Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of matrix metalloproteinase 7 (MMP7) is increased in the human colorectal carcinomas, and correlates with malignant progression. However, its contribution to colon cancer pathogenesis is not understood thoroughly. To investigate the roles of MMP7 in colon cancer progression, we introduced an Mmp7 knockout mutation into the cis-Apc/Smad4 mutant mouse, a model of invasive colon cancer in which SMAD4-dependent TGF-beta family signaling is inactivated. We demonstrate here that lack of MMP7 reduces the number and size of tumors in the cis-Apc/Smad4 mice. On the other hand, MMP7-deficiency does not affect the depth of tumor invasion, number of stromal fibroblasts or levels of extracellular matrix components in the tumors. These results indicate that MMP7 is required for tumor formation, but not for the invasion or fibrosis of the colon cancer whose SMAD4-dependent TGF-beta family signaling is blocked.
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PMID:Matrix metalloproteinase 7 is required for tumor formation, but dispensable for invasion and fibrosis in SMAD4-deficient intestinal adenocarcinomas. 1900 10

Matrix metalloproteinase-9 (MMP-9) has been proposed to be an important modulator of atherosclerotic plaque vulnerability. We generated a transgenic (tg) model expressing human proMMP-9 in macrophages, using the scavenger receptor enhancer/promoter A. This model was crossed into the double Apoe/Timp-1 knockout background. After 16 weeks of a high-fat diet, there were no significant changes in plaque size in the proximal aortas between the four groups of the study population (Apoe(-/-), Apoe(-/-)/MMP-9tg, Apoe(-/-)/Timp-1(-/-), and Apoe(-/-)/MMP-9tg/Timp-1(-/-)), and, in the Timp-1 knockout background, MMP-9 transgenic mice and control littermates had similar micro-aneurysm formation. However, lesions in Apoe(-/-)/MMP-9tg/Timp-1(-/-) mice contained significantly more collagen compared to the three other groups (P<0.005). Culture supernatants from elicited Apoe(-/-)/MMP-9tg/Timp-1(-/-) macrophages contained higher levels of active TGF-beta than the three other groups (P<0.05), suggesting that augmented collagen deposition resulted from an increase in TGF-beta activation due to transgenic MMP-9 in the Timp-1(-/-) background. This study indicates that, in human atherosclerosis, increased MMP-9 activity could up-regulate collagen deposition, possibly through TGF-beta activation.
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PMID:Transgenic expression of matrix metalloproteinase-9 modulates collagen deposition in a mouse model of atherosclerosis. 1914 35

The interaction of fibroblast growth factor-inducible 14 (Fn14) and, its ligand tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to be important in wound healing of tissues. However, to our knowledge, expression and function of Fn14 in corneal myofibroblasts, which have a crucial role in wound healing of corneal stroma, has not been investigated. In this study, we investigated the expression and function of Fn14 in corneal myofibroblasts. Expression of Fn14 protein was assessed by flow cytometry. Corneal myofibroblasts showed strong expression of Fn14 protein, while keratocytes did not. TGF-beta(1) promoted the differentiation of keratocytes into corneal myofibroblasts, and induced Fn14 expression. These data reveal that keratocytes phenotype determines the level of Fn14 expression. ELISA was used to detect chemokines and matrix metalloproteinases in the supernatant of corneal myofibroblasts cultured with or without stimulation by TWEAK and/or TGF-beta(1). TWEAK increased the production of IL-8, MCP-1, and RANTES by corneal myofibroblasts via Fn14. TGF-beta(1) augmented the TWEAK-induced production of these chemokines. TWEAK also increased the production of MMP-1 and -3 by corneal myofibroblasts via Fn14, while TGF-beta(1) inhibited this effect of TWEAK on MMP production. TWEAK-induced phosphorylation of NF-kappaB and MAP kinase in corneal myofibroblasts. Furthermore, TWEAK partially inhibited the differentiation of keratocytes into corneal myofibroblasts promoted by TGF-beta(1). These data suggest that the Fn14/TWEAK system may have several roles in wound healing by corneal myofibroblasts. In the future, modulation of the TWEAK/Fn14 system may become a novel approach for control corneal wound healing.
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PMID:Expression and function of fibroblast growth factor-inducible 14 in human corneal myofibroblasts. 1934 12

Cognitive impairment (CI) and dementia are frequent and debilitating features associated with Parkinson's disease (PD). Formal neuropsychological examination is required to ascertain the degree and pattern of CI over the course of the disease. The use of different tools may explain heterogeneous data obtained from studies to date. Normative data for extensively used scales [Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination (MMSE)] is incomplete in PD populations. According to sample characteristics, statistical analyses, and methodological quality, 33 studies using scales not specific to PD (MDRS, MMSE, Cambridge Cognitive Assessment, FAB) or PD-specific scales (Mini-Mental Parkinson, Scales for Outcomes of Parkinson's disease-Cognition, Parkinson's Disease-Cognitive Rating Scale, and Parkinson Neuropsychometric Dementia Assessment) were eligible for the critical analysis of their appropriateness to assess cognition in PD. Of the four scales specifically designed for PD, the SCOPA-COG and the PD-CRS have undergone extensive and rigorous validation processes. While the SCOPA-COG mainly assesses "frontal-subcortical" cognitive defects, the PD-CRS also assesses "instrumental-cortical" functions, allowing better characterization of the different patterns of CI that may be present in PD from the earliest stages. The MMP and PANDA scales were designed as brief screening tests for CI and have not yet been subjected to extensive clinimetric evaluations. Further research on PD-specific tools seems mandatory to help establish accurate cut-off scores for the diagnosis of mild PDD, detect cognitive profiles more prone to the future development of dementia, and allow comparisons between different descriptive or interventional studies.
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PMID:Cognitive impairment in Parkinson's disease: tools for diagnosis and assessment. 1935 27

The muscle wound healing occurs in three overlapping phases: (1) degeneration and inflammation, (2) muscle regeneration, and (3) fibrosis. Simultaneously to injury cellular infiltration by neutrophils and macrophages occur, as well as cellular 'respiratory burst' via activation of the enzyme NADPH oxidase. When skeletal muscle is stretched or injured, myogenic satellite cells are activated to enter the cell cycle, divide, differentiate and fuse with muscle fibers to repair damaged regions and to enhance hypertrophy of muscle fibers. This process depends on nitric oxide (NO) production, metalloproteinase (MMP) activation and release of hepatocyte growth factor (HGF) from the extracellular matrix. Generation of a fibrotic scar tissue, with partial loss of function, can also occur, and seems to be dependent, at least in part, on local TGF-beta expression, which can be downregulated by NO. Hence, regeneration the muscle depends on the type and severity of the injury, the appropriate inflammatory response and on the balance of the processes of remodeling and fibrosis. It appears that in all these phases NO exerts a significant role. Better comprehension of this role, as well as of the participation of other important mediators, may lead to development of new treatment strategies trying to tip the balance in favor of greater regeneration over fibrosis, resulting in better functional recovery.
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PMID:Nitric oxide and repair of skeletal muscle injury. 1968 96

The optimal oxygen concentration for newborn resuscitation is still discussed. Oxygen administration during reoxygenation may induce short- and long-term pathologic changes via oxidative stress and has been associated to later childhood cancer. The aim was to study changes in oxidative stress-associated markers in liver and lung tissue of newborn pigs after acute hypoxia followed by reoxygenation for 30 min with 21, 40, or 100% oxygen compared with room air or to ventilation with 100% oxygen without preceding hypoxia. Nine hours after resuscitation, we found a dose-dependent increase in the matrix metalloproteinase gelatinase activity in liver tissue related to percentage oxygen supply by resuscitation (100% versus 21%; p = 0.002) pointing at more extensive tissue damage. Receiving 100% oxygen for 30 min without preceding hypoxia decreased the expression of VEGFR2 and TGFBR3 mRNA in liver tissue, but not in lung tissue. MMP-, VEGF-, and TGFbeta-superfamily are vital for the development, growth, and functional integrity of most tissues and our data rise concern about both short- and long-term consequences of even a brief hyperoxic exposure.
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PMID:Resuscitation of hypoxic newborn piglets with supplementary oxygen induces dose-dependent increase in matrix metalloproteinase-activity and down-regulates vital genes. 2001 Mar 14

Diabetic nephropathy characterized as mesangial fibrosis and glomerulosclerosis results in renal failure and end-stage renal diseases. Enhanced expression and secretion of connective tissue growth factor (CTGF) play an important role in the expansion of glomerular mesangial matrix mostly composed of type IV collagen. Isoliquiritigenin can prevent various renal injuries via its anti-inflammatory action. However, the effect of isoliquiritigenin on diabetic nephropathy has never been explored. The present study was to investigate whether nontoxic isoliquiritigenin inhibited high glucose (HG)-induced mesangial fibrosis by retarding formation of type IV collagen as well as CTGF in human mesangial cells (HRMC). Serum starved cells were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 days with and without 1-20 microM isoliquiritigenin. Exposure of cells to HG caused marked increases in collagen secretion and CTGF expression, which was dose-dependently reversed by isoliquiritigenin at the transcriptional levels. Additionally, isoliquiritigenin boosted HG-plummeted type matrix metalloproteinase-1 (MT-1 MMP) expression and dampened HG-elevated tissue inhibitor of MMP-2 (TIMP-2) expression, facilitating the degradation of mesangial matrix. Isoliquiritigenin inhibited HG-upregulated CTGF and TIMP-2 expression via disturbing TGF-beta1 signaling in HRMC, as evidenced by TGF-beta receptor I kinase (TGF-beta RI) inhibitor. HG-activated SMAD2 through autocrine TGF-beta signaling was repealed by > or =10 microM isoliquiritigenin. HG induced SMAD4 expression of HRMC and obliterated antagonistic SMAD7, whereas isoliquiritigenin suppressed induction of TGF-beta RII and TGF-beta RI with blunting their downstream SMAD signaling. The results demonstrate that the bioactive isoliquiritigenin in licorice diminished mesangial matrix accumulation in response to ambient HG through retarding TGF-beta1-SMAD signaling transduction. Therefore, isoliquiritigenin may be a potential therapeutic agent for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetic nephropathy due to longstanding diabetes mellitus.
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PMID:Isoliquiritigenin entails blockade of TGF-beta1-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. 2014 76

Diabetic nephropathy (DN) characterized as nephrotic syndrome and diffuse glomerulosclerosis can cause renal failure and end-stage kidney disease. Expansion of mesangial matrix around capillaries in the kidney glomeruli is a prominent feature of DN. This study investigated whether licorice extracts inhibited mesangial cell (MC) proliferation and matrix accumulation induced by high glucose (HG). Human renal MC were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 d in the presence of water or ethanol extracts from raw licorice (LW, LE) or roasted licorice (RLW, RLE). Non-polar components including glycyrrhetic acid were elevated during licorice roasting, whereas polar components soluble in water extracts were diminished. Exposure of cells to HG caused significant increases in collagen IV secretion and connective tissue growth factor (CTGF) expression, which was appeased by RLW and RLE at transcriptional levels. The inhibitory potency was high in the order of RLE > or = RLW > or = LE > > LW. Non-polar glycyrrhetic acid but not glycyrrhizin retarded HG-stimulated mesangial matrix deposition through diminishing CTGF expression. In addition, RLW and RLE but not LW modulated membrane type matrix metalloproteinase-1 (MT-1 MMP) expression, MMP-2 activity and tissue inhibitor of MMP-2 (TIMP-2), which facilitated the degradation of mesangial matrix. Furthermore, the augmented expression of CTGF and TIMP-2 in HG-exposed cells was mediated by Akt activation and TGF-beta/Smad signaling through PKCbeta2-responsive signaling pathways. However, HG-down-regulated MT-1 MMP expression was independent of activation of ERK1/2 and Akt when using their inhibitors of DB98059 (ERK1/2) and LY294002 (Akt) alone or in combination. These results demonstrate that extracts from roasted licorice may be highly potent therapeutic agents for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetes nephropathy due to longstanding diabetes mellitus.
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PMID:Roasted licorice extracts dampen high glucose-induced mesangial hyperplasia and matrix deposition through blocking Akt activation and TGF-beta signaling. 2038 13

The chemotactic effects of chemokines on cells has long been known, but it is now clear that chemokines also have much broader activities and are also involved in a number of disease pathologies, such as rheumatoid arthritis, cancer metastasis and other inflammatory processes. This study investigates the effects of four C-C chemokines, CCL2, CCL3, CCL4 and CCL5 either alone or in the presence of two regulatory cytokines TNF-alpha and TGF-beta and their effect on secretion of two matrix metalloproteases MMP, MMP-2 and MMP-9, and the expression of one membrane bound MMP, MMP-14, by a monocytic human cell line, MonoMac6. All four C-C chemokines were shown to be chemotactic, but only CCL2 and CCL4 had any significant stimulatory effect on MMP-9 and MMP-2, respectively. Both TNF-alpha and TGF-beta were found to divergently enhance MMP-9 and MMP-2 secretion respectively, with stimulation indexes of two and five respectively. Simultaneous treatment with TNF-alpha and chemokine resulted in up to a fifteen-fold stimulation of MMP-9 secretion and treatment with TGF-beta and chemokine resulted in up to a fifteen-fold stimulation of MMP-2 secretion, while TNF-alpha in combination with CCL4 stimulated MMP-14 expression five-fold. Chemokine receptor expression was also investigated using a calcium-sensitive dye and FACS analysis. CCL2, CCL3, and CCL5 all resulted in a detectable enhancement of cytoplasmic Ca2+concentration. CCL4 was unable to activate Ca2+ mobilization, despite the presence of CCR5, the receptor for CCL4. There appeared to be no correlation between MMP production and chemotaxis. The strong synergy between chemokines and cytokines and the enhanced production of MMP may signify the differential regulatory mechanisms of the two cytokines and chemokines in disease pathology.
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PMID:Divergent and synergistic regulation of matrix metalloprotease production by cytokines in combination with C-C chemokines. 2094 41


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