RESUMO
AIM: Renal fibrosis is a common cause of renal dysfunction with chronic kidney diseases. This process is characterized by excessive production of extracellular matrix (ECM) or inhibition of ECM degradation. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteinases, which are widely presented in mammals, have very critical roles in ECM remodelling. We aimed to study the role of ADAMTS proteinases and some of the ECM markers in the pathogenesis of renal fibrosis and to investigate the effects of hypoxia on these biomarkers. METHODS: In addition to the control group, Adriamycin (ADR) treated rats were divided into four groups as ADR, sham and two hypoxia groups. Renal nephropathy was assessed biochemical assays, pathological and immunohistochemical staining methods. The expression of ADAMTSs and mRNA were determined using Western blotting and real-time PCR, respectively. RESULTS: Renal dysfuntion and tissue damage in favour of ECM accumulation and renal fibrosis were observed in the ADR group. This was approved by remarkable changes in the expression of ADAMTS such as increased ADAMTS-1, -12 and -15. In addition, it was found that hypoxia and duration of hypoxia enhanced markers of tubulointerstitial fibrosis in the rat kidney tissues. Also, expression differences especially in ADAMTS-1, -6 and -15 were observed in the hypoxia groups. The variable and different expression patterns of ADAMTS proteinases in the ADR-induced renal fibrosis suggest that ADAMTS family members are involved in the development and progression of fibrosis. CONCLUSION: The expression changes of ADAMTS proteinases in kidney and association with hypoxia have potential clues to contribute to the early diagnosis and treatment options of renal fibrosis.
Assuntos
Proteínas ADAMTS/análise , Matriz Extracelular/química , Rim/patologia , Animais , Biomarcadores/análise , Hipóxia Celular , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Fibrose/induzido quimicamente , Rim/química , Masculino , Ratos , Ratos WistarRESUMO
INTRODUCTION: The aim of this study was to immunohistochemically investigate the presence and localization of ADAMTS 1, 4, 5, 8 and 9 in decidual and chorionic tissues in first trimester pregnancy losses. MATERIALS AND METHODS: This study was conducted with early pregnancy failure decidual and chorionic tissue samples from 36 pregnant women in the first trimester of pregnancy (ongoing pregnancies, missed miscarriages, anembryonic pregnancies) Results: It was observed that the decidual and chorionic tissue levels of ADAMTS 1, 4, 5, and 8 in ongoing pregnancies were more intensely expressed when compared with miscarriages. ADAMTS 1 expression was not observed in the anembryonic pregnancies, ADAMTS 4, 5, and 8 were less intensely expressed. ADAMTS 9 showed no staining in any group. CONCLUSION: ADAMTS 1 may be necessary during the decidualization and implantation stages of early normal pregnancy.
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Proteína ADAMTS1/biossíntese , Aborto Espontâneo/metabolismo , Placenta/metabolismo , Primeiro Trimestre da Gravidez/metabolismo , Proteínas ADAMTS/biossíntese , Proteína ADAMTS4/biossíntese , Proteína ADAMTS5/biossíntese , Proteína ADAMTS9/biossíntese , Adulto , Feminino , Humanos , GravidezRESUMO
BACKGROUND: Disintegrin-like and Metalloproteinase with Thrombospondin Motifs (ADAMTS) proteins that are fundamentally located in the extracellular matrix (ECM) have critical roles on different cellular processes by altering the ECM architecture. It has been known that expression of some members of these proteinases increases in aneurismal and dissectional aortic tissue. The purpose of this study is to investigate ADAMTS1, 5, 16 and tissue inhibitors of metalloproteinases-1, -2 (TIMP-1, -2) levels in aortic tissue obtained from patients with thoracic aortic aneurysms and dissections and to achieve new insights about the function of ADAMTS family members. METHODS: We investigated ADAMTS1, 5, and 16 expression in human thoracic aortic aneurysms (TAA) (n = 22), thoracic aortic dissections (TAD) (n = 12), and thoracic aortas from age-matched control organ donors (n = 6) (a total number of 34 cases and 6 controls). The expression levels of ADAMTS proteins were determined by Western blot technique using anti-ADAMTS1, ADAMTS5, ADAMTS16, TIMP-1 and TIMP-2 antibodies. RESULTS: ADAMTS1, 5, and 16 protein expressions were significantly higher in thoracic aortic aneurysm and dissection tissues compared to control aortic tissues. Furthermore, TIMP-1 protein levels decreased in TAA and TAD tissues, TIMP-2 did not change. CONCLUSIONS: Under the light of our findings, increased expression of ADAMTS1, 5, and 16 proteins may promote deceleration in thoracic aortic aneurysm progression. This is the first study that demonstrates ADAMTS5 and ADAMTS16 proteolytic activity in aneurysm and dissection.
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Proteínas ADAM/análise , Aneurisma da Aorta Torácica/metabolismo , Dissecção Aórtica/metabolismo , Proteínas ADAMTS , Proteína ADAMTS1 , Proteína ADAMTS5 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/análise , Inibidor Tecidual de Metaloproteinase-2/análiseRESUMO
The pathways involved in the regulation of a disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression have not yet been elucidated. Therefore, the aim of this study was to investigate the involvement of nuclear factor-κB (NF-κB), mitogen activated protein kinases (MAPK) and Phosphatidylinositol 3-kinase (PI3 kinase) in ADAMTS9 gene regulation, with special focus on the involvement of NF-κB in IL-1ß-induced ADAMTS9 expression. The OUMS-27 chondrosarcoma cells were exposed to IL-1ß. They were pretreated with 20 µM PD98059 (specific inhibitor of p44/42 kinase), 10 µM SB203580 (specific inhibitor of p38 kinase), 20 µM SB600125 (MAPK inhibitor), and 1 µM Wortmannin and 10 µM LY294002 (specific inhibitors of PI3 kinase) for 30 min and subsequently incubated with IL-1ß. For the effects of NF-κB and IκB inhibitors, cells were pretreated with curcumin or BAY117085 for 30 min and subsequently incubated with IL-1ß. BAY117085 and different concentrations of curcumin were applied to the cells just after the first experiment to determine their concentration effect on ADAMTS9 gene expression. After total RNA was extracted, they were reversely transcribed with random primers and then real-time polymerase chain reaction (PCR) was performed on cDNA samples. There was a significant difference between control and stimulated cells in terms of ADAMTS9/ß-actin ratio. Wortmannin and LY294002 did not have any repressive effect on the OUMS-27 whereas SB203580 and SP600125 were found to decrease the expression of ADAMTS9 gene. BAY 117085 and curcumin, which are two NF-κB inhibitors, led to a decrease in the ratio of ADAMTS9/ß-actin. As a conclusion, the pathways MAPK and NF-κB were thought to be responsible pathways for the induction of ADAMTS9 gene.
Assuntos
Proteínas ADAM/genética , Interleucina-1beta/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Proteína ADAMTS9 , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Células Tumorais CultivadasRESUMO
During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.
Assuntos
Citocinas/metabolismo , Receptores de Hialuronatos/metabolismo , Monócitos/imunologia , Animais , Humanos , Receptores de Hialuronatos/análise , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/citologia , Fosforilação , Transdução de SinaisRESUMO
ADAMTS9 is a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes, with aggrecan-degrading activity. It has also been characterized to be reactive and highly activated ADAMTS by IL-1 beta in both chondrosarcoma cells and human chondrocytes (Demircan et al. Arthritis Rheum 52:1451-1460, 2005). In order to understand the regulation of ADAMTS9 gene expression a functional 3.0 kb human ADAMTS9 promoter has been cloned and characterized. A sequence analysis of the promoter revealed the presence of putative binding sites for Nuclear Factor of Activated T cells (NFAT), which is commonly found in the ADAMTS4 and ADAMTS5 promoters. NFATc1 was up-regulated in an activated form by IL-1 beta in human chondrocytes. The IL-1 beta inducible ADAMTS9 expression was inhibited by NFAT inhibitors, FK506 and 11Arg (11R)-VIVIT. Furthermore, direct binding of NFATc1 on distal and proximal promoters of ADAMTS9 was demonstrated by a chromatin immunoprecipitation assay. Promoter-reporter assays supported those results. These findings may provide a better understanding of the regulation of ADAMTS9 expression induced by inflammatory cytokines.
Assuntos
Proteínas ADAM/metabolismo , Condrócitos/metabolismo , Condrossarcoma/metabolismo , Interleucina-1beta/metabolismo , Fatores de Transcrição NFATC/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas ADAM/genética , Proteína ADAMTS9 , Animais , Sequência de Bases , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/citologia , Ativação Enzimática , Humanos , Interleucina-1beta/genética , Dados de Sequência Molecular , Fatores de Transcrição NFATC/genética , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , RatosRESUMO
ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an inflammatory-induced gene. We have previously reported that ADAMTS1 was strongly but transiently expressed in the infarcted heart. In this study, we investigated whether a 3'-untranslated region (UTR) affects the mRNA stability of this gene. When stimulated with tissue necrosis factor (TNF)-alpha, the expression level of ADAMTS1 mRNA rapidly increased, but the induction of ADAMTS1 mRNA peaked at 6h after stimulation, after which the expression levels of ADAMTS1 mRNA decreased. The 3'-UTR ADAMTS1 mRNA contains multiple adenine and uridine-rich elements, suggesting that the 3'-UTR may regulate gene stability. The addition of actinomycin D, an RNA synthesis inhibitor, demonstrated the decay of induced ADAMTS1 mRNA by TNF-alpha. Furthermore, a region containing multiple AUUUA motifs within the ADAMTS1 3'-UTR destabilized transfected Enhanced Green Fluorescence Protein (EGFP) mRNA expression. These results demonstrated that the ADAMTS1 3'-UTR may regulate the expression of ADAMTS1 mRNA.
Assuntos
Regiões 3' não Traduzidas/genética , Proteínas ADAM , Estabilidade de RNA/genética , RNA Mensageiro , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS1 , Animais , Sequência de Bases , Células COS , Chlorocebus aethiops , Dactinomicina/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Inibidores da Síntese de Ácido Nucleico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: The aim of this study is to investigate which ADAMTS genes play a major role in the development of primary hip osteoarthritis, by comparing the tissue and blood samples in patients with hip osteoarthritis and a control group. MATERIAL AND METHODS: Human articular cartilage was obtained from femoral heads of 15 patients with end stage osteoarthritis undergoing total hip replacement. As the control group, the cartilages was obtained from femoral heads of 15 patients, who did not have osteoarthritis or degenerative changes in hip joint, undergoing hip replacement following the fracture of the femoral neck. After the cartilage samples were taken from the resection materials, the DNA polymorphisms in the patients' cartilage samples were tested by Polymerase Chain Reaction (PCR), the serum levels of aggrecanase genes were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: The level of ADAMTS5 and ADAMTS9 genes were found significantly lower as a result of ELISA analysis degenerative arthritis group than the control group (p < 0,05). ADAMTS 1, 4, 8, 15 were similar between the two groups in ELISA analysis (p > 0,05). As a result of quantitative real time RT-PCR analysis, the level of ADAMTS8 mRNA increased 3.5 fold in hip degenerative arthritis group when compared with femoral neck fractures group. ADAMTS1, ADAMTS4 and ADAMTS5 expression levels in hip degenerative arthritis group were decreased 2.5, 2 and 2.5 fold, respectively. ADAMTS9, 15 were found to be similar between two groups. CONCLUSON: As a result of this study on hip osteoarthritis, the ADAMTS8 levels was found to be significantly higher in the end stage of hip osteoarthritis. Unlike similar studies on knee osteoarthritis, ADAMTS1,4,5 levels were found to be lower.
Assuntos
Proteínas ADAMTS/genética , Proteína ADAMTS1/genética , Cartilagem Articular , Endopeptidases , Osteoartrite do Quadril , Proteínas ADAMTS/análise , Idoso , Artroplastia de Quadril/métodos , Cartilagem Articular/enzimologia , Cartilagem Articular/patologia , Correlação de Dados , Endopeptidases/sangue , Endopeptidases/genética , Feminino , Fraturas do Colo Femoral/genética , Fraturas do Colo Femoral/patologia , Fraturas do Colo Femoral/cirurgia , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/sangue , Osteoartrite do Quadril/genética , Osteoartrite do Quadril/patologia , Osteoartrite do Quadril/cirurgiaRESUMO
The epidermal growth factor receptor (EGFR)-RAS-RAF-mitogen-activated protein kinase signaling cascade is an important pathway in cancer development and recent reports show that EGFR and its downstream signaling molecules are mutated in a number of cancers. We have analyzed 91 Japanese head and neck squamous cell carcinomas (HNSCC) and 12 HNSCC cell lines for mutations in EGFR, ErbB2, and K-ras. Exons encoding the hot-spot regions in the tyrosine kinase domain of both EGFR (exons 18, 19, and 21) and ErbB2 (exons 18-23), as well as exons 1 and 2 of K-ras were amplified by polymerase chain reaction and sequenced directly. EGFR expression was also analyzed in 65 HNSCC patients using immunohistochemistry. Only one silent mutation, C836T, was found in exon 21 of EGFR in the UT-SCC-16A cell line and its corresponding metastasic cell line UT-SCC-16B. No other mutation was found in EGFR, ErbB2, or K-ras. All tumors showed EGFR expression. In 21 (32%) tumors, EGFR was expressed weakly (+1). In 27 (42%) tumors it was expressed (+2) moderately, and in 17 (26%) tumors high expression (+3) was detected. Overexpression (+2, +3) was found in 44 tumors (68%). A worse tumor differentiation and a positive nodal stage were significantly associated with EGFR overexpression (P = 0.02, P = 0.032, respectively). Similar to patients from western ethnicity, mutations are absent or rare in Japanese HNSCC. Protein overexpression rather than mutation might be responsible for activation of the EGFR pathway in HNSCC.
Assuntos
Receptores ErbB/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Mutação , Neoplasias de Células Escamosas/metabolismo , Idoso , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Genes erbB-2/genética , Genes ras/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos , Imuno-Histoquímica , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/genética , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: The aim of this study is to determine the role of cytosine-adenine (CA) micro-satellite repeat sequence of ADAMTS9 gene on the development and progression of osteoarthritis (OA). METHODS: A total of 110 participants, including those with primary knee OA and healthy controls were enrolled in the study. Patients were stratified into two groups using the Kellgren-Lawrence staging (K-L staging) as group 1 for controls and mild OA and group 2 for moderate and severe OA. Genetic analyses were performed to determine the CA repeat length in ADAMTS9 gene. RESULTS: Twenty CA repeats were found to be statistically significant for differentiating groups 1 and 2 (P = 0.020). Age was the most significant risk factor involved, followed by ≥ 20 CA repeats and body mass index (P < 0.05). CA repeat length of ≥ 20 showed a 6.1-fold increase in probability for having OA at stage 3 or 4 compared to those of CA repeat length of < 20 (P = 0.004). In conclusion, the CA repeat length of ≥ 20 has a six-fold increase in probability for having severe OA. CONCLUSION: ADAMTS9 gene CA repeat polymorphism may be used to determine the prognosis for OA radiologic progression. Being the first in the literature reporting the CA repeat in the promotor region of ADAMTS9 gene in patients with OA, our study could be highlighted further in future research with larger sample size.
Assuntos
Proteína ADAMTS9/genética , Repetições de Microssatélites , Osteoartrite do Joelho/genética , Polimorfismo Genético , Adenina , Adulto , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Citosina , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/enzimologia , Fenótipo , Prognóstico , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy. METHODS: A total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically. RESULTS: In RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48 h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations. CONCLUSION: An increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.
Assuntos
Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Radioisótopos do Iodo/uso terapêutico , Glândulas Salivares/metabolismo , Glândulas Salivares/efeitos da radiação , Animais , Radioisótopos do Iodo/farmacocinética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Dosagem Radioterapêutica , Ratos , Distribuição TecidualRESUMO
About 2-5% of all pregnant women develop gestational diabetes mellitus (GDM) during pregnancy and its prevalence has increased markedly within the last decade. GDM is a metabolic syndrome produced by various degrees of carbohydrate intolerance during pregnancy. Various risk factors such as obesity, genetics, environmental factors, and hypertension have been described previously. Maternal and fetal complications occur in around 7% of pregnant women with GDM. In these patients, a relation between proteoglycans and ADAMTS proteases located in extracellular matrix in fetal membranes (placenta, cord, amnion) and complicated pregnancies has already been determined by various animal experiments. Changes in expression, structure and function of ADAMTS proteases and proteoglycans in fetal membranes lead to alteration in the structure of extracellular matrix. If we can establish a balance between these proteoglycans and ADMTS proteases or determine the changes in their structure and functions, it will be possible to predict the risk in high risk pregnancies at early weeks and to initiate treatment early or to follow the target population regularly. In addition, prevention or reduction of maternal and fetal complications may be possible. For this purpose, ADAMTS and proteoglycans the synthesis of which is too much or less, may be targeted and if we would be able to determine and prevent the changes in their levels in the early period of pregnancy, the development of GDM and its complications may be prevented or decreased. Thus, we may identify a marker for early diagnosis and treatment and reduce prematurity, which is the most common cause of fetal death. Fetal and maternal complications, and especially treatment and care costs of prematurity, may also be decreased.
Assuntos
Proteína ADAMTS9/metabolismo , Diabetes Gestacional/fisiopatologia , Membranas Extraembrionárias/fisiopatologia , Síndrome Metabólica/fisiopatologia , Placenta/fisiopatologia , Proteína ADAMTS9/genética , Feminino , Humanos , Gravidez , Cuidado Pré-Natal , Proteoglicanas/metabolismo , Fatores de RiscoRESUMO
INTRODUCTION: Despite recent diagnostic and therapeutic improvements, pancreas cancer remains one of the highly lethal cancers. The extracellular matrix (ECM) is a physiological barrier that limits the spread of cancer cells into surrounding tissues and distant organs. Disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a family of 19 proteases, which is involved in various biological processes such as ECM remodelling and anti-angiogenesis. AIM: To investigate the expression of ADAMTS1, 8, 9, and 18 proteinases in pancreas adenocarcinoma and its nodal metastasis. MATERIAL AND METHODS: The immunostaining status of ADAMTS1, 8, 9, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent pancreaticoduodenectomy for an adenocarcinoma located at the head of the pancreas. RESULTS: In semi-quantitive grading pathologically, ADAMTS1, 8, 9, and 18 were found to be highly stained in all cancerous pancreas samples compared with normal pancreas. In addition, the immune positivity of ADAMTS1, 9, and 18 was found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue. Tumour size was correlated with ADAMTS9 and 18 expressions in cancerous pancreas. CONCLUSIONS: According to the data obtained from the study, we suggest that these four ADAMTSs may have significant roles in the tumorigenesis and nodal spread of pancreas adenocarcinoma.
RESUMO
SWI/SNF is a multiprotein chromatin remodeling complex important for gene regulation. BRG1 and its close relative BRM, have ATPase activity necessary for transcriptional regulation by conformational change of nucleosomes. Due to this role on gene expression, several members of SWI/SNF complex including BRG1 and BRM function as a tumor suppressor or negative regulator of cellular proliferation. On the other hand, the shuttling of proteins between nucleus and cytoplasm is strongly involved in the regulation of cell cycle and proliferation. Many of tumor suppressor gene (TSG)s including p53, BRCA1, ING1 play some of their functions through nucleocytoplasmic shuttling. Abnormalities related with this process abrogate the subcellular localization of the TSGs and lead to cancer development. We recently demonstrated BRG1 as a TSG in oral cancer. Our analysis also revealed an interesting finding that one of the splicing forms of BRG1 is selectively lost in cancer tissue as compared to normal counterparts. Our further analysis revealed a putative nuclear retention signal domain for this splicing form. In this article, we speculate the possible mechanism for the inactivation of BRG1 gene in oral cancer through an abnormality in its subcellular localization.
Assuntos
Núcleo Celular/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Epigênese Genética , Modelos Genéticos , Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Processamento Alternativo , Citoplasma/metabolismo , HumanosRESUMO
PURPOSE: The aim of this study was to evaluate the alterations in ADAMTS12 expression after radioiodine-131 (RAI)-induced salivary gland damage. MATERIALS AND METHODS: A total of 30 Wistar male albino rats (260±45 g, 6 months old) were studied for ADAMTS12 gene expression levels and histological changes in the parotid and submandibular salivary glands of rats after the administration of RAI. A series of healthy rats were used as controls. A 3 mCi (111 MBq) dose of RAI was administered to rats in group 1 (n=6), group 2 (n=6), group 3 (n=6), and group 4 (n=6) to induce salivary gland damage. Evaluations were performed at 24 h in controls and at 4, 24 h, 7, and 30 days after the administration of RAI. Quantitative and statistical analyses were carried out. RESULTS: In RAI-administered groups, the mean values of ADAMTS12 gene expression showed a distinct suppression over time for the parotid gland (groups 1-4: 0.38, 0.11, 0.10, and 0.18, respectively; P<0.05), but the values remained similar over time for the submandibular gland (groups 1-4: 1.59, 1.57, 1.03, and 1.00, respectively; P>0.05) compared with the controls. Histological evaluation indicated that RAI-administered groups had significant common nuclear coarsening and focal subnuclear vacuolization, but not in the control samples. Histological changes were more prominent in the parotid gland samples. CONCLUSION: Alterations in ADAMTS12 gene expression may play a role in RAI-induced salivary gland damage in rats.
Assuntos
Proteínas ADAMTS/genética , Regulação da Expressão Gênica/efeitos da radiação , Radioisótopos do Iodo/administração & dosagem , Glândulas Salivares/metabolismo , Glândulas Salivares/efeitos da radiação , Animais , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
OBJECTIVE: To determine the role of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) and fragmented versican in the myocardial infarction (MI) process in humans and to evaluate the diagnostic efficacy of ADAMTS1 for postmortem diagnosis of MI. METHODS: Thirty autopsied individuals were allocated into 2 groups, namely, a study group of individuals who died of myocardial infarction (n = 20), and a control group who died of trauma (n = 10). We performed standard immunohistochemical staining on myocardial tissue specimens, studying anti-ADAMTS1, anti-versican, and anti-versican C terminal peptide sequence (DPEAAE) fragments. RESULTS: Strong, diffuse staining was observed throughout myocardial tissue for ADAMTS1 in the 2 groups. However, in the study group, we observed no expression for ADAMTS1 around fibrotic areas but detected slight staining in coagulative and necrotic zones. CONCLUSION: Similar localizations of ADAMTS and fragmented versican in human heart tissue indicate that versican presumably is cleaved by ADAMTS1. Hence, ADAMTS1 can be regarded as a new marker for postmortem differential diagnosis of MI.
Assuntos
Proteína ADAMTS1/análise , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/patologia , Miocárdio/patologia , Patologia/métodos , Versicanas/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: Pre-eclampsia is the result of impaired trophoblast invasion and spiral artery remodeling managed by inflammatory response in its etiology and physiopathology. The aim of this study was to compare serum molecules including IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels between pre-eclampsia and control groups and to investigate the role of these molecules in pre-eclampsia. METHODS: Forty-one women diagnosed as pre-eclampsia between 30 and 40 weeks of gestation and 41 non-complicated pregnant women were enrolled in this cross-sectional, case-control prospective study. ELISA method was used to determine IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels within serums in two groups. RESULTS: Serum ADAMTS12 and IL-33 levels were significantly lower in pre-eclampsia group (p < 0.001 and p: 0.028, respectively), however, in sub-group analysis, no significant difference was observed (p > 0.05). The cut-off value of ADAMTS12 levels to discriminate pre-eclampsia with %73.17 sensitivity and %92.68 specificity was 8.27 ng/ml while the cut-off value for IL-33 was 0.23 pg/ml with 82.93% sensitivity and 53.66% specificity. CONCLUSION: Pre-eclampsia is associated with lower serum IL-33 and ADAMTS12 levels.
Assuntos
Proteínas ADAMTS/sangue , Interleucina-33/sangue , Pré-Eclâmpsia/sangue , Adulto , Estudos de Casos e Controles , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Gravidez , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer.