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1.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 657-667, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594088

RESUMO

Hepatic fibrosis is a reparative response of diffuse over deposition and abnormal distribution of extracellular matrix (collagen, glycoprotein and proteoglycans) after exposure to various kinds of liver injuries, and is a key step in the developmental process of various chronic liver diseases to cirrhosis. Recently, many advances in our understanding of hepatic fibrosis have been recognized through the basic and clinical research. Therefore, we have organized the relevant domestic experts of this field to form consensus on the diagnosis and evaluation, treatment, and clinical development and application of therapy in order to better guide the diagnosis and treatment, and drug research and development.


Assuntos
Cirrose Hepática/diagnóstico , Cirrose Hepática/terapia , Consenso , Matriz Extracelular/patologia , Humanos , Fígado/patologia
2.
Life Sci ; 234: 116779, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430452

RESUMO

Emerging evidence has revealed that microRNAs (miRNAs) play critical roles in keloid pathogenesis. However, potential molecular mechanism of keloid formation remains unclear. In the present study, our findings showed that miR-152-3p mRNA expression level was notably up-regulated in keloid tissues and keloid fibroblasts compared with that of normal skin tissues and normal skin fibroblasts, respectively. Furthermore, miR-152-3p inhibition remarkably suppressed cell proliferation, which was increased by miR-152-3p overexpression. Cell invasion was also significantly decreased by miR-152-3p inhibition, whereas was increased by miR-152-3p overexpression. The mRNA and protein expression levels of extracellular matrix components including type I collagen, type III collagen and fibronectin were decreased by miR-152-3p inhibition, but were increased by miR-152-3p overexpression. In addition, results of dual-luciferase reporter assay indicated that FOXF1 is a direct target of miR-152-3p. FOXF1 overexpression significantly inhibits cell proliferation, invasion, and extracellular matrix in keloid fibroblasts, and the suppressive effects of miR-152-3p mimic on these functions were notably partly reversed by FOXF1 overexpression. Taken together, these findings indicated that miR-152-3p regulates cell proliferation, invasion and extracellular matrix expression through targeting FOXF1 in keloid fibroblasts, suggesting that miR-152-3p is a novel and promising molecular target for keloid treatment.


Assuntos
Matriz Extracelular/patologia , Fibroblastos/patologia , Fatores de Transcrição Forkhead/genética , Queloide/patologia , MicroRNAs/genética , Regiões 3' não Traduzidas , Adolescente , Adulto , Movimento Celular , Proliferação de Células , Células Cultivadas , Matriz Extracelular/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Queloide/genética , Regulação para Cima , Adulto Jovem
3.
Life Sci ; 234: 116786, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445934

RESUMO

Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA results in the loss of joint function, usually accompanied by severe pain, and are the most common type of arthritis, affecting more than 10% of adults. The characteristic signs of OA are progressive cartilage destruction and, eventually, complete loss of chondrocytes. A key enzyme responsible for these degenerative changes in cartilage is matrix metalloproteinase-13 (MMP-13), which is thought to be a major contributor to the degenerative process occurring during OA pathogenesis. The aim of the present review is to shed light on the general role of MMPs, with special emphasis on MMP-13, in the induction of OA and the general basis of OA treatment. The pathogenic mechanism of this highly prevalent disease is not clear, and no effective disease-modifying treatment is currently available. Any updated information about OA treatment in human patients will also benefit companion animals such as horses and dogs, which also suffer from OA. Selective inhibition of MMP-13 seems to be an attractive therapeutic strategy.


Assuntos
Cartilagem Articular/patologia , Matriz Extracelular/patologia , Metaloproteinases da Matriz/imunologia , Osteoartrite/patologia , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Humanos , Metaloproteinase 13 da Matriz/análise , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Metaloproteinases da Matriz/análise , Metaloproteinases da Matriz/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia , Osteoartrite/metabolismo
5.
J Fish Dis ; 42(8): 1169-1180, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180144

RESUMO

The incidence of skeletal anomalies in reared fish has been translated for years in important economic losses for the aquaculture industry. In the present study, we have analysed the gene expression of extracellular matrix components and transcription factors involved in bone development in gilthead sea bream presenting different skeletal anomalies: lordosis (LD), lordosis-scoliosis-kyphosis (LSK) or opercular, dental or jaw malformations in comparison with control (CT) specimens. Results showed a possible link between the presence of LD and LSK and the significant downregulation of genes involved in osteoblasts' maturation and matrix mineralization (collagen type 1-alpha, osteopontin, osteocalcin, matrix Gla protein and tissue non-specific alkaline phosphatase), as well as in bone resorption (cathepsin K and matrix metalloproteinase 9) compared to CT animals. Contrarily, the key osteogenic transcription factor runx2 was upregulated in the malformed vertebra suggesting impaired determination of mesenchymal stem cells towards the osteoblastic lineage. Despite the gene expression patterns of the other malformed structures were not affected in comparison with CT fish, the results of the present study may contribute in the long term to identify potential candidate gene profiles associated with column deformities that may help reducing the incidence of appearance of skeletal anomalies in this important aquaculture species.


Assuntos
Matriz Extracelular/patologia , Doenças dos Peixes/genética , Expressão Gênica , Anormalidades Musculoesqueléticas/veterinária , Dourada/genética , Animais , Desenvolvimento Ósseo/genética , Doenças dos Peixes/patologia , Regulação da Expressão Gênica no Desenvolvimento , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/patologia , Dourada/anormalidades
6.
Curr Pharm Biotechnol ; 20(6): 517-524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057106

RESUMO

BACKGROUND: The study aimed to investigate the effects of the active ingredient, nimodipine, on chondrocyte proliferation and extracellular matrix (ECM) structures in cartilage tissue cells. METHODS: Chondrocyte cultures were prepared from tissues resected via surgical operations. Nimodipine was then applied to these cultures and molecular analysis was performed. The data obtained were statistically calculated. RESULTS: Both, the results of the (3-(4,5 dimethylthiazol2-yl)-2,5-diphenyltetrazolium (MTT) assay and the fluorescence microscope analysis [a membrane permeability test carried out with acridine orange/ propidium iodide staining (AO/PI)] confirmed that the active ingredient, nimodipine, negatively affects the cell cultures. CONCLUSION: Nimodipine was reported to suppress cellular proliferation; chondroadherin (CHAD) and hypoxia-inducible factor-1 alpha (HIF-1α) expression thus decreased by 2.4 and 1.7 times, respectively, at 24 hrs when compared to the control group (p < 0.05). Furthermore, type II collagen (COL2A1) expression was not detected (p < 0.05). The risk that a drug prescribed by a clinician in an innocuous manner to treat a patient by relieving the symptoms of a disease may affect the proliferation, differentiation, and viability of other cells and/or tissues at the molecular level, beyond its known side effects or adverse events, should not be forgotten.


Assuntos
Bloqueadores dos Canais de Cálcio/toxicidade , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Nimodipina/toxicidade , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Colágeno Tipo II/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Cultura Primária de Células
7.
Int J Oncol ; 54(4): 1233-1244, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968153

RESUMO

Cathepsin B (CTSB) has been reported to be involved in cancer metastasis by altering extracellular matrix (ECM) remodeling and facilitating invasion. However, the contribution of CTSB to collective cell invasion in salivary adenoid cystic carcinoma (SACC) and the underlying mechanisms remain unclear. The present study demonstrated that collective cell invasion is commonly observed in SACC without a complete epithelial­mesenchymal transition signature. CTSB was found to be overexpressed in the invasive front of SACC compared to the tumor center, and was associated with a poor prognosis of patients with SACC. Subsequently, a 3D spheroid invasion assay was established in order to recapitulate the collective cell invasion of SACC and the results revealed that CTSB was only expressed in leader cells. The knockdown of CTSB by siRNA inhibited the migration and invasion of SACC­83 cells and impaired the formation of leader cells. CTSB knockdown also disrupted cytoskeletal organization, altered cell morphology and inhibited ECM remodeling by downregulating matrix metalloproteinase­9, focal adhesion kinase and Rho/ROCK function. Therefore, the present study provides evidence that CTSB may define leader cells in SACC and is required for collective cell invasion as a potential key regulator of ECM remodeling.


Assuntos
Carcinoma Adenoide Cístico/patologia , Catepsina B/metabolismo , Matriz Extracelular/patologia , Neoplasias das Glândulas Salivares/patologia , Catepsina B/genética , Linhagem Celular Tumoral , Movimento Celular , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , RNA Interferente Pequeno/metabolismo
8.
Monaldi Arch Chest Dis ; 89(1)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30968666

RESUMO

Both periodontitis and chronic obstructive pulmonary disease (COPD) are among the most common diseases associated with smoking. These conditions frequently present alongside comorbidities including diabetes, coronary heart disease, duodenal ulcer, deep vein thrombosis, pulmonary embolism, osteoporosis and muscle atrophy. Chronic inflammation contributes to the pathology of both periodontitis and COPD, and in patients suffering from both conditions treatment of periodontitis may lead to relief from COPD symptoms as well. Smoking contributes to the underlying pathophysiology by causing local inflammation, increasing the production of proinflammatory cytokines and most importantly, by locally increasing the activity of proteolytic enzymes which degrade the extracellular matrix in both periodontal and lung interstitial tissue. The increase in protease activity and extracellular matrix degradation may explain why periodontitis and COPD comorbidity is so common, a finding which also indicates that therapeutic interventions targeting protease activity and the inflammatory response may be beneficial for both conditions.


Assuntos
Periodontite/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar/efeitos adversos , Citocinas/metabolismo , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Peptídeo Hidrolases/metabolismo , Periodontite/etiologia , Periodontite/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Fumar/epidemiologia
9.
Life Sci ; 228: 30-34, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004660

RESUMO

Collagen is the most abundant protein in mammalian systems; it can be found in organs such as bones, the liver, kidney, heart, teeth, and skin. Collagen provides the necessary structural framework for tissues in which it is found. However, if there are any alterations in the delicate balance of collagen types in the extracellular matrix (ECM), then problems arise. For example, increasing collagen I:III ratio would provide additional rigidity to tissue structure, whereas decreasing this ratio would provide elasticity and flexibility to the tissue. The proper function of tissues is reliant on this scale not tipping too far in either direction. Major players in the process of ECM remodeling, both normal and adverse, are the fibroblast cells via the secretion of collagen precursors and matrix metalloproteinases, with the latter responsible for ECM degradation. The collagen peptides created by the proteolytic cleavage of these collagen fibrils, while once thought to have an absence of function, have been shown over recent years to potentiate and regulate a variety of cellular processes acting through integrin receptors. Many collagen peptides have been identified from many different collagen types and have been shown to regulate processes such as cell proliferation, migration, apoptosis, and reduce angiogenesis. The collagen peptides of interest are those generated from the primary collagen type of tissue interstitial matrix, collagen type I, and the basement membrane, collagen type IV. Thus, this review looks to highlight some examples of unorthodox functional roles of collagen and its peptides in regulating physiological health and disease.


Assuntos
Colágeno Tipo IV/metabolismo , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Colágeno Tipo I/análise , Colágeno Tipo IV/análise , Matriz Extracelular/química , Humanos , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/metabolismo , Proteólise
10.
Nat Commun ; 10(1): 1914, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015473

RESUMO

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Cartilagem Articular/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Fatores Imunológicos/farmacologia , Osteoartrite/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Cartilagem Articular/imunologia , Cartilagem Articular/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/imunologia , Condrócitos/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Injeções Intra-Articulares , Masculino , Osteoartrite/genética , Osteoartrite/imunologia , Osteoartrite/patologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia , Superóxidos/antagonistas & inibidores , Superóxidos/metabolismo , Transcriptoma/imunologia
11.
Nat Commun ; 10(1): 1848, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015465

RESUMO

Increased tissue stiffness is a driver of breast cancer progression. The transcriptional regulator YAP is considered a universal mechanotransducer, based largely on 2D culture studies. However, the role of YAP during in vivo breast cancer remains unclear. Here, we find that mechanotransduction occurs independently of YAP in breast cancer patient samples and mechanically tunable 3D cultures. Mechanistically, the lack of YAP activity in 3D culture and in vivo is associated with the absence of stress fibers and an order of magnitude decrease in nuclear cross-sectional area relative to 2D culture. This work highlights the context-dependent role of YAP in mechanotransduction, and establishes that YAP does not mediate mechanotransduction in breast cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Matriz Extracelular/patologia , Mecanotransdução Celular , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Mama/patologia , Densidade da Mama , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Progressão da Doença , Matriz Extracelular/metabolismo , Feminino , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Invasividade Neoplásica/patologia , Fosfoproteínas/genética
12.
Int J Mol Sci ; 20(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974795

RESUMO

Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1ß) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.


Assuntos
Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Degeneração do Disco Intervertebral/metabolismo , Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/biossíntese , Animais , Sinalização do Cálcio , Matriz Extracelular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/patologia , Camundongos , Camundongos Knockout , Núcleo Pulposo/patologia
13.
Fertil Steril ; 111(4): 687-698, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30929729

RESUMO

OBJECTIVE: To study pathogenic features of the somatic testicular microenvironment associated with idiopathic germ cell aplasia. DESIGN: Cross-sectional study. SETTING: Tertiary referral center for reproductive medicine. PATIENT(S): Testicular specimens from men with idiopathic nonobstructive azoospermia (iNOA) prospectively submitted to microdissection testicular sperm extraction. Of 20 specimens used for histology, 10 were also available for proteomic analysis. Primary Sertoli cells with normal karyotype and phenotype were also used. INTERVENTION(S): Patients with iNOA were dichotomized according to a positive versus negative sperm retrieval at microdissection testicular sperm extraction, and on the isolated extracellular matrix (ECM) the proteomic analysis was performed. MAIN OUTCOME MEASURE(S): Proteomic analysis of the ECM from testicular specimens with positive versus negative sperm retrieval. Gene ontology enrichment was used to identify upstream regulators based on the 11 deregulated ECM proteins, which were validated by immunohistochemistry and quantitative polymerase chain reaction. Continuous variables were expressed as medians and interquartile range. RESULT(S): Germ cell aplasia was characterized by an increased signaling of the retinoic acid in Sertoli cells and associated with decreased expression of the basal membrane markers nidogen-2 and heparan sulfate proteoglycan-2. Decreased levels of the interstitial matrisome-associated factor IX and its regulator VKORC1 were, instead, coupled with decreased signaling of vitamin K in Leydig cells. An altered expression of a further eight ECM proteins was also found, including laminin-4 and laminin-5. Peripheral levels of the two vitamins were within the reference range in the two cohorts of iNOA men. CONCLUSION(S): We identified the pathogenetic signature of the somatic human testicular microenvironment, providing two vitamin-related mechanistic insights related to the molecular determinants of the idiopathic germ cell aplasia.


Assuntos
Azoospermia/metabolismo , Azoospermia/patologia , Matriz Extracelular/patologia , Testículo/metabolismo , Vitamina A/metabolismo , Vitamina K/metabolismo , Adolescente , Células Cultivadas , Estudos Transversais , Matriz Extracelular/metabolismo , Humanos , Masculino , Microdissecção , Proteômica , Transdução de Sinais/fisiologia , Recuperação Espermática , Testículo/patologia , Adulto Jovem
14.
Methods Mol Biol ; 1944: 203-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840245

RESUMO

The tumor microenvironment is a heterogeneous tissue that in addition to tumor cells, contain tumor-associated cell types such as immune cells, fibroblasts, and endothelial cells. Considerably important in the tumor microenvironment is its noncellular component, namely, the extracellular matrix (ECM). In particular, the collagenous matrix is subjected to significant alterations in its composition and structure that create a permissive environment for tumor growth, invasion, and dissemination. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are numerous in the tumor stroma and are locally educated to mediate important biological functions that profoundly affect tumor initiation, growth, and dissemination. While the influence of TAMs and mechanical properties of the collagenous matrix on tumor invasion and progression have been comprehensively investigated individually, their interaction within the complex tumor microenvironment was overlooked. This review summarizes accumulating evidence that indicate the existence of an intricate tumorigenic crosstalk between TAMs and collagenous matrix. A better mechanistic comprehension of this reciprocal interplay may open a novel arena for cancer therapeutics.


Assuntos
Carcinogênese/patologia , Colágeno/metabolismo , Matriz Extracelular/patologia , Fibroblastos/patologia , Macrófagos/patologia , Neoplasias/patologia , Microambiente Tumoral , Carcinogênese/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Humanos , Macrófagos/metabolismo , Neoplasias/metabolismo
15.
J Shoulder Elbow Surg ; 28(7): 1265-1272, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30846222

RESUMO

BACKGROUND: Although frozen shoulder (FS) is a common shoulder disorder, its pathogenesis is not yet determined. The function of matrix metalloproteinases (MMPs) is related to extracellular matrix remodeling. The purposes of this study were to investigate the pattern of sequential expression of MMPs in a rat model of shoulder contracture and to compare the expression of MMPs in the joint capsule between patients with FS and a control group. METHODS: We obtained joint capsules from rats immobilized by molding plaster (a shoulder contracture model) at baseline, 3 days, 1 week, and 3 weeks (4 rats per time point; 16 rats in total). The expression of the inflammatory cytokine interleukin 6 (IL-6), MMP-2, and MMP-9 was examined by immunohistochemistry. We also obtained joint capsules from 21 patients with FS and 13 control patients with instability to quantify the expression levels of MMP-2 and MMP-9 by immunohistochemistry. RESULTS: In the rat model, IL-6 and MMP-9 tended to be overexpressed in the joint capsule at 3 days and 1 week and MMP-2 at 3 days, 1 week, and 3 weeks. MMP-2 and MMP-9 were significantly overexpressed in the joint capsules of the patients with FS compared with those of control patients. CONCLUSION: The results from both human and animal studies suggest the involvement of MMP-2 and MMP-9 in the development of FS. Animal study showed that the sequential expression of IL-6 and MMPs may be associated with fibrosis of the joint capsule.


Assuntos
Bursite/etiologia , Bursite/metabolismo , Cápsula Articular/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Adolescente , Adulto , Idoso , Animais , Bursite/patologia , Estudos de Casos e Controles , Contratura/metabolismo , Contratura/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/patologia , Feminino , Humanos , Interleucina-6/metabolismo , Cápsula Articular/patologia , Masculino , Pessoa de Meia-Idade , Ratos , Adulto Jovem
16.
Drugs Aging ; 36(6): 485-492, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30864023

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating, scarring lung disease with a worse prognosis than some cancers. The incidence of IPF is increasing and while current antifibrotic therapies slow disease progression, they do not offer a cure. The pathobiology of IPF is complex and is driven by aging-associated cellular dysfunction, epithelial injury, and an aberrant wound-healing response characterised by fibroblast activation and extracellular matrix accumulation (ECM) in the interstitium. As understanding of the underlying mechanisms has evolved, new targets for pharmacotherapy have emerged. Novel drugs currently in development for pulmonary fibrosis have diverse molecular properties and mechanisms of action, as well as different routes of administration. A shared primary goal of these agents is reduction of the profibrotic activity of fibroblasts and limitation of ECM deposition, which hinders gas exchange and ultimately leads to respiratory failure. This article provides an overview of some promising new therapeutic options for IPF and considers the challenges for future drug development.


Assuntos
Envelhecimento/patologia , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Envelhecimento/metabolismo , Desenvolvimento de Medicamentos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Methods Mol Biol ; 1952: 261-275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825181

RESUMO

Extracellular matrix (ECM) macromolecules, apart from structural role for the surrounding tissue, have also been defined as crucial mediators in several cell mechanisms. The proteolytic and cross-linking cascades of ECM have fundamental importance in health and disease, which is increasingly becoming acknowledged. However, formidable challenges remain to identify the diverse and novel role of ECM molecules, especially with regard to their distinct biophysical, biochemical, and structural properties. Considering the heterogeneous, dynamic, and hierarchical nature of ECM, the characterization of 3D functional molecular view of ECM in atomic detail will be very useful for further ECM-related studies. Nowadays, the creation of a pioneer ECM multidisciplinary integrated platform in order to decipher ECM homeostasis is more possible than ever. The access to cutting-edge technologies, such as optical imaging and electron and atomic force microscopies, along with diffraction and X-ray-based spectroscopic methods can integrate spanning wide ranges of spatial and time resolutions. Subsequently, ECM image-guided site-directed proteomics can reveal molecular compositions in defined native and reconstituted ECM microenvironments. In addition, the use of highly selective ECM enzyme inhibitors enables the comparative molecular analyses within pre-classified remodeled ECM microenvironments. Mechanistic information which will be derived can be used to develop novel protein-based inhibitors for effective diagnostic and/or therapeutic modalities targeting ECM reactions within tissue microenvironment.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteômica/métodos , Aminoácido Oxirredutases/análise , Aminoácido Oxirredutases/metabolismo , Animais , Descoberta de Drogas/métodos , Matriz Extracelular/química , Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/análise , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Proteína-Lisina 6-Oxidase/análise , Proteína-Lisina 6-Oxidase/metabolismo , Proteólise
18.
Biomed Pharmacother ; 113: 108652, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856535

RESUMO

Emerging evidence suggests that microRNAs (miRNAs, miRs) play important roles in the development of intervertebral disc degeneration (IVDD). Nonetheless, the expression level and biological function of miR-499a-5p in IVDD are still unclear. In this study, we found that miR-499a-5p was significantly downregulated in degenerative tissues of the human nucleus pulposus (NP) compared with healthy tissues. Knockdown of miR-499a-5p promoted NP cell (NPC) apoptosis, stimulated caspase activation, enhanced MMP3 and MMP13 expression, and downregulated aggrecan and type II collagen. Furthermore, TNF-α-treated NPCs showed increased apoptosis and induced an imbalance between anabolism and catabolism of the extracellular matrix (ECM); these changes were attenuated by miR-499a-5p overexpression. Research into possible mechanisms revealed that miR-499a-5p suppressed the expression of SOX4 both at mRNA and protein levels and directly bound to the 3' untranslated region of SOX4 mRNA. Ectopic expression of SOX4 attenuated the negative effect of miR-499a-5p on NPC apoptosis and the positive effect on ECM synthesis. Taken together, these results indicate that miR-499a-5p may attenuate TNF-α-induced NPC apoptosis and an imbalance between anabolism and catabolism of the ECM by downregulating SOX4.


Assuntos
Apoptose/genética , Matriz Extracelular/patologia , Degeneração do Disco Intervertebral/patologia , MicroRNAs/genética , Núcleo Pulposo/patologia , Fatores de Transcrição SOXC/metabolismo , Regiões 3' não Traduzidas , Células Cultivadas , Regulação para Baixo , Matriz Extracelular/metabolismo , Feminino , Humanos , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , Masculino , Pessoa de Meia-Idade , Núcleo Pulposo/metabolismo
19.
Int J Mol Sci ; 20(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884785

RESUMO

Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.


Assuntos
Fibrose/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Inflamação/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Matriz Extracelular/genética , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/genética , Histona Desacetilases/genética , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/genética , Hipertensão Portal/patologia , Inflamação/genética , Inflamação/patologia , Modelos Animais , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia
20.
Dermatol Surg ; 45(4): 547-551, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30893178

RESUMO

BACKGROUND: Previous studies have shown that calcium hydroxylapatite (CaHa) injected intradermally resulted in new collagen production at 6 months after injection, and a possible increase in elastin formation. In addition, a recent study showed the formation of new collagen, elastin, and angiogenesis after injection at 4 and 9 months. OBJECTIVE: To evaluate any changes in the presence of elastic fibers, proteoglycans, and elastin in photodamaged skin after injections with CaHa. METHODS AND MATERIALS: Fifteen subjects underwent a punch biopsy of the right infra-auricular areas before and after injection of CaHa on day 180. Specimens were stained for elastic fibers, elastin, and proteoglycan presence. RESULTS: Quantitative analysis demonstrated a percent change in elastic fibers varying between 29% and 179% at 6 months in comparison with baseline. Subjects showed an increase in elastin between 12% and 66%. Subjects had positive mean percentage change in proteoglycans of 76.27% (t-test of 0.198). CONCLUSION: This is the first study to show that CaHa can increase proteoglycans and echoed previous studies showing it can also have an effect on elastin, which indicates it can induce remodeling of all aspects of the extracellular matrix. Much larger and longer studies are required to confirm its unique impact on collagen, elastin, and proteoglycans.


Assuntos
Materiais Biocompatíveis/farmacologia , Durapatita/farmacologia , Tecido Elástico/patologia , Elastina/biossíntese , Proteoglicanas/biossíntese , Envelhecimento da Pele/efeitos dos fármacos , Materiais Biocompatíveis/administração & dosagem , Biópsia , Colágeno/biossíntese , Durapatita/administração & dosagem , Tecido Elástico/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Injeções Intradérmicas , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Envelhecimento da Pele/fisiologia
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