• Bulletin of the Korean Chemical Society
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• v.32 no.6
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• pp.2032-2038
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• 2011

Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases, participate in many normal processes such as embryonic development and wound repair, and in many pathological situations such as cancer, atherosclerosis, and arthritis. Peptidomimetic MMP inhibitors were designed and synthesized with N-formylhydroxylamine (retrohydroxamate) as a zinc-binding group and various side chains on the ${\alpha}$, P1', and P2' positions. Using in vitro MMP assays with purified MMPs (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-14) and fluorogenic peptide substrates, it was found that compounds 2d and 2g selectively inhibit gelatinases (MMP-2 and MMP-9) and interstitial collagenase (MMP-1). They also inhibited the chemo-invasion of fibrosarcoma HT-1080 cells and tube formation of human umbilical vascular endothelial cells in a dose-dependent manner. Our results suggest that retrohydroxamate-based MMP inhibitors, especially compounds 2d and 2g, have the potential to be used as therapeutic drugs for cancer and other MMP-related diseases.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.33 no.6
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• pp.636-642
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• 2007

Background: CpG DNA plays an important role in immune cell function. This study examined whether the temporal control of toll-like receptor (TLR)9 by CpG DNA can regulate the expression of matrix metalloproteinase-9(MMP-9). Methods and materials: Macrophages were cultured in the presence of 10% FBS. For the various MMP genes analysis, RT-PCR and real-time PCR were performed. In addition, zymography assay performed for the MMP activity. The phosphorylation assay did for the ERK1/2 and NF${\kappa}B$ activation, and luciferase promoter assay was for the NF${\kappa}B$ activity. Results: CpG DNA induced the mRNA expression of MMP-2, MMP-9, and MMP-13, but not of MMP-7, MMP-8, and MMP-12, in a time-dependent manner. Especially, the mRNA expression of MMP-9 was strongly induced by CpG DNA using real-time RT-PCR. The TLR9 inhibitor, chloroquine, suppressed CpG DNA-induced MMP-9 expression and its activity. Moreover, CpG DNA induced the phosphorylation of ERK and the inhibition of ERK by U0126 suppressed CpG DNA-induced MMP-9 expression and its activity. CpG DNA stimulated $I{\kappa}B-{\alpha}$ degradation and luciferase activity. In addition, pretreatment of SN-50, the inhibitor of NF${\kappa}B$, strongly blocked the CpG DNA-induced MMP-9 expression and activity. Conclusion: These observations suggest that CpG DNA may play important roles in the activation of macrophages by regulating the production of MMP-9 via the sequential TLR9-ERK-NF${\kappa}B$ signaling pathway.

• Journal of Life Science
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• v.22 no.12
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• pp.1600-1607
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• 2012

The matrix metalloproteinase (MMP) family plays essential roles in physiological processes such as embryonic development, angiogenesis, wound healing, and tissue homeostasis as a consequence of MMPr capacity for breaking down many types of extracellular matrix proteins. Imbalanced regulation of MMP expression can also lead to pathological conditions such as tumor progression. We recently reported that the Drosophila Mmp1 gene is highly expressed in the digestive tract and is required for the maintenance of intestinal homeostasis such as by restriction of uncontrolled intestinal stem cell proliferation. However, the regulatory mechanisms of MMP gene expression in the intestine remain unclear. In this study, we determined that the expression of Mmp1 is regulated by the homeodomain transcription factor Caudal. Experiments using the targeted expression of Caudal under the regulation of Gal4-UAS system indicated that endogenous Caudal is required for the Mmp1 gene expression in the adult Drosophila intestine and that exogenous Caudal induces Mmp1 expression. Transient transfection experiments indicated that Caudal can activate the promoter activity of Mmp1 and that several putative Caudal binding sites in the 5'-flanking region of the Mmp1 gene may be critical to the upregulation by Caudal. Our data suggest that Mmp1 is one of the target genes of Caudal in physiological normal condition and in tumorigenesis.

• Journal of Life Science
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• v.31 no.11
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• pp.980-986
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• 2021

Natural products have always been an attractive source in terms of novel anti-metastatic compounds which can hinder MMP expression and activity. Corydalis heterocarpa is a salt marsh plant found in the seashores throughout Korea. Its yellow flowers and spikes have been an ingredient in folk medicine to treat spasm and contractions. The present study assessed the potential of different solvent-based fractions from the crude extract of Corydalis heterocarpa (CHE), a halophyte with reported bioactivities, to suppress the PMA-induced MMP expression in human fibrosarcoma HT-1080 cells. The solvent fractions which were named after the solvent used for fractionation (n-hexane, 85% aqueous (aq.) methanol (MeOH), n-butanol (BuOH), and H₂O were shown to inhibit the both elevated mRNA and protein expression levels of MMP-2 and MMP-9 and simultaneously relieved the suppression on the expression of the endogenous MMP inhibitors TIMP-1 and TIMP-2. Results indicated that the CHE fractions might intervene with the PMA-induced activation of the MAPK signaling which is the upstream activator of MMP overexpression. Among tested samples, 85% aq. MeOH and n-hexane fractions of CHE was determined to be the most active and future studies to isolate the bioactive substances responsible for the regulation of the MMP expression are, therefore, urged. In conclusion, C. heterocarpa was shown to be a potential source of anti-metastatic compounds and n-Hexane and MeOH fractions might yield lead molecules to develop novel MMP inhibitors.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2001.11a
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• pp.106-106
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• 2001

Matrix metalloproteases (MMPs) 는 다양한 세포에서 전이와 침윤성에 중요한 역할을 한다. MMP의 내인성 저해제인 tissue inhibitor of motalloprotease-2 (TIMP-2) 는 MMP-2에 높은 특이성을 지닌다. MMP-2와 TIMP-2사이의 불균형은 침윤성과 전이와 같은 병리학적 과정과 관계되는 extracellular matrix (ECM)의 퇴화를 일으킨다. TIMPs는 분비되는 분자이기 때문에 특정한 암의 유전자 치료에 사용될 가능성을 지닌다. 본 연구에서는 MMP-2가 H-ras에 의해 유도된 침윤성에 책임지는 것으로 보여지는 H-ras MCF10A 세포에 TIMP-2 유전자를 함유하는 retrovirus를 이용하여 연구하였다. TIMP-2 유전자를 함유하는 재조합 retrovirus는 PG13 세포를 infection 시키는데 사용되었다. H-ras MCF10A 세포는 PGl3 세포의 conditioned media로 처리되었을 때, gelatin zymography에서 MMP-2의 분비가 농도의존적으로 저해되었다. 또한 retrovirus에 의한 TIMP-2의 과잉 발현은 농도의존적으로 H-ras MCF10A 세포의 침윤성과 이동성을 상당히 감소시킨다. 이와 같은 실험 결과는 TIMP-2가 H-ras MCF10A 세포에서 MMP-2 분비와 세포의 침윤성, 이동성을 감소시키는 역할을 지닌다는 것과 TIMP-2 유전자를 함유하는 retrovirus가 효과적으로 MMP-2 분비, 세포 침윤성, 세포 이동성을 감소시켰다는 것을 보여 준다. 이는 암의 예방과 치료를 위한 유전자 치료법의 적용에 상당한 가능성을 제시한다.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5709-5714
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• 2012

Objective: To evaluate the effects of curcumin on matrixmetalloproteinase-9 (MMP-9) and invasion ability induced by transforming growth factor-${\beta}1$ (TGF-${\beta}1$) in MDA-MB-231 cells and potential mechanisms. Methods: Human breast cancer MDA-MB-231 cells were used with the CCK-8 assay to measure the cytotoxicity of curcumin. After treatment with 10 ng/ml TGF-${\beta}1$, with or without curcumin (${\leq}10{\mu}M$), cell invasion was checked by transwell chamber. The effects of curcumin on TGF-${\beta}1$-stimulated MMP-9 and phosphorylation of Smad2, extracellular-regulated kinase (ERK), and p38 mitogen activated protein kinases (p38MAPK) were examined by Western blotting. Supernatant liquid were collected to analyze the activity of MMP-9 via zymography. Following treatment with PD98059, a specific inhibitor of ERK, and SB203580, a specific inhibitor of p38MAPK, Western blotting and zymography were employed to examine MMP-9 expression and activity, respectively. Results: Low dose curcumin (${\leq}10{\mu}M$) did not show any obvious toxicity to the cells, while $0{\sim}10{\mu}mol/L$ caused a concentration-dependent reduction in cell invasion provoked by TGF-${\beta}1$. Curcumin also markedly inhibited TGF-${\beta}1$-regulated MMP-9 and activation of Smad2, ERK1/2 and p38 in a dose- and time-dependent manner. Additionally, PD98059, but not SB203580, showed a similar pattern of inhibition of MMP-9 expression. Conclusion: Curcumin inhibited TGF-${\beta}1$-stimulated MMP-9 and the invasive phenotype in MDA-MB-231 cells, possibly associated with TGF-${\beta}$/Smad and TGF-${\beta}$/ERK signaling.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.873-876
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• 2013

Our aim was to test the hypothesis that preoperative serum levels of matrix metalloproteinase-7 (MMP-7) and -9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) levels correlate with pathological features. Serum levels of MMP-7, and MMP-9 and TIMP-1 were determined in 90 bladder cancer patients and 40 healthy controls using an enzyme linked immunosorbent assay. Preoperative serum MMP-7 and MMP-9 levels were significantly higher in cancer patients than control groups (p<0.001). In contast, serum TIMP-1 levels were lower (p<0.001). Alteration in MMP-7, and MMP-9, and TIMP-1 production may contribute to tumor angiogenesis and be associated with clinic-pathological features.

• KSBB Journal
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• v.16 no.3
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• pp.237-240
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• 2001

Epithelial cell migration plays an important role in many physiological processes such as morphogenesis and wound healing, and cell mobility requires the release of the cell from its adhesion site. This is directed, at least in part, by limited proteolysis of matrix molecules by matrix metalloproteinases (MMPs). MMPs are zinc-dependent proteases produced by a variety of cell types, and have a fundamental role in tissue remodelling, tumour invasion and metastasis. In addition, the ability of cells to mediate fibrinolytic agent, plasmin. The purpose of this study was to test if vascular endothlial growth factor (VEGF) can regulate the production of MMPs and plasmin by keratinocyte cells. Supernatants from a human keratinocyte cell line grown in the presence or absence of VEGF (10ng/mL) produced ?2.5 fold increases in cell proliferation, and ?3.0 fold increses in MMP-2 and plasmin levels. Our results suggest that VEGF may modulate keratinocyte cell proliferating activity by increasing the abundance of MMP-2 and plasmin, and indicates a role for VEGF in the regulation of keratinocyte behaviour in wound healing and tissue remodelling.

• Fisheries and Aquatic Sciences
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• v.15 no.2
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• pp.137-143
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• 2012

The abalone Haliotis discus hannai, is one of the economically important species in the fisheries industry. Abalone intestines are one of the by-products of its processing. To investigate its bioactive potential, abalone intestine was digested using an in vitro gastrointestinal (GI) digestion system containing pepsin, trypsin, and ${\alpha}$-chymotrypsin. The abalone intestine G1 digests (AIGIDs) produced by the GI digestion system were fractionated into AIGID I (> 100 kDa), AIGID II (10-100 kDa), and AIGID III (1-10 kDa) using an ultrafiltration membrane system. Of the three digests, AIGID II and AIGID III exhibited inhibitory effects against matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) in HT1080 human fibrosarcoma cells. Both fractions potently inhibited gelatine digestion by MMP-2 and MMP-9 treated with phorbol 12-myristate 13-acetate (PMA) and migration of HT1080 cells in dose dependently. Furthermore, AIGID II and III attenuated expression of p65, a component of nuclear transcription factor kappa B. These results indicate that of the abalone intestine digests inhibit MMP-2 and MMP-9. Thus, the AIGIDs or their active components may have preventive and therapeutic potential for diseases associated with MMP-2 and MMP-9 activation in fibrosarcoma cells.

• Journal of Life Science
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• v.32 no.1
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• pp.51-55
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• 2022

Matrix metalloproteinase (MMP) enzymes are responsible for the degradation and formation of the extracellular matrix (ECM), and overproduction of MMPs is observed in several diseases, such as cancer and asthma, that progress with metastatic characteristics. Natural products, especially phytochemicals, have been an important source of MMP inhibitors with reduced side effects. Although the majority of phytochemicals inhibit the enzymatic activity of MMPs, some suppress MMP production. In this context, the current study evaluated the potential of Corydalis heterocarpa, a halophyte with reported bioactivities, to inhibit MMP expression in PMA-stimulated HT-1080 cells. A crude C. heterocarpa extract was shown to decrease the mRNA and protein expression of MMP-2 and MMP-9 while increasing the endogenous MMP inhibitors TIMP-1 and TIMP-2 which regulate MMP expression in healthy tissues. In addition, our results show that the inhibitory effects of C. heterocarpa might occur through suppression of the phosphorylation of MAPK signaling, the upstream activator of MMP overexpression. In conclusion, C. heterocarpa is a potential source of antimetastatic compounds that might serve as lead molecules to develop novel MMP inhibitors.