Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.619
Filtrar
1.
Medicine (Baltimore) ; 100(11): e24818, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725949

RESUMO

ABSTRACT: Osteosarcoma is a malignant tumor that develops from a mesenchymal cell line and is caused by gene-environment interactions. This study aimed to explore whether TIMP2/TIMP3 polymorphisms influenced the osteosarcoma risk.The expression of the TIMP2 and TIMP3 genes in osteosarcoma histiocytes was analyzed by immunohistochemistry. In this case-control study, which includes samples from 499 patients and 500 healthy controls, 10 single-nucleotide polymorphisms (SNPs) in TIMP2 and TIMP3 were selected. Furthermore, we used the Agena MassARRAY platform for genotyping. The statistical analysis was performed using χ2 test/Fisher exact test, and logistic regression analysis.The immunohistochemistry results showed that the expression of TIMP2 is obvious higher in osteosarcoma histiocytes than in the normal histiocytes. The association study indicated that the allele of rs2277698 and rs4789936 were protective SNPs reducing the risk of osteosarcoma (odds ratios  > 1, P < .05) by the χ2 test. In the genetic model, logistic regression analyses revealed that the rs2277698 and rs4789936 were associated with decreasing the risk of osteosarcoma under the codominant model, dominant model, and log-additive model. Stratification analysis revealed that 2 SNPs (rs2277698 and rs4789936) were significantly associated with a reduced risk of osteosarcoma in allele and genetic model after stratification by gender or age (P < .05). In addition, the haplotype "Trs2277698Crs2009169Crs7342880" of TIMP2 was associated with decreasing the osteosarcoma risk. The "Ars9609634Trs11547635" of TIMP3 was associated with reducing the osteosarcoma risk.This finding shed new light on the high expression of TIMP2 polymorphisms may contribute to decreasing the osteosarcoma risk in Zhejiang populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Ósseas/genética , Osteossarcoma/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Adolescente , Idoso , Alelos , Neoplasias Ósseas/etnologia , Estudos de Casos e Controles , China/etnologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Osteossarcoma/etnologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
2.
Zhonghua Shao Shang Za Zhi ; 37(2): 143-149, 2021 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-33550768

RESUMO

Objective: To explore the value of renal injury marker protein in early diagnosis of acute kidney injury (AKI) in burn patients with delayed resuscitation. Methods: The retrospective case-control research was conducted. Forty-three burn patients with delayed resuscitation (27 males and 16 females, with age of 18-75 (35±3) years)who were admitted to Zhengzhou First People's Hospital from May 2018 to May 2020 met the inclusion criteria. The patients were divided into AKI group with 23 patients and non-AKI group with 20 patients according to whether AKI occurred within 7 days after burns. The gender, age, deep partial-thickness burn area, full-thickness burn area, and acute physiology and chronic health evaluation Ⅱ of patients were compared between the two groups.The fluid supplement volume and serum creatinine at 12, 24, and 48 h after burn, serum albumin/fibrinogen ratio (AFR), urinary heat shock protein 70 (HSP70), tissue inhibitor of metalloproteinase-2 (TIMP-2)×insulin-like growth factor binding protein 7 (IGFBP-7), and neutrophil gelatinase associated lipocalin (NGAL)at 12, 24, 48, 72, 120, and 168 h after burn were detected.Data were statistically analyzed with Mann-Whitney U test, analysis of variance for repeated measurement, independent-samples t test, chi-square test and Bonferroni correction. The independent variable to predict the occurrence of AKI was screened by multi-factor logistic regression analysis. The receiver's operating characteristic curve was drawn for predicting the occurrence of AKI in burn delayed resuscitation patients, and the area under the curve (AUC), the best threshold, and the sensitivity and specificity under the best threshold were calculated. Results: The gender, age, deep partial-thickness burn area, full-thickness burn area, acute physiology and chronic health evaluation Ⅱ of patients in two groups were similar (χ(2)=1.98, t=1.98, 1.99, 1.99, 1.99, P>0.05). The fluid supplement volume of patients in AKI group at 24 and 48 h after burn was significantly less than that in non-AKI group (t=15.37, 6.51, P<0.01). The serum creatinine of patients in AKI group at 12, 24, and 48 h after burn was significantly higher than that in non-AKI group (Z=2.16, 5.62, 6.72, P<0.01). The serum AFR of patients in AKI group at 12, 24, 48, 72, 120, and 168 h after burn was significantly lower than that in non-AKI group (t=16.14, 35.35, 19.60, 20.47, 30.20, 20.17, P<0.01). The levels of urinary HSP70 of patients in AKI group at 12, 24, 48, 72, 120, and 168 h after burn were (6.89±0.87), (6.42±0.73), (5.81±0.72), (5.17±0.56), (4.63±0.51), (3.89±0.51) µg/L, which were significantly higher than (3.89±0.75), (3.57±0.63), (2.66±0.41), (1.83±0.35), (1.48±0.19), (1.28±0.19) µg/L in non-AKI group (t=12.00, 13.61, 17.39, 22.98, 26.34, 21.59, P<0.01). Urinary TIMP-2×IGFBP-7 and NGAL of patients in AKI group at 12, 24, 48, 72, 120, 168 h after burn were significantly higher than those in non-AKI group (t=26.94, 101.11, 35.50, 66.89, 17.34, 14.30, 14.00, 13.78, 12.32, 14.80, 21.36, 22.62, P<0.01). Urinary HSP70 and serum AFR at 12 h after burn, urinary TIMP-2×IGFBP-7 and NGAL at 24 h after burn were included into multi-factor logistic regression analysis (odds ratio=2.42, 3.47, 7.52, 5.61, 95% confidence interval=1.99-2.95, 1.86-3.92, 2.87-9.68, 2.14-14.69, P<0.01). For 43 patients with burn delayed resuscitation, the AUC of receiver's operating characteristic curve of serum AFR at 12 h after burn for predicting AKI was 0.739 (95% confidence interval=0.576-0.903), the optimal threshold was 9.90, the sensitivity was 82%, and the specificity was 90%. The AUC of urinary HSP70 at 12 h after burn was 0.990 (95% confidence interval=0.920-1.000), the optimal threshold was 1.40 µg/L, the sensitivity was 98%, and the specificity was 96%. The AUC of urinary TIMP-2×IGFBP-7 at 24 h after burn was 0.715 (95% confidence interval=0.512-0.890), the optimal threshold was 114.20 µg(2)/L(2), the sensitivity was 91%, and the specificity was 95%. The AUC of urinary NGAL at 24 h after burn was 0.972 (95% confidence interval=0.860-1.000), the optimal threshold was 78 µg/L, the sensitivity was 95%, and the specificity was 96%. Conclusions: Urinary HSP70 and NGAL have higher value in early diagnosis of AKI in burn patients with delayed resuscitation.


Assuntos
Lesão Renal Aguda , Queimaduras , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Adolescente , Adulto , Idoso , Biomarcadores , Queimaduras/complicações , Diagnóstico Precoce , Feminino , Humanos , Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidor Tecidual de Metaloproteinase-2 , Adulto Jovem
3.
Artigo em Alemão | MEDLINE | ID: mdl-33607670

RESUMO

Acute kidney injury (AKI) is a major complication in critically ill patients and affects up to 50% of those admitted to intensive care units. Causes of AKI include patient specific factors (susceptibility: e.g. age, pre-existing chronic kidney disease, chronic heart failure, diabetes) and patient unspecific factors (exposure: e.g. sepsis, hypovolemia, cardiac surgery, nephrotoxin application). Mortality of severe AKI is in the range of 40 - 50%.AKI is accompanied by volume overload, electrolyte disorders, acidosis, and uremia. The diagnosis of AKI is based on an increase of creatinine levels and/or a decrease in urine output within 7 days after an insult. These 2 markers are late und unspecific, especially with regard to early identification of patients at risk of AKI. New AKI markers have been investigated within the last decade including NGAL (neutrophil gelatinase-associated lipocalin), the product of IGFBP-7 (insulin like growth factor binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2), KIM-1 (kidney injury molecule 1) and the cysteine-protease-inhibitor cystatin C. New markers or a panel of new markers might improve the diagnosis of patients at risk of AKI in the future.There are currently no specific therapeutics in the treatment of AKI. Therefore, the prevention of AKI is of an utmost importance. The recommended preventive measures include optimization of hemodynamics and volume status, close monitoring of creatinine levels and urine output, avoidance or discontinuation of nephrotoxic drugs, normoglycemia and the application of alternatives to radiocontrast agents if possible.As the long term prognosis of AKI highly depends on renal recovery, the 2 major goals for the future will be 1) the early identification of patients at AKI risk and 2) the support of renal recovery of AKI patients.


Assuntos
Lesão Renal Aguda , Inibidor Tecidual de Metaloproteinase-2 , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/epidemiologia , Biomarcadores , Creatinina , Estado Terminal , Humanos , Testes de Função Renal , Lipocalina-2
4.
J Ethnopharmacol ; 265: 113302, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32860893

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Laminaria japonica, a brown seaweed, has been used in Traditional Chinese Medicine (TCM) to treat a variety of diseases including lung cancer. AIM OF THE STUDY: To demonstrate the effects of Fucoxanthin (FX), a major active component extracted from Laminaria japonica on metastasis and Gefitinib (Gef) sensitivity in human lung cancer cells both in vitro and in vivo. MATERIALS AND METHODS: Invasion and migration of lung cancer cells were detected using the wound healing assay and transwell assay. Epithelial-to-mesenchymal transition (EMT) factors and PI3K/AKT/NF-κB pathways were analyzed by western blotting. RNA interference (RNAi) technology was used to silence TIMP-2 gene expression in A549 cells. The anti-metastatic effect of FX was evaluated in vivo in an experimental lung metastatic tumor model. On the other hand, cell counting kit-8 assay was used to study the cell viability of human lung cancer PC9 cells and Gef resistant PC9 cells (PC9/G) after Gef, FX or FX combined with Gef treatment. PC9 xenograft model was established to explore the anti-tumor effect of FX or combined with Gef. Immunohistochemistry staining assay and immunofluorescence staining assay were used to reveal the effects of FX on lung cancer cell proliferation and apoptosis. RESULTS: FX was able to significantly inhibit lung cancer cells migration and invasion in vitro. FX suppressed the expressions of Snail, Twist, Fibronectin, N-cadherin, MMP-2, PI3K, p-AKT and NF-κB, and increased the expression of TIMP-2. Furthermore, knockdown of TIMP-2 attenuated FX-mediated invasion inhibition. Additionally, we demonstrated that FX inhibited lung cancer cells metastasis in vivo. The anti-metastatic effects of FX on lung cancer cells might be attributed to inhibition of EMT and PI3K/AKT/NF-κB pathway. We further demonstrated that the anti-tumor activity of FX was not only limited to the drug sensitive cell lines, but also prominent on lung cancer cells with Gef resistant phenotype. Furthermore, in vivo xenograft assay confirmed that FX inhibited tumor growth and enhanced the sensitivity of lung cancer cells to Gef and this effect may be due to inhibition of tumor cell proliferation and activation of apoptosis. CONCLUSION: Collectively, our findings suggested that FX suppresses metastasis of lung cancer cells and overcomes EGFR TKIs resistance. Thus, FX is worthy of further investigation as a drug candidate for the treatment of lung cancer.


Assuntos
Gefitinibe/farmacologia , Laminaria/química , Neoplasias Pulmonares/tratamento farmacológico , Xantofilas/farmacologia , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Gefitinibe/administração & dosagem , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Inibidor Tecidual de Metaloproteinase-2/genética , Xantofilas/administração & dosagem , Xantofilas/isolamento & purificação , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Adv Clin Exp Med ; 29(9): 1083-1090, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32905666

RESUMO

BACKGROUND: Kidney injury in the course of chronic kidney disease (CKD) is a consequence of aggravated cell migration, inflammation, apoptosis, and fibrosis. However, the sequence of these phenomena, as well as of the reparatory mechanisms, are not fully known. Monocyte chemoattractant protein 1 (MCP-1) and macrophage colony-stimulating factor (MCSF) trigger monocyte migration to the sites of inflammation and their transition into macrophages. Tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) plays a protective role against excessive matrix remodeling, whereas survivin is known for its anti-apoptotic activity. OBJECTIVES: To analyze the serum, urine and fractional excretion (FE) values of MCP1, MCSF, TIMP-2, and survivin in children at subsequent stages of CKD being treated conservatively, and to analyze the potential applicability of these markers in the evaluation of CKD-related renal damage and protective mechanisms against it. MATERIAL AND METHODS: The study group consisted of 70 children with conservatively treated CKD, stages 1-5, and 12 controls. The serum and urine concentrations of MCP1, MCSF, TIMP-2, and survivin were assessed using enzyme-linked immunosorbent assay (ELISA). The FE of these parameters in the urine was also assessed. RESULTS: The serum values of all parameters were significantly elevated at CKD stage 1 compared to the controls. The urinary concentrations of MCP-1 and MCSF (stages 1-2) rose earlier than TIMP-2 and survivin (stage 4) concentrations. The FE values started increasing at CKD stage 3 (MCP-1) or stage 4 (other parameters). CONCLUSIONS: The complex analysis of serum/urinary/FE values of the selected parameters revealed a sequence of multifaceted CKD-related phenomena, when the migration of cells and inflammation were followed by delayed and insufficient anti-fibrotic and anti-apoptotic activity.


Assuntos
Insuficiência Renal Crônica , Biomarcadores , Quimiocina CCL2 , Criança , Humanos , Rim , Fator Estimulador de Colônias de Macrófagos , Survivina , Inibidor Tecidual de Metaloproteinase-2
8.
J Med Chem ; 63(13): 6979-6990, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32491863

RESUMO

We report on a cyclic peptide that inhibits matrix metalloproteinase-2 (MMP2) activation with a low-nM-level potency. This inhibitor specifically binds to the D570-A583 epitope on proMMP2 and interferes with the protein-protein interaction (PPI) between proMMP2 and tissue inhibitor of metalloproteinases-2 (TIMP2), thereby preventing the TIMP2-assisted proMMP2 activation process. We developed this cyclic peptide inhibitor through an epitope-targeted library screening process and validated its binding to proMMP2. Using a human melanoma cell line, we demonstrated the cyclic peptide's ability to modulate cellular MMP2 activities and inhibit cell migration. These results provide the first successful example of targeting the PPI between proMMP2 and TIMP2, confirming the feasibility of an MMP2 inhibition strategy that has been sought after for 2 decades.


Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Peptídeos Cíclicos/farmacologia , Sequência de Aminoácidos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidor Tecidual de Metaloproteinase-2/metabolismo
9.
Prostate ; 80(12): 977-985, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542727

RESUMO

BACKGROUND: Recently, resveratrol (Res) has been suggested to suppress the migration and invasion of prostate cancer (PCa). In the present study, we aimed to investigate the effects of Res on genomic DNA methylation, as well as the migration and invasion of PCa cells. METHODS: The suppression by Res of the growth of PCa cells was verified through a cytotoxicity assay. In addition, the effects of Res on 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and ten-eleven translocation 1 (TET1) levels were assessed, and the cell migration and invasion were also determined. The expressions of TET1, tissue inhibitor of metalloproteinases (TIMP) 2, TIMP3, MMP2, and MMP9 were detected through Western blot analysis. Afterward, TET1 was silenced using lentiviral short hairpin RNA to examine the effect of TET1 on the Res-triggered inhibition of migration and invasion of PCa cells. RESULTS: Our results showed that Res upregulated the 5hmC and TET1 levels and downregulated the 5mC level. Moreover, Res also inhibited the migration and invasion of PCa cells, promoted the demethylation of TIMP2 and TIMP3 to upregulate their expressions, and suppressed the expressions of MMP2 and MMP9. The silencing of TET1 in the presence of Res showed that Res could exert its effect through TET1. CONCLUSIONS: Our findings indicated that Res inhibited the migration and invasion of PCa cells via the TET1/TIMP2/TIMP3 pathway, which might potentially serve as a target for the treatment of PCa.


Assuntos
Oxigenases de Função Mista/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Resveratrol/farmacologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-3/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Oxigenases de Função Mista/biossíntese , Oxigenases de Função Mista/genética , Invasividade Neoplásica , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Resveratrol/farmacocinética , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/biossíntese , Inibidor Tecidual de Metaloproteinase-3/genética , Regulação para Cima
10.
Sci Rep ; 10(1): 5839, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246106

RESUMO

Anthracycline chemotherapy is commonly used to treat breast cancer yet may increase the level of matrix metalloproteinases (MMP) -2 and -9, which increase the risk of atherosclerosis. While exercise has been shown to reduce the level of MMP in patients with diabetes, high intensity interval training (HIIT) has not been utilized to improve level of MMP in women with breast cancer receiving anthracycline chemotherapy. Thirty women were randomized to either 8-week HIIT or control (CON) group. The CON group was offered the HIIT intervention after 8 weeks. MMP-1, -2 -7, -9, tissue inhibitor of MMP (TIMP) -1, and-2 were measured at baseline and post-intervention. Repeated measures ANCOVA and paired t-test were performed to assess changes in MMP and TIMP. Post-intervention, no significant between-group differences were observed for MMP and TIMP. However, within-group decrease in MMP-9 was observed in the HIIT group [104.3(51.9) to 65.2(69.1); P = 0.01]. MMP-9 in the CON group was not significantly changed [115.5(47.2) to 90.4(67.9);]. MMP-2 significantly increased in both the HIIT group [76.6(11.2) to 83.2(13.1); P = 0.007) and the CON group [69.0(8.9) to 77.6(11.1) P = 0.003). It is unclear whether an 8-week HIIT intervention influences MMP-9 in breast cancer patients undergoing anthracycline chemotherapy. Additional investigations are required to understand the exercise-induced changes in MMP-2 and -9 in women undergoing anthracycline chemotherapy.


Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Treinamento Intervalado de Alta Intensidade , Metaloproteinases da Matriz/sangue , Adulto , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/terapia , Feminino , Treinamento Intervalado de Alta Intensidade/métodos , Humanos , Metaloproteinase 1 da Matriz/sangue , Metaloproteinase 10 da Matriz/sangue , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue
11.
Life Sci ; 250: 117554, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32184123

RESUMO

BACKGROUND: Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. METHODS: Fourteen overweight/obese grade I men (27 ± 7 years; 29.7 ± 2.6 kg·m-2) underwent the Stroop Color Word Test for 5 min to induce MS after AA (3 g) or placebo (PL, 0.9% NaCl) intravenous infusions. Venous blood samples were collected at baseline and the last minute of MS to measure nitrite concentration (chemiluminescence), protein carbonylation, thiobarbituric acid reactive substances (TBARS) and catalase activity (colorimetric assays), superoxide dismutase (SOD; immunoenzymatic assay), activities of active/inactive (pro) forms of metalloproteinases-9 and -2 (MMP; zymography) and its respective tissue inhibitors concentration (TIMP-1 and TIMP-2; immunoenzymatic assays). RESULTS: At baseline, MMP-9 activity (p < 0.01), the MMP-9/proMMP-9 ratio (p = 0.02) and TIMP-1 concentration (p = 0.05) were reduced, whereas proMPP-9 activity was increased (p = 0.02) after AA compared to PL infusion. After PL infusion, MS increased protein carbonylation (p < 0.01), catalase (p < 0.01), and the MMP-9/proMMP-9 ratio (p = 0.04) when compared to baseline. AA infusion reduced protein carbonylation (p = 0.02), MMP-9 activity (p < 0.01), and MMP-9/pro-MMP-9 ratio (p < 0.01), while SOD (p = 0.04 vs baseline), proMPP-9 (p < 0.01 vs PL), MMP-2 (p < 0.01 vs PL) and TIMP-2 (p = 0.02 vs baseline) remained elevated during MS. CONCLUSIONS: AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.


Assuntos
Ácido Ascórbico/farmacologia , Obesidade/psicologia , Sobrepeso/psicologia , Estresse Psicológico , Remodelação Vascular/efeitos dos fármacos , Adulto , Antioxidantes/metabolismo , Catalase/metabolismo , Estudos Cross-Over , Endotélio Vascular/patologia , Humanos , Luminescência , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Oxidantes/metabolismo , Carbonilação Proteica , Fatores de Risco , Teste de Stroop , Superóxido Dismutase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Adulto Jovem
12.
Int J Clin Oncol ; 25(6): 1055-1066, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32103382

RESUMO

BACKGROUND: Filamin A is the most widely expressed isoform of filamin in mammalian tissues. It can be hydrolyzed by Calpain, producing a 90-kDa carboxyl-terminal fragment (ABP90). Calpeptin is a chemical inhibitor of Calpain, which can inhibit this effect. It has been shown that ABP90 acts as a transcription factor which is involved in mediating cell signaling. However, the significance of ABP90 and its clinical signature with underlying mechanisms have not been well studied in glioblastoma multiforme (GBM). METHODS: ABP90 protein was measured in 36 glioma patients by Western blot. Human GBM cell lines U87 and A172 were used to clarify the precise role of ABP90. CCK-8 assay was used to analyze the cell viability. Transwell invasion assay and wound healing assay were used to analyze the migration and invasion. Expression of matrix metalloproteinase 2/tissue inhibitors of metalloproteinase 2 (MMP2/TIMP2) protein was analyzed by Western blot. RESULTS: ABP90 protein expression was lower in GBM tissues. The patients with low ABP90 protein expression had a shorter OS time (p = 0.046). After being treated with Calpain, the expression of ABP90 was upregulated, which led to a decline of cell viability, enhanced the efficacy of temozolomide and restrained the cell invasion. Calpeptin could inhibit the effect. The mechanism might be involved in the balance of MMP2/TIMP2. CONCLUSIONS: Our present data suggest that ABP90 expression is a significant prognostic factor and may play an important role in cell viability, chemotherapeutic sensitivity and invasion of GBM.


Assuntos
Neoplasias Encefálicas/patologia , Calpaína/farmacologia , Proliferação de Células/efeitos dos fármacos , Filaminas/metabolismo , Glioblastoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Calpaína/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Glioblastoma/metabolismo , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Invasividade Neoplásica , Prognóstico , Temozolomida/farmacologia , Inibidor Tecidual de Metaloproteinase-2/metabolismo
13.
Int J Med Sci ; 17(1): 137-144, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929747

RESUMO

Human pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during chronic pancreatitis (CP). However, primary PSCs have a short lifespan in vitro, which seriously affects their use in various applications. We have established a stable immortalized human PSC line (HP-1) by RSV promoter/enhancer-driven SV40 T antigen expression in primary activated human PSCs. HP-1 cells express cytoskeleton proteins including glial fibrillary acidic protein (GFAP), α-smooth muscle actin (α-SMA), vimentin and desmin, and are typical of PSCs, which are high transfeciability and viable in 0.5% serum. The cells express receptors such as TGFßR2, PDGFR, TGF-ß pseudoreceptor Bambi and PPRPγ that are commonly found in PSCs. HP-1 cells are similar to activated human PSCs in that they have enhanced expression of α-SMA, CTGF, Col1 and TIMP-2 mRNAs or proteins, as well as decreased expression of MMP-1/2 mRNAs or proteins in response to TGF-ß1 stimulation. Comparative proteomics revealed 4,537 shared proteins between HP-1 cells and PSCs and no single protein in HP-1 cells versus PSCs. Statistical analysis reveals no significantly difference between HP-1 cells and PSCs in their expression of proteins associated with matrix and matrix remodeling. The similarity between HP-1 cell and PSC is further shown by the finding that only 9 proteins are differentially up-regulated > ± 2-fold in HP-1 cells and 13 proteins are up-regulated > ± 2-fold in PSCs and none of these proteins include ECM proteins, cytokines, growth factors or matrix remodeling regulatory proteins. Therefore, HP-1 cells can be used as an effective tool for the study of PSC-mediated pancreatic fibrosis.


Assuntos
Proliferação de Células/genética , Células Estreladas do Pâncreas/metabolismo , Pancreatite Crônica/genética , Proteômica , Actinas/genética , Linhagem Celular , Fator de Crescimento do Tecido Conjuntivo/genética , Fibrose/genética , Fibrose/patologia , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/genética , Humanos , Metaloproteinase 2 da Matriz/genética , Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/patologia , Inibidor Tecidual de Metaloproteinase-2/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1/genética
14.
Gene ; 730: 144320, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31887330

RESUMO

PURPOSE: The goal of this study is to evaluate the association between MMP-2, 3, TIMP-2, 3 polymorphisms and risk of colorectal cancer (CRC) in a Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNP) were genotyped in 505 CRC patients and 510 controls. The association between candidate SNPs and risk of CRC were evaluated using odds ratio (OR), 95% confidence interval (95% CI). RESULTS: The minor allele frequency of rs1053605 in cases was significantly lower than controls (p = 0.005). The CT genotype frequency of rs1053605 in cases was significantly lower than those in controls, while the frequencies of rs4789936-CT and rs715572-AG genotype of in cases were significantly higher than those in controls (p < 0.05). Genetic model analysis showed that rs522616 was associated with decreased risk of CRC under recessive model (p = 0.041); rs1053605 was correlated with decreased risk of CRC under dominant (p = 0.012) and additive (p = 0.009) models; rs4789936 also has association with decreased risk of CRC under recessive model (p = 0.021); while rs715572 was associated with increased risk of CRC under dominant (p = 0.007) and additive (p = 0.011) models. CONCLUSION: Our results shed new light on association between MMP and TIMP polymorphisms and CRC risk.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Colorretais/genética , Alelos , Estudos de Casos e Controles , Neoplasias do Colo/genética , Grupos Étnicos/genética , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética
15.
Mol Cell Biochem ; 464(1-2): 131-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734843

RESUMO

The purpose of this study is to evaluate anti-inflammatory and chondro-protective effects of 1,25(OH)2D3 in human chondrocytes and SW1353 cells via investigating expressions of MMPs, TIMPs, VDR, and intracellular signalling pathway mediators such as TLR-2 and -4. The HC and SW1353 cells were treated with 1,25(OH)2D3 at 10, 100, and 1000 nM concentrations in the absence/presence of TNF-α (20 ng/mL) for 48 h. The mRNA expressions of MMP-1, -2, -3, -9, and -13, TIMP-1 and -2, VDR, TLR-2 and -4 in HC and SW1353 cells were detected by qPCR after treatments. The cytotoxicity and cell proliferation analyses were assessed by LDH and WST-1 assay, respectively. Protein levels of MMPs, TIMPs, and VDR were analysed by immunocytochemistry and ELISA methods. TNF-α markedly increased cytotoxicity for 24, 48, 72 h (p < 0.05) and vitamin D treatment was shown to diminish the cytotoxic effect of TNF-α. Cell proliferations increased by Vitamin D in a dose-dependent manner. mRNA expressions of MMP-1, -2, -3, -9, and -13, TLR-2 and -4 genes decreased with 1,25(OH)2D3 treatment (p < 0.05). VDR, TIMP-1 and -2 levels elevated after TNF-α exposure compared with the control group in HC cells (p < 0.05). Protein expression levels were determined using Western blotting, ELISA and immunocytochemistry. 1,25(OH)2D3 via binding to VDR, reversed the effects of TNF-α by inhibiting TLR-2 and 4. Decreased levels of VDR, TIMP-1 and -2 after TNF-α treatment were elevated by 1,25(OH)2D3 proportional with increasing 1,25(OH)2D3 doses. 1,25(OH)2D3 and TNF-α co-treatment decreased MMP-1, -2, -3, -9, and -13 levels were after TNF-α exposure.


Assuntos
Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Condrócitos/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular , Condrócitos/patologia , Colagenases/biossíntese , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Inibidor Tecidual de Metaloproteinase-2/biossíntese
16.
Hemodial Int ; 24(2): 162-174, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31826326

RESUMO

BACKGROUND: Frequent hemodialysis modifies serum phosphorus, blood pressure, and left ventricular mass (LVM). We ascertained whether frequent hemodialysis is associated with specific changes in biomarker profile among patients enrolled in the frequent hemodialysis network (FHN) trials. METHODS: This was a post hoc analysis of biomarkers among patients enrolled to the FHN trials. In particular, we hypothesized that frequent hemodialysis is associated with changes in a specific set of biomarkers which are linked with changes in blood pressure or LVM. RESULTS: Among 332 randomized patients, 243 had biomarker data available. Of these, 124 patients were assigned to 3-times-a-week hemodialysis (94 [Daily Trial] and 30 [Nocturnal Trial]) and 119 patients were assigned to 6-times-a-week hemodialysis (87 [Daily Trial] and 32 [Nocturnal Trial]). Frequent hemodialysis lowered phosphate, blood pressures, LVM, log fibroblast growth factor (FGF)23, and tissue inhibitors of metalloproteinase (TIMP)-2 levels. The fall in phosphate was associated with changes in FGF23 (r = 0.48, P < 0.001) [Daily Trial] and (r = 0.55, P < 0.001) [Nocturnal Trial]) and tended to be associated with changes in systolic blood pressure (r = 0.18, P = 0.057) [Daily Trial] and (r = 0.31, P = 0.04) [Nocturnal Trial]. Within the Daily Trial, changes in MMP2 (r = 0.20, P = 0.034) were associated with changes in LVM. In the Nocturnal Trial, changes in TIMP-1 (r = 0.37, P = 0.029) and MMP 9 (r = -0.38, P = 0.01) were associated with LVM changes. MMP2 changes were associated with changes in systolic blood pressure. CONCLUSIONS: Reduction of serum phosphate by frequent hemodialysis may modulate FGF23 levels and systolic blood pressure. Markers of matrix turnover are associated with LVM changes. Frequent hemodialysis may affect pathological mediators of chronic kidney disease-mineral bone-metabolism disorder.


Assuntos
Biomarcadores/metabolismo , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Pressão Sanguínea , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Diálise Renal/métodos
17.
Carcinogenesis ; 41(3): 313-325, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31621840

RESUMO

Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36-50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.


Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Metástase Neoplásica , Fosfatidilinositol 3-Quinases , Análise de Sequência de RNA , Neoplasias de Mama Triplo Negativas/patologia , Via de Sinalização Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Lasers Med Sci ; 35(3): 633-640, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31420795

RESUMO

The extracellular matrix (ECM) is the main constituent of connective tissue with structural and regulatory functions, stimulating cell differentiation and proliferation. Moreover, ECM is a dynamic structure in the constant remodeling process, which is controlled by a balance between metalloproteinases (MMPs) and their inhibitors (TIMPs). Photobiomodulation (PBM) is widely described in the literature and applied in clinical practices, although its effects on ECM have not yet been elucidated. Therefore, it was evaluated if PBM could alter ECM components, such as MMP-2, -9, -13, and TIMP-2 from mice talocrural joints. Mice were divided into 3 groups (n = 6): control, PBM 3 J cm-2, and PBM 30 J cm-2. A low-level laser (830 nm, 10 mW, 0.05 irradiated area, energy densities 3 J cm-2 and 30 J cm-2, the irradiation time of 15 and 150 s, respectively, continuous wave) was applied on the joint for 4 consecutive days. mRNA levels of metalloproteinases genes (MMP-2, MMP-9, and MMP-13), their regulator (TIMP-2), and protein expressions of MMP-13 and TIMP-2 were quantified. PBM can alter only mRNA relative levels of MMP-2 at 30 J cm-2 (p < 0.05), while MMP-9, MMP-13, and TIMP-2 mRNA relative levels did not demonstrate statistical differences for any of the groups (p > 0.05). Regarding protein expressions, MMP-13 demonstrated positive-labeled cells, only in articular cartilage, although the cell quantification did not demonstrate statistical differences when compared with the control group (p > 0.05). TIMP-2 did not present positive-labeled cells for any tissues evaluated. Our results indicate that PBM can alter MMP-2 mRNA relative level but cannot alter MMP-9, MMP-13, and TIMP mRNA relative levels. Moreover, both MMP-13 and TIMP-2 proteins were also unaltered after PBM.


Assuntos
Articulações/enzimologia , Articulações/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Animais , Cartilagem Articular/metabolismo , Matriz Extracelular/metabolismo , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo
19.
Acta Ophthalmol ; 98(1): e107-e112, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31421016

RESUMO

BACKGROUND: To measure the amounts of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2 and bone morphogenetic protein (BMP)-4 in medial rectus muscle (MR) tissue obtained from intermittent exotropia (IXT) patients and to investigate the correlation between each protein amount and the clinical features of IXT including angles of deviation, age at surgery, duration of IXT and postoperative recurrence. METHODS: The protein amounts were measured by enzyme-linked immunosorbent assay (ELISA) in MR collected during surgery for 78 IXT patients. RESULTS: The mean amount of MMP-2 per mm of resected MR was 0.86 ng, of MMP-9, 2.72 ng, of TIMP-1, 1.99 ng, of TIMP-2, 0.92 ng and of BMP-4, 0.82 pg. MMP-2 showed a positive correlation with angle of deviation at distance and at near, age at surgery and duration of IXT (p = 0.000, p = 0.000, p = 0.000, p = 0.022, respectively, Spearman's rank correlation analysis). MMP-9 showed a positive correlation with angle of deviation at distance and at near (p = 0.001, p = 0.024) and BMP-4 showed a positive correlation with angle of deviation at distance (p = 0.012). TIMP-1 showed a negative correlation with angle of deviation at distance and at near (p = 0.003, p = 0.000). CONCLUSION: In IXT patients, MMPs and BMP-4 tended to increase and TIMPs to decrease with increasing angle of deviation, greater age at surgery and longer duration of IXT.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Exotropia/cirurgia , Metaloproteinases da Matriz/metabolismo , Procedimentos Cirúrgicos Oftalmológicos/métodos , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Acuidade Visual , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Exotropia/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Oculomotores/metabolismo , Músculos Oculomotores/cirurgia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
20.
J Cell Physiol ; 235(2): 1649-1662, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31392726

RESUMO

Hypoxia is a common pathological process caused by insufficient oxygen. Long noncoding RNAs (lncRNAs) have been proven to participate in this pathology. Hypoxia is reported to significantly reduce the secretion of tissue inhibitor of metalloproteinase 2 (TIMP2) and TIMP2 induces pheochromocytoma-12 (PC12) cell cycle arrest. Thus, our study aimed to explore the mechanism by which lncRNA maternally expressed gene 3 (MEG3) was implicated in hypoxia-induced PC12 cell injury through TIMP2 promoter methylation. To elucidate the potential biological significance of MEG3 and the regulatory mechanism between MEG3 and TIMP2, a hypoxia-induced PC12 cell injury model was generated. The hypoxia-exposed cells were subjected to a series of overexpression plasmids and short hairpin RNAs, followed by the measurement of levels of MEG3, TIMP2, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), Bcl-2-associated X protein, B-cell lymphoma-2, and caspase-3, as well as the changes in MMP, cell proliferation, apoptosis, and cell cycle progression. On the basis of the findings, MEG3 was upregulated in hypoxia-injured PC12 cells. MEG3 recruited methylation proteins DNMT3a, DNMT3b, and MBD1 and accelerated TIMP2 promoter methylation, which in turn inhibited its expression. Moreover, PC12 cells following MEG3 silencing and TIMP2 overexpression exhibited significantly decreased levels of LDH, MDA, and ROS along with cell apoptosis, yet increased SOD and MMP levels, as well as cell cycle entry to the S phase and cell proliferation. In conclusion, MEG3 silencing suppresses hypoxia-induced PC12 cell injury by inhibiting TIMP2 promoter methylation. This study may provide novel therapeutic targets for hypoxia-induced injury.


Assuntos
Hipóxia Celular/genética , Regulação da Expressão Gênica/genética , RNA Longo não Codificante/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Animais , Metilação de DNA/genética , Células PC12 , Regiões Promotoras Genéticas/genética , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...