• Genomics & Informatics
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• 제21권1호
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• pp.9.1-9.13
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• 2023

Matrix metalloproteinase-9 (MMP-9) is a zinc and calcium-dependent proteolytic enzyme involved in extracellular matrix degradation. Overexpression of MMP-9 has been confirmed in several disorders, including cancers, Alzheimer's disease, autoimmune diseases, cardiovascular diseases, and dental caries. Therefore, MMP-9 inhibition is recommended as a therapeutic strategy for combating various diseases. Cinnamic acid derivatives have shown therapeutic effects in different cancers, Alzheimer's disease, cardiovascular diseases, and dental caries. A computational drug discovery approach was performed to evaluate the binding affinity of selected cinnamic acid derivatives to the MMP-9 active site. The stability of docked poses for top-ranked compounds was also examined. Twelve herbal cinnamic acid derivatives were tested for possible MMP-9 inhibition using the AutoDock 4.0 tool. The stability of the docked poses for the most potent MMP-9 inhibitors was assessed by molecular dynamics (MD) in 10 nanosecond simulations. Interactions between the best MMP-9 inhibitors in this study and residues incorporated in the MMP-9 active site were studied before and after MD simulations. Cynarin, chlorogenic acid, and rosmarinic acid revealed a considerable binding affinity to the MMP-9 catalytic domain (ΔG_binding < -10 kcal/ mol). The inhibition constant value for cynarin and chlorogenic acid were calculated at the picomolar scale and assigned as the most potent MMP-9 inhibitor from the cinnamic acid derivatives. The root-mean-square deviations for cynarin and chlorogenic acid were below 2 Å in the 10 ns simulation. Cynarin, chlorogenic acid, and rosmarinic acid might be considered drug candidates for MMP-9 inhibition.

• KSBB Journal
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• 제25권3호
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• pp.265-270
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• 2010

본 연구에서는 simvastatin에 의한 U-373-MG 세포의 이동 및 침윤에 미치는 효과와 그 가능한 기작에 대해 조사하였다. U-373-MG 세포의 이동에 미치는 simvastatin의 효과를 확인한 결과, $0.01\;{\mu}M$의 simvastatin에서는 U-373-MG 세포의 이동이 약 43% 증가되었으나 $1\;{\mu}M$과 $20\;{\mu}M$에서는 세포의 이동이 각각 28%와 35% 억제되었다. 세포의 침윤 역시 $0.001\;{\mu}M$의 simvastatin에서는 23%, $0.01\;{\mu}M$에서는 26%의 침윤 증가가 관찰되었으나, $1\;{\mu}M$과 $10\;{\mu}M$에서는 세포의 침윤이 각각 45%와 54%가 억제되었다. $0.001\;{\mu}M$ 과 $0.01\;{\mu}M$의 simvastatin 처리에 의해 MMP-2의 분비량이 각각 30%와 59% 증가되었으나, $10\;{\mu}M$과 $20\;{\mu}M$의 simvastatin 처리에 의해 MMP-2의 분비량은 각각 31%와 60% 감소되었다. MMP-9 및 플라스민의 분비에 미치는 simvastatin의 효과도 MMP-2에 미치는 효과와 유사하였다. Simvastatin이 MMP-2와 MMP-9 단백질의 생성에 미치는 효과를 조사한 결과, $0.001{\sim}1\;{\mu}M$의 simvastatin에서는 MMP-2와 MMP-9 생성이 증가되었으나 $10{\sim}20\;{\mu}M$에서는 MMP-2와 MMP-9의 생성이 감소되었다. 이러한 결과는 낮은 농도의 simvastatin은 혈관신생을 유도하고 높은 농도의 simvastatin은 혈관신생을 억제한다는 것을 보여주는 것이다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1327-1330
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• 2015

Background: Squamous cell carcinoma (SCC) is the most common cancer in the oral area. Matrix metalloproteinases (MMPs) and especially MMP-2 and MMP-9 are increased in malignancy and lymph node involvement in oral SCCs. We aimed to evaluate the serum levels of MMP-2 and MMP-9 in patients with oral SCC compared to normal subjects and their relation with clinicopathological findings. Materials and Methods: In this case control study, 20 patients with oral SCC and 20 healthy subjects were included and serum levels of MMP-2 and MMP-9 were compared between groups. Also, the correlation between these markers with clinicopathological findings including grade (T) and node (N) were evaluated. Results: Patients with oral SCC had significantly higher serum levels of MMP-2 (p=0.01) and MMP-9 (p<0.001) compared to healthy subjects. With increase in grade T, MMP-2 was significantly increased (p=0.001), but in the MMP-9 case this was not significant (p=0.27). The levels of MMP-2 (p=0.002) and MMP-9 (p=0.01) in cases with lymph node involvement and that of MMP-2 in subjects with smoking history (p=0.001) were significantly high. There was significantly positive correlation between MMP-2 with grade T tumor (r=0.598, p=0.005), lymph node involvement (r=0.737, p<0.001) and smoking (r=0.674, p=0.001) and also between MMP-9 and lymph node involvement (r=0.474, p=0.03). Conclusions: Both markers are significantly increased in oral SCC compared to healthy subjects. However, MMP-2 was better for evaluating lymph node involvement and tumor grade.

• 대한의생명과학회지
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• 제18권2호
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• pp.104-111
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• 2012

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which degrade extracellular matrix (ECM) during embryogenesis, wound healing, and tissue remodeling. Dysregulation of MMP activity is also associated with various pathological inflammatory conditions. In this study, we examined the expression pattern of MMPs during PMA-induced differentiation of THP-1 monocytic cells into macrophages. We found that MMP1, MMP8, MMP3, MMP10, MMP12, MMP19, MMP9, and MMP7 were upregulated during differentiation whereas MMP2 remained unchanged. Expression of MMPs increased in a time-dependent manner; MMP1, MMP8, MMP3, MMP10, and MMP12 increased beginning at 60 hr post PMA treatment whereas MMP19, MMP9, and MMP7 increased beginning at 24 hr post PMA treatment. To identify signal transduction pathways involved in PMA-induced upregulation of MMPs, we treated PMA-differentiated THP-1 cells with specific inhibitors for PKC, MEK1, NF-${\kappa}B$, PI3K, p38 MAPK and PLC. We found that inhibition of the MEK1 pathway blocked PMA-induced upregulation of all MMPs to varying degrees except for MMP-2. In addition, expression of select MMPs was inhibited by PI3K, p38 MAPK and PLC inhibitors. In conclusion, we show that of the MMPs examined, most MMPs were up-regulated during differentiation of monocyte into macrophage via the MEK1 pathway. These results provide basic information for studying MMPs expression during macrophage differentiation.

• BMB Reports
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• 제41권12호
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• pp.858-862
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• 2008

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a zinc-dependent proteinase found in cholesterol-rich lipid rafts on the plasma membrane. MT1-MMP hydrolyzes extracellular matrix (ECM) proteins, activates pro-matrix metalloproteinase-2 (proMMP-2) and plays an important role in ECM remodeling, cancer cell migration and metastasis. The role of caveolin-1, an integral protein of caveolae, in the activation of MT1-MMP remains largely unknown. Here, we show that the expression of caveolin-1 attenuates the activation of proMMP-2, reduces proteolytic cleavage of ECM and inhibits cell migration. We utilized the cytoplasmic tail domain deletion (${\Delta}CT$) or the E240A mutant of MT1-MMP. Co-expression of caveolin-1 with the wild-type or the ${\Delta}CT$ MT1-MMP decreased the proMMP-2 activation and inhibited collagen degradation and cell migration. Caveolin-1 had no effect on the catalytically inert E240A MT1-MMP. Our findings suggest that caveolin-1 is essential in the down-regulation of MT1-MMP activity by promoting internalization from the cell surface.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6609-6613
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• 2015

Background: Matrix metalloproteinases (MMPs) are a family of zinc metalloproteinases capable of degrading components of connective tissues. MMP-10 is frequently expressed in human cancers. The aim of this study was to immunohistochemically evaluate its expression in oral squamous cell carcinoma (OSCC) and verrucous carcinoma (OVC). Materials and Methods: A retrospective analysis of 73 samples (31 OSCC, 22 OVC and 20 non-neoplastic epithelium) was performed. All samples were immunohistochemically stained with monoclonal MMP-10 antibody and expression levels and staining intensity were evaluated with respect to microscopic features. Data were analyzed by SPSS (V.21), Mann-Whitney and Kruskal Wallis tests. Results: MMP-10 was detected in all OSCC and OVC cases. The expression of MMP-10 in OSCC was intensive (score 3) and in OVC was low and moderate (score 1 and score 2) more frequently. Non- neoplastic epithelium did not show MMP-10 expression. Differences between groups was statistically significant (p<0.05). However, the expression of MMP-10 was not obviously different between various grades of OSCC. Conclusions: According to our study, MMP-10 protein can be important possible factor in the transformation of normal oral epithelium to OVC and OSCC, also the level of MMP-10 expression at invasion front of the lesions can be helpful in the differentiation of OVC and OSCC.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.1175-1179
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• 2015

Background: Expression of matrix metalloproteinases (MMPs) is up-regulated in human cancers. The aim of present study was to investigate the role of MMP-9 C-1562T polymorphism and its interaction with MMP-2 C-735T polymorphism in susceptibility to breast cancer in a population from Western Iran with Kurdish ethnic background. Materials and Methods: The study sample of 205 individuals consisted of 101 breast cancer patients and 104 healthy subjects. MMP-9 C-1562T and MMP-2 C-735T variants were identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: Among 67.4% of studied patients the breast cancer developed in the third and forth decades of the life. The frequency of MMP-9 T allele was 17.3% in patients and 10.1% in controls. The presence of T allele significantly increased the risk of breast cancer by 1.87-fold [OR=1.87 (95% CI 1.05-3.33, p=0.035)]. The frequency of MMP-9 CT+TT genotype tended to be higher in those patients with a family history of cancer in first degree-relatives (36.8%) than those without a family history (28.3%, p=0.37). We observed an interaction between the MMP-9 -1562 T allele with MMP-2 -735 C allele that significantly increased the risk of breast cancer [OR=1.42 (95% CI 1.02-1.98, p=0.036)]. Conclusions: The present study demonstrated that MMP-9 C-1562T polymorphism alone and in combination with MMP-2 C-735T polymorphism increased the risk of breast cancer that might be a useful biomarker in identifying women at risk of developing breast cancer. Also, this study revealed that in most women from Western Iran breast cancer presents in third and fourth decades of life.

• 한국콘텐츠학회논문지
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• 제20권6호
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• pp.124-130
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• 2020

본 연구에서는 시스플라틴과 백작약 에틸아세테이트 분획물의 병용 처리에 의한 암세포 성장억제 및 PMA에 의해 유도된 MMP-2 및 MMP-9 암전이 억제 효과를 조사하였다. 세포생존율 측정은 MTS법에 의해 조사하였고, MMP-2/-9의 유전자발현과 활성은 RT-PCR과 Zymography법을 통하여 확인하였다. 결과에 의하면, 백작약, 시스플라틴의 농도가 증가함에 따라 세포 성장억제 효과가 증가함을 보였다. 또한, 단독 처리에 비해 200 μM의 시스플라틴과 50 ㎍/ml의 백작약 병용 처리에 의해서는 YD-10B 세포의 성장이 50% 감소하였다. PMA 처리된 YD-10B 세포에서 50 ㎍/ml의 백작약과 200 μM의 시스플라틴을 병용 처리하였을 때, MMP-2 및 MMP-9의 mRNA 발현과 단백질 활성들이 모두 유의하게 억제하였다. 그러므로 본 연구에서는 시스플라틴과 백작약의 병용 처리는 시스플라틴 단독 처리보다 구강암의 암 침윤을 억제할 수 있는 효과적인 항암제로서의 가능성을 기대할 수 있다.

• 생명과학회지
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• 제14권2호
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• pp.263-268
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• 2004

본 연구에서는 FGF-2를 이용하여 혈관내피세포의 발아와 단백질분해효소의 분비 및 인테그린과의 관계를 관찰하여 다음과 같은 결과를 얻었다. PPAECs 세포의 발아에 미치는 FGF-2의 효과를 조사한 결과, 10 ng/ml에서 약 3.5배 증가되는 등 농도-의존적으로 발아가 증가되었다. MMPs에 대한 enzyme immunoassay결과, MMP-2에서만 약 1.9배의 분비증가가 유도되었다. MMP-1 및 MMP-3는 FGF-2에 의해 유의할만한 분비 증가가 나타나지 않았으며, 특이하게 MMP-3는 FGF-2의 처리 없이도 많은 양이 분비되었고, MMP-9은 0.6∼1.2 ng/$10^{6}$ cells 정도로 분비량이 적었다. FGF-2에 의한 플라스민의 분비증가 여부를 확인한 결과, 10 ng/ml에서 약 2.6배 증가하였으며, MMPs 억제제 및 인테그린 억제제에 의해 유의할만한 감소가 나타났고 플라스민 억제제인 $\alpha$2-antiplasmin에 의해서는 플라스민의 분비가 완전히 억제되었다. 또한, FGF-2 처리에 의해 농도-의존적으로 인테그린 Mac-1의 발현이 증가되었으며, 인테그린 억제제인 IS201를 전처리한 결과, 인테그린 Mac-1의 발현이 완전히 억제되었다. FGF-2에 의한 발아 유도효과는 IS201 처리에 의해 거의 완벽하게 억제되었으며, MMP-2 및 플라스민의 분비도 유의할만하게 감소시켰다. 이상의 결과를 요약하면, FGF-2에 의해 유도된 혈관내피세포의 발아 증가는 MMP-2 및 플라스민의 분비증가와 인테그린 Mac-1의 발현 증가에 의한 것이라 생각된다.

• Preventive Nutrition and Food Science
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• 제20권3호
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• pp.153-161
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• 2015

Matrix metalloproteinases (MMPs) are crucial extracellular matrices degrading enzymes that have important roles in metastasis of cancer progression as well as other significant conditions such as oxidative stress and hepatic fibrosis. Marine plants are on the rise for their potential to provide natural products that exhibit remarkable health benefits. In this context, brown algae species have been of much interest in the pharmaceutical field with reported instances of isolation of bioactive compounds against tumor growth and MMP activity. In this study, eight different brown algae species were harvested, and their extracts were compared in regard to their anti-MMP effects. According to gelatin zymography results, Ecklonia cava, Ecklonia bicyclis, and Ishige okamurae showed higher inhibitory effects than the other samples on MMP-2 and -9 activity at the concentrations of 10, 50, and $100{\mu}g/mL$. However, only I. okamurae was able to regulate the MMP activity through the expression of MMP and tissue inhibitor of MMP observed by mRNA levels. Overall, brown algae species showed to be good sources for anti-MMP agents, while I. okamurae needs to be further studied for its potential to yield pharmaceutical molecules that can regulate MMP-activity through cellular pathways as well as enzymatic inhibition.