantly higher in the study group than in the control group (p = 0.0004, p = 0.002, and p = 0.0001, respectively). A significantly higher TIMP-1 level in plasma was found in patients with poorly differentiated tumors compared to G1 and G2 (p = 0.046). MMP-9/TIMP-1 rate in serum was significantly higher in the study group than in the control group. The balance between the level of MMP-9 and TIMP-1 is disrupted in laryngeal cancer. The significant correlation between TIMP-1 expression and the presence of lymph node metastases, as well as that between TIMP-1 plasma concentration and stage of cancer histological differentiation, might indicate the importance of this molecule as a prognostic factor during carcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/metabolismo , Metaloproteinase 9 da Matriz/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Laríngeas/sangue , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Metástase Linfática , Masculino , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/metabolismo
7.
J Biol Chem ; 294(24): 9476-9488, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31040180

RESUMO

Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs), enzymes that contribute to cancer and many inflammatory and degenerative diseases. The TIMP N-terminal domain binds and inhibits an MMP catalytic domain, but the role of the TIMP C-terminal domain in MMP inhibition is poorly understood. Here, we employed yeast surface display for directed evolution of full-length human TIMP-1 to develop MMP-3-targeting ultrabinders. By simultaneously incorporating diversity into both domains, we identified TIMP-1 variants that were up to 10-fold improved in binding MMP-3 compared with WT TIMP-1, with inhibition constants (Ki ) in the low picomolar range. Analysis of individual and paired mutations from the selected TIMP-1 variants revealed cooperative effects between distant residues located on the N- and C-terminal TIMP domains, positioned on opposite sides of the interaction interface with MMP-3. Crystal structures of MMP-3 complexes with TIMP-1 variants revealed conformational changes in TIMP-1 near the cooperative mutation sites. Affinity was strengthened by cinching of a reciprocal "tyrosine clasp" formed between the N-terminal domain of TIMP-1 and proximal MMP-3 interface and by changes in secondary structure within the TIMP-1 C-terminal domain that stabilize interdomain interactions and improve complementarity to MMP-3. Our protein engineering and structural studies provide critical insight into the cooperative function of TIMP domains and the significance of peripheral TIMP epitopes in MMP recognition. Our findings suggest new strategies to engineer TIMP proteins for therapeutic applications, and our directed evolution approach may also enable exploration of functional domain interactions in other protein systems.


Assuntos
Evolução Molecular Direcionada , Metaloproteinase 3 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Metaloproteinase 3 da Matriz/química , Metaloproteinase 3 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/química , Mutação , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Inibidor Tecidual de Metaloproteinase-1/química , Inibidor Tecidual de Metaloproteinase-1/genética , Técnicas do Sistema de Duplo-Híbrido
8.
Genetics ; 212(2): 523-535, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30992386

RESUMO

Remodeling of the extracellular matrix supports tissue and organ development, by regulating cellular morphology and tissue integrity. However, proper extracellular matrix remodeling requires spatiotemporal regulation of extracellular metalloproteinase activity. Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, including MIG-17 and GON-1, are evolutionarily conserved, secreted, zinc-requiring metalloproteinases. Although these proteases are required for extracellular matrix remodeling during gonadogenesis in Caenorhabditis elegans, their in vivo regulatory mechanisms remain to be delineated. Therefore, we focused on the C. elegans tissue inhibitors of metalloproteinases (TIMPs), TIMP-1 and CRI-2 Analysis of the transcription and translation products for GFP/Venus fusions, with TIMP-1 or CRI-2, indicated that these inhibitors were secreted and localized to the basement membrane of gonads and the plasma membrane of germ cells. A timp-1 deletion mutant exhibited gonadal growth defects and sterility, and the phenotypes of this mutant were fully rescued by a TIMP-1::Venus construct, but not by a TIMP-1(C21S)::Venus mutant construct, in which the inhibitor coding sequence had been mutated. Moreover, genetic data suggested that TIMP-1 negatively regulates proteolysis of the α1 chain of type IV collagen. We also found that the loss-of-function observed for the mutants timp-1 and cri-2 involves a partial suppression of gonadal defects found for the mutants mig-17/ADAMTS and gon-1/ADAMTS, and that this suppression was canceled upon overexpression of gon-1 or mig-17, respectively. Based on these results, we propose that both TIMP-1 and CRI-2 act as inhibitors of MIG-17 and GON-1 ADAMTSs to regulate gonad development in a noncell-autonomous manner.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Desintegrinas/metabolismo , Gônadas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaloendopeptidases/metabolismo , Inibidor Tecidual de Metaloproteinase-1/fisiologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Animais , Membrana Basal/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Membrana Celular/metabolismo , Colágeno Tipo IV/metabolismo , Desintegrinas/genética , Matriz Extracelular/metabolismo , Células Germinativas/metabolismo , Gônadas/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/genética , Metaloendopeptidases/genética , Morfogênese/genética , Morfogênese/fisiologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores Teciduais de Metaloproteinases/genética
9.
J Immunol ; 202(11): 3267-3281, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019060

RESUMO

Matrix metalloproteinase (MMP)-8 and -9 released by degranulating polymorphonuclear cells (PMNs) promote pericellular proteolysis by binding to PMN surfaces in a catalytically active tissue inhibitor of metalloproteinases (TIMP)-resistant forms. The PMN receptor(s) to which MMP-8 and MMP-9 bind(s) is not known. Competitive binding experiments showed that Mmp-8 and Mmp-9 share binding sites on murine PMN surfaces. A novel form of TIMP-1 (an inhibitor of soluble MMPs) is rapidly expressed on PMN surfaces when human PMNs are activated. Membrane-bound TIMP-1 is the PMN receptor for pro- and active MMP-8 and -9 as shown by the following: 1) TIMP-1 is strikingly colocalized with MMP-8 and -9 on activated human PMN surfaces and in PMN extracellular traps; 2) minimal immunoreactive and active Mmp-8 or Mmp-9 are detected on the surface of activated Timp-1-/- murine PMNs; and 3) binding of exogenous Timp-1 (but not Timp-2) to Timp-1-/- murine PMNs reconstitutes the binding of exogenous pro-Mmp-8 and pro-Mmp-9 to the surface of Timp-1-/- PMNs. Unlike full-length pro-Mmp-8 and pro-Mmp-9, mutant pro-Mmp proteins lacking the COOH-terminal hemopexin domain fail to bind to Mmp-8-/-x Mmp-9-/- murine PMNs. Soluble hemopexin inhibits the binding of pro-Mmp-8 and pro-Mmp-9 to Mmp-8-/-x Mmp-9-/- murine PMNs. Thus, the COOH-terminal hemopexin domains of pro-Mmp-8 and pro-Mmp-9 are required for their binding to membrane-bound Timp-1 on murine PMNs. Exposing nonhuman primates to cigarette smoke upregulates colocalized expression of TIMP-1 with MMP-8 and MMP-9 on peripheral blood PMN surfaces. By anchoring MMP-8 and MMP-9 to PMN surfaces, membrane-bound TIMP-1 plays a counterintuitive role in promoting PMN pericellular proteolysis occurring in chronic obstructive pulmonary disease and other diseases.


Assuntos
Membrana Celular/metabolismo , Armadilhas Extracelulares/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neutrófilos/imunologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Células Cultivadas , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Domínios Proteicos/genética , Engenharia de Proteínas , Transporte Proteico , Proteólise , Inibidor Tecidual de Metaloproteinase-1/genética
10.
Microsc Res Tech ; 82(7): 1136-1144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974026

RESUMO

OBJECTIVE: We analysed lncRNA expression profiles in atrial samples from patients with rheumatic mitral valve disease (RMVD) to identify the potential differences in atrial fibrillation (AF)-associated lncRNAs between RMVD patients with AF and sinus rhythm (SR). METHODS: Masson's trichrome staining and scanning electron microscopy were performed to evaluate the tissue morphology. Western blotting was performed to detect the expression of fibrosis-related proteins. Difference analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene co-expression networks were also adopted to perform IncRNA expression profile analysis in atrial samples. RESULTS: Masson's trichrome staining indicated higher contents of fat deposition and fibrous tissue in atrial samples from patients with AF than from patients with SR. Western blotting showed that fibrosis-related proteins, including smad2, TGFß1, MMP9, and TIMP1, were upregulated in atrial samples from patients with AF compared to those from patients with SR. lncRNA expression profiles showed different lncRNA expression levels between RMVD patients with AF and SR. Moreover, GO, KEGG and gene co-expression networks showed consistent results and indicated that differentially expressed genes might contribute to the pathogenesis of AF. CONCLUSION: Our results revealed the potential roles of IncRNAs in the development of AF in patients with RMVD, and lncRNAs may be responsible for morphological and physiological differences in atria between RMVD patients with AF and SR.


Assuntos
Fibrilação Atrial/genética , Valva Mitral/patologia , RNA Longo não Codificante/genética , Cardiopatia Reumática/genética , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Humanos , Microscopia Eletrônica de Varredura , Valva Mitral/ultraestrutura , RNA Mensageiro/genética , Proteína Smad2/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Crescimento Transformador beta1/genética , Regulação para Cima
11.
Exp Mol Pathol ; 108: 97-104, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30986397

RESUMO

There is increasing awareness that in addition to the metabolic crisis of diabetic ketoacidosis (DKA) caused by severe insulin deficiency, the immune inflammatory response is likely an active multicomponent participant in both the acute and chronic insults of this medical crisis, with strong evidence of activation for both the cytokine and complement system. Recent studies report that the matrix metalloproteinase enzymes and their inhibitors are systemically activated in young Type 1 diabetes mellitus (T1D) patients during DKA and speculate on their involvement in blood-brain barrier (BBB) disruption. Based on our previous studies, we address the question if matrix metalloproteinase 9 (MMP9) is expressed in the brain in the fatal brain edema (BE) of DKA. Our data show significant expression of MMP9 on the cells present in brain intravascular areas. The presence of MMP9 in intravascular cells and that of MMP+ cells seen passing the BBB indicates a possible role in tight junction protein disruption of the BBB, possibly leading to neurological complications including BE. We have also shown that MMP9 is expressed on neurons in the hippocampal areas of both BE/DKA cases investigated, while expression of tissue inhibitor of metalloproteinases 1 (TIMP1) was reduced in the same areas. We can speculate that intraneuronal MMP9 can be a sign of neurodegeneration. Further studies are necessary to determine the role of MMP9 in the pathogenesis of the neurologic catastrophe of the brain edema of DKA. Inhibition of MMP9 expression might be helpful in preserving neuronal function and BBB integrity during DKA.


Assuntos
Cetoacidose Diabética/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Adolescente , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/genética , Edema Encefálico/metabolismo , Cetoacidose Diabética/mortalidade , Feminino , Hipocampo/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Neurônios/metabolismo , Junções Íntimas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Transcriptoma/genética
12.
Gene Expr Patterns ; 32: 1-11, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30822518

RESUMO

The main purpose of this in situ hybridization study was to investigate MMPs and TIMPs mRNA expression in developing mandibular condylar cartilage and limb bud cartilage. At E14.0, MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the periosteum of mandibular bone, and in the condylar anlage. At E15.0 MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the perichondrium of newly formed condylar cartilage and the periosteum of developing bone collar, whereas, expression of MMP-14 and TIMP-1 mRNAs were restricted to the inner layer of the periosteum/perichondrium. This expression patterns continued until E18.0. Further, from E13.0 to 14.0, in the developing tibial cartilage, MMP-2, -14, and TIMP-2 mRNAs were expressed in the periosteum/perichondrium, but weak MMP-14 and no TIMP-1 mRNA expression was recognized in the perichondrium. These results confirmed that the perichondrium of condylar cartilage has characteristics of periosteum, and suggested that MMPs and/or TIMPs are more actively involved in the development of condylar (secondary) cartilage than tibial (primary) cartilage. MMP-9-positive cells were observed in the bone collar of both types of cartilage, and they were consistent with osteoclasts/chondroclasts. MMP-13 mRNA expression was restricted to the chondrocytes of the lower hypertrophic cell zone in tibial cartilage at E14.0, indicating MMP-13 can be used as a marker for lower hypertrophic cell zone. It was also expressed in chondrocytes of newly formed condylar cartilage at E15.0, and continuously expressed in the lower hypertrophic cell zone until E18.0. These results confirmed that progenitor cells of condylar cartilage are rapidly differentiated into hypertrophic chondrocytes, which is a unique structural feature of secondary cartilage different from that of primary cartilage.


Assuntos
Cartilagem/metabolismo , Botões de Extremidades/metabolismo , Côndilo Mandibular/metabolismo , Animais , Cartilagem/fisiologia , Cartilagem Articular/embriologia , Condrócitos/metabolismo , Condrogênese/genética , Feto/metabolismo , Hibridização In Situ , Botões de Extremidades/fisiologia , Côndilo Mandibular/fisiologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Transcriptoma/genética
13.
J Biol Chem ; 294(20): 8037-8045, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30926607

RESUMO

The protease ADAMTS7 functions in the extracellular matrix (ECM) of the cardiovascular system. However, its physiological substrate specificity and mechanism of regulation remain to be explored. To address this, we conducted an unbiased substrate analysis using terminal amine isotopic labeling of substrates (TAILS). The analysis identified candidate substrates of ADAMTS7 in the human fibroblast secretome, including proteins with a wide range of functions, such as collagenous and noncollagenous extracellular matrix proteins, growth factors, proteases, and cell-surface receptors. It also suggested that autolysis occurs at Glu-729-Val-730 and Glu-732-Ala-733 in the ADAMTS7 Spacer domain, which was corroborated by N-terminal sequencing and Western blotting. Importantly, TAILS also identified proteolysis of the latent TGF-ß-binding proteins 3 and 4 (LTBP3/4) at a Glu-Val and Glu-Ala site, respectively. Using purified enzyme and substrate, we confirmed ADAMTS7-catalyzed proteolysis of recombinant LTBP4. Moreover, we identified multiple additional scissile bonds in an N-terminal linker region of LTBP4 that connects fibulin-5/tropoelastin and fibrillin-1-binding regions, which have an important role in elastogenesis. ADAMTS7-mediated cleavage of LTBP4 was efficiently inhibited by the metalloprotease inhibitor TIMP-4, but not by TIMP-1 and less efficiently by TIMP-2 and TIMP-3. As TIMP-4 expression is prevalent in cardiovascular tissues, we propose that TIMP-4 represents the primary endogenous ADAMTS7 inhibitor. In summary, our findings reveal LTBP4 as an ADAMTS7 substrate, whose cleavage may potentially impact elastogenesis in the cardiovascular system. We also identify TIMP-4 as a likely physiological ADAMTS7 inhibitor.


Assuntos
Proteínas ADAMTS , Fibroblastos/enzimologia , Proteínas de Ligação a TGF-beta Latente , Proteólise , Inibidores Teciduais de Metaloproteinases , Proteínas ADAMTS/química , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Células HEK293 , Humanos , Proteínas de Ligação a TGF-beta Latente/química , Proteínas de Ligação a TGF-beta Latente/genética , Proteínas de Ligação a TGF-beta Latente/metabolismo , Domínios Proteicos , Proteômica , Inibidor Tecidual de Metaloproteinase-1/química , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores Teciduais de Metaloproteinases/química , Inibidores Teciduais de Metaloproteinases/genética , Inibidores Teciduais de Metaloproteinases/metabolismo , Tropoelastina/química , Tropoelastina/genética , Tropoelastina/metabolismo
14.
Biomed Res Int ; 2019: 5408289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729126

RESUMO

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-ß1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.


Assuntos
Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Fosfocreatina/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/induzido quimicamente , Fibrose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Humanos , Isoproterenol/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Metaloproteinase 9 da Matriz/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NF-kappa B/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Crescimento Transformador beta1/genética
15.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30626725

RESUMO

The morphology and histology changes in the medial meniscus after posterior cruciate ligament (PCL) rupture are poorly understood. Forty-eight rabbits were divided into matched mode pairs; each rabbit had an experimental side, in which the PCL was transacted, and a control side. At the 4, 8, 16 and 24 weeks after the PCL transection, each of the 12 rabbits was killed. Histology was performed to detect the expression of the tissue inhibitors of metalloproteinases-1 (TIMP-1), matrix metalloproteinase (MMP)-1 and MMP-13 in the medial meniscus. We found that medial meniscus displayed significant degenerative characteristics in morphology. The histological evaluation of the degeneration found that the expression levels of TIMP-1, MMP-1 and MMP-13 in the medial meniscus were higher in the experiment side than those in the control side (P<0.05). The expression of both TIMP-1 and MMP-13 was initially elevated and then decreased. The MMP-1 expression reached its peak swiftly and then maintained a relatively high level. There were clear time-dependent degenerative changes in the histology of the medial meniscus after PCL rupture. The high expression of TIMP-1, MMP-1 and MMP-13 in the cartilage may be responsible for the degeneration, and PCL rupture may trigger meniscus degradation and ultimately osteoarthritis.


Assuntos
Metaloproteinase 13 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , Osteoartrite/genética , Ligamento Cruzado Posterior/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Traumatismos do Joelho/genética , Traumatismos do Joelho/fisiopatologia , Meniscos Tibiais/metabolismo , Meniscos Tibiais/fisiopatologia , Osteoartrite/fisiopatologia , Ligamento Cruzado Posterior/fisiopatologia , Coelhos
16.
Kardiol Pol ; 77(2): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30676640

RESUMO

BACKGROUND: An imbalance between the activity of matrix metalloproteinases (MMPs), particularly gelatinases, and tissue inhibitors of metalloproteinases (TIMPs) is considered as one of the mechanisms leading to aortocoronary graft failure. AIM: We aimed to assess the variability in gelatinase expression in the walls of aortocoronary conduits and to evaluate its impact on coronary artery bypass grafting (CABG) outcomes. METHODS: The study included 101 consecutive patients (61 men and 40 women) who underwent CABG. An immunohisto-chemical analysis of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression was performed on the cross-sections of the internal thoracic artery (ITA), radial artery (RA), and saphenous vein (SV). The histological findings were compared between patients with SV graft disease (SVGD[+] group) and those without occlusions in the SV (SVGD[-] group). RESULTS: The median MMP and TIMP expression was the weakest in the ITA wall. MMP expression was comparable between the RA and SV cross-sections, whereas TIMP expression was stronger in the RA than in the SV wall (p < 0.05). In most SV segments, but not in the arteries, immunostaining intensity for MMP was comparable to or stronger than for TIMPs. In the veins harvested from the SVGD(+) group, MMP-2 and MMP-9 tissue expression was more pronounced than in the SVGD(-) group. TIMP levels were comparable between groups. CONCLUSIONS: Imbalance in the metalloproteinase-to-inhibitor tissue expression in the vessel wall might predispose to graft failure. A stronger expression of TIMPs than MMPs in the arterial grafts might explain favourable long-term outcomes.


Assuntos
Vasos Sanguíneos/enzimologia , Ponte de Artéria Coronária , Doença das Coronárias/enzimologia , Gelatinases/genética , Inibidores Teciduais de Metaloproteinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasos Sanguíneos/metabolismo , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Doença das Coronárias/cirurgia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Radial/enzimologia , Artéria Radial/metabolismo , Veia Safena/enzimologia , Veia Safena/metabolismo , Artérias Torácicas/enzimologia , Artérias Torácicas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Resultado do Tratamento
17.
Bull Exp Biol Med ; 166(3): 383-385, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30617705

RESUMO

The benign and malignant neoplasms in parotid gland have similar clinical presentations despite different tumor growth rates. The study compared the clinical and morphological data as well as the results of ELISA for MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 in salivary fluid yielded during primary examination of the patients with pleomorphic adenoma and adenocarcinoma of parotid gland. The examined biomarkers detected in salivary fluid in patients with various cancer types differed significantly (p≤0.05). The correlations between clinical identification of adenoma or adenocarcinoma, on the one hand, and the levels of MMP-8, TIMP-1, and TIMP-2, on the other hand, makes it possible to use the latter as biomarkers for early detection and comprehensive noninvasive differential diagnostics of these neoplasms.


Assuntos
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Biomarcadores Tumorais/genética , Metaloproteinase 8 da Matriz/genética , Neoplasias/diagnóstico , Neoplasias Parotídeas/diagnóstico , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Diagnóstico Diferencial , Detecção Precoce de Câncer , Feminino , Expressão Gênica , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Glândula Parótida , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/metabolismo , Neoplasias Parotídeas/patologia , Saliva/química , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo
18.
Ann Thorac Surg ; 108(1): 59-66, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30690019

RESUMO

BACKGROUND: Global extracellular matrix (ECM)-related gene expression is decreased after myocardial infarction (MI) in fetal sheep when compared with adult sheep. Transforming growth factor (TGF)-ß1 is a key regulator of ECM; therefore we hypothesize that TGF-ß1 is differentially expressed in adult and fetal infarcts after MI. METHODS: Adult and fetal sheep underwent MI via ligation of the left anterior descending coronary artery. Expression of TGF-ß1 and ECM-related genes was evaluated by ovine-specific microarray and quantitative polymerase chain reaction. Fibroblasts from the left ventricle of adult and fetal hearts were treated with TGF-ß1 or a TGF-ß1 receptor inhibitor (LY36497) to evaluate the effect of TGF-ß1 on ECM-related genes. RESULTS: Col1a1, col3a1, and MMP9 expression were increased in adult infarcts 3 and 30 days after MI but were upregulated in fetal infarcts only 3 days after MI. Three days after MI elastin expression was increased in adult infarcts. Despite upregulation in adult infarcts both 3 and 30 days after MI, TGF-ß1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-ß1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-ß1 increased expression of these genes. CONCLUSIONS: TGF-ß1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-ß1 conveys an adult phenotype, inhibition of TGF-ß1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-ß1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.


Assuntos
Coração Fetal/fisiologia , Infarto do Miocárdio/fisiopatologia , Fator de Crescimento Transformador beta1/fisiologia , Animais , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Metaloproteinase 9 da Matriz/genética , Regeneração , Ovinos , Inibidor Tecidual de Metaloproteinase-1/genética
19.
Arch Physiol Biochem ; 125(4): 302-310, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29592769

RESUMO

Context: Our previous studies showed that all trans retinoic acid (ATRA) ameliorates alcohol-induced toxicity. Hence, we evaluated the efficacy of ATRA and abstention in the regression of alcohol-induced hepatotoxicity. Materials and methods: After ethanol administration to rats for 90 days, the regression of alcohol-induced toxicity was studied by supplementing ATRA at a dose of 100 µg/kg body weight for 30 days. It was also compared with animals in abstention. Results and discussion: Ethanol administration enhanced oxidative stress, activated HSCs and increased collagen deposition. All these alterations were reversed to a certain extent by ATRA supplementation. Conclusions: ATRA had better efficacy than just abstention in reducing ethanol-induced toxicity. The mechanism might be downregulation of CYP2E1, leading to reduced oxidative stress in the hepatocytes and thus impeding NFκB activation, cytokine production, activation of HSC and resulting in the reduction of inflammation and remodelling of fibrosis by modulating MMP and TIMP.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Etanol/efeitos adversos , Células Estreladas do Fígado/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Tretinoína/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Biomarcadores/metabolismo , Colágeno/metabolismo , Citocromo P-450 CYP2E1/genética , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , NF-kappa B/genética , RNA Mensageiro/genética , Ratos , Espécies Reativas de Oxigênio/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética
20.
Australas J Dermatol ; 60(1): e20-e28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29943461

RESUMO

OBJECTIVES: Currently, innovative methods to prevent photoaging are needed. Skin-derived precursors (SKP) have been shown to play a crucial role in resisting UVB-induced apoptosis in vitro. The objective of this study was to explore the effect of SKP on preventing skin photoaging in vivo. METHODS: Skin-derived precursors from neonatal BALB/c mice were isolated, identified and intradermally transplanted with a PKH26 label to track their survival. These were then injected at different concentrations into the buttock dermis of nude mice at 2-weekly intervals before UV irradiation. Photographs, assessment of live skin surface, histology with quantitative real-time polymerase chain reaction and immunohistochemistry were used to evaluate the impact of SKP on wrinkles and other relevant indicators of skin photoaging. RESULTS: SKP exhibited a sphere-like structure and could survive for at least 2 weeks after intradermal transplantation. A large dose of SKP transplantation (105 SKP +UV) at 2-weekly intervals were able to ameliorate coarse UV-induced wrinkles. Moreover, the skin smoothness value, dermal thickness and collagen percentage were significantly increased in mice that received a large dose of SKP (105 SKP +UV). UV radiation induced the mRNA expression of MMP-13 and decreased the mRNA and protein expression of TßRII, but these effects were diminished by SKP transplantation. The transplantation of SKP could increase the mRNA of TIMP-1. CONCLUSIONS: We found that transplanted SKP exert a beneficial impact on preventing UV-induced wrinkles in vivo, suggesting that SKP transplantation is a promising candidate for preventing photoaging.


Assuntos
Envelhecimento da Pele/patologia , Envelhecimento da Pele/fisiologia , Transplante de Células-Tronco , Células-Tronco/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Animais Recém-Nascidos , Masculino , Metaloproteinase 13 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nestina/metabolismo , RNA Mensageiro/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Envelhecimento da Pele/genética , Inibidor Tecidual de Metaloproteinase-1/genética
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