• Tuberculosis and Respiratory Diseases
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• v.65 no.1
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• pp.7-14
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• 2008

Background: Residual pleural thickening (RPT) is the most frequent complication of tuberculous pleurisy (TP), and this can happen despite of administering adequate anti-tuberculous (TB) therapy. Yet there was no definite relation between RPT and other variables. The aim of this study was to examine matrix metalloproteinases (MMPs) and the inhibitors of metalloproteinases (TIMPs) and to identify the factors that can predict the occurrence of RPT. Methods: The patients with newly-detected pleural effusions were prospectively enrolled in this study from January 2004 to June 2005. The levels of MMP-1, -2, -8 and -9, and TIMP-1 and -2 were determined in the serum and pleural fluid by ELISA. The residual pleural thickness was measured at the completion of treatment and at the point of the final follow-up with the chest X-ray films. Results: The study included 39 patients with pleural fluid (PF). Twenty-three had tuberculous effusion, 7 had parapneumonic effusion, 7 had malignant effusion and 2 had transudates. For the 17 patients who completed the anti-TB treatment among the 23 patients with TP, 7 (41%) had RPT and 10 (59%) did not. The level of PF TIMP-1 in the patients with RPT ($41,405.9{\pm}9,737.3ng/mL$) was significantly higher than that of those patients without RPT ($29,134.9{\pm}8,801.8$) at the completion of treatment (p=0.032). In 13 patients who were followed-up until a mean of $8{\pm}5$ months after treatment, 2 (15%) had RPT and 11 (85%) did not. The level of PF TIMP-2 in the patients with RPT ($34.4{\pm}6.5ng/mL$) was lower than that of those patients without RPT ($44.4{\pm}15.5$) at the point of the final follow-up (p=0.038). Conclusion: The residual pleural thickening in TP might be related to the TIMP-1 and TIMP-2 levels in the pleural fluid.

• Clinics in Shoulder and Elbow
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• v.17 no.2
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• pp.64-67
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• 2014

Background: The purpose of this study was to determine whether in patients with rotator cuff tears a correlation exists between molecular changes and clinical parameters such as age, duration of symptom, range of motion, and tear size. Molecular changes of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) were assessed by measuring messenger RNA (mRNA) levels of the two proteins. Methods: The rotator cuff tissue from was obtained from the edge of a torn tendon revealed after debridement by a motorized shaver. Using the sample of rotator cuff tissue, the reverse transcription polymerase chain reaction was performed to quantify MMP-2 and TIMP-2 mRNA expression. To determine whether mRNA levels and the clinical variables, such as age, defect size, range of motion (ROM) of shoulder, and duration of symptoms, show any correlation, Spearman's correlation coefficients were used to test for significant differences. Results: There was an inverse correlation between the mRNA levels of MMP-2 and TIMP-2 from the torn rotator cuff tendons regardless of the clinical variables. However, comparison of mRNA levels versus clinical parameters such as age, defect size, range of motion and duration of symptoms revealed a number of findings. We found a significant correlation between age and mRNA levels of MMP-2 from torn cuffs (r = 0.513, p = 0.021). Further, we found a significant correlation between defect size in the full thickness tears and mRNA levels of MMP-2 (r = 0.454, p = 0.045). Conversely, no significant association between mRNA levels of MMP-2 and ROM or duration of symptom was found. Conclusions: Our results suggest that both MMP-2 and TIMP-2 may be involved in the disease process of rotator cuff tears. Although the level of mRNA expression of MMP-2 and TMP-2 remain constant in torn rotator cuffs irrespective of the clinical variables, their levels may be influenced by age and defect size, which could account to change in tendon degradation and the healing process.

• Tuberculosis and Respiratory Diseases
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• v.52 no.5
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• pp.453-462
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• 2002

Background : Matrix metalloproteinases(MMPs) are a large family of proteolytic enzymes, which are involved in the degradation of many different components of the extracellular matrix. There is increasing evidence indicating that individual MMPs have important roles in tumor invasion by inactivating the MMPs. In this study, the correlation between MMPs and TIMPs expression, and the clinical outcome was investigated. Materials and Methods : Immunohistochemical staining of MMP-2, 9 and TIMP-1,2 were performed on paraffin-embedded tumor sections from 74 resected primary non-small cell lung cancers. Results : In 74 patients, MMP-2, MMP-9, TIMP-1, and TIMP-2 immunoreactivity was demonstrated in 24(34%), 19(26%) and 32(43%) of the paraffin-embedded tumors, respectively. The median survival of the MMP-2 positive cases was significantly shorter than that of the negative cases(20 vs 34 months). The median survival of the TIMP-2 positive cases was also was significantly longer than that of the negative cases (34 vs 18 months). The MMP-2, and MMP-9 expression level had a positively correlation with a more advanced stage and lymph node metastasis. There was inverse correlation between TIMP-2 expression and tumor invasion. The median survival of the MMP-2 negative/TIMP-2 positive cases was higher than that of the other cases. Conclusion : These results suggest that tumor invasion and lymph node metastasis are closely related to MMP-2 and MMP-9 expression. There was an inverse correlation between TIMP-2 and MMP-9 expression, and tumor invasion.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5747-5751
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• 2014

Background: Coptisine, an isoquinoline alkaloid extracted from Coptidis rhizoma, has many biological activities such as antidiabetic, antimicrobial and antiviral actions. However, whether coptisine exerts anti-cancer metastasis effects remains unknown. Materials and Methods: Effects of coptisine on highly metastatic human breast cancer cell MDA-MB-231 proliferation were evaluated by trypan blue assay and on cell adhesion, migration and invasion by gelatin adhesion, wound-healing and matrigel invasion chamber assays, respectively. Expression of two matrix metalloproteinases (MMPs), MMP-9, MMP-2 and their specific inhibitors tissue inhibitor of metalloproteinase 1 (TIMP-1) and tissue inhibitor of metalloproteinase 2 (TIMP-2) were analyzed by RT-PCR. Results: Coptisine obviously inhibited adhesion to an ECM-coated substrate, wound healing migration, and invasion through the matrigel in MDA-MB-231 breast cancer cells. RT-PCR revealed that coptisine reduced the expression of the ECM degradation-associated gene MMP-9 at the mRNA level, and the expression of TIMP-1 was upregulated in MDA-MB-231 cells, while the expression of MMP-2 and its specific inhibitor TIMP-2 was not affected. Conclusions: Taken together, our data showed that coptisine suppressed adhesion, migration and invasion of MDA-MB-231 breast cancer cells in vitro, the down-regulation of MMP-9 in combination with the increase of TIMP-1 possibly contributing to the anti-metastatic function. Coptisine might be a potential drug candidate for breast cancer therapy.

• Molecules and Cells
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• v.25 no.1
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• pp.105-111
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• 2008

Radiotherapy is an important treatment for many malignant tumors, but there are recent reports that radiation may increase the malignancy of cancer cells by stimulating expression of type IV collagenases. In this study, we examined changes in matrix metalloproteinase (MMP) inhibitors, such as the tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 and RECK, in response to irradiation in Panc-1 pancreatic cancer cells. Irradiation increased RECK protein levels but not mRNA levels, whereas no significant changes were found in TIMP-1 and TIMP-2. The enhanced RECK protein levels were associated with an increase in MMP inhibitory activity. However, irradiation slightly but reproducibly increased the invasiveness of the Panc-1 cells. Like irradiation, treatment of Panc-1 cells with transforming growth factor $(TGF)-{\beta}1$ led to a 2-fold increase in RECK protein levels. Transient transfection with Smad3 also increased RECK protein levels, but transfection with Smad7 markedly reduced them. Stable expression of Smad7 and treatment with SB431542, an inhibitor of $TGF-{\beta}$ receptor I kinase, abolished $TGF-{\beta}1$- and radiation-mediated effects on RECK. Furthermore, irradiation increased levels of phosphorylated Smad3. We conclude that radiation post-transciptionally enhances RECK protein levels in Panc-1 cells, at least in part, via $TGF-{\beta}$ signaling, and that irradiation increases Panc-1 invasiveness via a mechanism that may not be linked to MMP-2 activity.

• Tuberculosis and Respiratory Diseases
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• v.53 no.4
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• pp.420-430
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• 2002

Background : Excessive extracellular matrix (ECM) deposition by airway inflammation is presumed to play an important role in the pathogenesis of worsening airflow obstruction (Ed- acceptable three-word noun) seen during acute exacerbations of chronic bronchitis. Although many proteases can cleave ECM molecules, matrix metalloproteinases (MMPs) and their inhibitors are likely to be the physiologically relevant mediators of ECM degradation. Objectives ; The purpose of this study was to demonstrate that antibiotic treatment can change airway MMPs and TIMP-1 concentrations/levels by controlling airway inflammation in acute exacerbation of chronic bronchitis. Methods : We studied 40 patients, all of whom had an acute exacerbation of chronic bronchitis. The patients were treated with two different antibiotics, moxifloxacin and clarithromycin, in a double-blind manner for 7 days. Sputum samples were induced and collected before and after antibiotic therapy. We measured the sputum concentration of MMP-1,-9, TIMP-1, IL-8 and secretory leukocyte proteinase inhibitor (SLPI) in sputum supernatants by ELISA method. Results : There was no difference after antibiotic treatment in the sputum concentrations of MMP-1,-9, TIMP-1, IL-8 and SLPI between the patients treated with moxifloxacin and those treated with clarithromycin. But the sputum concentrations of TIMP-1, and SLPI, and the TIMP-1/MMP-1 ratio were significantly reduced by the antibiotic therapy. There were significant positive correlations between sputum TIMP-1 levels and IL-8 levels (p<0.01, r=0.751), and between the sputum TIMP-1/MMP-1 ratio and IL-8 levels (p<0.01, r=0.752). The sputum SLPI levels were significantly elevated by antibiotic treatment and were negatively correlated with sputum TIMP-1 levels (p<0.01, r=-0.496) and TIMP-1/MMP-1 levels (p<0.01, r=-0.456). Conclusion : The study shows that the worsening of airway inflammation in acute exacerbation of chronic bronchitis is associated with an imbalance between the concentrations/levels of TIMP-1 and MMPs. Antibiotic treatment can prevent progression of airway narrowing in acute exacerbation of chronic bronchitis by modulation of the protease and anti-protease imbalance.

• Clinical and Experimental Pediatrics
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• v.57 no.12
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• pp.526-532
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• 2014

Purpose: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis, and therefore, are considered risk factors for metabolic dysfunction in adults. However, there is little data on circulating levels of MMPs and tissue inhibitors of MMPs (TIMPs) with regard to obesity-related biomarkers in the general adolescent population. In the present study, we determined the associations of MMP-8, MMP-9, and TIMP-1 levels and MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios with obesity-related biomarkers in apparently healthy adolescent boys. Methods: We measured MMP and TIMP concentrations in plasma samples using the enzyme-linked immunosorbent assay and analyzed their associations with obesity-related biomarkers, such as liver enzymes and lipid profiles, in a sample of 91 Korean boys aged 13-14 years who participated in a general health check-up. Results: The mean age of the boys was $13.8{\pm}0.3years$; 72 boys were normal weight and 19 were overweight/obese. The Pearson correlation coefficients revealed a significant correlation between MMP-8 and aspartate aminotransferase (r=0.217, P=0.039) and alanine aminotransferase (r=0.250, P=0.017) and between TIMP-1 and aspartate aminotransferase (r=0.267, P=0.011). In a multivariate linear regression analysis, serum alanine aminotransferase was positively associated with the MMP-8 level. There were no significant differences in the MMP-8, MMP-9, and TIMP-1 levels or MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios between control and overweight/obese subjects. Conclusion: We found a significant association between the MMP-8 level and alanine aminotransferase in the apparently healthy adolescent boys. These findings indicate that there may be a pathophysiological mechanism underlying the relationship between MMP-8 and liver enzymes in young adolescents.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.4
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• pp.199-204
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• 2010

The potential therapeutic action of shikonin in an experimental model of rheumatoid arthritis (RA) was investigated. As a RA animal model, DBA/1J mice were immunized two times with type II collagen. After the second collagen immunization, mice were orally administered shikonin (2 mg/kg) once a day for 35 days, and the incidence, clinical score, bone mineral density (BMD), bone mineral content (BMC) and joint histopathology were evaluated. BMD in the proximal regions of the tibia largely increased in the shikonin treatment group compared with the control group. We also examined the effect of shikonin on inflammatory cytokines and cartilage protection. Shikonin treatment significantly reduced the incidence and severity of collagen-induced arthritis (CIA), markedly abrogating joint swelling and cartilage destruction. Shikonin also significantly inhibited the production of matrix metalloproteinase (MMP)-1 and up-regulated tissue inhibitors of metalloproteinase (TIMP)-1 in mice with CIA. In conclusion, shikonin exerted therapeutic effects through regulation of MMP/TIMP; these results suggest that shikonin is an outstanding candidate as a cartilage protective medicine for RA.

• Journal of Ginseng Research
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• v.36 no.1
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• pp.61-67
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• 2012

In the present study, effects of sun ginseng (SG) on the collagen synthesis and the proliferation of dermal fibroblast were investigated. Collagen synthesis was measured by assaying procollagen type I C-peptide production. In addition, the level of matrix metalloproteinase (MMP)-1 was assessed by western blot analysis. SG suppressed the MMP-1 protein level in a dose-dependent manner. In contrast, SG dose-dependently increased tissue inhibitors of MMP (TIMP)-1 production in fibroblasts. SG increased type I collagen production directly and/or indirectly by reducing MMP-1 and stimulating TIMP-1 production in human dermal fibroblasts. SG dose-dependently induced fibroblast proliferation and this, in turn, can trigger more collagen production. These results suggest that SG may be a potential pharmacological agent with anti-aging properties in cultured human skin fibroblast.

• Journal of Periodontal and Implant Science
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• v.35 no.1
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• pp.123-132
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• 2005

중등도 이상의 치주염 환자에서 치은 열구액내의 MMPs 및 TIMP-1 과 치주염과의 연관성을 규명하고, 치주 수술이 MMPs 및 TIMP-1의 정량에 미치는 영향을 연구하고자 하였다. 총 14명의 치주낭 깊이 6mm 이상의 중등도 이상의 치주 질환 이환자에서 치아를 선정하여, 치주낭 심도, 치은 지수(gingival index)를 측정하고, 치은의 조직학적 염증의 정도를 측정하기 위해, 해당 치아의 치주낭 연조직을 절취하여 H-E염색을 하고, 치은 절편에서 염증세포 침윤의 정도 및 분포를 비교하였다. Perio-paper를 이용하여 치은열구액을 얻고, pyrogen-free water에서 추출하였다. 채취한 치은 열구액에서 ELISA-kit를 이용하여 MMP-1, 8, 9, 13과 TIMP-1을 측정하여 수술 전과, 수술 후, 그리고 건강한 조직인 대조군을 비교하였으며, 통계처리는 Wilcoxon 검정을 사용하였다. 또한 MMPs 혹은 TIMP-1이 치주낭 심도나 치은지수등의 임상적 지표와 가지는 연관성을 Spearman's correlation coefficient를 이용하여 알아보았다. TIMP-1을 제외한 MMP-1, 8 ,9, 13 에서 수술 전보다 수술 후에 치은 열구액 내의 양이 현저하게 줄어든 것을 관찰할 수 있었으나, MMP-1(p=0.025), MMP-9(p=0.016) 와 MMP-13(p=0.009) 에서만 통계적으로 유의성있는 차이를 보였다. 한편 MMP-9 (p=0.011) 나 MMP-13(p=0.026) 은 건강한 대조군과 수술 전 사이에도 유의성있는 차이를 보였다. 연조직의 조직학적 관찰을 통하여 치은지수의 임상적 신뢰도를 평가한 결과 통계학적으로 유의한 결과를 얻을 수 있었으며, 치주 치료 전의 치주낭 심도와 치은지수와의 관계나, 수술 전과 수술 후의 치주낭 심도등의 변화도 통계적으로 유의성있는 결과를 보였다. 하지만 치주낭 심도나 치은지수등의 임상적 지표는 MMPs나 TIMP의 정량과는 별다른 연관성을 보이지 않았다. 이 실험의 결과로 보아 MMP-1, MMP-9나 MMP-13을 치주 수술 전과 수술 후의 치주염의 심도 변화를 반영할 수 있는 지표로 생각할 수 있으며, 특히 MMP-9와 MMP-13가 치주염과 가지는 연관성은 크다고 할 수 있겠다.