• Nutrition Research and Practice
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• v.2 no.2
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• pp.134-137
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• 2008

Atherosclerosis is characterized by a chronic inflammatory disease, and chemokines play an important role in both initiation and progression of atherosclerosis development. Leukotactin-1 (Lkn-1/CCLl5), a new member of the human CC chemokine family, is a potent chemoattractant for leukocytes. Our previous study has demonstrated that Lkn-1/CCL15 plays a role in the initiation of atherosclerosis, however, little is currently known whether Lkn-1/CCL15 is associated with the progression of atherosclerosis. Matrix metalloproteinases (MMPs) in human coronary atherosclerotic lesions playa crucial role in the progression of atherosclerosis by altering the vulnerability of plaque rupture. In the present study, we examined whether Lkn-1/CCLl5 modulates MMP-9 release, which is a prevalent form expressed by activated macrophages and foam cells. Human THP-1 monocytic cells and/or human peripheral blood monocytes (PBMC) were treated with phorbol myristate acetate to induce their differentiation into macrophages. Foam cells were prepared by the treatment of THP-1 macrophages with human oxidized LDL. The macrophages and foam cells were treated with Lkn-1/CCL15, and the levels of MMP-9 release were measured by Gelatin Zymography. Lkn-1/CCL15 significantly enhanced the levels of MMP-9 protein secretion from THP-1 monocytic cells-derived macrophages, human PBMC-derived macrophages, as well as macrophage-derived foam cell in a dose dependent manner. Our data suggest that the action of Lkn-1/CCL15 on macrophages and foam cells to release MMP-9 may contribute to plaque destabilization in the progression of atherosclerosis.

• Journal of Yeungnam Medical Science
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• v.23 no.1
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• pp.82-89
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• 2006

Background: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix, which is an important step in tumor invasion and metastasis. A positive correlation between the expression of MMP-9 and aggressive behavior of renal cell carcinomas (RCCs) has been reported. MMP-9 expression in RCCs and adjacent normal kidney tissues were examined in this study. Materials and Methods: Twenty-five patients pathologically diagnosed as clear cell RCCs, from specimens obtained at radical nephrectomy, between May 2003 and December 2004 were enrolled in this study. MMP-9 activity was estimated using gelatin zymography, and quantified using a laser densitometer. The results were compared with clinicopathological characteristics. Results: The expression of MMP-9 was significantly elevated in the RCC compared with non-tumor kidney specimens (p<0.01). The levels of MMP-9 expression in the RCC patients with large tumors (>4 cm) or vascular invasion were significantly higher than in those without these clinical manifestations (p<0.01). There were also significant differences in the expression of MMP-9 among T stages (p<0.01). The tissue MMP-9 level was the highest in nuclear grade 4, but there was no statistical significance between the histological grades (p=0.17). Conclusions: These results suggest that enhanced MMP-9 expression contributes to carcinogenesis and tumor progression in the later stages of RCC.

• Journal of Cancer Prevention
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• v.21 no.2
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• pp.88-94
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• 2016

Background: Breast cancer is the most common malignant disease in women. The patients with advanced breast cancer develop metastasis to bone. Bone metastasis and skeletal-related events by breast cancer are frequently associated with the invasiveness of breast cancer cells and osteoclasts-mediated bone resorption. Forsythia koreana is used in oriental traditional medicine to treat asthma, atopy, and allergic diseases. The aim of this study was to evaluate the inhibitory effects of F. koreana extracts on the invasion of breast cancer cells and bone resorption by osteoclasts. Methods: Cell viability was measured by an MTT assay and the migration and invasion of MDA-MB-231 cells were detected by a Boyden chamber assay. The formation of osteoclasts and pit was detected using tartrate-resistant acid phosphatase staining and calcium phosphate-coated plates, respectively. The activities of matrix metalloproteinases (MMPs) and cathepsin K were evaluated by gelatin zymography and a cathepsin K detection kit. Results: The fruit and leaf extracts of F. koreana significantly inhibited the invasion of MDA-MB-231 cells at noncytotoxic concentrations. The fruit extract of F. koreana reduced the transforming growth factor ${\beta}1-induced$ migration, invasion and MMPs activities of MDA-MB-231 cells. In addition, the fruit, branch, and leaf extracts of F. koreana also inhibited the receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and osteoclast-mediated bone-resorbing activity by reducing the activities of MMPs and cathepsin K. Conclusions: The extracts of F. koreana may possess the potential to inhibit the breast cancer-induced bone destruction through blocking invasion of breast cancer cells, osteoclastogenesis, and the activity of mature osteoclasts.

• YAKHAK HOEJI
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• v.48 no.3
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• pp.189-196
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• 2004

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) playa key role in tumor invasion and metastasis. As an inhibitor of MMP-2, TIMP-2 is known to block both the invasive and metastatic behavior of cancer cells, and decrease tumor growth activity. We performed this study to investigate the effects of TIMP-2 over-expression induced by retroviral mediated gene transfer in vitro and in vivo. The human colon cancer cell line SW480 was transfected with the retroviral vector encoding TIMP-2. The effects of TIMP-2 over-expression were analyzed by invasion assay and gelatinase activity test in colon cancer cells and tumorigencity in nude mice. In evaluation of the transfection efficiency of the retroviral vector encoding TIMP-2 in colon cancer cells, we confirmed up-regulation of TIMP-2 expression dependent on the time of cell culture. In addition, inhibition of MMP-2 expression in SW480/TIMP-2 was shown by gelatin zymography. In the in vitro invasion assay SW480/TIMP-2 inhibited the invasiveness on matrigel coated with collagen. To determine whether TIMP-2 can modulate in vivo tumorigenicity and metastasis, SW480/TIMP-2 cells were injected subcutaneously in nude mice. The tumor mass formation of SW480/TIMP-2 cells in nude mice was markedly decreased compared to nontransfected cancer cells. These results showed that colon cancer cells transfected with the retroviral vector encoding TIMP-2 inhibits the invasiveness in vitro and tumorigenicity in vivo.

• Asian Pacific Journal of Cancer Prevention
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• v.18 no.11
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• pp.2919-2923
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• 2017

Objective: Anthocyanins belong to a class of flavonoids, exhibiting antioxidant and anti-inflammatory actions have been reported to have anti-cancer effects. Here, we investigated whether anthocyanins can inhibit cancer cell proliferation, invasion, and angiogenesis in human lung cancer A549 cells, which are critically involved in cancer metastasis. Methods: We used anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs) which has been used in Korean folk medicine for the treatment of inflammatory diseases and cancers. We have performed cell proliferation assays, cell invasion assay, gelatin zymography, wound healing assay and western blotting to examine whether anthocyanins can inhibit cancer cell proliferation, invasion, and angiogenesis in A549 cells. Result: AIMs did not inhibit cancer cell proliferation on A549 cells. Also, AIMs suppressed cancer migration, and invasion by supressing MMP-2 and MMP-9 expression. The Immuno-blotting results also revealed that AIMs suppressed the proteins involved in cancer proliferation (COX-2, C-myc, cyclin D1), migration and invasion (MMP-2, MMP-9), anti-apoptosis (XIAP, and c-IAP2), adhesion and angiogenesis (ICAM-1, VEGF). Conclusion: This study demonstrates that the anthocyanins isolated from fruits of Vitis coignetiae Pulliat inhibit cancer proliferation, cancer migration, and invasion that is involve in cancer-metastasis. This study provides evidence that AIMs might have anti-cancer effects on human lung cancer.

• Journal of Ginseng Research
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• v.43 no.3
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• pp.488-495
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• 2019

Background: Timosaponin AIII (TA3) is a steroidal saponin extracted from Anemarrhena asphodeloides. Here, we investigated the anticancer effects of TA3 in MG63 human osteosarcoma cells. TA3 attenuates migration and invasion of MG63 cells via regulations of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, which are involved with cancer metastasis in various cancer cells. TA3 reduced enzymatic activities and transcriptional expressions of MMP-2 and MMP-9 in MG63 cells. TA3 also inhibited Src, focal adhesion kinase, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, ${\beta}-catenin$, and cAMP response element binding signaling, which regulate migration and invasion of cells. TA3 induced apoptosis of MG63 cells via regulations of caspase-3, caspase-7, and poly(ADP-ribose) polymerase (PARP). Then, we tested several ginsenosides to be used in combination with TA3 for the synergistic anticancer effects. We found that ginsenosides Rb1 and Rc have synergistic effects on TA3-induced apoptosis in MG63 cells. Methods: We investigated the anticancer effects of TA3 and synergistic effects of various ginseng saponins on TA3-induced apoptosis in MG63 cells. To test antimetastatic effects, we performed wound healing migration assay, Boyden chamber invasion assays, gelatin zymography assay, and Western blot analysis. Annexin V/PI staining apoptosis assay was performed to determine the apoptotic effect of TA3 and ginsenosides. Results: TA3 attenuated migration and invasion of MG63 cells and induced apoptosis of MG63 cells. Ginsenosides Rb1 and Rc showed the synergistic effects on TA3-induced apoptosis in MG63 cells. Conclusions: The results strongly suggest that the combination of TA3 and the two ginsenosides Rb1 and Rc may be a strong candidate for the effective antiosteosarcoma agent.

• The Korea Journal of Herbology
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• v.24 no.4
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• pp.77-86
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• 2009

Objectives : The proliferation and migration of human aortic smooth muscle cells (HASMC) in response to activation by various stimuli plays a critical role in the initiation and development of atherosclerosis. This study was conducted to examine the effects of Nelumbo nucifera leaves (NNL) on the proliferation and migration of HASMC. Additionally, the mechanisms involved in any observed effects were also evaluated. Methods : Apoptotic cells were measured by staining with FITC-labeled annexin V, followed by flow cytometric analysis. The expression level of apoptosis related proteins was confirmed by western blot. And MMP-9 activity was measured by gelatin zymography and MMP-9 expression was measured by ELISA Results : NNL completely inhibited the proliferation of HASMC via induction of the expression of apoptotic proteins including annexin V, cleaved poly ADP-ribose polymerase (PARP), and caspase-3 and -8. NNL treatment resulted in the release of cytochrome c into cytosol, a loss of mitochondrial membrane potential, a decrease in Bcl-2 and Bcl-xL and an increase in Bax expression. NNL also blocked HASMC migration via suppression of MMP-9. Conclusions : Taken together, these results indicate that NNL has the potential for use as an anti-artherosclerosis agent.

• Animal Bioscience
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• v.36 no.8
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• pp.1167-1179
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• 2023

Objective: Matrix metalloproteinases (MMPs) are a family of endoproteases produced by various tissues and cells and play important roles in angiogenesis, tissue repair, immune response, and endometrial remodeling. However, the expression and function of MMPs in the pig endometrium during the estrous cycle and pregnancy have not been fully elucidated. Thus, we determined the expression, localization, and regulation of MMP2, MMP8, MMP9, MMP12, and MMP13 in the endometrium throughout the estrous cycle and at the maternal-conceptus interface during pregnancy in pigs. Methods: Endometrial tissues during the estrous cycle and pregnancy and conceptus and chorioallantoic tissues during pregnancy were obtained and the expression of MMPs was analyzed. The effects of steroid hormones and cytokines on the expression of MMPs were determined in endometrial explant cultures. Results: Expression levels of MMP12 and MMP13 changed during the estrous cycle, while expression of MMP2, MMP9, MMP12, and MMP13 changed during pregnancy. Expression of MMP2, MMP8, and MMP13 mRNAs was cell type-specific at the maternal-conceptus interface. Gelatin zymography showed that enzymatically active MMP2 was present in endometrial tissues. In endometrial explant cultures, estradiol-17β induced the expression of MMP8 and MMP12, progesterone decreased the expression of MMP12, interleukin-1β increased the expression of MMP2, MMP8, MMP9, and MMP13, and interferon-γ increased the expression of MMP2. Conclusion: These results suggest that MMPs expressed in response to steroids and cytokines play an important role in the establishment and maintenance of pregnancy by regulating endometrial remodeling and processing bioactive molecules in pigs.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.3
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• pp.239-252
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• 2024

Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 ㎍/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 ㎍/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

• Tuberculosis and Respiratory Diseases
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• v.61 no.3
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• pp.256-264
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• 2006

Background: An acute lung injury(ALI) is characterized by the recruitment, activation, and apoptosis of inflammatory cells, numerous products released by inflammatory cells such as reactive oxygen species, inflammatory mediators, and a variety of proteolytic enzymes. It was reported that bacterial infections in diabetics showed impaired PMN functions such as reduced PMN respiratory burst and decreased microbicidal activity in inflamed tissue. However, the effect of the proteinase - inhibitor (MMP-9 vs TIMP-1) in ALI in diabetics is unclear. This study evaluated the differences in the expression of MMP-9 and TIMP-1 after the stimulation of endotoxin in a rat model. Methods: Six-week-old male Sprague-Dawley rats were classified into normal, DM, LPS and DM+LPS groups. The peripheral blood, BAL fluids, and lung tissues were obtained from individual rats. The MMP-9 activity was measured by gelatin zymography and the TIMP-1 level was measured by Western blotting. Results: The total BAL cells of the DM-LPS groups were significantly lower than the LPS groups (p < 0.01). The MMP-9 activities in the serum were higher in the DM+LPS groups than in the other groups. The MMP-9 activities in the BAL fluids were significantly higher in the DM+LPS group than in the normal and diabetic rats (p < 0.05). TIMP-1 expressions in the BAL fluids were significantly lower in the DM+LPS group than other groups (p < 0.05). The ratio between MMP-9 and TIMP-1 in the BAL fluids was significantly higher in the DM+LPS groups (p < 0.05). Conclusion: In ALI in diabetics the higher MMP-9 activity and lower TIMP-1 level are believed to prolonged and intensify the course of inflammation.