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Mindmap on MMP-9
There is an ongoing thread on MMP-9 at the ALSTDI forum: http://www.als.net/forum/yaf_postst53505_MMP9-why-motor-neurons.aspx (requires registration on the said forum).

 

  1. Z Cavdar, S Ozbal, A Celik, Bu Ergur, E Guneli, C Ural, T Camsari and Ga Guner.
    The effects of alpha-lipoic acid on MMP-2 and MMP-9 activities in a rat renal ischemia and re-perfusion model.. Biotechnic & histochemistry : official publication of the Biological Stain Commission 89(4):304–14, May 2014.
    Abstract Abstract Matrix metalloproteinases (MMPs) are enzymes that are responsible for degradation of extracellular matrix (ECM); they are involved in the pathogenesis of ischemia-re-perfusion (I-R) injury. We investigated the possible preventive effect of alpha-lipoic acid (LA) in a renal I-R injury model in rats by assessing its reducing effect on the expression and activation of MMP-2 and MMP-9 induced by I-R. Rats were assigned to four groups: control, sham-operated, I-R (saline, i.p.) and I-R+ LA (100 mg/kg, i.p.). After a right nephrectomy, I-R was induced by clamping the left renal pedicle for 1 h, followed by 6 h re-perfusion. In the sham group, a right nephrectomy was performed and left renal pedicles were dissected without clamping and the entire left kidney was excised after 6 h. LA pretreatment was started 30 min prior to induction of ischemia. Injury to tubules was evaluated using light and electron microscopy. The expressions of MMP-2 and MMP-9 were determined by immunohistochemistry and their activities were analyzed by gelatin zymography. Serum creatinine was measured using a quantitative kit based on the Jaffe colorimetric technique. Malondialdehyde (MDA) and glutathione (GSH) were analyzed using high performance liquid chromatography. Tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 were assessed using enzyme-linked immunosorbent assay (ELISA). I-R caused tubular dilatation and brush border loss. LA decreased both renal dysfunction and abnormal levels of MDA and GSH during I-R. Moreover, LA decreased significantly both MMP-2 and MMP-9 expressions and activations during I-R. TIMP-1 and TIMP-2 levels were increased significantly by LA administration. LA modulated increased MMP-2 and MMP-9 activities and decreased TIMP-1 and TIMP-2 levels during renal I-R.
    URL, DOI BibTeX

    @article{Cavdar2014,
    	abstract = "Abstract Matrix metalloproteinases (MMPs) are enzymes that are responsible for degradation of extracellular matrix (ECM); they are involved in the pathogenesis of ischemia-re-perfusion (I-R) injury. We investigated the possible preventive effect of alpha-lipoic acid (LA) in a renal I-R injury model in rats by assessing its reducing effect on the expression and activation of MMP-2 and MMP-9 induced by I-R. Rats were assigned to four groups: control, sham-operated, I-R (saline, i.p.) and I-R+ LA (100 mg/kg, i.p.). After a right nephrectomy, I-R was induced by clamping the left renal pedicle for 1 h, followed by 6 h re-perfusion. In the sham group, a right nephrectomy was performed and left renal pedicles were dissected without clamping and the entire left kidney was excised after 6 h. LA pretreatment was started 30 min prior to induction of ischemia. Injury to tubules was evaluated using light and electron microscopy. The expressions of MMP-2 and MMP-9 were determined by immunohistochemistry and their activities were analyzed by gelatin zymography. Serum creatinine was measured using a quantitative kit based on the Jaffe colorimetric technique. Malondialdehyde (MDA) and glutathione (GSH) were analyzed using high performance liquid chromatography. Tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 were assessed using enzyme-linked immunosorbent assay (ELISA). I-R caused tubular dilatation and brush border loss. LA decreased both renal dysfunction and abnormal levels of MDA and GSH during I-R. Moreover, LA decreased significantly both MMP-2 and MMP-9 expressions and activations during I-R. TIMP-1 and TIMP-2 levels were increased significantly by LA administration. LA modulated increased MMP-2 and MMP-9 activities and decreased TIMP-1 and TIMP-2 levels during renal I-R.",
    	author = "Cavdar, Z and Ozbal, S and Celik, A and Ergur, Bu and Guneli, E and Ural, C and Camsari, T and Guner, Ga",
    	doi = "10.3109/10520295.2013.847498",
    	issn = "1473-7760",
    	journal = "Biotechnic \& histochemistry : official publication of the Biological Stain Commission",
    	month = "may",
    	number = 4,
    	pages = "304--14",
    	pmid = 24160412,
    	title = "{The effects of alpha-lipoic acid on MMP-2 and MMP-9 activities in a rat renal ischemia and re-perfusion model.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24160412",
    	volume = 89,
    	year = 2014
    }
    
  2. M T Kato, A Bolanho, B L Zarella, T Salo, L Tjäderhane and M A R Buzalaf.
    Sodium fluoride inhibits MMP-2 and MMP-9.. Journal of dental research 93(1):74–7, January 2014.
    Abstract The importance of fluoride (F) in preventing dental caries by favorably interfering in the demineralization-remineralization processes is well-established, but its ability to inhibit matrix metalloproteinases (MMPs), which could also help to prevent dentin caries, has not been investigated. This study assessed the ability of F to inhibit salivary and purified human gelatinases MMPs-2 and -9. Saliva was collected from 10 healthy individuals. Pooled saliva was centrifuged, and supernatants were incubated for 1 hr at 37°C and subjected to zymography. Sodium fluoride (50-275 ppm F) was added to the incubation buffer. The reversibility of the inhibition of MMPs-2 and -9 by NaF was tested by the addition of NaF (250-5,000 ppm F) to the incubation buffer, after which an additional incubation was performed in the absence of F. F decreased the activities of pro- and active forms of salivary and purified human MMPs in a dose-response manner. Purified gelatinases were completely inhibited by 200 ppm F (IC50 = 100 and 75 ppm F for MMPs-2 and -9, respectively), and salivary MMP-9 by 275 ppm F (IC50 = 200 ppm F). Inhibition was partially reversible at 250-1,500 ppm F, but was irreversible at 5,000 ppm F. This is the first study to describe the ability of NaF to inhibit MMPs completely.
    URL, DOI BibTeX

    @article{Kato2014,
    	abstract = "The importance of fluoride (F) in preventing dental caries by favorably interfering in the demineralization-remineralization processes is well-established, but its ability to inhibit matrix metalloproteinases (MMPs), which could also help to prevent dentin caries, has not been investigated. This study assessed the ability of F to inhibit salivary and purified human gelatinases MMPs-2 and -9. Saliva was collected from 10 healthy individuals. Pooled saliva was centrifuged, and supernatants were incubated for 1 hr at 37°C and subjected to zymography. Sodium fluoride (50-275 ppm F) was added to the incubation buffer. The reversibility of the inhibition of MMPs-2 and -9 by NaF was tested by the addition of NaF (250-5,000 ppm F) to the incubation buffer, after which an additional incubation was performed in the absence of F. F decreased the activities of pro- and active forms of salivary and purified human MMPs in a dose-response manner. Purified gelatinases were completely inhibited by 200 ppm F (IC50 = 100 and 75 ppm F for MMPs-2 and -9, respectively), and salivary MMP-9 by 275 ppm F (IC50 = 200 ppm F). Inhibition was partially reversible at 250-1,500 ppm F, but was irreversible at 5,000 ppm F. This is the first study to describe the ability of NaF to inhibit MMPs completely.",
    	author = {Kato, M T and Bolanho, A and Zarella, B L and Salo, T and Tj\"{a}derhane, L and Buzalaf, M A R},
    	doi = "10.1177/0022034513511820",
    	issn = "1544-0591",
    	journal = "Journal of dental research",
    	keywords = "Adult,Cariostatic Agents,Cariostatic Agents: administration \& dosage,Cariostatic Agents: pharmacology,Dose-Response Relationship, Drug,Electrophoresis, Polyacrylamide Gel,Enzyme Precursors,Enzyme Precursors: antagonists \& inhibitors,Humans,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: drug effects,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: drug effects,Matrix Metalloproteinase Inhibitors,Matrix Metalloproteinase Inhibitors: administratio,Matrix Metalloproteinase Inhibitors: pharmacology,Saliva,Saliva: enzymology,Salivary Proteins and Peptides,Salivary Proteins and Peptides: antagonists \& inhi,Sodium Fluoride,Sodium Fluoride: administration \& dosage,Sodium Fluoride: pharmacology,Temperature,Time Factors,Young Adult",
    	month = "jan",
    	number = 1,
    	pages = "74--7",
    	pmid = 24196489,
    	title = "{Sodium fluoride inhibits MMP-2 and MMP-9.}",
    	url = "http://jdr.sagepub.com/content/93/1/74",
    	volume = 93,
    	year = 2014
    }
    
  3. Artem Kaplan, Krista J Spiller, Christopher Towne, Kevin C Kanning, Ginn T Choe, Adam Geber, Turgay Akay, Patrick Aebischer and Christopher E Henderson.
    Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.. Neuron 81(2):333–48, January 2014.
    Abstract Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration.
    URL, DOI BibTeX

    @article{Kaplan2014,
    	abstract = "Selective neuronal loss is the hallmark of neurodegenerative diseases. In patients with amyotrophic lateral sclerosis (ALS), most motor neurons die but those innervating extraocular, pelvic sphincter, and slow limb muscles exhibit selective resistance. We identified 18 genes that show >10-fold differential expression between resistant and vulnerable motor neurons. One of these, matrix metalloproteinase-9 (MMP-9), is expressed only by fast motor neurons, which are selectively vulnerable. In ALS model mice expressing mutant superoxide dismutase (SOD1), reduction of MMP-9 function using gene ablation, viral gene therapy, or pharmacological inhibition significantly delayed muscle denervation. In the presence of mutant SOD1, MMP-9 expressed by fast motor neurons themselves enhances activation of ER stress and is sufficient to trigger axonal die-back. These findings define MMP-9 as a candidate therapeutic target for ALS. The molecular basis of neuronal diversity thus provides significant insights into mechanisms of selective vulnerability to neurodegeneration.",
    	author = "Kaplan, Artem and Spiller, Krista J and Towne, Christopher and Kanning, Kevin C and Choe, Ginn T and Geber, Adam and Akay, Turgay and Aebischer, Patrick and Henderson, Christopher E",
    	doi = "10.1016/j.neuron.2013.12.009",
    	issn = "1097-4199",
    	journal = "Neuron",
    	keywords = "Action Potentials,Action Potentials: genetics,Action Potentials: physiology,Age Factors,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Cholera Toxin,Cholera Toxin: metabolism,DNA-Binding Proteins,DNA-Binding Proteins: metabolism,Dependovirus,Dependovirus: genetics,Disease Models, Animal,Gene Expression Regulation,Gene Expression Regulation: genetics,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: deficiency,Matrix Metalloproteinase 9: metabolism,Mice,Mice, Inbred C57BL,Mice, Transgenic,Motor Neurons,Motor Neurons: metabolism,Muscle Denervation,Muscle, Skeletal,Muscle, Skeletal: pathology,Muscle, Skeletal: physiopathology,Neurodegenerative Diseases,Neurodegenerative Diseases: genetics,Neurodegenerative Diseases: pathology,Phosphopyruvate Hydratase,Phosphopyruvate Hydratase: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Transcription Factors,Transcription Factors: metabolism,Vesicular Acetylcholine Transport Proteins,Vesicular Acetylcholine Transport Proteins: metabo",
    	language = "English",
    	month = "jan",
    	number = 2,
    	pages = "333--48",
    	pmid = 24462097,
    	publisher = "Elsevier",
    	title = "{Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.}",
    	url = "http://www.cell.com/article/S0896627313011392/fulltext",
    	volume = 81,
    	year = 2014
    }
    
  4. Mayank Chaturvedi and Leszek Kaczmarek.
    Mmp-9 inhibition: a therapeutic strategy in ischemic stroke.. Molecular neurobiology 49(1):563–73, 2014.
    Abstract Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood-brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia.
    URL, DOI BibTeX

    @article{Chaturvedi2014,
    	abstract = "Ischemic stroke is a leading cause of disability worldwide. In cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood-brain barrier (BBB) opening leading to cerebral edema, and hemorrhagic transformation. Moreover, the tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in ischemic stroke. Hence, combination therapies of MMP-9 inhibitor along with tPA can be beneficial in ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on ischemic stroke, commonly used models of ischemic stroke and a role of MMP-9 in ischemia. In next part, the literature is organized as various approaches which have proven neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as minocycline, new chemical entities like DP-b99, and finally other approaches like therapeutic hypothermia.",
    	author = "Chaturvedi, Mayank and Kaczmarek, Leszek",
    	doi = "10.1007/s12035-013-8538-z",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chaturvedi, Kaczmarek - 2014 - Mmp-9 inhibition a therapeutic strategy in ischemic stroke.pdf:pdf",
    	issn = "1559-1182",
    	journal = "Molecular neurobiology",
    	month = "",
    	number = 1,
    	pages = "563--73",
    	pmid = 24026771,
    	title = "{Mmp-9 inhibition: a therapeutic strategy in ischemic stroke.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3918117\&tool=pmcentrez\&rendertype=abstract",
    	volume = 49,
    	year = 2014
    }
    
  5. Deep Sankar Rudra, Uttam Pal, Nakul Chandra Maiti, Russel J Reiter and Snehasikta Swarnakar.
    Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site.. Journal of pineal research 54(4):398–405, May 2013.
    Abstract The zinc-dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP-9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP-9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP-9 inhibitors including an indole scaffold were recently reported in an X-ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP-9 function. Gelatin zymographic analysis showed a significant reduction in pro- and active MMP-9 activity in vitro in a dose- and time-dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (\~50%) MMP-9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP-9. Atomic-level interaction between melatonin and MMP-9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP-9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP-9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP-9-mediated inflammatory signals.
    URL, DOI BibTeX

    @article{Rudra2013,
    	abstract = "The zinc-dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP-9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP-9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP-9 inhibitors including an indole scaffold were recently reported in an X-ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP-9 function. Gelatin zymographic analysis showed a significant reduction in pro- and active MMP-9 activity in vitro in a dose- and time-dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (\~{}50\%) MMP-9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP-9. Atomic-level interaction between melatonin and MMP-9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP-9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP-9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP-9-mediated inflammatory signals.",
    	author = "Rudra, Deep Sankar and Pal, Uttam and Maiti, Nakul Chandra and Reiter, Russel J and Swarnakar, Snehasikta",
    	doi = "10.1111/jpi.12034",
    	issn = "1600-079X",
    	journal = "Journal of pineal research",
    	month = "may",
    	number = 4,
    	pages = "398--405",
    	pmid = 23330737,
    	title = "{Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23330737",
    	volume = 54,
    	year = 2013
    }
    
  6. Delphine Stephan, Oualid Sbai, Jing Wen, Pierre-Olivier Couraud, Chaim Putterman, Michel Khrestchatisky and Sophie Desplat-Jégo.
    TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier.. Journal of neuroinflammation 10:9, January 2013.
    Abstract BACKGROUND: The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells. METHODS: In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model. RESULTS: We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model. CONCLUSIONS: Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.
    URL, DOI BibTeX

    @article{Stephan2013,
    	abstract = "BACKGROUND: The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells. METHODS: In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model. RESULTS: We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model. CONCLUSIONS: Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.",
    	author = "Stephan, Delphine and Sbai, Oualid and Wen, Jing and Couraud, Pierre-Olivier and Putterman, Chaim and Khrestchatisky, Michel and Desplat-J\'{e}go, Sophie",
    	doi = "10.1186/1742-2094-10-9",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Stephan et al. - 2013 - TWEAKFn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier.pdf:pdf",
    	issn = "1742-2094",
    	journal = "Journal of neuroinflammation",
    	keywords = "Blood-Brain Barrier,Blood-Brain Barrier: pathology,Blood-Brain Barrier: physiology,Cell Line, Tumor,Cell Survival,Cell Survival: physiology,Endothelium, Vascular,Endothelium, Vascular: pathology,Endothelium, Vascular: physiology,Human Umbilical Vein Endothelial Cells,Human Umbilical Vein Endothelial Cells: pathology,Human Umbilical Vein Endothelial Cells: physiology,Humans,Models, Neurological,Receptors, Tumor Necrosis Factor,Receptors, Tumor Necrosis Factor: physiology,Signal Transduction,Signal Transduction: physiology,Tumor Necrosis Factors,Tumor Necrosis Factors: physiology",
    	month = "jan",
    	pages = 9,
    	pmid = 23320797,
    	title = "{TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3570290\&tool=pmcentrez\&rendertype=abstract",
    	volume = 10,
    	year = 2013
    }
    
  7. Xianghua He, Lifang Zhang, Xiaoli Yao, Jing Hu, Lihua Yu, Hua Jia, Ran An, Zhuolin Liu and Yanming Xu.
    Association studies of MMP-9 in Parkinson's disease and amyotrophic lateral sclerosis.. PloS one 8(9):e73777, 2013.
    Abstract {Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(-1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(-1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(-1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506-3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95% CI 1.233-3.796
    URL, DOI BibTeX

    @article{He2013,
    	abstract = "{Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(-1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(-1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(-1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95\% CI 1.506-3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95\% CI 1.233-3.796",
    	p = "",
    	author = "He, Xianghua and Zhang, Lifang and Yao, Xiaoli and Hu, Jing and Yu, Lihua and Jia, Hua and An, Ran and Liu, Zhuolin and Xu, Yanming",
    	doi = "10.1371/journal.pone.0073777",
    	editor = "Oreja-Guevara, Celia",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/He et al. - 2013 - Association studies of MMP-9 in Parkinson's disease and amyotrophic lateral sclerosis.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Research Article",
    	month = "",
    	number = 9,
    	pages = "e73777",
    	pmid = 24040066,
    	publisher = "Public Library of Science",
    	title = "{Association studies of MMP-9 in Parkinson's disease and amyotrophic lateral sclerosis.}",
    	url = "http://dx.plos.org/10.1371/journal.pone.0073777",
    	volume = 8,
    	year = 2013
    }
    
  8. M Hemshekhar, M Sebastin Santhosh, K Sunitha, R M Thushara, K Kemparaju, K S Rangappa and K S Girish.
    A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status.. Biochimie 94(12):2723–33, December 2012.
    Abstract Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-$\kappa$B pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-$\alpha$, IL-1$\beta$, NF-$\kappa$B, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.
    URL, DOI BibTeX

    @article{Hemshekhar2012,
    	abstract = "Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15\% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-$\kappa$B pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-$\alpha$, IL-1$\beta$, NF-$\kappa$B, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.",
    	author = "Hemshekhar, M and {Sebastin Santhosh}, M and Sunitha, K and Thushara, R M and Kemparaju, K and Rangappa, K S and Girish, K S",
    	doi = "10.1016/j.biochi.2012.08.013",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hemshekhar et al. - 2012 - A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage.pdf:pdf",
    	issn = "1638-6183",
    	journal = "Biochimie",
    	keywords = "Acid Phosphatase,Acid Phosphatase: antagonists \& inhibitors,Acid Phosphatase: metabolism,Animals,Antioxidants,Antioxidants: metabolism,Arthritis, Experimental,Arthritis, Experimental: blood,Arthritis, Experimental: complications,Arthritis, Experimental: prevention \& control,Blotting, Western,Bone Resorption,Bone Resorption: metabolism,Bone Resorption: prevention \& control,Carotenoids,Carotenoids: administration \& dosage,Carotenoids: pharmacology,Cartilage, Articular,Cartilage, Articular: drug effects,Cartilage, Articular: metabolism,Cartilage, Articular: pathology,Cathepsin D,Cathepsin D: antagonists \& inhibitors,Cathepsin D: metabolism,Cytokines,Cytokines: blood,Dietary Supplements,Glutathione,Glutathione: blood,Hyaluronoglucosaminidase,Hyaluronoglucosaminidase: blood,Inflammation,Inflammation Mediators,Inflammation Mediators: blood,Inflammation: etiology,Inflammation: metabolism,Inflammation: prevention \& control,Isoenzymes,Isoenzymes: antagonists \& inhibitors,Isoenzymes: metabolism,Liver,Liver: drug effects,Liver: enzymology,Matrix Metalloproteinase 13,Matrix Metalloproteinase 13: blood,Matrix Metalloproteinase 3,Matrix Metalloproteinase 3: blood,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: blood,Rats,Rats, Wistar,Superoxide Dismutase,Superoxide Dismutase: metabolism",
    	month = "dec",
    	number = 12,
    	pages = "2723--33",
    	pmid = 22939988,
    	title = "{A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0300908412003379",
    	volume = 94,
    	year = 2012
    }
    
  9. Hongli Li, Hao Xu and Baogui Sun.
    Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-$\kappa$B signaling in human arterial smooth muscle cells.. Molecular medicine reports 6(4):774–8, October 2012.
    Abstract Matrix metalloproteinases (MMPs) are critical to vascular smooth muscle cell migration in vivo. The dysregulation of MMPs is involved in the pathogenesis of abnormal arterial remodeling, aneurysm formation and atherosclerotic plaque instability. It has been confirmed that lipopolysaccharides (LPS) constitute a strong risk factor for the development of atherosclerosis. In this study, we aimed to determine a potential mechanism of LPS on MMP-9 expression in human arterial smooth muscle cells (HASMCs). RT-PCR analysis was used to detect MMP-9 mRNA expression and western blot analysis was performed to examine MMP-9 protein expression. An electrophoretic mobility shift assay was also employed to determine NF-$\kappa$B binding activity. Results showed that LPS induced MMP-9 mRNA and protein expression in HASMCs in a TLR4-dependent manner. Notably, upon blocking the NF-$\kappa$B binding with pyrrolidine dithiocarbamate, it was demonstrated that the expression of MMP-9 by LPS occurs through TLR4/NF-$\kappa$B pathways. It was concluded that LPS induced MMP-9 expression through the TLR4/NF-$\kappa$B pathway. Thus, the TLR4/NF-$\kappa$B pathway may be involved in the pathogenesis of atherosclerosis.
    URL, DOI BibTeX

    @article{Li2012,
    	abstract = "Matrix metalloproteinases (MMPs) are critical to vascular smooth muscle cell migration in vivo. The dysregulation of MMPs is involved in the pathogenesis of abnormal arterial remodeling, aneurysm formation and atherosclerotic plaque instability. It has been confirmed that lipopolysaccharides (LPS) constitute a strong risk factor for the development of atherosclerosis. In this study, we aimed to determine a potential mechanism of LPS on MMP-9 expression in human arterial smooth muscle cells (HASMCs). RT-PCR analysis was used to detect MMP-9 mRNA expression and western blot analysis was performed to examine MMP-9 protein expression. An electrophoretic mobility shift assay was also employed to determine NF-$\kappa$B binding activity. Results showed that LPS induced MMP-9 mRNA and protein expression in HASMCs in a TLR4-dependent manner. Notably, upon blocking the NF-$\kappa$B binding with pyrrolidine dithiocarbamate, it was demonstrated that the expression of MMP-9 by LPS occurs through TLR4/NF-$\kappa$B pathways. It was concluded that LPS induced MMP-9 expression through the TLR4/NF-$\kappa$B pathway. Thus, the TLR4/NF-$\kappa$B pathway may be involved in the pathogenesis of atherosclerosis.",
    	author = "Li, Hongli and Xu, Hao and Sun, Baogui",
    	doi = "10.3892/mmr.2012.1010",
    	issn = "1791-3004",
    	journal = "Molecular medicine reports",
    	keywords = "Antioxidants,Antioxidants: pharmacology,Cells, Cultured,Humans,Lipopolysaccharides,Lipopolysaccharides: toxicity,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: metabolism,Myocytes, Smooth Muscle,Myocytes, Smooth Muscle: cytology,Myocytes, Smooth Muscle: drug effects,Myocytes, Smooth Muscle: metabolism,NF-kappa B,NF-kappa B: metabolism,Protein Binding,Protein Binding: drug effects,Pyrrolidines,Pyrrolidines: pharmacology,RNA, Messenger,RNA, Messenger: metabolism,Signal Transduction,Thiocarbamates,Thiocarbamates: pharmacology,Toll-Like Receptor 4,Toll-Like Receptor 4: metabolism",
    	month = "oct",
    	number = 4,
    	pages = "774--8",
    	pmid = 22842850,
    	title = "{Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-$\kappa$B signaling in human arterial smooth muscle cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22842850",
    	volume = 6,
    	year = 2012
    }
    
  10. Rich Everson and Jason S Hauptman.
    From the bench to the bedside: Brain-machine interfaces in spinal cord injury, the blood-brain barrier, and neurodegeneration, using the hippocampus to improve cognition, metabolism, and epilepsy, and understanding axonal death.. Surgical neurology international 3(1):108, January 2012.
    URL, DOI BibTeX

    @article{Everson2012,
    	annote = "nf-kB -> mmp-9",
    	author = "Everson, Rich and Hauptman, Jason S",
    	doi = "10.4103/2152-7806.101002",
    	issn = "2152-7806",
    	journal = "Surgical neurology international",
    	language = "en",
    	month = "jan",
    	number = 1,
    	pages = 108,
    	pmid = 23087824,
    	publisher = "Medknow Publications and Media Pvt. Ltd.",
    	title = "{From the bench to the bedside: Brain-machine interfaces in spinal cord injury, the blood-brain barrier, and neurodegeneration, using the hippocampus to improve cognition, metabolism, and epilepsy, and understanding axonal death.}",
    	url = "http://www.surgicalneurologyint.com/article.asp?issn=2152-7806;year=2012;volume=3;issue=1;spage=108;epage=108;aulast=Everson",
    	volume = 3,
    	year = 2012
    }
    
  11. Ross Vlahos, Peter A B Wark, Gary P Anderson and Steven Bozinovski.
    Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.. PloS one 7(3):e33277, January 2012.
    Abstract BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD. METHODS: Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated. RESULTS: Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation. CONCLUSIONS: As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.
    URL, DOI BibTeX

    @article{Vlahos2012,
    	abstract = "BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD. METHODS: Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated. RESULTS: Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation. CONCLUSIONS: As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.",
    	author = "Vlahos, Ross and Wark, Peter A B and Anderson, Gary P and Bozinovski, Steven",
    	doi = "10.1371/journal.pone.0033277",
    	editor = "Hartl, Dominik",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Vlahos et al. - 2012 - Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Aged,Aged, 80 and over,Animals,Disease Progression,Drug Resistance,Female,Glucocorticoids,Glucocorticoids: pharmacology,Humans,Inflammation,Inflammation: metabolism,Leukocyte Elastase,Leukocyte Elastase: metabolism,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Mice,Mice, Inbred BALB C,Middle Aged,Neutrophil Activation,Neutrophil Activation: drug effects,Neutrophil Activation: immunology,Neutrophils,Neutrophils: drug effects,Neutrophils: enzymology,Pulmonary Disease, Chronic Obstructive,Pulmonary Disease, Chronic Obstructive: enzymology",
    	month = "jan",
    	number = 3,
    	pages = "e33277",
    	pmid = 22413009,
    	publisher = "Public Library of Science",
    	title = "{Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.}",
    	url = "http://dx.plos.org/10.1371/journal.pone.0033277",
    	volume = 7,
    	year = 2012
    }
    
  12. Hui-Hsin Wang, Hsi-Lung Hsieh and Chuen-Mao Yang.
    Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9.. Journal of cellular physiology 226(9):2244–56, September 2011.
    Abstract The deleterious effects of endothelin-1 (ET-1) in the central nervous system (CNS) include disturbance of water homeostasis and blood-brain barrier (BBB) integrity. In the CNS, ischemic injury elicits ET-1 release from astrocytes, behaving through G-protein coupled ET receptors. These considerations raise the question of whether ET-1 influences cellular functions of astrocytes, the major cell type that provides structural and functional support for neurons. Uncontrolled nitric oxide (NO) production has been implicated in sterile brain insults, neuroinflammation, and neurodegenerative diseases, which involve astrocyte activation and neuronal death. However, the detailed mechanisms of ET-1 action related to NO release on rat brain astrocytes (RBA-1) remain unknown. In this study, we demonstrate that exposure of astrocytes to ET-1 results in the inducible nitric oxide synthase (iNOS) up-regulation, NO production, and matrix metalloproteinase-9 (MMP-9) activation in astrocytes. The data obtained with Western blot, reverse transcription-PCR (RT-PCR), and immunofluorescent staining analyses showed that ET-1-induced iNOS expression and NO production were mediated through an ET(B)-dependent transcriptional activation. Engagement of G(i/o)–and G(q) -coupled ET(B) receptors by ET-1 led to activation of c-Src-dependent phosphoinositide 3-kinase (PI3K)/Akt and p42/p44 mitogen-activated protein kinase (MAPK) and then activated transcription factor nuclear factor-$\kappa$B (NF-$\kappa$B). The activated NF-$\kappa$B was translocated into nucleus and thereby promoted iNOS gene transcription. Ultimately, NO production stimulated by ET-1 enhanced the migration of astrocytes through the tyrosine nitration of MMP-9. Taken together, these results suggested that in astrocytes, activation of NF-$\kappa$B by ET(B)-dependent c-Src, PI3K/Akt, and p42/p44 MAPK signalings is necessary for ET-1-induced iNOS gene up-regulation.
    URL, DOI BibTeX

    @article{Wang2011,
    	abstract = "The deleterious effects of endothelin-1 (ET-1) in the central nervous system (CNS) include disturbance of water homeostasis and blood-brain barrier (BBB) integrity. In the CNS, ischemic injury elicits ET-1 release from astrocytes, behaving through G-protein coupled ET receptors. These considerations raise the question of whether ET-1 influences cellular functions of astrocytes, the major cell type that provides structural and functional support for neurons. Uncontrolled nitric oxide (NO) production has been implicated in sterile brain insults, neuroinflammation, and neurodegenerative diseases, which involve astrocyte activation and neuronal death. However, the detailed mechanisms of ET-1 action related to NO release on rat brain astrocytes (RBA-1) remain unknown. In this study, we demonstrate that exposure of astrocytes to ET-1 results in the inducible nitric oxide synthase (iNOS) up-regulation, NO production, and matrix metalloproteinase-9 (MMP-9) activation in astrocytes. The data obtained with Western blot, reverse transcription-PCR (RT-PCR), and immunofluorescent staining analyses showed that ET-1-induced iNOS expression and NO production were mediated through an ET(B)-dependent transcriptional activation. Engagement of G(i/o)--and G(q) -coupled ET(B) receptors by ET-1 led to activation of c-Src-dependent phosphoinositide 3-kinase (PI3K)/Akt and p42/p44 mitogen-activated protein kinase (MAPK) and then activated transcription factor nuclear factor-$\kappa$B (NF-$\kappa$B). The activated NF-$\kappa$B was translocated into nucleus and thereby promoted iNOS gene transcription. Ultimately, NO production stimulated by ET-1 enhanced the migration of astrocytes through the tyrosine nitration of MMP-9. Taken together, these results suggested that in astrocytes, activation of NF-$\kappa$B by ET(B)-dependent c-Src, PI3K/Akt, and p42/p44 MAPK signalings is necessary for ET-1-induced iNOS gene up-regulation.",
    	author = "Wang, Hui-Hsin and Hsieh, Hsi-Lung and Yang, Chuen-Mao",
    	doi = "10.1002/jcp.22560",
    	issn = "1097-4652",
    	journal = "Journal of cellular physiology",
    	keywords = "Animals,Astrocytes,Astrocytes: cytology,Astrocytes: drug effects,Astrocytes: enzymology,Cell Movement,Cell Movement: drug effects,Endothelin-1,Endothelin-1: pharmacology,Enzyme Activation,Enzyme Activation: drug effects,Enzyme Induction,Enzyme Induction: drug effects,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinase 3: metabolism,Models, Biological,NF-kappa B,NF-kappa B: metabolism,Nitric Oxide,Nitric Oxide Synthase Type II,Nitric Oxide Synthase Type II: biosynthesis,Nitric Oxide Synthase Type II: genetics,Nitric Oxide: biosynthesis,Nitrosation,Nitrosation: drug effects,Phosphatidylinositol 3-Kinases,Phosphatidylinositol 3-Kinases: metabolism,Phosphorylation,Phosphorylation: drug effects,Promoter Regions, Genetic,Promoter Regions, Genetic: genetics,Proto-Oncogene Proteins c-akt,Proto-Oncogene Proteins c-akt: metabolism,Proto-Oncogene Proteins pp60(c-src),Proto-Oncogene Proteins pp60(c-src): metabolism,Rats,Receptor, Endothelin B,Receptor, Endothelin B: metabolism,Tyrosine,Tyrosine: metabolism,Up-Regulation,Up-Regulation: drug effects",
    	month = "sep",
    	number = 9,
    	pages = "2244--56",
    	pmid = 21660948,
    	title = "{Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21660948",
    	volume = 226,
    	year = 2011
    }
    
  13. Yuki Morizane, Aristomenis Thanos, Kimio Takeuchi, Yusuke Murakami, Maki Kayama, George Trichonas, Joan Miller, Marc Foretz, Benoit Viollet and Demetrios G Vavvas.
    AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts.. The Journal of biological chemistry 286(18):16030–8, May 2011.
    Abstract Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9 expression is low in most cells and is tightly controlled, the mechanism of its regulation is poorly understood. We utilized mouse embryonic fibroblasts (MEFs) that were nullizygous for the catalytic $\alpha$ subunit of AMP-activated protein kinase (AMPK), which is a key regulator of energy homeostasis, to identify AMPK as a suppressor of MMP-9 expression. Total AMPK$\alpha$ deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPK$\alpha$1 and AMPK$\alpha$2 caused minimal change in the level of MMP-9 expression. The suppressive role of AMPK on MMP-9 expression was mediated through both its activity and presence. The AMPK activators 5-amino-4-imidazole carboxamide riboside and A769662 suppressed MMP-9 expression in WT MEFs, and AMPK inhibition by the overexpression of dominant negative (DN) AMPK$\alpha$ elevated MMP-9 expression. However, in AMPK$\alpha$(-/-) MEFs transduced with DN AMPK$\alpha$, MMP-9 expression was suppressed. AMPK$\alpha$(-/-) MEFs showed increased phosphorylation of I$\kappa$B$\alpha$, expression of I$\kappa$B$\alpha$ mRNA, nuclear localization of nuclear factor-$\kappa$B (NF-$\kappa$B), and DNA-binding activity of NF-$\kappa$B compared with WT. Consistently, selective NF-$\kappa$B inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPK$\alpha$(-/-) MEFs. Overall, our results suggest that both AMPK$\alpha$ isoforms suppress MMP-9 expression and that both the activity and presence of AMPK$\alpha$ contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-$\kappa$B pathway.
    URL, DOI BibTeX

    @article{Morizane2011,
    	abstract = "Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9 expression is low in most cells and is tightly controlled, the mechanism of its regulation is poorly understood. We utilized mouse embryonic fibroblasts (MEFs) that were nullizygous for the catalytic $\alpha$ subunit of AMP-activated protein kinase (AMPK), which is a key regulator of energy homeostasis, to identify AMPK as a suppressor of MMP-9 expression. Total AMPK$\alpha$ deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPK$\alpha$1 and AMPK$\alpha$2 caused minimal change in the level of MMP-9 expression. The suppressive role of AMPK on MMP-9 expression was mediated through both its activity and presence. The AMPK activators 5-amino-4-imidazole carboxamide riboside and A769662 suppressed MMP-9 expression in WT MEFs, and AMPK inhibition by the overexpression of dominant negative (DN) AMPK$\alpha$ elevated MMP-9 expression. However, in AMPK$\alpha$(-/-) MEFs transduced with DN AMPK$\alpha$, MMP-9 expression was suppressed. AMPK$\alpha$(-/-) MEFs showed increased phosphorylation of I$\kappa$B$\alpha$, expression of I$\kappa$B$\alpha$ mRNA, nuclear localization of nuclear factor-$\kappa$B (NF-$\kappa$B), and DNA-binding activity of NF-$\kappa$B compared with WT. Consistently, selective NF-$\kappa$B inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPK$\alpha$(-/-) MEFs. Overall, our results suggest that both AMPK$\alpha$ isoforms suppress MMP-9 expression and that both the activity and presence of AMPK$\alpha$ contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-$\kappa$B pathway.",
    	author = "Morizane, Yuki and Thanos, Aristomenis and Takeuchi, Kimio and Murakami, Yusuke and Kayama, Maki and Trichonas, George and Miller, Joan and Foretz, Marc and Viollet, Benoit and Vavvas, Demetrios G",
    	doi = "10.1074/jbc.M110.199398",
    	issn = "1083-351X",
    	journal = "The Journal of biological chemistry",
    	keywords = "AMP-Activated Protein Kinases,AMP-Activated Protein Kinases: antagonists \& inhib,AMP-Activated Protein Kinases: genetics,AMP-Activated Protein Kinases: metabolism,Animals,Benzamides,Benzamides: pharmacology,Cell Line,Embryo, Mammalian,Embryo, Mammalian: cytology,Embryo, Mammalian: enzymology,Enzyme Activators,Enzyme Activators: pharmacology,Fibroblasts,Fibroblasts: cytology,Fibroblasts: enzymology,Gene Expression Regulation, Enzymologic,Gene Expression Regulation, Enzymologic: drug effe,Gene Expression Regulation, Enzymologic: physiolog,I-kappa B Proteins,I-kappa B Proteins: genetics,I-kappa B Proteins: metabolism,Imidazoles,Imidazoles: pharmacology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: biosynthesis,Matrix Metalloproteinase 9: genetics,Mice,Mice, Knockout,NF-kappa B,NF-kappa B: antagonists \& inhibitors,NF-kappa B: genetics,NF-kappa B: metabolism,Phosphorylation,Phosphorylation: drug effects,Phosphorylation: physiology,Quinoxalines,Quinoxalines: pharmacology,RNA, Messenger,RNA, Messenger: biosynthesis,RNA, Messenger: genetics,Ribonucleotides,Ribonucleotides: pharmacology,Thiazoles,Thiazoles: pharmacology",
    	month = "may",
    	number = 18,
    	pages = "16030--8",
    	pmid = 21402702,
    	title = "{AMP-activated protein kinase suppresses matrix metalloproteinase-9 expression in mouse embryonic fibroblasts.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3091212\&tool=pmcentrez\&rendertype=abstract",
    	volume = 286,
    	year = 2011
    }
    
  14. Kazunori Miyazaki, Yasuyuki Ohta, Makiko Nagai, Nobutoshi Morimoto, Tomoko Kurata, Yasushi Takehisa, Yoshio Ikeda, Tohru Matsuura and Koji Abe.
    Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis.. Journal of neuroscience research 89(5):718–28, May 2011.
    Abstract Recent reports suggest that functional or structural defect of vascular components are implicated in amyotrophic lateral sclerosis (ALS) pathology. In the present study, we examined a possible change of the neurovascular unit consisting of endothelium (PCAM-1), tight junction (occludin), and basement membrane (collagen IV) in relation to a possible activation of MMP-9 in ALS patients and ALS model mice. We found that the damage in the neurovascular unit was more prominent in the outer side and preferentially in the anterior horn of ALS model mice. This damage occurred prior to motor neuron degeneration and was accompanied by MMP-9 up-regulation. We also found the dissociation between the PCAM-1-positive endothelium and GFAP-positive astrocyte foot processes in both humans and the animal model of ALS. The present results indicate that perivascular damage precedes the sequential changes of the disease, which are held in common between humans and the animal model of ALS, suggesting that the neurovascular unit is a potential target for therapeutic intervention in ALS.
    URL, DOI BibTeX

    @article{Miyazaki2011,
    	abstract = "Recent reports suggest that functional or structural defect of vascular components are implicated in amyotrophic lateral sclerosis (ALS) pathology. In the present study, we examined a possible change of the neurovascular unit consisting of endothelium (PCAM-1), tight junction (occludin), and basement membrane (collagen IV) in relation to a possible activation of MMP-9 in ALS patients and ALS model mice. We found that the damage in the neurovascular unit was more prominent in the outer side and preferentially in the anterior horn of ALS model mice. This damage occurred prior to motor neuron degeneration and was accompanied by MMP-9 up-regulation. We also found the dissociation between the PCAM-1-positive endothelium and GFAP-positive astrocyte foot processes in both humans and the animal model of ALS. The present results indicate that perivascular damage precedes the sequential changes of the disease, which are held in common between humans and the animal model of ALS, suggesting that the neurovascular unit is a potential target for therapeutic intervention in ALS.",
    	author = "Miyazaki, Kazunori and Ohta, Yasuyuki and Nagai, Makiko and Morimoto, Nobutoshi and Kurata, Tomoko and Takehisa, Yasushi and Ikeda, Yoshio and Matsuura, Tohru and Abe, Koji",
    	doi = "10.1002/jnr.22594",
    	issn = "1097-4547",
    	journal = "Journal of neuroscience research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Blood-Brain Barrier,Blood-Brain Barrier: pathology,Blood-Brain Barrier: physiopathology,Disease Models, Animal,Endothelial Cells,Endothelial Cells: metabolism,Endothelial Cells: pathology,Female,Humans,Male,Mice,Mice, Inbred C57BL,Mice, Transgenic,Middle Aged,Motor Neurons,Motor Neurons: pathology,Nerve Degeneration,Nerve Degeneration: pathology,Nerve Degeneration: physiopathology,Spinal Cord,Spinal Cord: pathology,Spinal Cord: physiopathology",
    	month = "may",
    	number = 5,
    	pages = "718--28",
    	pmid = 21337372,
    	title = "{Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21337372",
    	volume = 89,
    	year = 2011
    }
    
  15. Hongli Li, Hao Xu and Shaowen Liu.
    Toll-like receptors 4 induces expression of matrix metalloproteinase-9 in human aortic smooth muscle cells.. Molecular biology reports 38(2):1419–23, February 2011.
    Abstract Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. It was confirmed that the presence of functional TLR4 promotes a proinflammatory phenotype and proliferation of vascular smooth muscle cells (VSMCs). Here we tested whether designed TLR4 small interfering RNAs (TLR4 siRNAs) is capable of inducing TLR4 deficient and simultaneously regulating the expression of matrix metalloproteinase-9 (MMP-9) in human aortic smooth muscle cells (HASMCs). Human aortic smooth muscle cells were obtained from Cascade Biologics (Portland, USA). The siRNAs used in this study were chemically synthesized by Ambion, diluted in RNase free water at concentration of 2 $\mu$g/ml. The TLR4 siRNAs were complexed with Lipofectamine(TM) 2000 in transfection buffer. After 30 min incubation at room temperature, the complexes were added to the cells. Subsequent to 5 h incubation, cells were treated with 10 ng/ml LPS for 24 h. RT-PCR analysis was used to detect mRNA expression of GAPDH, TLR4 and MMP-9; Western blot analysis was used to examine GAPDH, TLR4 and MMP-9 protein expression. It was shown that all three designed TLR4 siRNAs inhibited the expression of TLR4 in HASMCs as compared to nontargeting siRNA. Notably, TLR4 siRNA-1 exhibited the strongest inhibition effect. Transfection of HASMCs with TLR4 siRNA-1 resulted in down-regulation of LPS-induced expression of MMP-9. It was concluded that TLR4 siRNA-transfected HASMCs were capable for regulating the expression of MMP-9, providing support for the rational design of siRNAs as atherosclerotic therapy.
    URL, DOI BibTeX

    @article{Li2011,
    	abstract = "Recent evidence supports a role of Toll-like receptor (TLR) signaling in the development of atherosclerotic lesions. It was confirmed that the presence of functional TLR4 promotes a proinflammatory phenotype and proliferation of vascular smooth muscle cells (VSMCs). Here we tested whether designed TLR4 small interfering RNAs (TLR4 siRNAs) is capable of inducing TLR4 deficient and simultaneously regulating the expression of matrix metalloproteinase-9 (MMP-9) in human aortic smooth muscle cells (HASMCs). Human aortic smooth muscle cells were obtained from Cascade Biologics (Portland, USA). The siRNAs used in this study were chemically synthesized by Ambion, diluted in RNase free water at concentration of 2 $\mu$g/ml. The TLR4 siRNAs were complexed with Lipofectamine(TM) 2000 in transfection buffer. After 30 min incubation at room temperature, the complexes were added to the cells. Subsequent to 5 h incubation, cells were treated with 10 ng/ml LPS for 24 h. RT-PCR analysis was used to detect mRNA expression of GAPDH, TLR4 and MMP-9; Western blot analysis was used to examine GAPDH, TLR4 and MMP-9 protein expression. It was shown that all three designed TLR4 siRNAs inhibited the expression of TLR4 in HASMCs as compared to nontargeting siRNA. Notably, TLR4 siRNA-1 exhibited the strongest inhibition effect. Transfection of HASMCs with TLR4 siRNA-1 resulted in down-regulation of LPS-induced expression of MMP-9. It was concluded that TLR4 siRNA-transfected HASMCs were capable for regulating the expression of MMP-9, providing support for the rational design of siRNAs as atherosclerotic therapy.",
    	author = "Li, Hongli and Xu, Hao and Liu, Shaowen",
    	doi = "10.1007/s11033-010-0246-4",
    	issn = "1573-4978",
    	journal = "Molecular biology reports",
    	keywords = "Aorta,Aorta: cytology,Cell Survival,Cells, Cultured,Gene Expression Regulation, Enzymologic,Humans,Lipopolysaccharides,Lipopolysaccharides: metabolism,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Models, Biological,Myocytes, Smooth Muscle,Myocytes, Smooth Muscle: cytology,Phenotype,RNA, Messenger,RNA, Messenger: metabolism,RNA, Small Interfering,RNA, Small Interfering: metabolism,Reverse Transcriptase Polymerase Chain Reaction,Toll-Like Receptor 4,Toll-Like Receptor 4: metabolism,Transfection",
    	month = "feb",
    	number = 2,
    	pages = "1419--23",
    	pmid = 20725790,
    	title = "{Toll-like receptors 4 induces expression of matrix metalloproteinase-9 in human aortic smooth muscle cells.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20725790",
    	volume = 38,
    	year = 2011
    }
    
  16. Denise E Lackey and Kathleen A Hoag.
    Vitamin A upregulates matrix metalloproteinase-9 activity by murine myeloid dendritic cells through a nonclassical transcriptional mechanism.. The Journal of nutrition 140(8):1502–8, August 2010.
    Abstract Myeloid dendritic cells (DC) are specialized antigen-presenting immune cells. Upon activation in peripheral tissues, DC migrate to lymph nodes to activate T lymphocytes. Matrix metalloproteinase (MMP)-9 is a gelatinase essential for DC migration. We have previously shown that all-trans retinoic acid (atRA), a bioactive metabolite of vitamin A, significantly augmented DC MMP-9 mRNA and protein production. We investigated the mechanisms by which atRA increased MMP-9 activity in vitro. Mouse myeloid DC cultured with atRA demonstrated increased gelatinase activity compared with cells cultured with retinoic acid receptor (RAR)-alpha antagonist. Adding MMP-9 inhibitor significantly blocked DC gelatinase activity and increased adherence of DC in a dose-dependent manner. AtRA-induced Mmp-9 gene expression in DC was blocked by transcriptional inhibition. Because the Mmp-9 promoter contains no canonical retinoic acid response element (RARE), we performed additional studies to determine how atRA regulated DC Mmp-9 transcription. Electrophoretic mobility shift assays for the consensus Sp1, activating protein-1, and nuclear factor-kappaB binding sites located in the Mmp-9 promoter did not indicate greater nuclear protein binding in response to atRA. Chromatin immunoprecipitation assays indicated RARalpha and histone acetyltransferase p300 recruitment to, and acetylation of, histone H3 at the Mmp-9 promoter was greater after atRA treatment. These data suggest that atRA regulated DC adhesion in vitro partly through MMP-9 gelatinase activity. Mmp-9 expression was enhanced through a transcriptional mechanism involving greater RARalpha promoter binding, recruitment of p300, and subsequent histone H3 acetylation, despite the absence of a consensus RARE.
    URL, DOI BibTeX

    @article{Lackey2010,
    	abstract = "Myeloid dendritic cells (DC) are specialized antigen-presenting immune cells. Upon activation in peripheral tissues, DC migrate to lymph nodes to activate T lymphocytes. Matrix metalloproteinase (MMP)-9 is a gelatinase essential for DC migration. We have previously shown that all-trans retinoic acid (atRA), a bioactive metabolite of vitamin A, significantly augmented DC MMP-9 mRNA and protein production. We investigated the mechanisms by which atRA increased MMP-9 activity in vitro. Mouse myeloid DC cultured with atRA demonstrated increased gelatinase activity compared with cells cultured with retinoic acid receptor (RAR)-alpha antagonist. Adding MMP-9 inhibitor significantly blocked DC gelatinase activity and increased adherence of DC in a dose-dependent manner. AtRA-induced Mmp-9 gene expression in DC was blocked by transcriptional inhibition. Because the Mmp-9 promoter contains no canonical retinoic acid response element (RARE), we performed additional studies to determine how atRA regulated DC Mmp-9 transcription. Electrophoretic mobility shift assays for the consensus Sp1, activating protein-1, and nuclear factor-kappaB binding sites located in the Mmp-9 promoter did not indicate greater nuclear protein binding in response to atRA. Chromatin immunoprecipitation assays indicated RARalpha and histone acetyltransferase p300 recruitment to, and acetylation of, histone H3 at the Mmp-9 promoter was greater after atRA treatment. These data suggest that atRA regulated DC adhesion in vitro partly through MMP-9 gelatinase activity. Mmp-9 expression was enhanced through a transcriptional mechanism involving greater RARalpha promoter binding, recruitment of p300, and subsequent histone H3 acetylation, despite the absence of a consensus RARE.",
    	author = "Lackey, Denise E and Hoag, Kathleen A",
    	doi = "10.3945/jn.110.122556",
    	issn = "1541-6100",
    	journal = "The Journal of nutrition",
    	keywords = "Acetylation,Animals,Cell Adhesion,Cell Adhesion: drug effects,Cells, Cultured,DNA,DNA: metabolism,Dendritic Cells,Dendritic Cells: cytology,Dendritic Cells: enzymology,Enzyme Inhibitors,Enzyme Inhibitors: pharmacology,Histones,Histones: metabolism,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinase Inhibitors,Mice,Mice, Inbred C57BL,Nuclear Proteins,Nuclear Proteins: metabolism,Promoter Regions, Genetic,Promoter Regions, Genetic: genetics,RNA, Messenger,RNA, Messenger: analysis,Receptors, Retinoic Acid,Receptors, Retinoic Acid: antagonists \& inhibitors,Receptors, Retinoic Acid: genetics,Transcription, Genetic,Tretinoin,Tretinoin: pharmacology,Up-Regulation,Up-Regulation: drug effects,Vitamin A,Vitamin A: pharmacology,p300-CBP Transcription Factors,p300-CBP Transcription Factors: metabolism",
    	month = "aug",
    	number = 8,
    	pages = "1502--8",
    	pmid = 20534877,
    	title = "{Vitamin A upregulates matrix metalloproteinase-9 activity by murine myeloid dendritic cells through a nonclassical transcriptional mechanism.}",
    	url = "http://jn.nutrition.org/content/140/8/1502.full",
    	volume = 140,
    	year = 2010
    }
    
  17. Lubin Fang, Marko Teuchert, Friederike Huber-Abel, Dagmar Schattauer, Corinna Hendrich, Johannes Dorst, Heinz Zettlmeissel, Meinhard Wlaschek, Karin Scharffetter-Kochanek, Tamara Kapfer, Hayrettin Tumani, Albert C Ludolph and Johannes Brettschneider.
    MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS.. Journal of the neurological sciences 294(1-2):51–6, July 2010.
    Abstract {We aimed to clarify the role of matrix metalloproteinases (MMP) as a possible link between neurodegeneration and skin pathology in ALS by determination of gelatinase MMP-2 and MMP-9 in spinal cord and skin of transgenic SOD1((G93A)) mice. To elucidate mechanisms influencing MMPs, markers of oxidative damage (malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and 8-hydroxy-2'-deoxyguanosine (8OH2'dG)) as well as cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin 1ss (IL-1ss)) were determined. We measured MMP-9, MMP-2, 3-NT, TNF-alpha, and IL-1ss using ELISA, MDA using High Performance Liquid Chromatography (HPLC) and 8OH2'dG using HPLC with electrochemical detection (HPLC-ECD) in SOD1 and WT. MMP-9 was elevated in spinal cord and skin of SOD1 at 90 days (p=0.009, p<0.001) and 120 days (p<0.01
    URL, DOI BibTeX

    @article{Fang2010,
    	abstract = "{We aimed to clarify the role of matrix metalloproteinases (MMP) as a possible link between neurodegeneration and skin pathology in ALS by determination of gelatinase MMP-2 and MMP-9 in spinal cord and skin of transgenic SOD1((G93A)) mice. To elucidate mechanisms influencing MMPs, markers of oxidative damage (malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and 8-hydroxy-2'-deoxyguanosine (8OH2'dG)) as well as cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin 1ss (IL-1ss)) were determined. We measured MMP-9, MMP-2, 3-NT, TNF-alpha, and IL-1ss using ELISA, MDA using High Performance Liquid Chromatography (HPLC) and 8OH2'dG using HPLC with electrochemical detection (HPLC-ECD) in SOD1 and WT. MMP-9 was elevated in spinal cord and skin of SOD1 at 90 days (p=0.009, p<0.001) and 120 days (p<0.01",
    	p = "",
    	author = "Fang, Lubin and Teuchert, Marko and Huber-Abel, Friederike and Schattauer, Dagmar and Hendrich, Corinna and Dorst, Johannes and Zettlmeissel, Heinz and Wlaschek, Meinhard and Scharffetter-Kochanek, Karin and Kapfer, Tamara and Tumani, Hayrettin and Ludolph, Albert C and Brettschneider, Johannes",
    	doi = "10.1016/j.jns.2010.04.005",
    	issn = "1878-5883",
    	journal = "Journal of the neurological sciences",
    	keywords = "Aging,Aging: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Animals,Cytokines,Cytokines: metabolism,Disease Models, Animal,Humans,Interleukin-1beta,Interleukin-1beta: metabolism,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: metabolism,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Mice,Mice, Transgenic,Models, Neurological,Oxidative Stress,Oxidative Stress: physiology,Skin,Skin: metabolism,Spinal Cord,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Tumor Necrosis Factor-alpha,Tumor Necrosis Factor-alpha: metabolism",
    	month = "jul",
    	number = "1-2",
    	pages = "51--6",
    	pmid = 20441996,
    	publisher = "Elsevier",
    	title = "{MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS.}",
    	url = "http://www.jns-journal.com/article/S0022-510X(10)00164-4/abstract",
    	volume = 294,
    	year = 2010
    }
    
  18. K Bahar-Shany, A Ravid and R Koren.
    Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D.. Journal of cellular physiology 222(3):729–37, March 2010.
    Abstract MMP-9, a member of the matrix metalloproteinase family that degrades collagen IV and processes chemokines and cytokines, participates in epidermal remodeling in response to stress and injury. Limited activity of MMP-9 is essential while excessive activity is deleterious to the healing process. Tumor necrosis factor (TNFalpha), a key mediator of cutaneous inflammation, is a powerful inducer of MMP-9. Calcitriol, the hormonally active vitamin D metabolite, and its analogs are known to attenuate epidermal inflammation. We aimed to examine the modulation of MMP-9 by calcitriol in TNFalpha-treated keratinocytes. The immortalized HaCaT keratinocytes were treated with TNFalpha in the absence of exogenous growth factors or active ingredients. MMP-9 production was quantified by gelatin zymography and real-time RT-PCR. Activation of signaling cascades was assessed by western blot analysis and DNA-binding activity of transcription factors was determined by EMSA. Exposure to TNFalpha markedly increased the protein and mRNA levels of MMP-9, while pretreatment with calcitriol dose dependently reduced this effect. Employing specific inhibitors we established that the induction of MMP-9 by TNFalpha was dependent on the activity of the epidermal growth factor receptor, c-Jun-N-terminal kinase (JNK), NFkappaB and extracellular signal-regulated kinase-1/2. The effect of calcitriol was associated with inhibition of JNK activation and reduction of DNA-binding activities of the transcription factors activator protein-1 (AP-1) and NFkappaB following treatment with TNFalpha. By down-regulating MMP-9 levels active vitamin D derivatives may attenuate deleterious effects due to excessive TNFalpha-induced proteolytic activity associated with cutaneous inflammation.
    URL, DOI BibTeX

    @article{Bahar-Shany2010,
    	abstract = "MMP-9, a member of the matrix metalloproteinase family that degrades collagen IV and processes chemokines and cytokines, participates in epidermal remodeling in response to stress and injury. Limited activity of MMP-9 is essential while excessive activity is deleterious to the healing process. Tumor necrosis factor (TNFalpha), a key mediator of cutaneous inflammation, is a powerful inducer of MMP-9. Calcitriol, the hormonally active vitamin D metabolite, and its analogs are known to attenuate epidermal inflammation. We aimed to examine the modulation of MMP-9 by calcitriol in TNFalpha-treated keratinocytes. The immortalized HaCaT keratinocytes were treated with TNFalpha in the absence of exogenous growth factors or active ingredients. MMP-9 production was quantified by gelatin zymography and real-time RT-PCR. Activation of signaling cascades was assessed by western blot analysis and DNA-binding activity of transcription factors was determined by EMSA. Exposure to TNFalpha markedly increased the protein and mRNA levels of MMP-9, while pretreatment with calcitriol dose dependently reduced this effect. Employing specific inhibitors we established that the induction of MMP-9 by TNFalpha was dependent on the activity of the epidermal growth factor receptor, c-Jun-N-terminal kinase (JNK), NFkappaB and extracellular signal-regulated kinase-1/2. The effect of calcitriol was associated with inhibition of JNK activation and reduction of DNA-binding activities of the transcription factors activator protein-1 (AP-1) and NFkappaB following treatment with TNFalpha. By down-regulating MMP-9 levels active vitamin D derivatives may attenuate deleterious effects due to excessive TNFalpha-induced proteolytic activity associated with cutaneous inflammation.",
    	author = "Bahar-Shany, K and Ravid, A and Koren, R",
    	doi = "10.1002/jcp.22004",
    	issn = "1097-4652",
    	journal = "Journal of cellular physiology",
    	keywords = "Blotting, Western,Calcitriol,Calcitriol: metabolism,Cell Line,Electrophoretic Mobility Shift Assay,Humans,JNK Mitogen-Activated Protein Kinases,JNK Mitogen-Activated Protein Kinases: antagonists,JNK Mitogen-Activated Protein Kinases: metabolism,Keratinocytes,Keratinocytes: drug effects,Keratinocytes: enzymology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: metabolism,Mitogen-Activated Protein Kinase 1,Mitogen-Activated Protein Kinase 1: antagonists \& ,Mitogen-Activated Protein Kinase 1: metabolism,Mitogen-Activated Protein Kinase 3,Mitogen-Activated Protein Kinase 3: antagonists \& ,Mitogen-Activated Protein Kinase 3: metabolism,NF-kappa B,NF-kappa B: antagonists \& inhibitors,NF-kappa B: metabolism,Protein Kinase Inhibitors,Protein Kinase Inhibitors: pharmacology,RNA, Messenger,RNA, Messenger: metabolism,Receptor, Epidermal Growth Factor,Receptor, Epidermal Growth Factor: antagonists \& i,Receptor, Epidermal Growth Factor: metabolism,Recombinant Proteins,Recombinant Proteins: metabolism,Reverse Transcriptase Polymerase Chain Reaction,Signal Transduction,Time Factors,Transcription Factor AP-1,Transcription Factor AP-1: metabolism,Tumor Necrosis Factor-alpha,Tumor Necrosis Factor-alpha: metabolism,Up-Regulation,p38 Mitogen-Activated Protein Kinases,p38 Mitogen-Activated Protein Kinases: antagonists,p38 Mitogen-Activated Protein Kinases: metabolism",
    	month = "mar",
    	number = 3,
    	pages = "729--37",
    	pmid = 20020446,
    	title = "{Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/20020446",
    	volume = 222,
    	year = 2010
    }
    
  19. Oualid Sbai, Adlane Ould-Yahoui, Lotfi Ferhat, Yatma Gueye, Anne Bernard, Eliane Charrat, Ali Mehanna, Jean-Jacques Risso, Jean-Paul Chauvin, Emmanuel Fenouillet, Santiago Rivera and Michel Khrestchatisky.
    Differential vesicular distribution and trafficking of MMP-2, MMP-9, and their inhibitors in astrocytes.. Glia 58(3):344–66, February 2010.
    Abstract Astrocytes play an active role in the central nervous system and are critically involved in astrogliosis, a homotypic response of these cells to disease, injury, and associated neuroinflammation. Among the numerous molecules involved in these processes are the matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, secreted or membrane-bound, that regulate by proteolytic cleavage the extracellular matrix, cytokines, chemokines, cell adhesion molecules, and plasma membrane receptors. MMP activity is tightly regulated by the tissue inhibitors of MMPs (TIMPs), a family of secreted multifunctional proteins. Astrogliosis in vivo and astrocyte reactivity induced in vitro by proinflammatory cues are associated with modulation of expression and/or activity of members of the MMP/TIMP system. However, nothing is known concerning the intracellular distribution and secretory pathways of MMPs and TIMPs in astrocytes. Using a combination of cell biology, biochemistry, fluorescence and electron microscopy approaches, we investigated in cultured reactive astrocytes the intracellular distribution, transport, and secretion of MMP-2, MMP-9, TIMP-1, and TIMP-2. MMP-2 and MMP-9 demonstrate nuclear localization, differential intracellular vesicular distribution relative to the myosin V and kinesin molecular motors, and LAMP-2-labeled lysosomal compartment, and we show vesicular secretion for MMP-2, MMP-9, and their inhibitors. Our results suggest that these proteinases and their inhibitors use different pathways for trafficking and secretion for distinct astrocytic functions.
    URL, DOI BibTeX

    @article{Sbai2010,
    	abstract = "Astrocytes play an active role in the central nervous system and are critically involved in astrogliosis, a homotypic response of these cells to disease, injury, and associated neuroinflammation. Among the numerous molecules involved in these processes are the matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, secreted or membrane-bound, that regulate by proteolytic cleavage the extracellular matrix, cytokines, chemokines, cell adhesion molecules, and plasma membrane receptors. MMP activity is tightly regulated by the tissue inhibitors of MMPs (TIMPs), a family of secreted multifunctional proteins. Astrogliosis in vivo and astrocyte reactivity induced in vitro by proinflammatory cues are associated with modulation of expression and/or activity of members of the MMP/TIMP system. However, nothing is known concerning the intracellular distribution and secretory pathways of MMPs and TIMPs in astrocytes. Using a combination of cell biology, biochemistry, fluorescence and electron microscopy approaches, we investigated in cultured reactive astrocytes the intracellular distribution, transport, and secretion of MMP-2, MMP-9, TIMP-1, and TIMP-2. MMP-2 and MMP-9 demonstrate nuclear localization, differential intracellular vesicular distribution relative to the myosin V and kinesin molecular motors, and LAMP-2-labeled lysosomal compartment, and we show vesicular secretion for MMP-2, MMP-9, and their inhibitors. Our results suggest that these proteinases and their inhibitors use different pathways for trafficking and secretion for distinct astrocytic functions.",
    	author = "Sbai, Oualid and Ould-Yahoui, Adlane and Ferhat, Lotfi and Gueye, Yatma and Bernard, Anne and Charrat, Eliane and Mehanna, Ali and Risso, Jean-Jacques and Chauvin, Jean-Paul and Fenouillet, Emmanuel and Rivera, Santiago and Khrestchatisky, Michel",
    	doi = "10.1002/glia.20927",
    	issn = "1098-1136",
    	journal = "Glia",
    	keywords = "Active Transport, Cell Nucleus,Active Transport, Cell Nucleus: physiology,Animals,Animals, Newborn,Astrocytes,Astrocytes: enzymology,Astrocytes: ultrastructure,Cell Compartmentation,Cell Compartmentation: physiology,Cells, Cultured,Encephalitis,Encephalitis: enzymology,Encephalitis: physiopathology,Gliosis,Gliosis: enzymology,Gliosis: physiopathology,Lysosomal-Associated Membrane Protein 2,Lysosomal-Associated Membrane Protein 2: metabolis,Lysosomes,Lysosomes: metabolism,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: metabolism,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Mice,Molecular Motor Proteins,Molecular Motor Proteins: metabolism,Protein Transport,Protein Transport: physiology,Signal Transduction,Signal Transduction: physiology,Tissue Inhibitor of Metalloproteinase-1,Tissue Inhibitor of Metalloproteinase-1: metabolis,Tissue Inhibitor of Metalloproteinase-2,Tissue Inhibitor of Metalloproteinase-2: metabolis,Transport Vesicles,Transport Vesicles: enzymology,Transport Vesicles: ultrastructure",
    	month = "feb",
    	number = 3,
    	pages = "344--66",
    	pmid = 19780201,
    	title = "{Differential vesicular distribution and trafficking of MMP-2, MMP-9, and their inhibitors in astrocytes.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19780201",
    	volume = 58,
    	year = 2010
    }
    
  20. Cynthia P W Soon, Peter J Crouch, Bradley J Turner, Catriona A McLean, Katrina M Laughton, Julie D Atkin, Colin L Masters, Anthony R White and Qiao-Xin Li.
    Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice.. Neuromuscular disorders : NMD 20(4):260–6, 2010.
    Abstract Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.
    URL, DOI BibTeX

    @article{Soon2010,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.",
    	author = "Soon, Cynthia P W and Crouch, Peter J and Turner, Bradley J and McLean, Catriona A and Laughton, Katrina M and Atkin, Julie D and Masters, Colin L and White, Anthony R and Li, Qiao-Xin",
    	doi = "10.1016/j.nmd.2009.11.015",
    	issn = "1873-2364",
    	journal = "Neuromuscular disorders : NMD",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: diagnosis,Amyotrophic Lateral Sclerosis: enzymology,Animals,Biological Markers,Biological Markers: analysis,Biological Markers: blood,Disease Models, Animal,Disease Progression,Gene Dosage,Gene Dosage: genetics,Gene Expression Regulation, Enzymologic,Gene Expression Regulation, Enzymologic: genetics,Genetic Predisposition to Disease,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: analysis,Matrix Metalloproteinase 2: blood,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: analysis,Matrix Metalloproteinase 9: blood,Mice,Mice, Transgenic,Motor Neurons,Motor Neurons: enzymology,Motor Neurons: pathology,Mutation,Mutation: genetics,Neuroglia,Neuroglia: enzymology,Spinal Cord,Spinal Cord: enzymology,Spinal Cord: pathology,Spinal Cord: physiopathology,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "",
    	number = 4,
    	pages = "260--6",
    	pmid = 20097566,
    	publisher = "Elsevier",
    	title = "{Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice.}",
    	url = "http://www.nmd-journal.com/article/S0960-8966(09)00699-3/abstract",
    	volume = 20,
    	year = 2010
    }
    
  21. Michel Steenport, Faisal K M Khan, Baoheng Du, Sarah E Barnhard, Andrew J Dannenberg and Domenick J Falcone.
    Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2.. Journal of immunology (Baltimore, Md. : 1950) 183(12):8119–27, December 2009.
    Abstract Matrix metalloproteinase (MMP)-9 (gelatinase B) participates in a variety of diverse physiologic and pathologic processes. We recently characterized a cyclooxygenase-2 (COX-2)–>PGE(2)–>EP4 receptor axis that regulates macrophage MMP-9 expression. In the present studies, we determined whether MMPs, commonly found in inflamed and neoplastic tissues, regulate this prostanoid-EP receptor axis leading to enhanced MMP-9 expression. Results demonstrate that exposure of murine peritoneal macrophages and RAW264.7 macrophages to MMP-1 (collagenase-1) or MMP-3 (stromelysin-1) lead to a marked increase in COX-2 expression, PGE(2) secretion, and subsequent induction of MMP-9 expression. Proteinase-induced MMP-9 expression was blocked in macrophages preincubated with the selective COX-2 inhibitor celecoxib or transfected with COX-2 small interfering RNA (siRNA). Likewise, proteinase-induced MMP-9 was blocked in macrophages preincubated with the EP4 antagonist ONO-AE3-208 or transfected with EP4 siRNA. Exposure of macrophages to MMP-1 and MMP-3 triggered the rapid release of TNF-alpha, which was blocked by MMP inhibitors. Furthermore, both COX-2 and MMP-9 expression were inhibited in macrophages preincubated with anti-TNF-alpha IgG or transfected with TNF-alpha siRNA. Thus, proteinase-induced MMP-9 expression by macrophages is dependent on the release of TNF-alpha, induction of COX-2 expression, and PGE(2) engagement of EP4. The ability of MMP-1 and MMP-3 to regulate macrophage secretion of PGE(2) and expression of MMP-9 defines a nexus between MMPs and prostanoids that is likely to play a role in the pathogenesis of chronic inflammatory diseases and cancer. These data also suggest that this nexus is targetable utilizing anti-TNF-alpha therapies and/or selective EP4 antagonists.
    URL, DOI BibTeX

    @article{Steenport2009,
    	abstract = "Matrix metalloproteinase (MMP)-9 (gelatinase B) participates in a variety of diverse physiologic and pathologic processes. We recently characterized a cyclooxygenase-2 (COX-2)-->PGE(2)-->EP4 receptor axis that regulates macrophage MMP-9 expression. In the present studies, we determined whether MMPs, commonly found in inflamed and neoplastic tissues, regulate this prostanoid-EP receptor axis leading to enhanced MMP-9 expression. Results demonstrate that exposure of murine peritoneal macrophages and RAW264.7 macrophages to MMP-1 (collagenase-1) or MMP-3 (stromelysin-1) lead to a marked increase in COX-2 expression, PGE(2) secretion, and subsequent induction of MMP-9 expression. Proteinase-induced MMP-9 expression was blocked in macrophages preincubated with the selective COX-2 inhibitor celecoxib or transfected with COX-2 small interfering RNA (siRNA). Likewise, proteinase-induced MMP-9 was blocked in macrophages preincubated with the EP4 antagonist ONO-AE3-208 or transfected with EP4 siRNA. Exposure of macrophages to MMP-1 and MMP-3 triggered the rapid release of TNF-alpha, which was blocked by MMP inhibitors. Furthermore, both COX-2 and MMP-9 expression were inhibited in macrophages preincubated with anti-TNF-alpha IgG or transfected with TNF-alpha siRNA. Thus, proteinase-induced MMP-9 expression by macrophages is dependent on the release of TNF-alpha, induction of COX-2 expression, and PGE(2) engagement of EP4. The ability of MMP-1 and MMP-3 to regulate macrophage secretion of PGE(2) and expression of MMP-9 defines a nexus between MMPs and prostanoids that is likely to play a role in the pathogenesis of chronic inflammatory diseases and cancer. These data also suggest that this nexus is targetable utilizing anti-TNF-alpha therapies and/or selective EP4 antagonists.",
    	author = "Steenport, Michel and Khan, K M Faisal and Du, Baoheng and Barnhard, Sarah E and Dannenberg, Andrew J and Falcone, Domenick J",
    	doi = "10.4049/jimmunol.0901925",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Steenport et al. - 2009 - Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9 evidence for the role of TNF-alpha and cycl.pdf:pdf",
    	issn = "1550-6606",
    	journal = "Journal of immunology (Baltimore, Md. : 1950)",
    	keywords = "Animals,Cell Line,Chronic Disease,Cyclooxygenase 2,Cyclooxygenase 2: biosynthesis,Cyclooxygenase 2: physiology,Cyclooxygenase 2: secretion,Enzyme Induction,Enzyme Induction: genetics,Enzyme Induction: immunology,Extracellular Fluid,Extracellular Fluid: enzymology,Extracellular Fluid: immunology,Extracellular Fluid: secretion,Gene Expression Regulation,Gene Expression Regulation: immunology,Humans,Inflammation Mediators,Inflammation Mediators: physiology,Macrophages,Macrophages, Peritoneal,Macrophages, Peritoneal: enzymology,Macrophages, Peritoneal: immunology,Macrophages, Peritoneal: pathology,Macrophages, Peritoneal: secretion,Macrophages: enzymology,Macrophages: immunology,Macrophages: pathology,Macrophages: secretion,Matrix Metalloproteinase 1,Matrix Metalloproteinase 1: physiology,Matrix Metalloproteinase 3,Matrix Metalloproteinase 3: physiology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: biosynthesis,Matrix Metalloproteinase 9: genetics,Mice,Neoplasms,Neoplasms: genetics,Neoplasms: immunology,Neoplasms: secretion,Receptors, Prostaglandin E,Receptors, Prostaglandin E, EP4 Subtype,Receptors, Prostaglandin E: metabolism,Tumor Necrosis Factor-alpha,Tumor Necrosis Factor-alpha: physiology,Tumor Necrosis Factor-alpha: secretion",
    	language = "en",
    	month = "dec",
    	number = 12,
    	pages = "8119--27",
    	pmid = 19923455,
    	publisher = "American Association of Immunologists",
    	title = "{Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2.}",
    	url = "http://www.jimmunol.org/content/183/12/8119.full",
    	volume = 183,
    	year = 2009
    }
    
  22. Jan H N Lindeman, Hazem Abdul-Hussien, Hajo J Bockel, Ron Wolterbeek and Robert Kleemann.
    Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells.. Circulation 119(16):2209–16, April 2009.
    Abstract BACKGROUND: Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation. METHODS AND RESULTS: Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the effect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72% reduction of the aortic wall neutrophils and a 95% reduction of the aortic wall cytotoxic T-cell content (median values; P<0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (P<0.0158, NS) and reduced vascular interleukin-6 (P<0.00115), interleukin-8 (P<0.00246, NS), interleukin-13 (P<0.0184, NS), and granulocyte colony-stimulating factor (P<0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects. CONCLUSIONS: A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells.
    URL, DOI BibTeX

    @article{Lindeman2009,
    	abstract = "BACKGROUND: Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation. METHODS AND RESULTS: Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the effect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72\% reduction of the aortic wall neutrophils and a 95\% reduction of the aortic wall cytotoxic T-cell content (median values; P<0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (P<0.0158, NS) and reduced vascular interleukin-6 (P<0.00115), interleukin-8 (P<0.00246, NS), interleukin-13 (P<0.0184, NS), and granulocyte colony-stimulating factor (P<0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects. CONCLUSIONS: A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells.",
    	author = "Lindeman, Jan H N and Abdul-Hussien, Hazem and van Bockel, J Hajo and Wolterbeek, Ron and Kleemann, Robert",
    	doi = "10.1161/CIRCULATIONAHA.108.806505",
    	issn = "1524-4539",
    	journal = "Circulation",
    	keywords = "Aged,Aged, 80 and over,Anti-Bacterial Agents,Anti-Bacterial Agents: administration \& dosage,Aorta,Aorta: cytology,Aorta: immunology,Aortic Aneurysm, Abdominal,Aortic Aneurysm, Abdominal: drug therapy,Aortic Aneurysm, Abdominal: immunology,Aortic Aneurysm, Abdominal: surgery,CCAAT-Enhancer-Binding Proteins,CCAAT-Enhancer-Binding Proteins: metabolism,Doxycycline,Doxycycline: administration \& dosage,Enzyme Inhibitors,Enzyme Inhibitors: administration \& dosage,Female,Humans,Interleukin-6,Interleukin-6: metabolism,Interleukin-8,Interleukin-8: metabolism,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinase Inhibitors,Middle Aged,Neutrophils,Neutrophils: drug effects,Neutrophils: enzymology,Neutrophils: immunology,T-Lymphocytes, Cytotoxic,T-Lymphocytes, Cytotoxic: drug effects,T-Lymphocytes, Cytotoxic: immunology,Transcription Factor AP-1,Transcription Factor AP-1: metabolism,Transcription Factor RelA,Transcription Factor RelA: metabolism,Vasculitis,Vasculitis: drug therapy,Vasculitis: immunology",
    	month = "apr",
    	number = 16,
    	pages = "2209--16",
    	pmid = 19364980,
    	title = "{Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells.}",
    	url = "http://circ.ahajournals.org/content/119/16/2209.full",
    	volume = 119,
    	year = 2009
    }
    
  23. Qin Hu, Chunhua Chen, Junhao Yan, Xiaomei Yang, Xianzhong Shi, Jing Zhao, Jiliang Lei, Lei Yang, Ke Wang, Lin Chen, Hongyun Huang, Jingyan Han, John H Zhang and Changman Zhou.
    Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model.. Experimental neurology 216(1):35–46, 2009.
    Abstract RNA interference appears to have a great potential not only as an in vitro target validation, but also as a novel therapeutic strategy based on the highly specific and efficient silencing of a target gene. We hypothesize that MMP-9 siRNA can be effective as an MMP-9 protein inhibitor in a rat focal ischemia model. Male Sprague-Dawley rats (156) were subjected to 2 h of middle cerebral artery occlusion (by using the suture insertion method) followed by 24 h of reperfusion. In the treatment group, 5 microl MMP-9 siRNA was administrated by intracerebroventricular injection within 60 min after 2 h of focal ischemia. The siRNA transfection was demonstrated by fluorescence conjugated siRNA. Treatment with MMP-9 siRNA produced a significant reduction in the cerebral infarction volume, brain water content, mortality rate and accompanying neurological deficits. The followings were recorded: Evan's blue and IgG extravasation were reduced; the expression of MMP-9 mRNA and protein were significantly silenced; and immunohistochemistry and Western blot analysis revealed that the expression of MMP-9 and VEGF were reduced while occludin and collagen-IV were up-regulated in brain tissues. Our findings provide evidence that a liposomal formulation of siRNA might be used in vivo to silence the MMP-9 gene and could potentially serve as an important therapeutic alternative in patients with cerebral ischemia.
    URL, DOI BibTeX

    @article{Hu2009,
    	abstract = "RNA interference appears to have a great potential not only as an in vitro target validation, but also as a novel therapeutic strategy based on the highly specific and efficient silencing of a target gene. We hypothesize that MMP-9 siRNA can be effective as an MMP-9 protein inhibitor in a rat focal ischemia model. Male Sprague-Dawley rats (156) were subjected to 2 h of middle cerebral artery occlusion (by using the suture insertion method) followed by 24 h of reperfusion. In the treatment group, 5 microl MMP-9 siRNA was administrated by intracerebroventricular injection within 60 min after 2 h of focal ischemia. The siRNA transfection was demonstrated by fluorescence conjugated siRNA. Treatment with MMP-9 siRNA produced a significant reduction in the cerebral infarction volume, brain water content, mortality rate and accompanying neurological deficits. The followings were recorded: Evan's blue and IgG extravasation were reduced; the expression of MMP-9 mRNA and protein were significantly silenced; and immunohistochemistry and Western blot analysis revealed that the expression of MMP-9 and VEGF were reduced while occludin and collagen-IV were up-regulated in brain tissues. Our findings provide evidence that a liposomal formulation of siRNA might be used in vivo to silence the MMP-9 gene and could potentially serve as an important therapeutic alternative in patients with cerebral ischemia.",
    	author = "Hu, Qin and Chen, Chunhua and Yan, Junhao and Yang, Xiaomei and Shi, Xianzhong and Zhao, Jing and Lei, Jiliang and Yang, Lei and Wang, Ke and Chen, Lin and Huang, Hongyun and Han, Jingyan and Zhang, John H and Zhou, Changman",
    	doi = "10.1016/j.expneurol.2008.11.007",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hu et al. - 2009 - Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat mode.pdf:pdf",
    	issn = "1090-2430",
    	journal = "Experimental neurology",
    	keywords = "Animals,Brain,Brain Edema,Brain Edema: enzymology,Brain Edema: genetics,Brain Edema: therapy,Brain Infarction,Brain Infarction: enzymology,Brain Infarction: genetics,Brain Infarction: therapy,Brain: blood supply,Brain: enzymology,Brain: physiopathology,Collagen Type IV,Collagen Type IV: metabolism,Disease Models, Animal,Down-Regulation,Down-Regulation: genetics,Gene Expression Regulation, Enzymologic,Gene Expression Regulation, Enzymologic: genetics,Hypoxia-Ischemia, Brain,Hypoxia-Ischemia, Brain: enzymology,Hypoxia-Ischemia, Brain: genetics,Hypoxia-Ischemia, Brain: therapy,Infarction, Middle Cerebral Artery,Infarction, Middle Cerebral Artery: enzymology,Infarction, Middle Cerebral Artery: genetics,Infarction, Middle Cerebral Artery: therapy,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinase Inhibitors,Membrane Proteins,Membrane Proteins: metabolism,Occludin,RNA Interference,RNA, Messenger,RNA, Messenger: metabolism,RNA, Small Interfering,RNA, Small Interfering: genetics,Rats,Rats, Sprague-Dawley,Transfection,Transfection: methods,Up-Regulation,Up-Regulation: genetics,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism",
    	month = "",
    	number = 1,
    	pages = "35--46",
    	pmid = 19073180,
    	title = "{Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0014488608004305",
    	volume = 216,
    	year = 2009
    }
    
  24. Lubin Fang, Friederike Huber-Abel, Marko Teuchert, Corinna Hendrich, Johannes Dorst, Dagmar Schattauer, Heinz Zettlmeissel, Meinhard Wlaschek, Karin Scharffetter-Kochanek, Hayrettin Tumani, Albert C Ludolph and Johannes Brettschneider.
    Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS).. Journal of the neurological sciences 285(1-2):62–6, 2009.
    Abstract {Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001
    URL, DOI BibTeX

    @article{Fang2009,
    	abstract = "{Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001",
    	p = "",
    	r = "",
    	author = "Fang, Lubin and Huber-Abel, Friederike and Teuchert, Marko and Hendrich, Corinna and Dorst, Johannes and Schattauer, Dagmar and Zettlmeissel, Heinz and Wlaschek, Meinhard and Scharffetter-Kochanek, Karin and Tumani, Hayrettin and Ludolph, Albert C and Brettschneider, Johannes",
    	doi = "10.1016/j.jns.2009.05.025",
    	issn = "1878-5883",
    	journal = "Journal of the neurological sciences",
    	keywords = "Adult,Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Amyotrophic Lateral Sclerosis: metabolism,Chromatography, High Pressure Liquid,Disease Progression,Enzyme-Linked Immunosorbent Assay,Female,Humans,Male,Malondialdehyde,Malondialdehyde: blood,Malondialdehyde: cerebrospinal fluid,Malondialdehyde: metabolism,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: blood,Matrix Metalloproteinase 2: cerebrospinal fluid,Matrix Metalloproteinase 2: metabolism,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: blood,Matrix Metalloproteinase 9: cerebrospinal fluid,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinases,Matrix Metalloproteinases: blood,Matrix Metalloproteinases: cerebrospinal fluid,Matrix Metalloproteinases: metabolism,Middle Aged,Skin,Skin: metabolism,Time Factors",
    	month = "",
    	number = "1-2",
    	pages = "62--6",
    	pmid = 19523650,
    	publisher = "Elsevier",
    	title = "{Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS).}",
    	url = "http://www.jns-journal.com/article/S0022-510X(09)00630-3/abstract",
    	volume = 285,
    	year = 2009
    }
    
  25. Neetu Tyagi, William Gillespie, Jonathan C Vacek, Utpal Sen, Suresh C Tyagi and David Lominadze.
    Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway.. Journal of cellular physiology 220(1):257–66, 2009.
    Abstract Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and leads to blood-brain barrier dysfunction. Hcy competitively binds to gamma-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter receptors. However, the role of GABA-A receptor in Hcy-induced cerebrovascular remodeling is not clear. We hypothesized that Hcy causes cerebrovascular remodeling by increasing redox stress and MMP-9 activity via the extracellular signal-regulated kinase (ERK) signaling pathway and by inhibition of GABA-A receptors, thus behaving as an inhibitory neurotransmitter. Hcy-induced reactive oxygen species production was detected using the fluorescent probe, 2'-7'-dichlorodihydrofluorescein diacetate. Hcy increased nicotinamide adenine dinucleotide phosphate-oxidase-4 concomitantly suppressing thioredoxin. Hcy caused activation of MMP-9, measured by gelatin zymography. The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation. In parallel, Hcy caused phosphorylation of ERK and selectively decreased levels of tissue inhibitors of metalloproteinase-4 (TIMP-4). Treatment of the endothelial cell with muscimol restored the levels of TIMP-4 to the levels in control group. Hcy induced expression of iNOS and decreased eNOS expression, which lead to a decreased NO bioavailability. Furthermore muscimol attenuated Hcy-induced MMP-9 via ERK signaling pathway. These results suggest that Hcy competes with GABA-A receptors, inducing the oxidative stress transduction pathway and leading to ERK activation.
    URL, DOI BibTeX

    @article{Tyagi2009,
    	abstract = "Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and leads to blood-brain barrier dysfunction. Hcy competitively binds to gamma-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter receptors. However, the role of GABA-A receptor in Hcy-induced cerebrovascular remodeling is not clear. We hypothesized that Hcy causes cerebrovascular remodeling by increasing redox stress and MMP-9 activity via the extracellular signal-regulated kinase (ERK) signaling pathway and by inhibition of GABA-A receptors, thus behaving as an inhibitory neurotransmitter. Hcy-induced reactive oxygen species production was detected using the fluorescent probe, 2'-7'-dichlorodihydrofluorescein diacetate. Hcy increased nicotinamide adenine dinucleotide phosphate-oxidase-4 concomitantly suppressing thioredoxin. Hcy caused activation of MMP-9, measured by gelatin zymography. The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation. In parallel, Hcy caused phosphorylation of ERK and selectively decreased levels of tissue inhibitors of metalloproteinase-4 (TIMP-4). Treatment of the endothelial cell with muscimol restored the levels of TIMP-4 to the levels in control group. Hcy induced expression of iNOS and decreased eNOS expression, which lead to a decreased NO bioavailability. Furthermore muscimol attenuated Hcy-induced MMP-9 via ERK signaling pathway. These results suggest that Hcy competes with GABA-A receptors, inducing the oxidative stress transduction pathway and leading to ERK activation.",
    	author = "Tyagi, Neetu and Gillespie, William and Vacek, Jonathan C and Sen, Utpal and Tyagi, Suresh C and Lominadze, David",
    	doi = "10.1002/jcp.21757",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tyagi et al. - 2009 - Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway.pdf:pdf",
    	issn = "1097-4652",
    	journal = "Journal of cellular physiology",
    	keywords = "Animals,Cell Line,Collagen Type IV,Collagen Type IV: metabolism,Elastin,Elastin: metabolism,Endothelial Cells,Endothelial Cells: drug effects,Endothelial Cells: enzymology,Enzyme Activation,Extracellular Signal-Regulated MAP Kinases,Extracellular Signal-Regulated MAP Kinases: metabo,GABA Agonists,GABA Agonists: pharmacology,GABA-A Receptor Agonists,Homocysteine,Homocysteine: metabolism,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Mice,Muscimol,Muscimol: pharmacology,NADPH Oxidase,NADPH Oxidase: metabolism,Nitric Oxide,Nitric Oxide Synthase Type II,Nitric Oxide Synthase Type II: metabolism,Nitric Oxide Synthase Type III,Nitric Oxide Synthase Type III: metabolism,Nitric Oxide: metabolism,Oxidative Stress,Oxidative Stress: drug effects,Phosphorylation,Reactive Oxygen Species,Reactive Oxygen Species: metabolism,Receptors, GABA-A,Receptors, GABA-A: metabolism,Signal Transduction,Signal Transduction: drug effects,Thioredoxins,Thioredoxins: metabolism,Tissue Inhibitor of Metalloproteinases,Tissue Inhibitor of Metalloproteinases: metabolism",
    	month = "",
    	number = 1,
    	pages = "257--66",
    	pmid = 19308943,
    	title = "{Activation of GABA-A receptor ameliorates homocysteine-induced MMP-9 activation by ERK pathway.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2811271\&tool=pmcentrez\&rendertype=abstract",
    	volume = 220,
    	year = 2009
    }
    
  26. Karim Hnia, Jérôme Gayraud, Gérald Hugon, Michèle Ramonatxo, Sabine De La Porte, Stefan Matecki and Dominique Mornet.
    L-arginine decreases inflammation and modulates the nuclear factor-kappaB/matrix metalloproteinase cascade in mdx muscle fibers.. The American journal of pathology 172(6):1509–19, 2008.
    Abstract Duchenne muscular dystrophy (DMD) is a lethal, X-linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine, the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with l-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappaB levels and activity. NF-kappaB serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappaB signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-kappaB. We show that the inhibitory effect of L-arginine on the NF-kappaB/MMP cascade reduces beta-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-kappaB-related signaling cascades could be potential therapeutic targets for DMD management.
    URL, DOI BibTeX

    @article{Hnia2008,
    	abstract = "Duchenne muscular dystrophy (DMD) is a lethal, X-linked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine, the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with l-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-kappaB levels and activity. NF-kappaB serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-kappaB signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-kappaB. We show that the inhibitory effect of L-arginine on the NF-kappaB/MMP cascade reduces beta-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-kappaB-related signaling cascades could be potential therapeutic targets for DMD management.",
    	author = "Hnia, Karim and Gayraud, J\'{e}r\^{o}me and Hugon, G\'{e}rald and Ramonatxo, Mich\`{e}le and {De La Porte}, Sabine and Matecki, Stefan and Mornet, Dominique",
    	doi = "10.2353/ajpath.2008.071009",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hnia et al. - 2008 - L-arginine decreases inflammation and modulates the nuclear factor-kappaBmatrix metalloproteinase cascade in mdx mu.pdf:pdf",
    	issn = "1525-2191",
    	journal = "The American journal of pathology",
    	keywords = "Animals,Arginine,Arginine: pharmacology,Inflammation,Inflammation: metabolism,Inflammation: pathology,MAP Kinase Signaling System,MAP Kinase Signaling System: physiology,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: physiology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: physiology,Mice,Mice, Inbred mdx,Muscle Fibers, Skeletal,Muscle Fibers, Skeletal: physiology,Muscle, Skeletal,Muscle, Skeletal: pathology,Muscular Dystrophy, Duchenne,Muscular Dystrophy, Duchenne: drug therapy,Muscular Dystrophy, Duchenne: metabolism,Muscular Dystrophy, Duchenne: pathology,NF-kappa B,NF-kappa B: physiology,Nitric Oxide Synthase,Nitric Oxide Synthase: metabolism,Regeneration,Signal Transduction",
    	month = "",
    	number = 6,
    	pages = "1509--19",
    	pmid = 18458097,
    	title = "{L-arginine decreases inflammation and modulates the nuclear factor-kappaB/matrix metalloproteinase cascade in mdx muscle fibers.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2408412\&tool=pmcentrez\&rendertype=abstract",
    	volume = 172,
    	year = 2008
    }
    
  27. Margrit Hollborn, Christina Stathopoulos, Anja Steffen, Peter Wiedemann, Leon Kohen and Andreas Bringmann.
    Positive feedback regulation between MMP-9 and VEGF in human RPE cells.. Investigative ophthalmology & visual science 48(9):4360–7, September 2007.
    Abstract PURPOSE: The proteolytic activity of matrix metalloproteinases (MMPs) is involved in pathologic angiogenesis in the eye. However, it is unknown whether MMPs may stimulate the production of the major angiogenic factor, vascular endothelial growth factor (VEGF). The authors investigated whether MMP-2 and MMP-9 alter the expression of VEGF by retinal pigment epithelial (RPE) cells. They also sought to determine the effects of MMPs on cellular proliferation and migration and the effect of triamcinolone acetonide on MMP-9-evoked cellular responses. METHODS: Human RPE cell cultures were stimulated with MMP-2 or MMP-9. The gene expression and secretion of MMP-9 and VEGF were determined by real-time RT-PCR and ELISA, respectively. Cellular proliferation was investigated with a bromodeoxyuridine immunoassay, and chemotaxis was examined with a Boyden chamber assay. RESULTS: Under control conditions, RPE cells in vitro expressed a significantly higher amount of mRNA for MMP-2 than for MMP-9. Chemical hypoxia caused upregulation of the gene expression of both MMPs, whereas VEGF increased the gene expression and secretion of MMP-9. The hypoxic expression of MMP-9 was mediated by autocrine VEGF signaling. Exogenous MMP-9 increased the gene expression and secretion of VEGF, whereas MMP-2 reduced the secretion of VEGF. MMP-2 and MMP-9 did not alter the proliferation but stimulated the migration of RPE cells. Triamcinolone fully inhibited the stimulatory effect of MMP-9 on the expression of VEGF and the VEGF-evoked increase in the expression of MMP-9. However, triamcinolone had no effect on the motogenic effect of MMP-9. CONCLUSIONS: There is a positive feedback regulation between MMP-9 and VEGF in RPE cells. The hypoxic expression of MMP-9 may stimulate the production and secretion of VEGF under pathologic conditions. Triamcinolone inhibits the positive feedback regulation between MMP-9 and VEGF under hypoxic conditions through inhibition of the gene expression of MMP-9 and the secretion of VEGF.
    URL, DOI BibTeX

    @article{Hollborn2007,
    	abstract = "PURPOSE: The proteolytic activity of matrix metalloproteinases (MMPs) is involved in pathologic angiogenesis in the eye. However, it is unknown whether MMPs may stimulate the production of the major angiogenic factor, vascular endothelial growth factor (VEGF). The authors investigated whether MMP-2 and MMP-9 alter the expression of VEGF by retinal pigment epithelial (RPE) cells. They also sought to determine the effects of MMPs on cellular proliferation and migration and the effect of triamcinolone acetonide on MMP-9-evoked cellular responses. METHODS: Human RPE cell cultures were stimulated with MMP-2 or MMP-9. The gene expression and secretion of MMP-9 and VEGF were determined by real-time RT-PCR and ELISA, respectively. Cellular proliferation was investigated with a bromodeoxyuridine immunoassay, and chemotaxis was examined with a Boyden chamber assay. RESULTS: Under control conditions, RPE cells in vitro expressed a significantly higher amount of mRNA for MMP-2 than for MMP-9. Chemical hypoxia caused upregulation of the gene expression of both MMPs, whereas VEGF increased the gene expression and secretion of MMP-9. The hypoxic expression of MMP-9 was mediated by autocrine VEGF signaling. Exogenous MMP-9 increased the gene expression and secretion of VEGF, whereas MMP-2 reduced the secretion of VEGF. MMP-2 and MMP-9 did not alter the proliferation but stimulated the migration of RPE cells. Triamcinolone fully inhibited the stimulatory effect of MMP-9 on the expression of VEGF and the VEGF-evoked increase in the expression of MMP-9. However, triamcinolone had no effect on the motogenic effect of MMP-9. CONCLUSIONS: There is a positive feedback regulation between MMP-9 and VEGF in RPE cells. The hypoxic expression of MMP-9 may stimulate the production and secretion of VEGF under pathologic conditions. Triamcinolone inhibits the positive feedback regulation between MMP-9 and VEGF under hypoxic conditions through inhibition of the gene expression of MMP-9 and the secretion of VEGF.",
    	author = "Hollborn, Margrit and Stathopoulos, Christina and Steffen, Anja and Wiedemann, Peter and Kohen, Leon and Bringmann, Andreas",
    	doi = "10.1167/iovs.06-1234",
    	issn = "0146-0404",
    	journal = "Investigative ophthalmology \& visual science",
    	keywords = "Cell Hypoxia,Cell Movement,Cell Proliferation,Cells, Cultured,Feedback, Physiological,Feedback, Physiological: drug effects,Feedback, Physiological: physiology,Gene Expression Regulation,Glucocorticoids,Glucocorticoids: pharmacology,Humans,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: genetics,Matrix Metalloproteinase 2: metabolism,Matrix Metalloproteinase 2: pharmacology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinase 9: pharmacology,Pigment Epithelium of Eye,Pigment Epithelium of Eye: drug effects,Pigment Epithelium of Eye: metabolism,RNA, Messenger,RNA, Messenger: metabolism,Triamcinolone Acetonide,Triamcinolone Acetonide: pharmacology,Up-Regulation,Vascular Endothelial Growth Factor A,Vascular Endothelial Growth Factor A: genetics,Vascular Endothelial Growth Factor A: metabolism",
    	month = "sep",
    	number = 9,
    	pages = "4360--7",
    	pmid = 17724228,
    	title = "{Positive feedback regulation between MMP-9 and VEGF in human RPE cells.}",
    	url = "http://www.iovs.org/content/48/9/4360",
    	volume = 48,
    	year = 2007
    }
    
  28. Mahmoud Kiaei, Khatuna Kipiani, Noel Y Calingasan, Elizabeth Wille, Junyu Chen, Beate Heissig, Shahin Rafii, Stefan Lorenzl and Flint M Beal.
    Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis.. Experimental neurology 205(1):74–81, 2007.
    Abstract Whether increased levels of matrix metalloproteinases (MMPs) correspond to a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) needs to be determined and it is actively being pursued. Here we present evidence suggesting that MMP-9 contributes to the motor neuron cell death in ALS. We examined the role of MMP-9 in a mouse model of familial ALS and found that lack of MMP-9 increased survival (31%) in G93A SOD1 mice. Also, MMP-9 deficiency in G93A mice significantly attenuated neuronal loss, and reduced neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord. These findings suggest that MMP-9 is an important player in the pathogenesis of ALS. Our data suggest that the mechanism for MMP-9 neurotoxicity in ALS may be by upregulating neuronal TNF-alpha and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.
    URL, DOI BibTeX

    @article{Kiaei2007,
    	abstract = "Whether increased levels of matrix metalloproteinases (MMPs) correspond to a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) needs to be determined and it is actively being pursued. Here we present evidence suggesting that MMP-9 contributes to the motor neuron cell death in ALS. We examined the role of MMP-9 in a mouse model of familial ALS and found that lack of MMP-9 increased survival (31\%) in G93A SOD1 mice. Also, MMP-9 deficiency in G93A mice significantly attenuated neuronal loss, and reduced neuronal TNF-alpha and FasL immunoreactivities in the lumbar spinal cord. These findings suggest that MMP-9 is an important player in the pathogenesis of ALS. Our data suggest that the mechanism for MMP-9 neurotoxicity in ALS may be by upregulating neuronal TNF-alpha and FasL expression and activation. This study provides new mechanism and suggests that MMP inhibitors may offer a new therapeutic strategy for ALS.",
    	author = "Kiaei, Mahmoud and Kipiani, Khatuna and Calingasan, Noel Y and Wille, Elizabeth and Chen, Junyu and Heissig, Beate and Rafii, Shahin and Lorenzl, Stefan and Beal, M Flint",
    	doi = "10.1016/j.expneurol.2007.01.036",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kiaei et al. - 2007 - Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extend.pdf:pdf",
    	issn = "0014-4886",
    	journal = "Experimental neurology",
    	keywords = "ADAM Proteins,Alanine,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Fas Ligand Protein,Fas Ligand Protein: metabolism,Glycine,Humans,Immunologic Techniques,Longevity,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: deficiency,Matrix Metalloproteinase 9: metabolism,Mice,Mice, Inbred Strains,Mice, Transgenic,Mutation,Nervous System,Nervous System: metabolism,Nervous System: pathology,Neuroglia,Neuroglia: metabolism,Neurons,Neurons: metabolism,Staining and Labeling,Superoxide Dismutase,Superoxide Dismutase: genetics,Tumor Necrosis Factor-alpha,Tumor Necrosis Factor-alpha: metabolism",
    	month = "",
    	number = 1,
    	pages = "74--81",
    	pmid = 17362932,
    	title = "{Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0014488607000398",
    	volume = 205,
    	year = 2007
    }
    
  29. Susanne Petri, Mahmoud Kiaei, Elizabeth Wille, Noel Y Calingasan and M Flint Beal.
    Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.. Journal of the neurological sciences 251(1-2):44–9, December 2006.
    Abstract ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.
    URL, DOI BibTeX

    @article{Petri2006,
    	abstract = "ALS is a devastating neurodegenerative disorder for which no effective treatment exists. The precise molecular mechanisms underlying the selective degeneration of motor neurons are still unknown. A motor neuron specific apoptotic pathway involving Fas and NO has been discovered. Motor neurons from ALS-mice have an increased sensitivity to Fas-induced cell death via this pathway. In this study we therefore crossed G93A-SOD1 overexpressing ALS mice with Fas ligand (FasL) mutant (gld) mice to investigate whether the reduced Fas signaling could have beneficial effects on motor neuron death. G93A-SOD1 mutant mice with a homozygous FasL mutant showed a modest but statistically significant extension of survival, and reduced loss of motor neurons. These results indicate that motor neuron apoptosis triggered by Fas is relevant in ALS pathogenesis.",
    	author = "Petri, Susanne and Kiaei, Mahmoud and Wille, Elizabeth and Calingasan, Noel Y and {Flint Beal}, M",
    	doi = "10.1016/j.jns.2006.08.013",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Petri et al. - 2006 - Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.pdf:pdf",
    	issn = "0022-510X",
    	journal = "Journal of the neurological sciences",
    	keywords = "Age Factors,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: mortality,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Behavior, Animal,Cell Count,Cell Count: methods,Disease Models, Animal,Fas Ligand Protein,Fas Ligand Protein: metabolism,Fas Ligand Protein: physiology,Immunohistochemistry,Immunohistochemistry: methods,Mice,Mice, Inbred C57BL,Mice, Transgenic,Motor Activity,Motor Activity: physiology,Motor Neurons,Motor Neurons: metabolism,Nitric Oxide Synthase Type I,Nitric Oxide Synthase Type I: metabolism,Probability,Spinal Cord,Spinal Cord: pathology,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Survival Analysis,Tyrosine,Tyrosine: analogs \& derivatives,Tyrosine: metabolism",
    	month = "dec",
    	number = "1-2",
    	pages = "44--9",
    	pmid = 17049562,
    	title = "{Loss of Fas ligand-function improves survival in G93A-transgenic ALS mice.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0022510X06003741",
    	volume = 251,
    	year = 2006
    }
    
  30. Véronique Masson, Laura Rodriguez Ballina, Carine Munaut, Ben Wielockx, Maud Jost, Catherine Maillard, Silvia Blacher, Khalid Bajou, Takeshi Itoh, Shige Itohara, Zena Werb, Claude Libert, Jean-Michel Foidart and Agnès Noël.
    Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19(2):234–6, February 2005.
    Abstract The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP-9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP-2 and MMP-3 were stromal. Neither the single deficiency of MMP-2, MMP-3, or MMP-9, nor the combined absence of MMP-9 and MMP-3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP-2:MMP-9-deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP-2 and MMP-9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP-2 and MMP-9. Our data demonstrate for the first time in an experimental model that MMP-2 and MMP-9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes.
    URL, DOI BibTeX

    @article{Masson2005,
    	abstract = "The matrix metalloproteinases (MMPs) play a key role in normal and pathological angiogenesis by mediating extracellular matrix degradation and/or controlling the biological activity of growth factors, chemokines, and/or cytokines. Specific functions of individual MMPs as anti- or proangiogenic mediators remain to be elucidated. In the present study, we assessed the impact of single or combined MMP deficiencies in in vivo and in vitro models of angiogenesis (malignant keratinocyte transplantation and the aortic ring assay, respectively). MMP-9 was predominantly expressed by neutrophils in tumor transplants, whereas MMP-2 and MMP-3 were stromal. Neither the single deficiency of MMP-2, MMP-3, or MMP-9, nor the combined absence of MMP-9 and MMP-3 did impair tumor invasion and vascularization in vivo. However, there was a striking cooperative effect in double MMP-2:MMP-9-deficient mice as demonstrated by the absence of tumor vascularization and invasion. In contrast, the combined lack of MMP-2 and MMP-9 did not impair the in vitro capillary outgrowth from aortic rings. These results point to the importance of a cross talk between several host cells for the in vivo tumor promoting and angiogenic effects of MMP-2 and MMP-9. Our data demonstrate for the first time in an experimental model that MMP-2 and MMP-9 cooperate in promoting the in vivo invasive and angiogenic phenotype of malignant keratinocytes.",
    	author = {Masson, V\'{e}ronique and de la Ballina, Laura Rodriguez and Munaut, Carine and Wielockx, Ben and Jost, Maud and Maillard, Catherine and Blacher, Silvia and Bajou, Khalid and Itoh, Takeshi and Itohara, Shige and Werb, Zena and Libert, Claude and Foidart, Jean-Michel and No\"{e}l, Agn\`{e}s},
    	doi = "10.1096/fj.04-2140fje",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Masson et al. - 2005 - Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.pdf:pdf",
    	issn = "1530-6860",
    	journal = "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
    	keywords = "Animals,Cell Line, Tumor,Keratinocytes,Keratinocytes: chemistry,Keratinocytes: metabolism,Keratinocytes: pathology,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: deficiency,Matrix Metalloproteinase 2: physiology,Matrix Metalloproteinase 3,Matrix Metalloproteinase 3: deficiency,Matrix Metalloproteinase 3: physiology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: deficiency,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: physiology,Mice,Mice, Inbred Strains,Mice, Mutant Strains,Neoplasm Invasiveness,Neoplasm Invasiveness: genetics,Neoplasm Invasiveness: pathology,Neoplasm Transplantation,Neoplasm Transplantation: methods,Neoplasm Transplantation: pathology,Neoplasms,Neoplasms: blood supply,Neoplasms: enzymology,Neoplasms: genetics,Neoplasms: pathology,Neovascularization, Pathologic,Neovascularization, Pathologic: enzymology,Promoter Regions, Genetic,Promoter Regions, Genetic: genetics",
    	month = "feb",
    	number = 2,
    	pages = "234--6",
    	pmid = 15550552,
    	title = "{Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2771171\&tool=pmcentrez\&rendertype=abstract",
    	volume = 19,
    	year = 2005
    }
    
  31. Enrico Giraudo, Masahiro Inoue and Douglas Hanahan.
    An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.. The Journal of clinical investigation 114(5):623–33, 2004.
    Abstract A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA's actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an "unconventional" MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.
    URL, DOI BibTeX

    @article{Giraudo2004,
    	abstract = {A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA's actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an "unconventional" MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.},
    	author = "Giraudo, Enrico and Inoue, Masahiro and Hanahan, Douglas",
    	doi = "10.1172/JCI22087",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Giraudo, Inoue, Hanahan - 2004 - An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcin.pdf:pdf",
    	issn = "0021-9738",
    	journal = "The Journal of clinical investigation",
    	keywords = "Angiogenesis Inhibitors,Angiogenesis Inhibitors: pharmacology,Animals,Cell Movement,Cell Movement: drug effects,Cervical Intraepithelial Neoplasia,Cervical Intraepithelial Neoplasia: blood supply,Cervical Intraepithelial Neoplasia: enzymology,Cervical Intraepithelial Neoplasia: pathology,Diphosphonates,Diphosphonates: pharmacology,Enzyme Activation,Enzyme Activation: drug effects,Female,Humans,Imidazoles,Imidazoles: pharmacology,Macrophage Activation,Macrophage Activation: drug effects,Macrophages,Macrophages: drug effects,Macrophages: enzymology,Macrophages: pathology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: metabolism,Matrix Metalloproteinase Inhibitors,Mice,Mice, Transgenic,Neovascularization, Pathologic,Neovascularization, Pathologic: drug therapy,Neovascularization, Pathologic: enzymology,Neovascularization, Pathologic: pathology,Uterine Cervical Neoplasms,Uterine Cervical Neoplasms: blood supply,Uterine Cervical Neoplasms: drug therapy,Uterine Cervical Neoplasms: genetics,Uterine Cervical Neoplasms: pathology,Vascular Endothelial Growth Factors,Vascular Endothelial Growth Factors: metabolism",
    	language = "en",
    	month = "",
    	number = 5,
    	pages = "623--33",
    	pmid = 15343380,
    	publisher = "American Society for Clinical Investigation",
    	title = "{An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis.}",
    	url = "http://www.jci.org/articles/view/22087",
    	volume = 114,
    	year = 2004
    }
    
  32. Marta Toth, Irina Chvyrkova, M.Margarida Bernardo, Sonia Hernandez-Barrantes and Rafael Fridman.
    Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes. Biochemical and Biophysical Research Communications 308(2):386–395, August 2003.
    Abstract MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.
    URL, DOI BibTeX

    @article{Toth2003,
    	abstract = "MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.",
    	author = "Toth, Marta and Chvyrkova, Irina and Bernardo, M.Margarida and Hernandez-Barrantes, Sonia and Fridman, Rafael",
    	doi = "10.1016/S0006-291X(03)01405-0",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Toth et al. - 2003 - Pro-MMP-9 activation by the MT1-MMPMMP-2 axis and MMP-3 role of TIMP-2 and plasma membranes.pdf:pdf",
    	issn = "0006291X",
    	journal = "Biochemical and Biophysical Research Communications",
    	keywords = "Matrix metalloproteinases,Plasma membrane,Protease,Protease inhibitor,Zymogen",
    	month = "aug",
    	number = 2,
    	pages = "386--395",
    	title = "{Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0006291X03014050",
    	volume = 308,
    	year = 2003
    }
    
  33. S Lorenzl.
    Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. Neurochemistry International 43(3):191–196, 2003.
    Abstract Matrix metalloproteinases (MMPs) may play a role in the pathophysiology of Alzheimer’s disease (AD). MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are elevated in postmortem brain tissue of AD patients. MMPs and TIMPs are found in neurons, microglia, vascular endothelial cells and leukocytes. The aim of this study was to determine whether circulating levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 are elevated in the plasma of AD patients. We compared AD patients to age- and gender-matched controls as well as to Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) patients. There was constitutive expression of gelatinase A (MMP-2), and gelatinase B (MMP-9), in all the samples as shown by zymographic analysis. Levels of MMP-9 were significantly (P=0.003) elevated in the plasma of AD patients as compared to controls. Plasma levels of MMP-2, TIMP-1 and TIMP-2 were unchanged. There were no significant changes of MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in PD and ALS samples. TIMP-1 and TIMP-2 were significantly correlated with MMP-9 in the AD patients. ApoE genotyping of plasma samples showed that levels of MMP-2, TIMP-1 and TIMP-2 and MMP-9 were not significantly different between the ApoE subgroups. These findings indicate that circulating levels of MMP-9 are increased in AD and may contribute to disease pathology.
    URL, DOI BibTeX

    @article{Lorenzl2003,
    	abstract = "Matrix metalloproteinases (MMPs) may play a role in the pathophysiology of Alzheimer’s disease (AD). MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) are elevated in postmortem brain tissue of AD patients. MMPs and TIMPs are found in neurons, microglia, vascular endothelial cells and leukocytes. The aim of this study was to determine whether circulating levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 are elevated in the plasma of AD patients. We compared AD patients to age- and gender-matched controls as well as to Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) patients. There was constitutive expression of gelatinase A (MMP-2), and gelatinase B (MMP-9), in all the samples as shown by zymographic analysis. Levels of MMP-9 were significantly (P=0.003) elevated in the plasma of AD patients as compared to controls. Plasma levels of MMP-2, TIMP-1 and TIMP-2 were unchanged. There were no significant changes of MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in PD and ALS samples. TIMP-1 and TIMP-2 were significantly correlated with MMP-9 in the AD patients. ApoE genotyping of plasma samples showed that levels of MMP-2, TIMP-1 and TIMP-2 and MMP-9 were not significantly different between the ApoE subgroups. These findings indicate that circulating levels of MMP-9 are increased in AD and may contribute to disease pathology.",
    	author = "Lorenzl, S",
    	doi = "10.1016/S0197-0186(03)00004-4",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lorenzl - 2003 - Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease.pdf:pdf",
    	issn = 01970186,
    	journal = "Neurochemistry International",
    	keywords = "Alzheimer’s disease,Amyotrophic lateral sclerosis,Matrix metalloproteinases,Parkinson’s disease,Tissue inhibitors of metalloproteinases",
    	month = "",
    	number = 3,
    	pages = "191--196",
    	title = "{Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0197018603000044",
    	volume = 43,
    	year = 2003
    }
    
  34. Vincent Lambert, Ben Wielockx, Carine Munaut, Catherine Galopin, Maud Jost, Takeshi Itoh, Zena Werb, Andrew Baker, Claude Libert, Hans-Willi Krell, Jean-Michel Foidart, Agnès Noël and Jean-Marie Rakic.
    MMP-2 and MMP-9 synergize in promoting choroidal neovascularization.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17(15):2290–2, 2003.
    Abstract Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization.
    URL, DOI BibTeX

    @article{Lambert2003,
    	abstract = "Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization.",
    	author = {Lambert, Vincent and Wielockx, Ben and Munaut, Carine and Galopin, Catherine and Jost, Maud and Itoh, Takeshi and Werb, Zena and Baker, Andrew and Libert, Claude and Krell, Hans-Willi and Foidart, Jean-Michel and No\"{e}l, Agn\`{e}s and Rakic, Jean-Marie},
    	doi = "10.1096/fj.03-0113fje",
    	issn = "1530-6860",
    	journal = "FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
    	keywords = "Animals,Choroid,Choroid: chemistry,Choroid: enzymology,Choroid: pathology,Choroidal Neovascularization,Choroidal Neovascularization: enzymology,Choroidal Neovascularization: etiology,Choroidal Neovascularization: pathology,Fibrin,Fibrin: analysis,Fibrinogen,Fibrinogen: analysis,Gene Expression Regulation,Matrix Metalloproteinase 2,Matrix Metalloproteinase 2: genetics,Matrix Metalloproteinase 2: physiology,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: genetics,Matrix Metalloproteinase 9: physiology,Matrix Metalloproteinase Inhibitors,Mice,Mice, Knockout,Models, Biological,Protease Inhibitors,Protease Inhibitors: pharmacology",
    	month = "",
    	number = 15,
    	pages = "2290--2",
    	pmid = 14563686,
    	title = "{MMP-2 and MMP-9 synergize in promoting choroidal neovascularization.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/14563686",
    	volume = 17,
    	year = 2003
    }
    
  35. F Menzies.
    Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochemistry International 40(6):543–551, May 2002.
    Abstract The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.
    URL, DOI BibTeX

    @article{Menzies2002,
    	abstract = "The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.",
    	author = "Menzies, F",
    	doi = "10.1016/S0197-0186(01)00125-5",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Menzies - 2002 - Mitochondrial involvement in amyotrophic lateral sclerosis.pdf:pdf",
    	issn = 01970186,
    	journal = "Neurochemistry International",
    	keywords = "Amyotrophic lateral sclerosis,Electron transfer chain,Excitotoxicity,Mitochondria,Neurodegeneration,Oxidative stress,Superoxide dismutase",
    	month = "may",
    	number = 6,
    	pages = "543--551",
    	title = "{Mitochondrial involvement in amyotrophic lateral sclerosis}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0197018601001255",
    	volume = 40,
    	year = 2002
    }
    
  36. S M Plummer, K A Holloway, M M Manson, R J Munks, A Kaptein, S Farrow and L Howells.
    Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.. Oncogene 18(44):6013–20, October 1999.
    Abstract Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.
    URL, DOI BibTeX

    @article{Plummer1999,
    	abstract = "Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90\%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention.",
    	author = "Plummer, S M and Holloway, K A and Manson, M M and Munks, R J and Kaptein, A and Farrow, S and Howells, L",
    	doi = "10.1038/sj.onc.1202980",
    	issn = "0950-9232",
    	journal = "Oncogene",
    	keywords = "Antineoplastic Agents,Antineoplastic Agents: pharmacology,Caffeic Acids,Caffeic Acids: pharmacology,Colonic Neoplasms,Colonic Neoplasms: drug therapy,Colonic Neoplasms: metabolism,Curcumin,Curcumin: pharmacology,Cyclooxygenase 2,Dose-Response Relationship, Drug,Enzyme Inhibitors,Enzyme Inhibitors: pharmacology,Humans,I-kappa B Kinase,I-kappa B Proteins,I-kappa B Proteins: drug effects,I-kappa B Proteins: metabolism,Isoenzymes,Isoenzymes: drug effects,Isoenzymes: metabolism,Membrane Proteins,NF-kappa B,NF-kappa B: drug effects,NF-kappa B: genetics,NF-kappa B: metabolism,Phenylethyl Alcohol,Phenylethyl Alcohol: analogs \& derivatives,Phenylethyl Alcohol: pharmacology,Polyenes,Polyenes: pharmacology,Prostaglandin-Endoperoxide Synthases,Prostaglandin-Endoperoxide Synthases: drug effects,Prostaglandin-Endoperoxide Synthases: metabolism,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: drug effects,Protein-Serine-Threonine Kinases: metabolism,Signal Transduction,Tetradecanoylphorbol Acetate,Tetradecanoylphorbol Acetate: pharmacology,Tumor Necrosis Factor-alpha,Tumor Necrosis Factor-alpha: pharmacology",
    	month = "oct",
    	number = 44,
    	pages = "6013--20",
    	pmid = 10557090,
    	title = "{Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10557090",
    	volume = 18,
    	year = 1999
    }
    
  37. S Bellosta, D Via, M Canavesi, P Pfister, R Fumagalli, R Paoletti and F Bernini.
    HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology 18(11):1671–1678, 1998.
    Abstract Abstract–Macrophages secrete matrix metalloproteinases (MMPs) that may weaken the fibrous cap of atherosclerotic plaque, predisposing its fissuration. The 92-kDa gelatinase B (MMP-9) has been identified in abdominal aortic aneurysms and in atherosclerotic tissues. Fluvastatin, through the inhibition of the isoprenoid pathway, inhibits major processes of atherogenesis in experimental models (smooth muscle cell migration and proliferation and cholesterol accumulation in macrophages). We studied the effect of fluvastatin on the activity of MMP-9 in mouse and human macrophages in culture. Conditioned media of cells treated for 24 hours with fluvastatin were analyzed by gelatin zymography. In mouse macrophages, fluvastatin (5 to 100 micromol/L) significantly inhibited in a dose-dependent manner MMP-9 activity from 20% to 40% versus control. The drug, at a concentration as low as 5 micromol/L, inhibited MMP-9 activity (approx30%) in human monocyte-derived macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated MMP-9 activity by 50%, and fluvastatin inhibited this enhanced activity up to 50% in both mouse and human macrophages. The above results on the secretion of MMP-9 were confirmed by Western blotting and ELISA. The inhibitory effect of fluvastatin was overcome by the simultaneous addition of exogenous mevalonate (100 micromol/L), a precursor of isoprenoids. Fluvastatin's effect was fully reversible, and the drug did not cause any cellular toxicity. The statin did not block directly the in vitro activation of the secreted protease. Similar data were obtained with simvastatin. Altogether, our data indicate an inhibition of MMP-9 secretion by the drug. This effect is mediated by the inhibition of synthesis of mevalonate, a precursor of numerous derivatives essential for several cellular functions.
    URL, DOI BibTeX

    @article{Bellosta1998,
    	abstract = "Abstract--Macrophages secrete matrix metalloproteinases (MMPs) that may weaken the fibrous cap of atherosclerotic plaque, predisposing its fissuration. The 92-kDa gelatinase B (MMP-9) has been identified in abdominal aortic aneurysms and in atherosclerotic tissues. Fluvastatin, through the inhibition of the isoprenoid pathway, inhibits major processes of atherogenesis in experimental models (smooth muscle cell migration and proliferation and cholesterol accumulation in macrophages). We studied the effect of fluvastatin on the activity of MMP-9 in mouse and human macrophages in culture. Conditioned media of cells treated for 24 hours with fluvastatin were analyzed by gelatin zymography. In mouse macrophages, fluvastatin (5 to 100 \{micro\}mol/L) significantly inhibited in a dose-dependent manner MMP-9 activity from 20\% to 40\% versus control. The drug, at a concentration as low as 5 \{micro\}mol/L, inhibited MMP-9 activity (\{approx\}30\%) in human monocyte-derived macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated MMP-9 activity by 50\%, and fluvastatin inhibited this enhanced activity up to 50\% in both mouse and human macrophages. The above results on the secretion of MMP-9 were confirmed by Western blotting and ELISA. The inhibitory effect of fluvastatin was overcome by the simultaneous addition of exogenous mevalonate (100 \{micro\}mol/L), a precursor of isoprenoids. Fluvastatin's effect was fully reversible, and the drug did not cause any cellular toxicity. The statin did not block directly the in vitro activation of the secreted protease. Similar data were obtained with simvastatin. Altogether, our data indicate an inhibition of MMP-9 secretion by the drug. This effect is mediated by the inhibition of synthesis of mevalonate, a precursor of numerous derivatives essential for several cellular functions.",
    	author = "Bellosta, S. and Via, D. and Canavesi, M. and Pfister, P. and Fumagalli, R. and Paoletti, R. and Bernini, F.",
    	doi = "10.1161/01.ATV.18.11.1671",
    	issn = "1079-5642",
    	journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
    	month = "",
    	number = 11,
    	pages = "1671--1678",
    	title = "{HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages}",
    	url = "http://atvb.ahajournals.org/content/18/11/1671.short",
    	volume = 18,
    	year = 1998
    }
    

  38. Int J Dev Biol - Distinct patterns of MMP-9 and MMP-2 activity in slow and fast twitch skeletal muscle regeneration in vivo.
    URL BibTeX

    @misc{,
    	keywords = "MMP-2,MMP-9,myogenesis in vitro,skeletal muscle regeneration",
    	title = "{Int J Dev Biol - Distinct patterns of MMP-9 and MMP-2 activity in slow and fast twitch skeletal muscle regeneration in vivo}",
    	url = "http://www.ijdb.ehu.es/web/paper.php?doi=072331mz",
    	urldate = "01/05/14"
    }
    
  39. J Iłzecka, Z Stelmasiak and B Dobosz.
    [Matrix metalloproteinase-9 (MMP-9) activity in cerebrospinal fluid of amyotrophic lateral sclerosis patients].. Neurologia i neurochirurgia polska 35(6):1035–43.
    Abstract Matrix metalloproteinase-9 (MMP-9) is a member of the family of zinc-dependent endopeptidases that degrade extracellular matrix proteins. It can be activated by serine proteinases or by superoxide radicals. The motor neurons in amyotrophic lateral sclerosis patients express significantly higher levels of MMP-9, suggesting a role in neurodegeneration. The aim of the study was to investigate MMP-9 in cerebrospinal fluid from amyotrophic lateral sclerosis patients. MMP-9 was measured by enzyme-linked immunosorbent assay ELISA in cerebrospinal fluid from 24 amyotrophic lateral sclerosis patients and 15 controls. The mean amyotrophic lateral sclerosis duration was 18 months. According to Munsat ALS Health State Scale, the patients were divided into four groups: mild, moderate, severe, terminal. The patients were also divided into groups with shorter (below 12 months) and longer (above 12 months) duration of the disease. MMP-9 level was insignificantly lower in the cerebrospinal fluid from amyotrophic lateral sclerosis patients compared with controls. MMP-9 level showed a tendency to decrease with clinical status worsening, however this correlation was not statistically significant. The difference between MMP-9 level in the cerebrospinal fluid between the groups of patients with shorter and longer duration of amyotrophic lateral sclerosis was not significant.
    URL BibTeX

    @article{Izecka,
    	abstract = "Matrix metalloproteinase-9 (MMP-9) is a member of the family of zinc-dependent endopeptidases that degrade extracellular matrix proteins. It can be activated by serine proteinases or by superoxide radicals. The motor neurons in amyotrophic lateral sclerosis patients express significantly higher levels of MMP-9, suggesting a role in neurodegeneration. The aim of the study was to investigate MMP-9 in cerebrospinal fluid from amyotrophic lateral sclerosis patients. MMP-9 was measured by enzyme-linked immunosorbent assay ELISA in cerebrospinal fluid from 24 amyotrophic lateral sclerosis patients and 15 controls. The mean amyotrophic lateral sclerosis duration was 18 months. According to Munsat ALS Health State Scale, the patients were divided into four groups: mild, moderate, severe, terminal. The patients were also divided into groups with shorter (below 12 months) and longer (above 12 months) duration of the disease. MMP-9 level was insignificantly lower in the cerebrospinal fluid from amyotrophic lateral sclerosis patients compared with controls. MMP-9 level showed a tendency to decrease with clinical status worsening, however this correlation was not statistically significant. The difference between MMP-9 level in the cerebrospinal fluid between the groups of patients with shorter and longer duration of amyotrophic lateral sclerosis was not significant.",
    	author = "Iłzecka, J and Stelmasiak, Z and Dobosz, B",
    	issn = "0028-3843",
    	journal = "Neurologia i neurochirurgia polska",
    	keywords = "Aged,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Amyotrophic Lateral Sclerosis: enzymology,Biological Markers,Biological Markers: cerebrospinal fluid,Case-Control Studies,Enzyme-Linked Immunosorbent Assay,Female,Humans,Male,Matrix Metalloproteinase 9,Matrix Metalloproteinase 9: cerebrospinal fluid,Middle Aged,Reference Values,Time Factors",
    	number = 6,
    	pages = "1035--43",
    	pmid = 11987700,
    	title = "{[Matrix metalloproteinase-9 (MMP-9) activity in cerebrospinal fluid of amyotrophic lateral sclerosis patients].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/11987700",
    	volume = 35
    }
    

Gene Tied to Motor Neuron Loss in ALS

http://www.sciencenewsline.com/articles/2014012316570004.html

Published: January 23, 2014. By Columbia University Medical Center
http://www.cumc.columbia.edu 

NEW YORK, NY (January 22, 2014) — Columbia University Medical Center (CUMC) researchers have identified a gene, called matrix metalloproteinase-9 (MMP-9), that appears to play a major role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. The findings, made in mice, explain why most but not all motor neurons are affected by the disease and identify a potential therapeutic target for this still-incurable neurodegenerative disease. The study was published today in the online edition of the journal Neuron.

"One of the most striking aspects of ALS is that some motor neurons—specifically, those that control eye movement and eliminative and sexual functions—remain relatively unimpaired in the disease," said study leader Christopher E. Henderson, PhD, the Gurewitsch and Vidda Foundation Professor of Rehabilitation and Regenerative Medicine, professor of pathology & cell biology and neuroscience (in neurology), and co-director of Columbia's Motor Neuron Center. "We thought that if we could find out why these neurons have a natural resistance to ALS, we might be able to exploit this property and develop new therapeutic options."

 

http://www.healthnewsdigest.com/news/Research_270/Gene-Tied-to-Motor-Neuron-Loss-in-ALS.shtml

By Staff Editor
Jan 22, 2014 - 6:16:51 PM

In a follow-up experiment, the researchers confirmed that the product of MMP-9, MMP-9 protein, is present in ALS-vulnerable motor neurons, but not in ALS-resistant ones. Further, the researchers found that MMP-9 can be detected not just in lumbar 5 neurons, but also in other types of motor neurons affected by ALS. "It was a perfect correlation." said Dr. Henderson. "In other words, having MMP-9 is an absolute predictor that a motor neuron will die if the disease strikes, at least in mice."

 

Association Studies of MMP-9 in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0073777

  • Published: September 09, 2013

Abstract

Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(−1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(−1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(−1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506–3.416, p<0.001) as well as risk of sALS (odds ratio = 2.163, 95% CI 1.233–3.796, p = 0.006), supporting a role for MMP-9 polymorphism in the risk for PD and sALS.

 

Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis

http://brain.oxfordjournals.org/content/121/1/159.full.pdf

Brain (1998), 121, 159–166

Introduction

The matrix metalloproteinases (MMPs) belong to a large subgroup of proteinases which includes the collagenases, gelatinases and the stromelysins, all of which contain tightly bound zinc (Birkedal-Hansen, 1995; Ries and Petrides, 1995). Several MMPs have been identified but the exact role of their involvement in various physiological and pathological processes is only incompletely understood. There is emerging evidence that MMPs might be involved in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis and the Guillain–Barre´ syndrome (Opdenakker and van Damme, 1994). In a first study, Cuzner et al. (1978) demonstrated increased neutral proteinase activity in the CSF during exacerbations of multiple sclerosis. More recently, certain MMPs, i.e. 72-kDa gelatinase, stromelysin-1, interstitial collagenase, matrilysin (MMP-7) and 92-kDa gelatinase (MMP-9), were shown to degrade myelin basic protein (MBP) in vitro (Chandler et al., 1995). Furthermore, evidence is emerging that MMPs might be involved in blood–brain barrier (BBB) breakdown. Thus, non-specific inhibition of MMPs was shown to protect the BBB and could suppress, and even reverse, ongoing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (Gijbels et al., 1994; Hewson et al., 1995). Among all known MMPs, the 92-kDa gelatinase might be particularly involved in BBB breakdown, as increased CSF levels of 92-kDa gelatinase in multiple sclerosis patients are associated with a leaky BBB on magnetic resonance imaging (Rosenberg et al., 1996). Moreover, in multiple sclerosis lesions increased levels of 92-kDa gelatinase were described (Cuzner et al., 1996), where endothelial cells, astrocytes and microglia were all thought to be potential source of production (Maeda and Sobel, 1996). However, besides a recent report on MMP expression and its regulation by a hydroxamate-based inhibitor in actively induced EAE (Clements et al., 1997), there are no data about the temporospatial regulation of 92-kDa gelatinase and other MMPs during the course of neuroinflammatory diseases.