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  1. MMP-9: biomarker for abdominal aneurysm
    Affirul CA, Azim IM, Hanafiah H, Nor Azmi K, Rozman Z
    Clin Ter, 2013;164(6):e479-83.
    PMID: 24424226 DOI: 10.7417/CT.2013.1640
    INTRODUCTION: Matrix Metalloproteinase 9 (MMP-9) has been shown to express significantly on organ tissue culture in Abdominal Aortic Aneurysm (AAA) patients. Prior studies have shown the correlation between MMP-9 concentration levels with AAA raising the probability of its usage as a biomarker in AAA disease. However, results of previous studies have been conflicting. The purpose of this study is to identify the correlation between MMP-9 concentration levels with AAA disease and further define the utility as a biomarker for our center population.

    MATERIALS AND METHODS: This is prospective controlled trial. Peripheral venous blood sample is obtained from 20 patients with AAA and 36 normal control subjects. MMP-9 concentration levels were determined by an enzyme-linked immunosorbent assay and compared with subjects abdominal ultrasonography or computed tomography of abdomen.

    RESULTS: Mean (± SE) MMP-9 was 23.94 ± 0.60 ng/mL in normal control subjects and 21.39 ± 1.03 ng/mL in patients with AAAs (p ← 0.05 versus normal control subjects). MMP-9 correlate significantly with AAA (p=0.004). There was no correlation of MMP-9 levels with age, gender, or other risk factors. The cutoff point is 12.54 for aorta size <3.0 cm. The sensitivity and specificity of MMP-9 were 60% and 64% respectively.

    CONCLUSIONS: MMP-9 levels correlate significantly with AAA with a cutoff point of 12.54. However, the utility of MMP-9 as a diagnostic test is limited due to low sensitivity and specificity. An elevated MMP-9 has limited use to predict the presence of AAA (positive predictive value: 60%) and a normal MMP-9 level was insufficient to determine the absence of AAA (negative predictive value: 36.1%).

    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism*
  2. Fulltext Antimetastatic and anti-inflammatory potentials of essential oil from edible Ocimum sanctum leaves
    Manaharan T, Thirugnanasampandan R, Jayakumar R, Ramya G, Ramnath G, Kanthimathi MS
    ScientificWorldJournal, 2014;2014:239508.
    PMID: 25431779 DOI: 10.1155/2014/239508
    Antimetastatic and anti-inflammatory activities of Ocimum sanctum essential oil (OSEO) have been assessed in this study. OSEO at the concentration of 250 μg/mL and above showed a significant ((*) P < 0.05) decrease in the number of migrated cancer cells. In addition, OSEO at concentration of 250 μg/mL and above suppressed MMP-9 activity in lipopolysaccharide (LPS) induced inflammatory cells. A dose-dependent downregulation of MMP-9 expression was observed with the treatment of OSEO compared to the control. Our findings indicate that OSEO has both antimetastatic and anti-inflammatory potentials, advocating further investigation for clinical applications in the treatment of inflammation associated cancer.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  3. 2-Methoxy-1,4-Naphthoquinone (MNQ) suppresses the invasion and migration of a human metastatic breast cancer cell line (MDA-MB-231)
    Liew K, Yong PV, Lim YM, Navaratnam V, Ho AS
    Toxicol In Vitro, 2014 Apr;28(3):335-9.
    PMID: 24291160 DOI: 10.1016/j.tiv.2013.11.008
    Metastasis contributes to the escalating mortality rate among cancer patients worldwide. The search for novel and more effective anti-metastatic agent is crucial owing to the lack of anticancer drugs that can successfully combat metastasis. Hence, this study aims to examine the effects of 2-Methoxy-1,4-Naphthoquinone (MNQ) towards the metastasis of MDA-MB-231 cells. In invasion assays, the number of cells permeating across a Matrigel barrier was found to be decreased in a dose-dependent manner upon treatment with MNQ (0-7.5 μM). In wound-healing migration assays, MNQ exhibited dose-dependent inhibition of cell migration in which significant reduction in the zone of closure was observed as compared to untreated controls. Furthermore, the proteolytic activity of a pivotal metastatic mediator, matrix metalloproteinase-9 (MMP-9) was also downregulated by MNQ as determined by gelatin zymography. This study reports for the first time, the ability of MNQ to inhibit the invasion and migration characteristics of a highly metastatic MDA-MB-231 cancer cell line.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism*
  4. Effect of dexamethasone on the expression of MMPs, adenosine A1 receptors and NFKB by human trabecular meshwork cells
    Mohd Nasir NA, Agarwal R, Krasilnikova A, Sheikh Abdul Kadir SH, Iezhitsa I
    J Basic Clin Physiol Pharmacol, 2020 Jul 22;31(6).
    PMID: 32697755 DOI: 10.1515/jbcpp-2019-0373
    Objectives Steroid-induced ocular hypertension and glaucoma are associated with extracellular matrix remodeling at the trabecular meshwork (TM) of the eye due to reduced secretion of matrix metalloproteinases (MMPs), a family of enzymes regulating extracellular matrix proteolysis. Several biological functions of steroids are known to involve regulation of adenosine A1 receptors (A1AR) and nuclear factor kappa B (NFKB). Since MMPs expression in TM has been shown to be regulated by A1AR as well as transcription factors, it is likely that dexamethasone-induced changes in aqueous humor dynamics involve reduced MMP and A1AR expression and reduced NFKB activation. Hence, the current study investigated the association of dexamethasone-induced reduction in MMP secretion with reduced NFKB activation and A1AR expression. Methods Human trabecular meshwork cells (HTMCs) were characterized by estimating myocilin and alpha smooth muscle actin expression and then were treated with dexamethasone 100 nM for 2, 5 and 7 days. The MMP secretion was estimated in culture media using Western blot. Immunocytochemistry (ICC) and ELISA were done to investigate the effect of dexamethasone on NFKB phosphorylation. A1AR expression in HTMCs was determined using Western blot and ELISA. Results Dexamethasone caused a significant reduction in both MMP-2 and -9 expression compared to untreated group after five and seven days but not after two days of culture. Significantly reduced phosphorylated NFKB and A1AR protein levels were detected in dexamethasone treated compared to vehicle treated HTMCs after five days of culture. Conclusions Dexamethasone reduces MMP-2 and -9 secretion by HTMCs and this effect of dexamethasone is associated with reduced NFKB phosphorylation and A1AR expression.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  5. Fulltext Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study (Part II)
    Hariono M, Rollando R, Yoga I, Harjono A, Suryodanindro A, Yanuar M, et al.
    Molecules, 2021 Mar 08;26(5).
    PMID: 33800366 DOI: 10.3390/molecules26051464
    In our previous work, the partitions (1 mg/mL) of Ageratum conyzoides (AC) aerial parts and Ixora coccinea (IC) leaves showed inhibitions of 94% and 96%, respectively, whereas their fractions showed IC50 43 and 116 µg/mL, respectively, toward Matrix Metalloproteinase9 (MMP9), an enzyme that catalyzes a proteolysis of extracellular matrix. In this present study, we performed IC50 determinations for AC n-hexane, IC n-hexane, and IC ethylacetate partitions, followed by the cytotoxicity study of individual partitions against MDA-MB-231, 4T1, T47D, MCF7, and Vero cell lines. Successive fractionations from AC n-hexane and IC ethylacetate partitions led to the isolation of two compounds, oxytetracycline (OTC) and dioctyl phthalate (DOP). The result showed that AC n-hexane, IC n-hexane, and IC ethylacetate partitions inhibit MMP9 with their respective IC50 as follows: 246.1 µg/mL, 5.66 µg/mL, and 2.75 × 10-2 µg/mL. Toward MDA-MB-231, 4T1, T47D, and MCF7, AC n-hexane demonstrated IC50 2.05, 265, 109.70, and 2.11 µg/mL, respectively, whereas IC ethylacetate showed IC50 1.92, 57.5, 371.5, and 2.01 µg/mL, respectively. The inhibitions toward MMP9 by OTC were indicated by its IC50 18.69 µM, whereas DOP was inactive. A molecular docking study suggested that OTC prefers to bind to PEX9 rather than its catalytic domain. Against 4T1, OTC showed inhibition with IC50 414.20 µM. In conclusion, this study furtherly supports the previous finding that AC and IC are two herbals with potential to be developed as triple-negative anti-breast cancer agents.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism*
  6. Enzymatic inhibitory activity of Ficus deltoidea leaf extract on matrix metalloproteinase-2, 8 and 9
    Abu Bakar AR, Ripen AM, Merican AF, Mohamad SB
    Nat Prod Res, 2019 Jun;33(12):1765-1768.
    PMID: 29394875 DOI: 10.1080/14786419.2018.1434631
    Dysregulation of matrix metalloproteinases (MMPs) activity is known in many pathological conditions with which most of the conditions are related to elevate MMPs activities. Ficus deltoidea (FD) is a plant known for its therapeutic properties. In order to evaluate the therapeutic potential of FD leaf extract, we study the enzymatic inhibition properties of FD leaf extract and its major bioactive compounds (vitexin and isovitexin) on a panel of MMPs (MMP-2, MMP-8 and MMP-9) using experimental and computational approaches. FD leaf extract and its major bioactive compounds showed pronounced inhibition activity towards the MMPs tested. Computational docking analysis revealed that vitexin and isovitexin bind to the active site of the three tested MMPs. We also evaluated the cytotoxicity and cell migration inhibition activity of FD leaf extract in the endothelial EA.hy 926 cell line. Conclusively, this study provided additional information on the potential of FD leaf extract for therapeutical application.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  7. Fulltext The Molecular Targets and Anti-Invasive Effects of 2,6-bis-(4-hydroxyl-3methoxybenzylidine) cyclohexanone or BHMC in MDA-MB-231 Human Breast Cancer Cells
    Harun SNA, Israf DA, Tham CL, Lam KW, Cheema MS, Md Hashim NF
    Molecules, 2018 Apr 10;23(4).
    PMID: 29642589 DOI: 10.3390/molecules23040865
    In order to metastasize, tumor cells need to migrate and invade the surrounding tissues. It is important to identify compound(s) capable of disrupting the metastasis of invasive cancer cells, especially for hindering invadopodia formation, so as to provide anti-metastasis targeted therapy. Invadopodia are thought to be specialized actin-rich protrusions formed by highly invasive cancer cells to degrade the extracellular matrix (ECM). A curcuminoid analogue known as 2,6-bis-(4-hydroxy-3-methoxybenzylidine)cyclohexanone or BHMC has shown good potential in inhibiting inflammation and hyperalgesia. It also possesses an anti-tumor effects on 4T1 murine breast cancer cells in vivo. However, there is still a lack of empirical evidence on how BHMC works in preventing human breast cancer invasion. In this study, we investigated the effect of BHMC on MDA-MB-231 breast cancer cells and its underlying mechanism of action to prevent breast cancer invasion, especially during the formation of invadopodia. All MDA-MB-231 cells, which were exposed to the non-cytotoxic concentrations of BHMC, expressed the proliferating cell nuclear antigen (PCNA), which indicate that the anti-proliferative effects of BHMC did not interfere in the subsequent experiments. By using a scratch migration assay, transwell migration and invasion assays, we determined that BHMC reduces the percentage of migration and invasion of MDA-MB-231 cells. The gelatin degradation assay showed that BHMC reduced the number of cells with invadopodia. Analysis of the proteins involved in the invasion showed that there is a significant reduction in the expressions of Rho guanine nucleotide exchange factor 7 (β-PIX), matrix metalloproteinase-9 (MMP-9), and membrane type 1 matrix metalloproteinase (MT1-MMP) in the presence of BHMC treatment at 12.5 µM. Therefore, it can be postulated that BHMC at 12.5 µM is the optimal concentration for preventing breast cancer invasion.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  8. Fulltext Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?
    Agarwal R, Agarwal P
    Exp Biol Med (Maywood), 2017 Feb;242(4):374-383.
    PMID: 27798117 DOI: 10.1177/1535370216675065
    Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  9. Fulltext Interleukins, laminin and Epstein - Barr virus latent membrane protein 1 (EBV LMP1) promote metastatic phenotype in nasopharyngeal carcinoma
    Chew MM, Gan SY, Khoo AS, Tan EL
    BMC Cancer, 2010;10:574.
    PMID: 20964870 DOI: 10.1186/1471-2407-10-574
    Nasopharyngeal carcinoma (NPC) is a type of neoplasm that is highly prevalent in East Asia and Africa with Epstein-Barr virus (EBV), genetic, and dietary factors implicated as possible aetiologic factors. Previous studies suggested the association of certain cytokines with the invasion and metastatic properties of NPC. The present study examined the roles of EBV latent membrane protein-1 (LMP1), interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta 1 (TGF-β1) and laminin in the regulation of matrix-metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) in NPC. The effects of these factors on bmi-1, an oncogene, and ngx6, a tumour suppressor gene, were also investigated.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  10. Strobilanthes crispus inhibits migration, invasion and metastasis in breast cancer
    Baraya YS, Wong KK, Yaacob NS
    J Ethnopharmacol, 2019 Apr 06;233:13-21.
    PMID: 30594607 DOI: 10.1016/j.jep.2018.12.041
    ETHNOPHARMACOLOGICAL RELEVANCE: Strobilanthes crispus (L.) Blume, locally known in Malaysia as "Pecah kaca" or "Jin batu", has been traditionally used for treatment of various ailments including cancer. We previously demonstrated that a standardized bioactive subfraction of S. crispus, termed as F3, possessed potent anticancer effects in both in vitro and in vivo breast cancer models.

    AIM OF THE STUDY: To investigate the potential of F3 from S. crispus to prevent metastasis in breast cancer.

    MATERIALS AND METHODS: The antimetastatic effects of F3 were first investigated on murine 4T1 and human MDA-MB-231 breast cancer cell (BCC) lines using cell proliferation, wound healing and invasion assays. A 4T1-induced mouse mammary carcinoma model was then used to determine the expression of metastasis tumor markers, epithelial (E)-cadherin, matrix metalloproteinase (MMP)-9, mucin (MUC)-1, nonepithelial (N)-cadherin, Twist, vascular endothelial growth factor (VEGF) and vimentin, using immunohistochemistry, following oral treatment with F3 for 30 days.

    RESULTS: Significant growth arrest was observed with F3 IC50 values of 84.27 µg/ml (24 h) and 74.41 µg/ml (48 h) for MDA-MB-231, and 87.35 µg/ml (24 h) and 78.75 µg/ml (48 h) for 4T1 cells. F3 significantly inhibited migration of both BCC lines at 50 μg/ml for 24 h (p = 0.018 and p = 0.015, respectively). Similarly, significant inhibition of invasion was demonstrated in 4T1 (75 µg/ml, p = 0.016) and MDA-MB-231 (50 µg/ml, p = 0.040) cells compared to the untreated cultures. F3 treatment resulted in reduced tumor growth compared to untreated mice (p 9, MUC1, N-cadherin, Twist, VEGF and vimentin in comparison with the TM (p 9, MUC1, N-cadherin, Twist, VEGF and vimentin expression in breast cancer.

    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  11. Fulltext Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study
    Hariono M, Rollando R, Karamoy J, Hariyono P, Atmono M, Djohan M, et al.
    Molecules, 2020 Oct 14;25(20).
    PMID: 33066411 DOI: 10.3390/molecules25204691
    Matrix metalloproteinase9 (MMP9) is known to be highly expressed during metastatic cancer where most known potential inhibitors failed in the clinical trials. This study aims to select local plants in our state, as anti-breast cancer agent with hemopexin-like domain of MMP9 (PEX9) as the selective protein target. In silico screening for PEX9 inhibitors was performed from our in house-natural compound database to identify the plants. The selected plants were extracted using methanol and then a step-by-step in vitro screening against MMP9 was performed from its crude extract, partitions until fractions using FRET-based assay. The partitions were obtained by performing liquid-liquid extraction on the methanol extract using n-hexane, ethylacetate, n-butanol, and water representing nonpolar to polar solvents. The fractions were made from the selected partition, which demonstrated the best inhibition percentage toward MMP9, using column chromatography. Of the 200 compounds screened, 20 compounds that scored the binding affinity -11.2 to -8.1 kcal/mol toward PEX9 were selected as top hits. The binding of these hits were thoroughly investigated and linked to the plants which they were reported to be isolated from. Six of the eight crude extracts demonstrated inhibition toward MMP9 with the IC50 24 to 823 µg/mL. The partitions (1 mg/mL) of Ageratum conyzoides aerial parts and Ixora coccinea leaves showed inhibition 94% and 96%, whereas their fractions showed IC50 43 and 116 µg/mL, respectively toward MMP9. Using MTT assay, the crude extract of Ageratum exhibited IC50 22 and 229 µg/mL against 4T1 and T47D cell proliferations, respectively with a high safety index concluding its potential anti-breast cancer from herbal.
    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
  12. A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL-40/Interleukin-13 Receptor α2 Axis
    van Sleen Y, Jiemy WF, Pringle S, van der Geest KSM, Abdulahad WH, Sandovici M, et al.
    Arthritis Rheumatol, 2021 12;73(12):2327-2337.
    PMID: 34105308 DOI: 10.1002/art.41887
    OBJECTIVE: Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA.

    METHODS: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).

    RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation.

    CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.

    Matched MeSH terms: Matrix Metalloproteinase 9/metabolism
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