• Biomolecules & Therapeutics
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• 제10권4호
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• pp.240-245
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• 2002

Cancer metastasis represents the most important cause of cancer death and antitumor agents that may inhibit this process have been extensively pursued. Invasion and metastasis of malignantly transformed cells involve degradation of the extracellular matrix (ECM) components by matrix metalloproteinases (MMP), especially MMP-2 and -9. We previously showed that H-ras-induced invasive phenotype may involve MMP-2, rather than MMP-9, in MCF10A cells. In the present study, we investigated the chemopreventive effect of Aster, a widely used culinary vegetable in Korea. We screened twelve extracts from three Aster species (Aster scaber, Aster oharai and Aster glehni) for the inhibitory effect on MMP activities of H-ras MCF10A human breast epithelial cells. All of the extracts tested in this study efficiently inhibited the gelatinolytic activities of MMP-2 and MMP-9. A more prominent inhibition was observed in MMP-2 activity compared to MMP-9. Out of twelve extracts, eight extracts showed>90％ inhibition of MMP-2 activity in H-ras MCF10A cells while only one extract showed>90％ inhibition of MMP-9 activity. We selected three extracts (AO-3, AG-3 and AS-EA) for further studies since they exerted a marked inhibition in the ratio of MMP-2 to MMP-9. Treatment with AO-3, AG-3 and AS-EA in H-ras MCF10A cells caused a significant inhibition of invasive phenotype and migration, proving a chemopreventive potential of these extracts. Taken together, our results demonstrate that extracts of Aster effectively inhibit invasion and migration of highly malignant human breast cells, possibly via downregulation of MMP-2 and MMP-9.

• 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.

• Animal cells and systems
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• 제10권2호
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• pp.79-83
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• 2006

Tissue plasminogen activator (tPA) is used to lyse clots and reperfuse brain in ischemic stroke. However, sideeffects of intracerebral hemorrhage (ICH) and edema limit their clinical application. In part, these phenomena has been linked with elevations in matrix metalloproteinase-9 (MMP-9) in neurovascular unit. However little is known about their regulatory signaling pathways in brain cells. Here, I examine the role of MAP kinase pathways in tPA-induced MMP-9 regulation in rat cortical astrocytes. tPA $(1-10\;{\mu}g/ml)$ induced dose-dependent elevations in MMP-9 and MMP-2 in conditioned media. Although tPA increased phosphorylation in two MAP kinases (ERK, JNK), only inhibition of the JNK pathway by the JNK inhibitor SP600126 significantly reduced MMP-9 upregulation. Neither ERK inhibition with U0126 nor p38 inhibition with SB203580 had any significant effects. Taken together, these results suggest that c-jun N-terminal kinase (JNK) plays an essential role for tPA-induced MMP-9 upregulation.

• Biomolecules & Therapeutics
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• 제22권5호
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• pp.414-419
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• 2014

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that regulate cell-matrix composition and are also involved in processing various bioactive molecules such as cell-surface receptors, chemokines, and cytokines. Our group recently reported that MMP-3, -8, and -9 are upregulated during microglial activation and play a role as proinflammatory mediators (Lee et al., 2010, 2014). In particular, we demonstrated that MMP-8 has tumor necrosis factor alpha (TNF-${\alpha}$)-converting enzyme (TACE) activity by cleaving the prodomain of TNF-${\alpha}$ and that inhibition of MMP-8 inhibits TACE activity. The present study was undertaken to compare the effect of MMP-8 inhibitor (M8I) with those of inhibitors of other MMPs, such as MMP-3 (NNGH) or MMP-9 (M9I), in their regulation of TNF-${\alpha}$ activity. We found that the MMP inhibitors suppressed TNF-${\alpha}$ secretion from lipopolysaccharide (LPS)-stimulated BV2 microglial cells in an order of efficacy: M8I>NNGH>M9I. In addition, MMP inhibitors suppressed the activity of recombinant TACE protein in the same efficacy order as that of TNF-${\alpha}$ inhibition (M8I>NNGH>M9I), proving a direct correlation between TACE activity and TNF-${\alpha}$ secretion. A subsequent pro-TNF-${\alpha}$ cleavage assay revealed that both MMP-3 and MMP-9 cleave a prodomain of TNF-${\alpha}$, suggesting that MMP-3 and MMP-9 also have TACE activity. However, the number and position of cleavage sites varied between MMP-3, -8, and -9. Collectively, the concurrent inhibition of MMP and TACE by NNGH, M8I, or M9I may contribute to their strong anti-inflammatory and neuroprotective effects.

• 대한화장품학회지
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• 제32권3호
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• pp.129-134
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• 2006

본 연구는 곰취 추출물의 항산화, 지질과산화 억제 및 자외선 조사에 의해 유도된 MMP-1 발현에 대한 영향을 사람 섬유아세포를 이용하여 확인하였다 곰취의 DPPH와 superoxide radical 소거효과는 처리농도가 증가함에 따라 농도 의존적으로 소거효과를 나타냈으며, 각각 5mg/mL에서 82.3%와 79.3%로 DPPH와 superoxide radical을 소거하여 우수한 항산화 효과를 나타내었다. 곰취 추출물의 지질과산화 억제효과는 $500{\mu}g/mL$에서 97.0%로 지질과산화 억제효과도 우수하게 나타났다. 또한 자외선에 의해 증가된 사람 섬유아세포의 MMP-1 단백질 발현양은 곰취 추출물을 $100{\mu}g/mL$ 농도를 처리함으로써 약 35%로 감소되었다. 곰취 추출물은 항산화 효과, 지질과산화 억제효과 및 자외선 조사에 의해 유도되는 MMP-1 단백질 발현량을 조절하는 기능을 갖는 것을 확인하였다. 따라서 곰취는 항산화, 지질과산화 억제 및 자외선에 의해 유도되는 MMP-1 발현을 저해함으로써 항노화 소재로써 이용될 수 있을 것으로 사료된다.

• 대한화장품학회:학술대회논문집
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• 대한화장품학회 2003년도 IFSCC Conference Proceeding Book II
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• pp.12-25
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• 2003

L-camitine ($\beta$ -hydroxy-${\gamma}$ -trimethyl-ammoniumbutyric acid) is a small water-soluble molecule important in mammalian fat metabolism. It is essential for the normal oxidation of fatty acids by the mitochondria, and is involved in the trans-esterification and excretion of acyl-CoA esters. In this paper, to investigate the relationship between aging and L-camitine, we investigated the effects of in vitro MMP inhibition and activity and expression of UVA-induced MMP 1 in human skin fibroblasts. Fluorometric assays of the proteolytic activities of MMP-l were performed using fluorescent collagen substrates. ELISA (enzyme linked immuno sorbent assay), gelatin-substrate zymography, and RT-PCR ELISA techniques were used for the effects of L-camitine on MMP expression and activity, MMP mRNA expression in UVA irradiated fibroblast. L-camitine inhibited the activities of MMP-l in a dose-dependent manner and the $IC_{50}$/ values calculated from semi-log plots were 2.45mM, and L-carnitine showed strong inhibition on MMP-2 (gelatinase) activity in UVA irradiated fibroblast by zymography. Also, UVA induced MMP expression was reduced 40% by treated with L-carnitine, and MMP-l mRNA expression was reduced dose-dependent manner. Therefore L-carnitine was able to significantly inhibition the MMP activity, regulation of MMP expression in protein and mRNA level. All these results suggest that L-carnitine may be useful as new anti-aging cofactor for protection against UVA induced MMP expression and activity.

• 한국응용과학기술학회지
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• 제35권3호
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• pp.797-806
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• 2018

본 연구는 적작약 꽃 추출물의 활성산소 억제와 항염증 및 MMP-1 발현 억제능 효과에 관해 알아보고 기능성 화장품 소재로써의 가능성을 확인하고자 하였다. 본 실험 방법으로는 세포 내 ROS 측정을 통한 활성산소 억제효과와 세포 독성 평가 및 항염증 측정, HDF 세포에서의 MMP-1의 발현 억제능 효과를 측정하고자 하였다. 실험 결과, RAW 264.7 세포와 HDF 세포 내에서 ROS로 억제효과를 확인하였고, 세포 독성평가는 적작약 꽃 추출물 5, $10{\mu}g/mL$ 처리 농도에서 90% 이상의 세포 생존율, 그 외 처리 농도에서는 80% 이상의 세포 생존율을 확인하였다. 또한 RAW 264.7 세포에서의 NO 생성 억제와 HDF 세포에서 MMP-1의 발현 억제능이 유의하게 억제되는 것을 확인하였다. 이상의 결과를 종합하면, 적작약 꽃 추출물의 세포 내 ROS 생성억제와 NO 생성 억제로 항산화와 항염증 효과, 피부세포에 대한 낮은 독성, MMP-1의 발현 억제를 통한 노화 효과가 확인됨에 따라 기능성 화장품 소재로써의 활용 가능성을 확인할 수 있었다.

• 동의생리병리학회지
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• 제23권5호
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• pp.974-979
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• 2009

Proliferation of vascular smooth muscle cell(VSMC) is one of the key features in onset of atherosclerosis and restenosis after vascular surgery such as stent implant. Atherosclerotic plaques are usually composed of collagen, elatsin and smooth muscle cells. Release of matrix metalloproteinases(MMPs) is considered to have correlation with development of atherosclerotic plaques. Based on the hypothesis that MMP inhibition would be helpful in the treatment of atherosclerosis, we investigated inhibition of MMP activity and migration of TNF-$\alpha$-induced human aortic smooth muscle cell(HASMC) by Cinnamomi Ramulus(CC). The result from gelatin zymography showed that CC inhibited MMP-9 activity in a dose-dependent manner. In addition, CC considerably inhibited the migration of HASMC induced by TNF-$\alpha$, while it showed little cytotoxic effect on HASMC. These results suggest that CC can be a potential anti-atherosclerotic agent through inhibition of MMP-9 activity and SMC migration.

• 생약학회지
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• 제46권2호
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• pp.154-159
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• 2015

This study was to evaluate the effect of isopropyl alcohol fraction of ultrasonication processed ginseng flower buds(GFB-IF) on the collagen synthesis activity and inhibition of MMP-1 suppression in UV-irradiated human dermal fibroblasts. The higher contents of ginsenoside Rg2(8.234%), Rh1(5.749%), F4(3.881%) in isopropyl alcohol fraction of ginseng flower buds obtained by ultrasonication process at 600W(100℃) for 16 hours. GFB-IF had collagen synthesis effect. GFB-IF induced a significant dose-dependent decrease in the expression for MMP-1 protein. These results suggest that GFB-IF is a potential candidate for the prevention and treatment of wrinkle improving.

• Natural Product Sciences
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• 제18권4호
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• pp.261-265
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• 2012

Xanthohumol was isolated from hops (Humulus lupulus L.), and then investigated anti-oxidant effect by AAPH-induced LLC-PK1 cell and oxygen radical absorbance capacity (ORCA) assays and MMP-12 inhibitory effect by direct MMP-12 inhibition assay. The treatment of xanthohumol protected LLC-PK1 cells from AAPH-induced cell damage such as cell viability, SOD and GSH-px reduction in a dose dependant manner (0.1, 1, and $5{\mu}M$), the SOD value was 2.98, 4.51, and 5.77 U/mg protein, and GSH-px value was 30.12, 49.32, and 60.11 U/mg protein. ORAC value of xanthohumol was showed as 4320, 12004, and $14209{\mu}M$ TE/g at the concentration 0.1, 1, and $5{\mu}M$, respectively. The change of SOD and GSH-px values was significantly correlated with the results of ORAC assay, that is, AAPH-induced cell and ORCA assays. In addition, inhibition of MMP-12 that is known to play an important role in skin aging was 14%, 37%, 46%, and 79% at the concentration of 0.01, 0.1, 1, and $5{\mu}M$, respectively. On the basis of these results, xanthohumol from hops (Humulus lupulus L.) showed interesting biological and pharmacological activity such as anti-oxidant effect and anti-aging.