• 대한의생명과학회지
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• 제20권3호
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• pp.103-110
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• 2014

Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They are multidomain proteins and their activities are regulated by tissue inhibitor of metalloproteinases (TIMPs). The uncontrolled regulation of MMPs is involved in various pathologic processes, such as tumor invasion, migration, host immune escape, extravasation, angiogenesis, and tumor growth. Especially, matrix metalloproteinase-9 (MMP-9) is one of the metastasis-accelerating genes involved in metastasis of various types of human cancers. Here, we review the member of MMP family and discusses their domain structure and function, enzyme activation, the mechanism of inhibition by TIMPs. In particular, we focus the role of MMP-9 in relation to cancer metastasis.

• Journal of Nutrition and Health
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• 제36권3호
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• pp.280-286
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• 2003

Conjugated linoleic acid (CLA) consists of several geometric isomers of linoleic acid. CLA is found in foods derived from ruminants and exhibits strong anticarcinogenic effects in a variety of animal models. Matrix metalloproteinases (MMPs) play a key role in cancer progression. Specifically, MMP-2 and -9, which hydrolyze the basal membrane type IV collagen, are involved in the initial breakdown of collagen and basement membrane components during tumor growth and invasion. However, the effects of CLA on cancer cell motility and MMP expression and activity are not currently well known. Therefore, the present study examined whether CLA reduces the activity of MMP and cell motility in SW480 and SW620 cells, the human colon cancer cell lines. Gelatin zymography and Western blot analysis revealed that phorbol 12-myristate 13-acetate (PMA) induced the activity and protein expression of Mr 92,000 MMP-9 in both cell lines. To examine whether CLA inhibits the MMP activity, cells were incubated with 100 ngfmL PMA in the presence of various concentrations of CLA. PMA-induced MMP-9 activity was decreased by 20 $\mu$ M CLA in SW480 cells, and by 10 $\mu$ M and 20 $\mu$ M CLA in SW620 cells. Results from the Hoyden chamber assay showed that cell motility was increased by PMA and that PMA-induced cell motility was significantly decreased by 20 $\mu$ M CLA in SW480 cells. These results indicate that CLA may reduce the motility and MMP activity in human colon cancer cells.

• 생명과학회지
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• 제19권6호
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• pp.836-838
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• 2009

뇌졸중 치료에 사용되는 tPA는 탁월한 혈전 용해 효과를 보이고 있어 혈액의 흐름을 용이하게 하는데 중요한 역할을 한다. 그러나 tPA 치료법은 매우 짧은 시간 내에 사용해야하는 단점과 출혈, 부종과 같은 여러 가지 부작용이 수반될 수 있기 때문에 매우 제한적이다. 이전의 실험 결과에 따르면 tPA의 이러한 양면적인 현상은 MMP의 활성 조절과 관련이 있는 것으로 보고되어 있으나 세포시스템을 활용한 이들의 직접적인 효과나 조절 기전에 대한 연구는 거의 알려져 있지 않다. 본 연구는 임상에서 사용되는 tPA의 부정적인 효과를 극복하기 위한 방안을 모색하고자 tPA와 MMP 활성과의 조절 기전을 살펴보았다. 랫트의 뇌로부터 추출한 신경세포에서 tPA의 처리는 MMP의 발현을 촉진시켰고 저산소상태에서 tPA에 의한 MMP활성 증가가 더욱 가속화되었으며 JNK 신호전달 경로를 통해 조절되는 것을 확인하였다.

• Preventive Nutrition and Food Science
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• 제22권3호
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• pp.184-190
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• 2017

Matrix metalloproteinases (MMPs) are endopeptidases that take significant roles in extracellular matrix degradation and therefore linked to several complications such as metastasis of cancer progression, oxidative stress, and hepatic fibrosis. Hizikia fusiformis, a brown algae, was reported to possess bioactivities, including but not limited to, antiviral, antimicrobial, and anti-inflammatory partly due to bioactive polysaccharide contents. In this study, the potential of H. fusiformis against cancer cell invasion was evaluated through the MMP inhibitory effect in HT1080 fibrosarcoma cells in vitro. H. fusiformis crude extract was fractionated with organic solvents, $H_2O$, n-BuOH, 85% aqueous MeOH, and n-hexane (n-Hex). The non-toxicity of the fractions was confirmed by MTT assay. All fractions inhibited the enzymatic activities of MMP-2 and MMP-9 according to the gelatin zymography assay. Cell migration was also significantly inhibited by the n-Hex fraction. In addition, both gene and protein expressions of MMP-2 and -9, and tissue inhibitor of MMPs (TIMPs) were evaluated by reverse transcription-polymerase chain reaction and Western blotting, respectively. The fractions suppressed the mRNA and protein levels of MMP-2, MMP-9 while elevating the TIMP-1 and TIMP-2, with the $H_2O$ fraction being the least effective while n-Hex fraction the most. Collectively, the n-Hex fraction from brown algae H. fusiformis could be a potential inhibitor of MMPs, suggesting the presence of various derivatives of polysaccharides in high amounts.

• 대한의생명과학회지
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• 제19권1호
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• pp.9-16
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• 2013

Elevated blood triglyceride (TG) levels correlate with development of atherosclerosis suggesting that TG may promote the development of this disease. During atherosclerosis, TG is taken up by tissue macrophages which result in dramatic changes in various secreted factors. One such factor is the family of matrix metalloproteases (MMP) which are involved in tissue remodeling during both physiological and pathological processes. In this study, we examined the MMP expression profile in PMA-differentiated THP-1 macrophages treated with TG. We found that TG-treated THP-1 macrophages showed decreased expression of MMP-3, MMP-7, MMP-8 and MMP-9 in a time- and dose-dependent manner. In contrast, expression of MMP-1, MMP-2, and MMP-10 remained relatively unchanged after TG treatment. In addition, we found that expression of select MMPs was affected by various inhibitors of signaling pathways. In particular, expression of MMP-3 was slightly recovered by cRAF and PLC signaling pathway inhibitors. These data suggests a possible role of MMPs in macrophages during TG-induced atherosclerosis.

• 생명과학회지
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• 제33권5호
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• pp.414-421
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• 2023

갯사상자는 염생식물의 일종으로 염분이 높은 토양에서 자생하는 식물로 선행연구에 따르면 갯사상자는 항암효과를 가진다고 알려져 있다. 그러나 UVB로 유도된 광노화에 대한 효과는 아직 알려져 있지 않은 실정이다. 본 연구에서는 갯사상자 조추출물이 산화스트레스에 미치는 영향과 UVB 유래 광손상에 미치는 효과와 그 작용기전에 대하여 밝히고자 하였다. 갯사상자 추출물의 항산화 활성은 ROS 생성 억제능을 통해 확인하였으며, 광노화에 대한 효능은 피부노화 관련 인자인 MMP-1, MMP-3 및 MMP-9 발현 저해 효과와 MAPKs 발현기전을 통해 확인하였다. 세포생존율 실험결과를 바탕으로 UVB 조사 기준은 15 mJ/cm² 로 설정하였으며, 갯사상자 추출물의 농도는 10, 50, 그리고 100 ㎍/ml로 설정하였다. 결과적으로 갯사상자 추출물은 농도의존적으로 활성산소종을 억제하는 효과를 가짐을 확인하였고, 피부노화 관련인자인 MMP-1, MMP-3 및 MMP-9 발현을 감소시키는 것을 확인하였다. 노화관련인자인 MMP 발현 억제는 MAPK 전사인자의 발현 억제효과에 의한 것임을 확인할 수 있었다. 이들 결과로부터 갯사상자 추출물이 광노화에 효능을 가진 천연 화장품 소재로서 개발이 가능할 것으로 기대된다.

• Journal of Ginseng Research
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• 제46권4호
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• pp.536-542
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• 2022

Background: In aged skin, reactive oxygen species (ROS) induces degradation of the extracellular matrix (ECM), leading to visible aging signs. Collagens in the ECM are cleaved by matrix metalloproteinases (MMPs). Syringaresinol (SYR), isolated from Panax ginseng berry, has various physiological activities, including anti-inflammatory action. However, the anti-aging effects of SYR via antioxidant and autophagy regulation have not been elucidated. Methods: The preventive effect of SYR on skin aging was investigated in human HaCaT keratinocytes in the presence of H₂O₂, and the keratinocyte cells were treated with SYR (0-200 ㎍/mL). mRNA and protein levels of MMP-2 and -9 were determined by real-time PCR and Western blotting, respectively. Radical scavenging activity was researched by 2,2 diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. LC3B level was assessed by Western blotting and confocal microscopy. Results: SYR significantly reduced gene expression and protein levels of MMP-9 and -2 in both H₂O₂-treated and untreated HaCaT cells. SYR did not show cytotoxicity to HaCaT cells. SYR exhibited DPPH and ABTS radical scavenging activities with an EC₅₀ value of 10.77 and 10.35 ㎍/mL, respectively. SYR elevated total levels of endogenous and exogenous LC3B in H₂O₂-stimulated HaCaT cells. 3-Methyladenine (3-MA), an autophagy inhibitor, counteracted the inhibitory effect of SYR on MMP-2 expression. Conclusion: SYR showed antioxidant activity and up-regulated autophagy activity in H₂O₂-stimulated HaCaT cells, lowering the expression of MMP-2 and MMP-9 associated with skin aging. Our results suggest that SYR has potential value as a cosmetic additive for prevention of skin aging.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.3697-3701
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• 2015

Background: Cholangiocarcinoma (CHCA) is serious public health problem in Thailand, especially in the northeastern and northern regions. CHCA is known as one of the most aggressive malignant tumors associated with local invasion and a high rate of metastasis. A crucial step in the invasion process is the proteolytic degradation of the extracellular matrix (ECM) and basal membranes, for which several studies have shown a critical role played by matrix metalloproteinase-11 (MMP-11). Objective: This study aim to detect MMP-11 expression in CHCA specimens and any correlation with survival time. Materials and Methods: A retrospective analysis was conducted of 30 patients with CHCA in Rajvithi hospital, who had undergone immunohistochemical staining of MMP-11. Relationships between clinicopathological data and MMP-11 expression in CHCA specimens were analyzed by the ${\chi}^2$ test or Fisher's exact test. The estimated survival and the survival differences were analyzed by the Kaplan-Meier method and the log-rank test, respectively. Results: MMP-11 expression was found in 15 specimens (50%). The overall mean survival time is 237.0 days (95% CI 135.4-338.5, SD 271.9). Specimens with a positive MMP-11 had an average survival time of 136.7 days (95%CI 50.3-223.1, SD 156.0). Survival differences was signficant for the positive and negative MMP-11(p=0.022), but not well differentiated tumor and moderate to poor differentiated tumor (p=0.755), CA19-9 level of >1,000 and <1,000 (p=0.488), and between advanced and non-advanced staging (p=0.388). Conclusions: The positive MMP-11 expression indicates poor prognosis in CHCA specimens.

• Tuberculosis and Respiratory Diseases
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• 제51권4호
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• pp.303-314
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• 2001

연구배경 : 특발성 폐섬유회증은 병리학적으로 폐구조가 파괴되면서 섬유아세포 및 교원질이 간질 및 폐포내에 침작하는 질환으로 교원질의 침착은 cytokine 및 성장촉진인자들에 의한 교원질생성의 증가 뿐 아니라 교원질의 분해흡수의 감소도로 초래될 수 있다. IPF의 또 다른 특징인 폐구조의 파괴 및 폐보내 섬유화 현상은 기저막 파괴로 인한 섬유아세포 등의 폐포내 유입 및 비정상적 증식이 기전으로 생각되므로 기저막의 주요 성분인 제4형 교훤질올 분해하는 Matrix metalloproteinase(MMP)-2와 MMP-9이 IPF의 발병기전에 중요한 역할을 할 것으로 추정되고 있다. 또한 병이 계속 활발히 진행되는 상태에서는 이들 효소의 농도도 높올 것이 예상되므로 본 연구는 특발성 폐섬유화증에서 질병의 진행파정에 따른 기관지폐포세척액(BALF)내 MMP 농도 및 BALF내 세포분포와의 IPF에서 MMP의 역할 및 예후인자로서의 가능성을 규명하고자 시행되었다. 방 법 : 서울중앙병원에서 진단된 41명(연령 $59.82{\pm}1.73$세, 남:여=23:18)의 IPF환자들과, IPF진단은 받았으나 1년 이상 치료하지 않고도 병이 진행되지 않았던 안정군 16명($63.6{\pm}2.8$세, 남:여=13:3) 및 정상 대조군 7명을 대상으로 BAL액과 AM배양 배지에서 MMP-2와 MMP-9농도를 zymography와 densitometry에 의한 정량분석을 시행하였고, TIMP-1 농도는 상업용 ELISA kit로 측정하였다. 결 과 : 1) BAL 액내 총 세포수(${\times}10^6/ml$)는 IPF환자군($3.40{\pm}0.20$), 안정군($2.92{\pm}0.39$), 대조군($0.91{\pm}0.15$)간 유의한 차이를 보였고 AM수효(${\times}10^5/ml$)와 호중구 수(${\times}10^5/ml$)는 IPF 환자군($24.74{\pm}1.88$, $2.15{\pm}0.35$)과 안정군($19.16{\pm}2.26$, $0.63{\pm}0.11$)에서 대조군($7.36{\pm}1.04$, $0.052{\pm}0.038$)에 비하여 유의하게 높았다(p<0.05). 호산구비율도 IPF 환자군($2.83{\pm}0.66%$)과 안정군($1.50{\pm}0.42%$)에서 대조군($0{\pm}0%$)에 비하여 유의하게 높았으나(p<0.05), 림파구수나 비율은 차이가 없었다. 2) Zymography에 의한 육안적 관찰에서 IPF환자군은 34/41(82.9%), 안정군은 9/15(60%), 각각 band를 관찰하여 대조군 0/6(0%)과 차이를 보였다. 3) BALF내 MMP-2는 IPF환자군($1.36{\pm}0.28$)은 안정군($0.46{\pm}0.13$)에 비하여, 또 안정군도 대조군($0.08{\pm}0.09$)에 비하여 유의하게 높았다. MMP-9은 IPF 환자군($0.31{\pm}0.058$)과 안정군($0.22{\pm}0.078$)에서 대조군($0.002{\pm}0.004$)보다 높았다. TIMP-1도 IPF환자군($36.34{\pm}8.62{\mu}g/ml$)과 안정군($20.83{\pm}8.53{\mu}g/ml$)에서 대조군($2.80{\pm}1.05{\mu}g/ml$)에 비하여 유의하게 높았다(p<0.05). 4) AM배양액에서는 MMP-9만이 역시 IPF군에서($0.80{\pm}0.10$) 대조군보다($0.23{\pm}0.081$) 높았다. 5) BALF내 MMP-2는 전체 세 포수(r=0.298)와 호중구수(r=0.357)와 유의한 상관관계를 보였으나(p<0.05), AM수(r=0.096)나 임파구수(r=0.100)와는 상관관계가 없었고, MMP-9은 호중구수(r=0.407) 및 임파구수(r=0.574)와 유의한 상관관계를 보였다. TIMP-1은 전체 세포수(r=0.338, p<0.05) 및 호중구수(r=0.449, p=0.059)와 상관관계의 경향을 보였다. 결 론 : 본 연구의 결과로 MMP와 TIMP는 IPF의 병인에 있어서 중요한 역할을 하며, BALF내 MMP농도는 IPF의 활성도와 연관이 었을 것으로 추정된다.

• Journal of Periodontal and Implant Science
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• 제33권2호
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• pp.277-288
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• 2003

It has been suggested that increased number and activity of phagocytes in periodontitis lesion results in a high degree of reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, nitric oxide and peroxynitrite. There are few reports on the relationship between ROS and MMPs expressions in gingival fibroblast. We studied to elucidate whether and how ROS, especially nitric oxide affects the MMP expression. Human gingival fibroblasts and HTl080 cells (human fibrosarcoma sell line as reference) were grown in DMEM supplemented with 10 mM HEPES, 50 mg/L gentamicin, and 10% heat inactivated fetal bovine serum with addition of various reactive oxygen species (ROS). Culture media conditioned by cells were examined by gelatin zymography. HT1080 cells expressed proMMP-2 and proMMP-9, but human gingival fibroblasts (HGF) produced only proMMP-2. Hydrogen peroxide upregulated MMP-9 expression in HT1080 cells, whereas in human gingival fibroblast SNP treatment showed marked increase in MMP-2 level compared to other ROS. These results suggest that the effects of ROS on MMPs expressions are cell-type specific. RT-PCR for MMP-2 and TIMP-2 m-RNA were performed using total RNA from cultured cells under the influence various kinase inhibitors. In HT1080 cells, treatment with FPTI III (Ras processing inhibitor) and LY294002 (PI3-kinase inhibitor) resulted in inhibition of MMP-2 and MMP-9 expressions, suggesting that Ras/P13-kinase pathway is important for MMPs expression in HT1080 cells. In gingival fibroblasts, treatment with FPTI III and PDTC (NF-kB inhibitor) showed marked decrease in MMP-2 regardless of the of SNP , suggesting that Ras/NF-kB could be the key pathway for NO-induced MMP-2 expression in gingival fibroblasts. This study showed that ROS, especially nitric oxide, could be the critical mediator of periodontal disease progression through control of MMP-2 expression in gingival fibroblasts possibly via Ras/NF-kB pathway.