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Fulltext Role of Matrix Metalloproteinase-2 in the Development of Atherosclerosis among Patients with Coronary Artery Disease

Samah N, Ugusman A, Hamid AA, Sulaiman N, Aminuddin A

Mediators Inflamm, 2023;2023:9715114.
PMID: 37457745 DOI: 10.1155/2023/9715114

Coronary artery disease (CAD) is a caused by atherosclerotic plaque buildup in the coronary arteries that supply blood and oxygen to the heart. Matrix metalloproteinase (MMP) is a family of zinc-dependent endopeptidase that is involved in various stages of atherosclerosis as demonstrated in in vitro and in vivo studies. MMP-2 is associated with both stable and unstable atherosclerotic plaque formation. The current review aimed to identify the role of MMP-2 in atherosclerosis development among CAD patients. Literature search was conducted through four online databases and only studies that were published from 2018 until February 2023 were included. The risk of bias was assessed by using the Newcastle-Ottawa Scale. A total of 10,622 articles were initially identified, and only eight studies that fulfilled the selection criteria were included in this review. The results showed that MMP-2 levels and activity were higher in patients with unstable CAD than those with stable CAD and healthy subjects. There was a significant association between MMP-2 levels and cardiovascular disease with MMP-14 levels, which is a pro-MMP-2 activator. In addition, two single nucleotide polymorphisms of the MMP-2 gene (rs243865 and rs243866) were significantly associated with the development of atherosclerosis. In conclusion, MMP-2 plays a crucial role in the development of atherosclerosis among patients with CAD and could be a potential target for CAD therapy.

Matched MeSH terms: Matrix Metalloproteinase 2/genetics
Inhibition of angiogenesis and metastasis in colorectal cancer cell lines through KRAS-associated signaling pathways by 2-methoxy-6-undecyl-1,4-benzoquinone

Abd Rahman NI, Tham CL, Abd Hamid R

Chem Biol Interact, 2024 Aug 25;399:111151.
PMID: 39025287 DOI: 10.1016/j.cbi.2024.111151

Colorectal cancer (CRC), the third most prevalent cancer globally, presents formidable hurdles in treatment owing to factors such as therapeutic resistance and genetic mutations affecting primary drug targets. 2-methoxy-6-undecyl-1,4-benzoquinone (BQ), derived from Ardisia crispa roots, has emerged as a potent anti-inflammatory and anti-angiogenic compound with substantial potential, as evidenced by previous studies. This study aimed to explore the potential of BQ in suppressing angiogenesis and metastasis in the human CRC cell lines LoVo and HCT116. Various in vitro and in silico studies have been conducted to elucidate the potential pathway(s) of BQ. BQ was highly cytotoxic, with an IC50 of 7.01 ± 0.6 μM in HCT116 and 9.58 ± 0.8 μM in LoVo cells. Moreover, BQ induced notable apoptotic activity and suppressed migration, invasion, and adhesion in both cell lines. The inhibition of MMP-2 suggests the potential of BQ to impede extracellular matrix degradation and CRC cell metastasis. BQ inhibits the expression of key proteins involved in angiogenesis and metastasis, including VEGF-A, VEGF-C, BRAF, ERK, KRAS, PI3K, and AKT. Molecular docking simulations illustrated the robust binding of BQ to CRC protein receptors. BQ holds promise in impeding CRC progression by targeting angiogenesis and metastasis, particularly through inhibition of the KRAS/BRAF/ERK and KRAS/PI3K/AKT signaling pathways.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
(R)-(-)-Xanthorrhizol Inhibits the Migration and Invasion of Triple-Negative Breast Cancer Cells by Suppressing Matrix Metalloproteinases via the NF-κB Signaling Pathway

Al-Amin M, Fazalul Rahiman SS, Khairuddean M, Muhamad Salhimi S

Planta Med, 2024 Aug;90(10):785-791.
PMID: 38838716 DOI: 10.1055/a-2339-2633

(R)-(-)-xanthorrhizol is a bioactive sesquiterpenoid and major chemical constituent of Curcuma zanthorrhiza rhizomes. It was reported to have many pharmacological activities including nephroprotective, hepatoprotective, antimicrobial, anti-inflammatory, antioxidant, antihypertensive, antihyperglycemic, antiplatelet, estrogenic, and antiestrogenic properties. (R)-(-)-xanthorrhizol was also investigated for antiproliferative activity against many cancer cells including breast, lung, liver, ovarian, and colon cancer. It was also revealed to have a potential effect on TNBC cells MDA-MB-231. Considering the previous studies, this study has aimed to investigate the antimigratory and anti-invasive properties, as well as the possible molecular mechanisms, behind these properties. The findings of (R)-(-)-xanthorrhizol on MDA-MB-231 cell migration and invasion demonstrated significant inhibition at three different concentrations in a concentration-dependent manner, which was observed in the scratch, transwell migration, and invasion assays. Further investigation of the molecular mechanism using gelatin zymography revealed that (R)-(-)-xanthorrhizol prevented cell migration and invasion of breast cancer cells through the inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9 expression. Western blot analysis indicated that the inhibition of matrix metalloproteinases is possibly the result of the inhibition of phosphorylation in the NF-κB signaling pathway. These findings corroborate (R)-(-)-xanthorrhizol to proceed for the further studies as a possible future drug candidate for cancer patients.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
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 2/metabolism; Matrix Metalloproteinase 2/chemistry
Effect of trans-resveratrol on dexamethasone-induced changes in the expression of MMPs by human trabecular meshwork cells: Involvement of adenosine A1 receptors and NFkB

Mohd Nasir NA, Agarwal R, Krasilnikova A, Sheikh Abdul Kadir SH, Iezhitsa I

Eur J Pharmacol, 2020 Nov 15;887:173431.
PMID: 32758568 DOI: 10.1016/j.ejphar.2020.173431

Intraocular pressure (IOP) lowering in glaucomatous eyes is currently achieved mainly by improved aqueous outflow via alternate drainage pathways. However, the focus is now shifting to trabecular meshwork (TM), the site or major pathological changes including increased extracellular matrix (ECM) deposition and reduced matrix metalloproteinases (MMPs) secretion by TM cells. Trans-resveratrol was previously shown to lower IOP and reduce ECM deposition; however, the mechanisms of action remain unclear. Therefore, we determined the effect of trans-resveratrol on MMP-2 and -9 expression by human TM cells (HTMCs) in the presence of dexamethasone and whether it also affects adenosine A1 receptors (A1AR) expression and nuclear factor kappa B (NFkB) activation. We observed that trans-resveratrol, 12.5 μM, increased MMP-2 and -9 protein expression by HTMCs despite exposure to dexamethasone (1.89- and 1.53-fold, respectively; P 2 and -9 expression. It could be concluded that trans-resveratrol prevents dexamethasone-induced reduction in MMP-2 and -9 secretion by NFkB activation in HTMCs. This effect of trans-resveratrol is likely to involve increased A1AR expression.

Matched MeSH terms: Matrix Metalloproteinase 2
Fulltext Expression of osteopontin, matrix metalloproteinase-2 and -9 proteins in vascular instability in brain arteriovenous malformation

Anbarasen L, Lim J, Rajandram R, Mun KS, Sia SF

PeerJ, 2019;7:e7058.
PMID: 31275742 DOI: 10.7717/peerj.7058

Background: Matrix metalloproteinase (MMP)-2 and -9 are Osteopontin (OPN) dependent molecules implicated in the destabilization of blood vessels. OPN and MMPs have been studied in brain arteriovenous malformation (BAVM) patients' tissues and blood samples before intervention. In this study, we compared the serum level of these markers before and after treatment, as well as assessed their protein expressions in BAVM tissues to evaluate their roles in this disease.
Methodology: Serum samples from six BAVM patients and three control subjects were analyzed using enzyme-linked immunoabsorbent assay (ELISA) for OPN. A total of 10 BAVM patients and five control subjects were analyzed using Multiplex ELISA for MMPs. A total of 16 BAVM tissue samples and two normal brain tissue samples were analyzed using immunohistochemistry.
Result: MMP-2 and -9 were significantly higher in the serum of BAVM patients before and after treatment than in control patients. There were no significant differences of OPN and MMP-9 serum level in BAVM patients before and after treatment. MMP-2 showed a significant elevation after the treatment. Expression of OPN, MMP-2 and -9 proteins were seen in endothelial cells, perivascular cells and brain parenchyma of BAVM tissues.
Conclusion: Findings revealed that the level of MMP-2 and -9 in the serum correlated well with the expression in BAVM tissues in several cases. Knockdown studies will be required to determine the relationships and mechanisms of action of these markers in the near future. In addition, studies will be required to investigate the expression of these markers' potential applications as primary medical therapy targets for BAVM patients.

Matched MeSH terms: Matrix Metalloproteinase 2
Fulltext Matrix metalloproteinases and tissue inhibitors of metalloproteinases in the aqueous humour of patients with primary angle closure glaucoma - a quantitative study

Nga AD, Yap SL, Samsudin A, Abdul-Rahman PS, Hashim OH, Mimiwati Z

BMC Ophthalmol, 2014;14:33.
PMID: 24655889 DOI: 10.1186/1471-2415-14-33

Altered levels of specific matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the aqueous humour of primary open-angle glaucoma (POAG) eyes have been described. In this study, levels of specific MMPs and TIMPs in the aqueous humour of primary angle-closure glaucoma (PACG) eyes were measured and compared with those of POAG as well as non-glaucoma control eyes.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism*
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 2/metabolism
In vitro assessment of ribose modified two-step etch-and-rinse dentine adhesive

Daood U, Tsoi JKH, Neelakantan P, Matinlinna JP, Omar HAK, Al-Nabulsi M, et al.

Dent Mater, 2018 08;34(8):1175-1187.
PMID: 29779627 DOI: 10.1016/j.dental.2018.05.005

OBJECTIVE: Collagen fibrils aid in anchoring resin composite restorations to the dentine substrate. The aim of the study was to investigate effect of non-enzymatic glycation on bond strength and durability of demineralized dentine specimens in a modified two-step etch-and-rinse dentine adhesive.
METHODS: Dentine surfaces were etched with 37% phosphoric acid, bonded with respective in vitro ethanol and acetone adhesives modified with (m/m, 0, 1%, 2% and 3% ribose), restored with restorative composite-resin, and sectioned into resin-dentine slabs and beams to be stored for 24h or 12 months in artificial saliva. Bond-strength testing was performed with bond failure analysis. Pentosidine assay was performed on demineralized ribose modified dentine specimens with HPLC sensitive fluorescent detection. The structural variations of ribose-modified dentine were analysed using TEM and human dental pulpal cells were used for cell viability. Three-point bending test of ribose-modified dentine beams were performed and depth of penetration of adhesives evaluated with micro-Raman spectroscopy. The MMP-2 and cathepsin K activities in ribose-treated dentine powder were also quantified using ELISA. Bond strength data was expressed using two-way ANOVA followed by Tukey's test. Paired T tests were used to analyse the specimens for pentosidine crosslinks. The modulus of elasticity and dentinal MMP-2 and cathepsin K concentrations was separately analyzed using one-way ANOVA.
RESULTS: The incorporation of RB in the experimental two-step etch-and-rinse adhesive at 1% improved the adhesive bond strength without adversely affecting the degree of polymerisation. The newly developed adhesive increases the resistance of dentine collagen to degradation by inhibiting endogenous matrix metalloproteinases and cysteine cathepsins. The application of RB to acid-etched dentine helps maintain the mechanical properties.
SIGNIFICANCE: The incorporation of 1%RB can be considered as a potential candidate stabilizing resin dentine bond.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
Fulltext Concentration-Dependent Multi-Potentiality of L-Arginine: Antimicrobial Effect, Hydroxyapatite Stability, and MMPs Inhibition

Bijle MN, Pichika MR, Mak KK, Parolia A, Babar MG, Yiu C, et al.

Molecules, 2021 Oct 31;26(21).
PMID: 34771014 DOI: 10.3390/molecules26216605

This study's objective was to examine L-arginine (L-arg) supplementation's effect on mono-species biofilm (Streptococcus mutans/Streptococcus sanguinis) growth and underlying enamel substrates. The experimental groups were 1%, 2%, and 4% arg, and 0.9% NaCl was used as the vehicle control. Sterilised enamel blocks were subjected to 7-day treatment with test solutions and S. mutans/S. sanguinis inoculum in BHI. Post-treatment, the treated biofilms stained for live/dead bacterial cells were analysed using confocal microscopy. The enamel specimens were analysed using X-ray diffraction crystallography (XRD), Raman spectroscopy (RS), and transmission electron microscopy (TEM). The molecular interactions between arg and MMP-2/MMP-9 were determined by computational molecular docking and MMP assays. With increasing arg concentrations, bacterial survival significantly decreased (p < 0.05). The XRD peak intensity with 1%/2% arg was significantly higher than with 4% arg and the control (p < 0.05). The bands associated with the mineral phase by RS were significantly accentuated in the 1%/2% arg specimens compared to in other groups (p < 0.05). The TEM analysis revealed that 4% arg exhibited an ill-defined shape of enamel crystals. Docking of arg molecules to MMPs appears feasible, with arg inhibiting MMP-2/MMP-9 (p < 0.05). L-arginine supplementation has an antimicrobial effect on mono-species biofilm. L-arginine treatment at lower (1%/2%) concentrations exhibits enamel hydroxyapatite stability, while the molecule has the potential to inhibit MMP-2/MMP-9.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
Differential effects of activated protein C on synovial fibroblasts in response to hypoxia and normoxia

Park YG, Choi J, Song I, Park SY, Seol JW, Jackson CJ

Sains Malaysiana, 2017;46:1895-1902.

Rheumatoid arthritis (RA) is a chronic disease characterized by inflammation of the joints and their lining or synovium. Previous studies showed that the synovium in RA patients is more hypoxic than normal synovium. Activated protein C (APC) has anticoagulant and anti-inflammatory effects and is highly expressed in the joints of RA patients. We examined the effect of APC on RA and normal synovial fibroblasts under hypoxic conditions. Human synovial fibroblasts were isolated from the synovial tissues of RA patients and normal controls and cells were exposed to recombinant APC under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions. Cell proliferation was measured using MTT assays. Cell lysates and conditioned media were collected and assayed for matrix metalloproteinase (MMP)-2, MMP-9 and p38 using zymography and western blots. Proliferation of both normal and RA synovial fibroblasts dose-dependently increased after APC treatment in normoxic conditions. Under hypoxia, APC enhanced RA cell proliferation but had no effect on normal fibroblasts. MMP-2 production and activation were significantly augmented by APC in both cell types under normoxia and hypoxia conditions. However, activated MMP-2 was more reduced in cells under hypoxia than normoxia. APC substantially reduced the phosphorylation of p38 in normal and RA synovial fibroblasts under hypoxia. No difference in p38 phosphorylation was observed under normoxia. The receptor for APC, endothelial protein C receptor (EPCR), was elevated in normal fibroblasts under hypoxic conditions whereas in RA cells, EPCR was highly expressed under both normoxic and hypoxic conditions. We found that hypoxia enhanced the effect of APC on RA synovial fibroblasts through activation of MMP2 and inhibition of p38 phosphorylation. Our results suggested that APC may suppress joint destruction and progression of inflammation in a hypoxic RA environment.

Matched MeSH terms: Matrix Metalloproteinase 2
Fulltext Cellular prion protein and γ-synuclein overexpression in LS 174T colorectal cancer cell drives endothelial proliferation-to-differentiation switch

Ong SH, Goh KW, Chieng CK, Say YH

PeerJ, 2018;6:e4506.
PMID: 29527422 DOI: 10.7717/peerj.4506

Background: Tumor-induced angiogenesis is an imperative event in pledging new vasculature for tumor metastasis. Since overexpression of neuronal proteins gamma-synuclein (γ-Syn) and cellular prion protein (PrPC) is always detected in advanced stages of cancer diseases which involve metastasis, this study aimed to investigate whether γ-Syn or PrPCoverexpression in colorectal adenocarcinoma, LS 174T cells affects angiogenesis of endothelial cells, EA.hy 926 (EA).
Methods: EA cells were treated with conditioned media (CM) of LS 174T-γ-Syn or LS 174T-PrP, and their proliferation, invasion, migration, adhesion and ability to form angiogenic tubes were assessed using a range of biological assays. To investigate plausible background mechanisms in conferring the properties of EA cells above, nitrite oxide (NO) levels were measured and the expression of angiogenesis-related factors was assessed using a human angiogenesis antibody array.
Results: EA proliferation was significantly inhibited by LS 174T-PrP CM whereas its telomerase activity was reduced by CM of LS 174T-γ-Syn or LS 174T-PrP, as compared to EA incubated with LS 174T CM. Besides, LS 174T-γ-Syn CM or LS 174T-PrP CM inhibited EA invasion and migration in Boyden chamber assay. Furthermore, LS 174T-γ-Syn CM significantly inhibited EA migration in scratch wound assay. Gelatin zymography revealed reduced secretion of MMP-2 and MMP-9 by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM. In addition, cell adhesion assay showed lesser LS 174T-γ-Syn or LS 174T-PrP cells adhered onto EA, as compared to LS 174T. In tube formation assay, LS 174T-γ-Syn CM or LS 174T-PrP CM induced EA tube formation. Increased NO secretion by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM was also detected. Lastly, decreased expression of pro-angiogenic factors like CXCL16, IGFBP-2 and amphiregulin in LS 174T-γ-Syn CM or LS 174T-PrP CM was detected using the angiogenesis antibody array.
Discussion: These results suggest that overexpression of γ-Syn or PrPCcould possibly be involved in colorectal cancer-induced angiogenesis by inducing an endothelial proliferation-differentiation switch. NO could be the main factor in governing this switch, and modulation on the secretion patterns of angiogenesis-related proteins could be the strategy of colorectal cancer cells overexpressing γ-Syn or PrPCin ensuring this transition.

Matched MeSH terms: Matrix Metalloproteinase 2
Fulltext Mechanism of Hepatoprotective Effect of Boesenbergia rotunda in Thioacetamide-Induced Liver Damage in Rats

Salama SM, Abdulla MA, Alrashdi AS, Hadi AH

Evid Based Complement Alternat Med, 2013;2013:157456.
PMID: 23997791 DOI: 10.1155/2013/157456

Background. Researchers focused on developing traditional therapies as pharmacological medicines to treat liver cirrhosis. Objectives. Evaluating the hepatoprotective activity of Boesenbergia rotunda (BR) rhizome ethanolic extract on thioacetamide-induced liver cirrhosis in rats. Methods. Male Sprague-Dawley rats were intraperitoneally injected with 200 mg/kg TAA 3 times/week and daily oral administration of 250 mg/kg, 500 mg/kg of BR extract, and 50 mg/kg of the reference drug Silymarin for 8 weeks. At the end of the experiment, Masson's trichrome staining was used to measure the degree of liver fibrosis. Hepatic antioxidant enzymes (CAT and GPx), nitrotyrosine, cytochrome (P450 2E1), matrix metalloproteinase (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), and urinary 8-hydroxyguanosine were measured. Serum levels of transforming growth factor TGF- β 1, nuclear transcription factor NF- κ B, proinflammatory cytokine IL-6, and caspase-3 were evaluated. Serum protein expression and immunohistochemistry of proapoptotic Bax and antiapoptotic Bcl-2 proteins were measured and confirmed by immunohistochemistry of Bax, Bcl-2, and proliferating cell nuclear antigen (PCNA). Results. BR treatment improved liver histopathology, immunohistochemistry, and biochemistry, triggered apoptosis, and inhibited cytokines, extracellular matrix proteins, and hepatocytes proliferation. Conclusion. Liver cirrhosis progression can be inhibited by the antioxidant and anti-inflammatory activities of BR ethanolic extract while preserving the normal liver status.

Matched MeSH terms: Matrix Metalloproteinase 2
Topical trans-resveratrol ameliorates steroid-induced anterior and posterior segment changes in rats

Razali N, Agarwal R, Agarwal P, Tripathy M, Kapitonova MY, Kutty MK, et al.

Exp Eye Res, 2016 Feb;143:9-16.
PMID: 26424219 DOI: 10.1016/j.exer.2015.09.014

Steroid-induced hypertension and glaucoma is associated with increased extracellular meshwork (ECM) deposition in trabecular meshwork (TM). Previous studies have shown that single drop application of trans-resveratrol lowers IOP in steroid-induced ocular hypertensive (SIOH) rats. This IOP lowering is attributed to activation of adenosine A1 receptors, which may lead to increased matrix metalloproteinase (MMP)-2 activity. This study evaluated the effect of repeated topical application of trans-resveratrol for 21 days in SIOH animals on IOP, changes in MMP-2 level in aqueous humor, trabecular meshwork and retinal morphology and retinal redox status. We observed that treatment with trans-resveratrol results in significant and sustained IOP reduction in SIOH rats. This IOP reduction is associated with significantly higher aqueous humor total MMP-2 level; significantly reduced TM thickness and increased number of TM cells. Treatment with trans-resveratrol also significantly increased ganglion cell layer (GCL) thickness, the linear cell density in the GCL and inner retina thickness; and significantly reduced retinal oxidative stress compared to the SIOH vehicle-treated group. In conclusion, repeated dose topical application of trans-resveratrol produces sustained IOP lowering effect, which is associated with increased level of aqueous humor MMP-2, normalization of TM and retinal morphology and restoration of retinal redox status.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
Fulltext In vitro and in vivo anti-angiogenic activities of Panduratin A

Lai SL, Cheah SC, Wong PF, Noor SM, Mustafa MR

PLoS One, 2012;7(5):e38103.
PMID: 22666456 DOI: 10.1371/journal.pone.0038103

BACKGROUND: Targeting angiogenesis has emerged as an attractive and promising strategy in anti-cancer therapeutic development. The present study investigates the anti-angiogenic potential of Panduratin A (PA), a natural chalcone isolated from Boesenbergia rotunda by using both in vitro and in vivo assays.
METHODOLOGY/PRINCIPAL FINDINGS: PA exerted selective cytotoxicity on human umbilical vein endothelial cells (HUVECs) with IC(50) value of 6.91 ± 0.85 µM when compared to human normal fibroblast and normal liver epithelial cells. Assessment of the growth kinetics by cell impedance-based Real-Time Cell Analyzer showed that PA induced both cytotoxic and cytostatic effects on HUVECs, depending on the concentration used. Results also showed that PA suppressed VEGF-induced survival and proliferation of HUVECs. Furthermore, endothelial cell migration, invasion, and morphogenesis or tube formation demonstrated significant time- and dose-dependent inhibition by PA. PA also suppressed matrix metalloproteinase-2 (MMP-2) secretion and attenuated its activation to intermediate and active MMP-2. In addition, PA suppressed F-actin stress fiber formation to prevent migration of the endothelial cells. More importantly, anti-angiogenic potential of PA was also evidenced in two in vivo models. PA inhibited neo-vessels formation in murine Matrigel plugs, and angiogenesis in zebrafish embryos.
CONCLUSIONS/SIGNIFICANCE: Taken together, our study demonstrated the distinctive anti-angiogenic properties of PA, both in vitro and in vivo. This report thus reveals another biological activity of PA in addition to its reported anti-inflammatory and anti-cancer activities, suggestive of PA's potential for development as an anti-angiogenic agent for cancer therapy.

Matched MeSH terms: Matrix Metalloproteinase 2/metabolism
Fulltext Panduratin A, a possible inhibitor in metastasized A549 cells through inhibition of NF-kappa B translocation and chemoinvasion

Cheah SC, Lai SL, Lee ST, Hadi AH, Mustafa MR

Molecules, 2013 Jul 24;18(8):8764-78.
PMID: 23887718 DOI: 10.3390/molecules18088764

In the present study, we investigated the effects of panduratin A (PA), isolated from Boesenbergia rotunda, on apoptosis and chemoinvasion in A549 human non-small cell lung cancer cells. Activation of the executioner procaspase-3 by PA was found to be dose-dependent. Caspase-3 activity was significantly elevated at the 5 µg/mL level of PA treatment and progressed to a maximal level. However, no significant elevated level was detected on procaspase-8. These findings suggest that PA activated caspase-3 but not caspase-8. Numerous nuclei of PA treated A549 cells stained brightly by anti-cleaved PARP antibody through High Content Screening. This result further confirmed that PA induced apoptotic cell death was mediated through activation of caspase-3 and eventually led to PARP cleavage. Treatment of A549 cells with PA resulted in a strong inhibition of NF-κB activation, which was consistent with a decrease in nuclear levels of NF-κB/p65 and NF-κB/p50 and the elevation of p53 and p21. Besides that, we also showed that PA significantly inhibited the invasion of A549 cells in a dose-dependent manner through reducing the secretion of MMP-2 of A549 cells gelatin zymography assay. Our findings not only provide the effects of PA, but may also be important in the design of therapeutic protocols that involve targeting of either p53 or NF-κB.

Matched MeSH terms: Matrix Metalloproteinase 2
Fulltext Formononetin: A Review of Its Anticancer Potentials and Mechanisms

Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al.

Front Pharmacol, 2019;10:820.
PMID: 31402861 DOI: 10.3389/fphar.2019.00820

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Matched MeSH terms: Matrix Metalloproteinase 2

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