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1.
Gene ; 850: 146927, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36228865

RESUMO

Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzyme families that play an important role in regulating human physiological as well as pathological processes, especially in malignant tumors. Numerous experimental studies have shown that MMPs are not only involved in the occurrence and development of solid tumors but also play a key role in the staging and grading of tumors. The specific processes by which MMPs are involved in tumor cell invasion and metastasis mainly include degradation of the extracellular matrix, regulation of gene polymorphism, promotion of epithelial-mesenchymal transformation, and induction of adhesion molecule expression. The correlated expression of MMPs in different solid tumors provides a basis for tumor markers, tumor prognosis, and drug targets. In this review, the function, classification, and nomenclature of MMPs will be summarized, and the relevant expression of MMPs in solid tumors, as well as the clinical survival rate and general prognosis associated with MMPs, will be elaborated to provide useful information on which to base the search for new targets for tumor therapy.


Assuntos
Metaloproteinases da Matriz , Neoplasias , Humanos , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Neoplasias/patologia , Transição Epitelial-Mesenquimal , Matriz Extracelular/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Zinco/metabolismo
2.
Turk J Med Sci ; 52(4): 1355-1361, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36326383

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) family members and their associated ligands may be related to bone and joint destruction in rheumatoid arthritis. Matrix metalloproteinases are responsible for joint and bone tissue degradation. This study is intended to investigate the effect of epidermal growth factor receptor inhibition by lapatinib on the synthesis of matrix metalloproteinases in in vitro. METHODS: Synovial fibroblast cell culture was obtained from a patient with rheumatoid arthritis who underwent knee arthroplasty. Interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were added to the cell culture to stimulate synovial fibroblast cells and create an inflammatory character. Understimulated and nonstimulated conditions, lapatinib was applied to the culture in four different concentrations of 25, 50, 100, and 200 µmol. Then, matrix metalloproteinase -1, -3, and, -13 levels were assessed. RESULTS: When stimulated with IL-1ß and TNF-α, the synthesis of matrix metalloproteinases from synovial fibroblast was increased significantly. When lapatinib is added to the stimulated synovial fibroblasts, matrix metalloproteinases synthesis is significantly suppressed. DISCUSSION: Inhibition of the EGFR pathway with lapatinib suppresses matrix metalloproteinases synthesis. Our results suggest EGFR pathway inhibition may be a promising option to prevent joint destruction in the treatment of rheumatoid arthritis.


Assuntos
Artrite Reumatoide , Membrana Sinovial , Humanos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa , Lapatinib/farmacologia , Lapatinib/metabolismo , Metaloproteinases da Matriz/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Artrite Reumatoide/patologia , Receptores ErbB/metabolismo , Células Cultivadas
3.
Nat Commun ; 13(1): 6409, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36302921

RESUMO

Macrophages and cancer cells populations are posited to navigate basement membrane barriers by either mobilizing proteolytic enzymes or deploying mechanical forces. Nevertheless, the relative roles, or identity, of the proteinase -dependent or -independent mechanisms used by macrophages versus cancer cells to transmigrate basement membrane barriers harboring physiologically-relevant covalent crosslinks remains ill-defined. Herein, both macrophages and cancer cells are shown to mobilize membrane-anchored matrix metalloproteinases to proteolytically remodel native basement membranes isolated from murine tissues while infiltrating the underlying interstitial matrix ex vivo. In the absence of proteolytic activity, however, only macrophages deploy actomyosin-generated forces to transmigrate basement membrane pores, thereby providing the cells with proteinase-independent access to the interstitial matrix while simultaneously exerting global effects on the macrophage transcriptome. By contrast, cancer cell invasive activity is reliant on metalloproteinase activity and neither mechanical force nor changes in nuclear rigidity rescue basement membrane transmigration. These studies identify membrane-anchored matrix metalloproteinases as key proteolytic effectors of basement membrane remodeling by macrophages and cancer cells while also defining the divergent invasive strategies used by normal and neoplastic cells to traverse native tissue barriers.


Assuntos
Matriz Extracelular , Neoplasias , Humanos , Camundongos , Animais , Membrana Basal/metabolismo , Matriz Extracelular/metabolismo , Macrófagos , Metaloproteinases da Matriz/metabolismo , Neoplasias/metabolismo
4.
Nature ; 610(7931): 366-372, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36198801

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)-NF-κB-p62-NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I-DDR1-NF-κB-NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.


Assuntos
Carcinoma Ductal Pancreático , Colágeno Tipo I , Receptor com Domínio Discoidina 1 , Transdução de Sinais , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Colágeno Tipo I/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Taxa de Sobrevida
5.
Biomolecules ; 12(10)2022 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-36291577

RESUMO

Matrix metalloproteinases (MMPs) are enzymes that decompose extracellular matrix (ECM) proteins. MMPs are thought to play important roles in cellular processes, such as cell proliferation, differentiation, angiogenesis, migration, apoptosis, and host defense. MMPs are distributed in almost all intraocular tissues and are involved in physiological and pathological mechanisms of the eye. MMPs are also associated with glaucoma, a progressive neurodegenerative disease of the eyes. MMP activity affects intraocular pressure control and apoptosis of retinal ganglion cells, which are the pathological mechanisms of glaucoma. It also affects the risk of glaucoma development based on genetic pleomorphism. In addition, MMPs may affect the treatment outcomes of glaucoma, including the success rate of surgical treatment and side effects on the ocular surface due to glaucoma medications. This review discusses the various relationships between MMP and glaucoma.


Assuntos
Glaucoma , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/metabolismo , Glaucoma/metabolismo , Metaloproteinases da Matriz/metabolismo , Pressão Intraocular , Células Ganglionares da Retina/metabolismo , Matriz Extracelular/metabolismo
6.
Placenta ; 129: 36-42, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36208531

RESUMO

INTRODUCTION: Enzymes, including matrix metalloproteinases (MMPs), play a significant role in trophoblast invasion - the cornerstone of preeclampsia pathogenesis. METHODS: This study aimed to explore the dynamics of the MMP-12 concentration in blood serum during the gestational period at determined weeks in preeclampsia and physiological pregnancy to compare the results with the expression of MMP-12 in placental tissue and reveal the MMP-12 predicting role in preeclampsia. RESULTS: Circulating serum MMP-12 was significantly decreased. The level of 0.5 ng/ml had high sensitivity and low false positivity at 11-13 weeks of pregnancy in women destined to develop pre-eclampsia in the case-control study. The dynamics curve of serum MMP-12 varied between study groups: a sharp decrease in MMP-12 concentration was found from the first trimester to the second trimester, followed by a slight increase in the third trimester of pregnancy in controls compared to the increase in concentration from the first trimester to the second trimester in pre-eclampsia. The absence of a significant difference in the concentration of MMP-12 in the II and III trimesters as well as no difference in the expression of MMP-12 protein in placental tissue in the third trimester indicates a decrease in its role after the end of placentation. DISCUSSION: To our knowledge, this is the first study to show the dynamics of serum MMP-12 concentration during the gestational period and indicates a significant role for MMP-12 in the initial stages of placentation. The data obtained may pave the way to new early prediction strategies for preeclampsia.


Assuntos
Pré-Eclâmpsia , Feminino , Humanos , Gravidez , Biomarcadores/metabolismo , Estudos de Casos e Controles , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Placenta/metabolismo
7.
In Vivo ; 36(6): 2531-2541, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36309355

RESUMO

Human papillomavirus (HPV) infections are associated with cervical cancer and other anogenital cancers. Despite progresses in HPV vaccination and screening, these cancers still show high incidence and mortality, requiring improved prognostic markers and tailored therapies. This review addresses the role of Matrix metalloproteinases (MMPs) in HPV-induced cancers and the modulation of MMP expression by HPV oncoproteins. Scientific literature indexed in PubMed and ScienceDirect about Human papillomavirus modulates matrix metalloproteinases was retrieved and critically analyzed, to obtain an overview of expression patterns and their implications for carcinogenesis and patient prognosis. Matrix metalloproteinases such as MMP1, MMP9 and MMP13 have been associated with patient prognosis in HPV-induced cancers and play a major role in the degradation of the extracellular matrix, tumor invasion and metastasis. The HPV E2 and E7 oncoproteins regulate MMP expression via AKT, MEK/ERK and AP-1 signaling among other mechanisms. Increased expression of MMPs is associated with cancer progression and poor prognosis in multiple HPV-induced cancers, suggesting their potential use as prognostic markers. The identification of specific signaling pathways that mediate MMP regulation by HPV is essential for developing efficient new cancer therapies.


Assuntos
Alphapapillomavirus , Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Alphapapillomavirus/metabolismo , Metaloproteinase 2 da Matriz , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus , Neoplasias do Colo do Útero/patologia , Metaloproteinases da Matriz/metabolismo , Carcinogênese/genética
8.
Food Res Int ; 161: 111798, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36192942

RESUMO

Long-term exposure to UVB can trigger acute inflammation of the skin and lead to skin photoaging. To scrutinize the anti-photoaging functions of peptides obtained from milk, the physicochemical including molecular weight and amino acid compositions were first analyzed. Totally 267 peptides were screened out and identified by PEAKS X software, and then evaluated through Peptide Ranker and BIOPEP-UMW. Six peptides with the highest antioxidant ability and relative abundance were selected. This study was then conducted in UVB-damaged human foreskin fibroblasts with proadministration of peptides. The results indicated that at concentrations of 0.08-0.10 mg/mL, milk-derived peptides could realize a damage prevention effect through inhibiting the generation of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA). Also, these peptides were found to promote the photoaging related enzyme activities of superoxide dismutase (SOD) and catalase (CAT), while to block the production of matrix metalloproteinases-1. Through this study, we found that milk-derived peptide mixture is effective in preventing photoaging damage. Milk-derived peptides found in this study could serve as raw materials for future development of antioxidant functional foods.


Assuntos
Antioxidantes , Prepúcio do Pênis , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Catalase/metabolismo , Fibroblastos , Prepúcio do Pênis/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/farmacologia , Leite/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Raios Ultravioleta/efeitos adversos
9.
Aging (Albany NY) ; 14(17): 7137-7155, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36107005

RESUMO

OBJECTIVE: To investigate the mechanism of alanine aminotransferase 1 (ALT1) in the progression of HCC, the differentially expressed proteins (DEPs) in the ALT1 interaction network were identified by targeted proteomic analysis. METHODS: Wound healing and transwell assays were conducted to assess the effect of ALT1 on cellular migration and invasion. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were performed to identify alterations in proliferation and apoptosis. After coimmunoprecipitation processing, mass spectrometry with iso-baric tags for relative and absolute quantitation was utilized to explore the protein interactions in ALT1 knockdown HepG2 cells. RESULTS: The results showed that ALT1 knockdown inhibits the migration, invasion, proliferation of HepG2 cells, and promotes apoptosis. A total of 116 DEPs were identified and the bioinformatics analysis suggested that the ALT1-interacting proteins were primarily associated with cellular and metabolic processes. Knockdown of ALT1 in HepG2 cells reduced the expression of Ki67 and epithelial cell adhesion molecule (EP-CAM), while the expression of apoptosis-stimulating protein 2 of p53 (ASPP2) was increased significantly. Suppression of the ALT1 and EP-CAM expression contributed to alterations in epithelial-mesenchymal transition (EMT) -associated markers and matrix metalloproteinases (MMPs). Additionally, inhibition of ALT1 and Ki67 also decreased the expression of apoptosis and proliferation factors. Furthermore, inhibition of ALT1 and ASPP2 also changed the expression of P53, which may be the signaling pathway by which ALT regulates these biological behaviors. CONCLUSIONS: This study indicated that the ALT1 protein interaction network is associated with the biological behaviors of HepG2 cells via the p53 signaling pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante/metabolismo , Alanina Transaminase/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Molécula de Adesão da Célula Epitelial/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metaloproteinases da Matriz/metabolismo , Proteômica , Sincalida/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Int J Pharm ; 627: 122162, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36122617

RESUMO

Retinoic acid (RA) is an approved treatment for skin photoaging induced by ultraviolet (UVA). Topically applied RA is mainly located in the stratum corneum (SC) with limited diffusion into the deeper strata. A delivery system capable of facilitating dermal delivery and cellular internalization for RA is critical for a successful photoaging therapy. Two delivery approaches, namely nanoparticles and laser ablation, were combined to improve RA's absorption efficacy and safety. The nanoparticle absorption enhancement by the lasers was compared between full-ablative (Er:YAG) and fractional (CO2) modalities. We fabricated poly-L-lactic acid (PLA) and PLA/poly(lactic-co-glycolic acid) (PLGA) nanoparticles by an emulsion-solvent evaporation technique. The mean size of PLA and PLA/PLGA nanocarriers was 237 and 222 nm, respectively. The RA encapsulation percentage in both nanosystems was > 96 %. PLA and PLA/PLGA nanocarriers promoted RA skin deposition by 5- and 3-fold compared to free control. The ablative lasers further enhanced the skin deposition of RA-loaded nanoparticles, with the full-ablative laser showing greater permeation enhancement than the fractional mode. The skin biodistribution assay evaluated by confocal and fluorescence microscopies demonstrated that the laser-assisted nanoparticle delivery achieved a significant dermis and follicular accumulation. The cell-based study indicated a facile uptake of the nanoparticles into the human dermal fibroblasts. The nanoparticulate RA increased type I collagen and elastin production in the UVA-treated fibroblasts. A reduction of matrix metalloproteinase (MMP)-1 was also highlighted in the photoaging cells. The calculation of therapeutic index (TI) by multiplying collagen/elastin elevation percentage and skin deposition predicted better anti-photoaging performance in Er:YAG laser-assisted nanoparticle delivery than CO2 laser. Nanoencapsulation of RA decreased the cytotoxicity against skin fibroblasts. In vivo skin tolerance test on a nude mouse showed less skin damage after topical application of the nanoparticles than free RA. Our results hypothesized that the laser-mediated nanoparticle delivery provided an efficient and safe use for treating photoaging.


Assuntos
Lasers de Estado Sólido , Nanopartículas , Dermatopatias , Camundongos , Animais , Humanos , Absorção Cutânea , Elastina/metabolismo , Tretinoína , Administração Cutânea , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Colágeno Tipo I/metabolismo , Distribuição Tecidual , Emulsões/metabolismo , Dióxido de Carbono/metabolismo , Pele/metabolismo , Dermatopatias/metabolismo , Camundongos Nus , Solventes/metabolismo , Metaloproteinases da Matriz/metabolismo
11.
J Cell Sci ; 135(20)2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36172824

RESUMO

Extracellular matrix (ECM) is an important component of stem cell niche. Remodeling of ECM mediated by ECM regulators, such as matrix metalloproteinases (MMPs) plays a vital role in stem cell function. However, the mechanisms that modulate the function of ECM regulators in the stem cell niche are understudied. Here, we explored the role of the transcription factor (TF) ETS-1, which is expressed in the cathepsin-positive cell population, in regulating the expression of the ECM regulator, mt-mmpA, thereby modulating basement membrane thickness. In planarians, the basement membrane around the gut/inner parenchyma is thought to act as a niche for pluripotent stem cells. It has been shown that the early epidermal progenitors migrate outwards from this region and progressively differentiate to maintain the terminal epidermis. Our data shows that thickening of the basement membrane in the absence of ets-1 results in defective migration of stem cell progeny. Furthermore, the absence of ets-1 leads to a defective epidermal progenitor landscape, despite its lack of expression in those cell types. Together, our results demonstrate the active role of ECM remodeling in regulating tissue homeostasis and regeneration in the planarian Schmidtea mediterranea. This article has an associated First Person interview with one of the co-first authors of the paper.


Assuntos
Mediterranea , Planárias , Animais , Humanos , Diferenciação Celular , Catepsinas/metabolismo , Planárias/metabolismo , Epiderme/metabolismo , Metaloproteinases da Matriz/metabolismo , Membrana Basal/metabolismo , Fatores de Transcrição/metabolismo
12.
Stroke ; 53(11): 3514-3523, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36148658

RESUMO

Binswanger disease is the small vessel form of vascular cognitive impairment and dementia. Deposition of Alzheimer disease proteins can begin in midlife and progress slowly, whereas aging of the vasculature also can begin in midlife, continuing to progress into old age, making mixed dementia the most common type of dementia. Biomarkers facilitate the early diagnosis of dementias. It is possible to diagnose mixed dementia before autopsy with biomarkers for vascular disease derived from diffusor tensor images on magnetic resonance imaging and Alzheimer disease proteins, Aß (amyloid ß), and phosphorylated tau, in cerebrospinal fluid or in brain with positron emission tomography. The presence of vascular disease accelerates cognitive decline. Both misfolded proteins and vascular disease promote inflammation, which can be detected in cerebrospinal fluid by the presence of MMPs (matrix metalloproteinases), angiogenic growth factors, and cytokines. MMPs disrupt the blood-brain barrier and break down myelin, producing Binswanger disease's 2 main pathological features. Advances in detecting biomarkers in plasma will provide early detection of dementia and aided by machine learning and artificial intelligence, will enhance diagnosis and form the basis for early treatments.


Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Disfunção Cognitiva , Demência Vascular , Substância Branca , Humanos , Demência Vascular/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Substância Branca/patologia , Medicina de Precisão , Inteligência Artificial , Disfunção Cognitiva/diagnóstico por imagem , Biomarcadores , Tomografia por Emissão de Pósitrons , Transtornos Cerebrovasculares/patologia , Metaloproteinases da Matriz/metabolismo , Citocinas/metabolismo
13.
Am J Physiol Cell Physiol ; 323(4): C1290-C1303, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36094433

RESUMO

Maintenance of skin homeostasis is a highly regulated and complex process involving a continuous remodeling by several extracellular matrix proteases, including metalloproteinases. The expression and activity of all metalloproteinases are under strict control, and their deregulation is often associated with diseases or chronic conditions, thereby being considered popular targets for developing new therapeutics. This review will highlight metalloproteinases of the MMP and ADAM families with functions in dermal homeostasis and give some insights into the mechanisms regulating their activity and expression. Furthermore, we discuss how the dysregulation of the most prominent family members affects dermal homeostasis by triggering disease development and influencing progression, focusing on cancer and aging. Here, recent discoveries and new approaches that target or exploit metalloproteinase activity in therapy are emphasized. The potential of naturally derived components in regulating metalloproteinase expression and activity in disease is discussed.


Assuntos
Matriz Extracelular , Neoplasias , Matriz Extracelular/metabolismo , Homeostase , Humanos , Metaloproteinases da Matriz/metabolismo , Neoplasias/metabolismo , Proteólise
14.
Int J Mol Sci ; 23(18)2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36142454

RESUMO

Matrix metalloproteinases (MMPs) are involved in extracellular matrix remodeling through the degradation of extracellular matrix components and are also involved in the inflammatory response by regulating the pro-inflammatory cytokines TNF-α and IL-1ß. Dysregulation in the inflammatory response and changes in the extracellular matrix by MMPs are related to the development of various diseases including lung and cardiovascular diseases. Therefore, numerous studies have been conducted to understand the role of MMPs in disease pathogenesis. MMPs are involved in the pathogenesis of infectious diseases through a dysregulation of the activity and expression of MMPs. In this review, we discuss the role of MMPs in infectious diseases and inflammatory responses. Furthermore, we present the potential of MMPs as therapeutic targets in infectious diseases.


Assuntos
Doenças Transmissíveis , Fator de Necrose Tumoral alfa , Doenças Transmissíveis/metabolismo , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Humanos , Inflamação/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Sci Rep ; 12(1): 16006, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36163231

RESUMO

The objective of the current study was to examine the effects of fibroblast growth factor-2 (FGF-2) on conjunctival fibrogenesis that was induced by the presence of transforming growth factor-ß2 (TGF-ß2). Two-dimension (2D) and three-dimension (3D) cultured human conjunctival fibroblasts (HconF) were used for this purpose. The 2D and 3D cultured HconF were characterized by transendothelial electrical resistance (TEER) and FITC dextran permeability measurements (2D), real-time metabolic analyses (2D), size and stiffness measurements (3D), and the mRNA expression of extracellular matrix molecules, their modulators, Tissue inhibitor of metalloproteinases and matrix metalloproteinases and ER-stress related genes (2D and 3D). FGF-2 significantly increased planar proliferation, as evidenced by TEER values and FITC dextran permeability, and shifted glucose metabolism to the energetic phenotype of 2D HconF cells, and the stiffness of the 3D spheroids, and these effects were further enhanced in the presence of TGF-ß2. Analyses of the expression of possible candidate molecules involved in cell architecture and stress indicated that some additive effects caused by both factors were also recognized in some of these molecules. The findings reported herein indicate that the FGF-2, either along or additively with TGF- ß2 increased the fibrogenetic changes on the plane as well as in the spatial space of HconF cells.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Fator de Crescimento Transformador beta2 , Células Cultivadas , Dextranos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibroblastos/metabolismo , Fluoresceína-5-Isotiocianato/análogos & derivados , Glucose/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , RNA Mensageiro/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Fator de Crescimento Transformador beta2/farmacologia , Fatores de Crescimento Transformadores/metabolismo , Fatores de Crescimento Transformadores/farmacologia
16.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076910

RESUMO

Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.


Assuntos
Matriz Extracelular , Metaloproteinase 14 da Matriz , Metaloproteinase 2 da Matriz , Neoplasias , Matriz Extracelular/metabolismo , Humanos , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Metaloendopeptidases/metabolismo , Neoplasias/metabolismo
17.
Life Sci ; 308: 120932, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36067841

RESUMO

Cancer is one of the leading causes of death in patients worldwide, where invasion and metastasis are directly responsible for this statement. Although cancer therapy has progressed in recent years, current therapeutic approaches are ineffective due to toxicity and chemoresistance. Therefore, it is essential to evaluate other treatment options, and natural products are a promising alternative as they show antitumor properties in different study models. This review describes the regulation of tissue inhibitors of metalloproteinases (TIMPs) expression and the role of flavonoids as molecules with the antitumor activity that targets TIMPs therapeutically. These inhibitors regulate tissue extracellular matrix (ECM) turnover; they inhibit matrix metalloproteinases (MMPs), cell migration, invasion, and angiogenesis and induce apoptosis in tumor cells. Data obtained in cell lines and in vivo models suggest that flavonoids are chemopreventive and cytotoxic against various types of cancer through several mechanisms. Flavonoids also regulate crucial signaling pathways such as focal adhesion kinase (FAK), phosphatidylinositol-3-kinase (PI3K)-Akt, signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NFκB), and mitogen-activated protein kinase (MAPK) involved in cancer cell migration, invasion, and metastasis. All these data reposition flavonoids as excellent candidates for use in cancer therapy.


Assuntos
Produtos Biológicos , Neoplasias , Inibidores Teciduais de Metaloproteinases/metabolismo , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo
18.
Front Immunol ; 13: 986469, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119117

RESUMO

Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Basigina/metabolismo , Isquemia Encefálica/metabolismo , Hemorragia Cerebral , Humanos , Metaloproteinases da Matriz/metabolismo
19.
BMC Complement Med Ther ; 22(1): 232, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36123596

RESUMO

BACKGROUND: Chronic ultraviolet (UV) exposure is one of the major external factors in skin aging, and repetitive UVB exposure induces extracellular matrix (ECM) damage as well as metabolic disease. Alpinia officinarum Rhizome (AOR) is a medicinal plant that has been traditionally used for treating rheumatism and whooping cough. However, the antiphotoaging effects of AOR remain unclear. We investigated the protective effects of water extracts of AOR (WEAOR) in terms of UVB-mediated ECM damage, wrinkle formation, inflammatory responses, and intracellular signaling on hairless mice and NIH-3T3 skin fibroblast cells. METHODS: WEAOR was administered to UVB-irradiated hairless mice. Wrinkle formation was assessed using the replica assay, epidermal changes through H&E staining, and collagen contents in mice skin through Masson's trichrome staining. The expression of procollagen type-1 (COL1A1), metalloproteinase-1a (MMP-1a), and inflammatory cytokines (IL-6, IL-8, and MCP-3) in hairless mice skin and NIH-3T3 cells was investigated through qRT-PCR. The effects of WEAOR or signaling inhibitors on UVB-induced expression of intracellular mitogen-activated protein kinases (MAPKs) were estimated by Western blotting and qRT-PCR, respectively. RESULTS: Topical WEAOR significantly attenuated the UVB-induced wrinkle formation and epidermal thickening in the skin of hairless mice. WEAOR treatment also attenuated the UVB-induced expression of MMP-1a and COL1A1 and recovered the reduction of collagen content in mouse skin. These effects were confirmed in NIH-3T3 skin fibroblast cells. WEAOR treatment restored the UVB-induced COL1A1 and MMP-1a gene expression and attenuated the UVB-induced expression of IL-6, IL-8, and MCP-3 in NIH-3T3 cells. Notably, WEAOR attenuated UVB-induced phosphorylation of AKT and ERK, but not that of p38 and JNK in NIH-3T3 cells. In addition, the administration of AKT and ERK inhibitors restored the UVB-induced expression of MMP-1a and COL1A1 to an equal extent as WEAOR in NIH-3T3 cells. CONCLUSIONS: The antiphotoaging properties of WEAOR were first evaluated in this study. Our results suggest that WEAOR may be a potential antiphotoaging agent that ameliorates UVB-induced photoaging processes via the AKT and ERK signaling pathways.


Assuntos
Alpinia , Envelhecimento da Pele , Alpinia/metabolismo , Animais , Colágeno/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Pelados , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Pró-Colágeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rizoma , Raios Ultravioleta/efeitos adversos , Água
20.
J Biol Chem ; 298(9): 102335, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35926707

RESUMO

Disordered expression and distribution of plasma membrane proteins at the cell surface leads to diverse malignant phenotypes in tumors, including cell invasion. The ubiquitin-specific protease TRE17/USP6, an oncogene identified in Ewing sarcoma, is highly expressed in several cancers and locally aggressive tumor-like lesions. We have previously demonstrated that TRE17 regulates the trafficking of plasma membrane proteins that enter cells via clathrin-independent endocytosis (CIE); TRE17 prevents CIE cargo proteins from being targeted to lysosomes for degradation by deubiquitylating them. However, functional insights into the effects of TRE17-mediated CIE cargo trafficking on cell invasion remain unknown. Here, we show that increased expression of TRE17 enhances invasiveness of the human sarcoma cell line HT-1080 by elevating the cell surface levels of the membrane glycoprotein CD147, which plays a central role in tumor progression. We demonstrate overexpression of TRE17 decreases ubiquitylated CD147, which is accompanied by suppression of CD147 transport to lysosomes, resulting in the stabilization and increase of cell surface-localized CD147. On the other hand, we show knockdown of TRE17 decreases cell surface CD147, which is coupled with reduced production of matrix metalloproteinases, the enzymes responsible for extracellular matrix degradation. Furthermore, we demonstrate that inhibition of CD147 by a specific inhibitor alleviated the TRE17-promoted tumor cell invasion. We therefore propose a model for the pathogenesis of TRE17-driven tumors in which TRE17 increases CD147 at the cell surface by preventing its lysosomal degradation, which in turn enhances matrix metalloproteinase synthesis and matrix degradation, thereby promoting tumor cell invasion.


Assuntos
Basigina , Neoplasias Ósseas , Proteínas de Membrana , Sarcoma de Ewing , Ubiquitina Tiolesterase , Proteases Específicas de Ubiquitina , Basigina/metabolismo , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Clatrina/genética , Humanos , Metaloproteinases da Matriz/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Invasividade Neoplásica , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo
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