Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D00115 (Gelatin)
1,732 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) may contribute to tissue damage after cerebral ischemia. In this study, wildtype and MMP-2 knockout mice were subjected to permanent and transient (2 h) occlusions of the middle cerebral artery. Gelatin zymography showed that MMP-9 levels were increased in all brains after ischemia. MMP-2 levels did not show a significant increase in wildtype mice, and were not detectable in knockout mice. Laser doppler flowmetry demonstrated equivalent ischemic reductions in perfusion in wildtype and knockout mice. In both permanent and transient occlusion paradigms, there were no statistically significant differences between wildtype and knockout mice in terms of 24 h ischemic lesion volumes. These data suggest that MMP-2 does not contribute to acute tissue damage in this model of focal ischemia.
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PMID:Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. 1158 20

Although ischemia is the leading cause of acute renal failure in human, there is little information on the remodeling the kidney endothelium matrix during ischemic injury. In this study, we investigated the activity and expression of MMP-2 and MMP-9, in an isolated endothelial fraction following an acute in vivo reversible ischemia induced in rats by vascular clamping. Ischemia increased serum creatinine levels 1.4-fold, hallmark of acute renal failure. Isolation of the endothelial cell fraction was performed by affinity chromatography using an anti-PECAM-1 antibody. The isolated fraction was assessed by Western blotting analysis of endothelial cell markers. The positively selected fractions were enriched in the endothelial markers eNOS and PECAM-1 by 128-fold and 44-fold, respectively. Gelatin zymography showed that ischemia strongly stimulated proteolytic activity of proMMP-2 (1.8-fold), proMMP-9 (3-fold) and MMP-9 (4-fold) in the endothelial fractions. Western blot analysis indicated that TIMP-2 protein level increased by 3.2-fold in the endothelial fractions during ischemia. Surprisingly, TIMP-1 was absent from the endothelial preparations but was easily detected in the non-endothelial cells. Levels of the endocytic receptor LRP were increased by 2-fold during ischemia in the endothelial fractions. Occludin, a known in vivo MMP-9 substrate, was partly degraded in the endothelial fractions during ischemia, suggesting that the MMP-9 which was upregulated during ischemia was functional. These data suggest that ischemia in kidney could lead to the degradation of the vascular basement membrane and to increased permeability. This suggests new therapeutic approaches for ischemic pathologies by targeting MMP-9 and its regulators.
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PMID:Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. 1611 9

Previous studies have demonstrated that quercetin, a bioflavonoid shows the inhibitory effect against ischemia and reperfusion-induced injury in various tissues including neural tissue. Quercetin is also reported to have an inhibitory effect against matrix metalloproteinases (MMPs). Because MMPs are known to play a main role in the pathophysiology of brain ischemic insult, their mechanisms of possible protective effect of quercetin against brain ischemia remain to be clarified. In the present study, C57BL/6 mice were subjected to 20 min transient global brain ischemia. Cerebral blood flow was monitored by laser doppler flowmeter. Animals were sacrificed 72 h after ischemia. Quercetin (50 mg/kg, dissolved in saline) was intraperitoneally administered to mice at 30 min before and immediately after ischemia and from the second day, quercetin was then administered once daily until sacrifice. The present study was undertaken to test the effect of quercetin on neuronal damage after transient cerebral ischemia. Neuronal damages were remarkable in the medial portion of CA1 and CA2 areas after ischemic insult. In quercetin-treated mice, delayed neuronal damage was significantly decreased compared with vehicle-treated mice. Mice treated with quercetin showed attenuated brain MMP-9 activity. Gelatin gel zymography showed an induction of MMP-9 protein after ischemia. Quercetin significantly inhibited ischemia-induced elevation of MMP-9. In situ zymography showed elevations in gelatinase activities after brain ischemia. Quercetin also inhibited TdT-mediated dUTP nick end labeling (TUNEL) staining in CA1 and CA2 areas. These results demonstrate that quercetin, a natural flavonoid reduces global ischemia-induced neuronal damage through inhibition of MMP-9 activity.
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PMID:Protective effect of quercetin, a natural flavonoid against neuronal damage after transient global cerebral ischemia. 1680 98

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia-ischemia (HI) is unknown. We exposed MMP-9(-/-) [MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36 degrees C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 +/- 1.7 mm3; n = 22) compared with WT (32.3 +/- 2.1 mm3; n = 22; p < 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 +/- 5.4%; KO, 18.4 +/- 3.1%; p < 0.0001; myelin basic protein: WT, 57.5 +/- 5.8%; KO, 23.2 +/- 3.5%; p = 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood-brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochrome c) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.
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PMID:Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. 1730 Nov 59

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, inhibits ischemia-induced injury in various tissues including neural tissue. Pioglitazone has also been shown to reduce matrix metalloproteinase (MMP) activity. Because MMP is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to test whether pioglitazone attenuates ischemic neuronal damage through MMP inhibition. C57BL/6 mice were subjected to global brain ischemia for 20 min. Animals were killed 72 h after ischemia. Oral pioglitazone (40 mg/kg/day, as a suspension in 0.5% carboxymethylcellulose) was administered to mice twice daily for 3 days before ischemia and twice daily after ischemia until the animals were killed. We investigated gelatinase activity by zymography and laminin immunohistochemistry. Histological analysis was also performed to test the protective effect of pioglitazone on neuronal damage. Mice treated with pioglitazone had attenuated gelatinase activity. Gelatin gel and in situ zymography showed up-regulation of gelatinase activity after ischemia. Pioglitazone significantly inhibited ischemia-induced elevation of the active form of MMP-9. Pioglitazone also reduced up-regulation of in situ gelatinase activity and laminin breakdown induced by ischemia in the hippocampus. There was marked neuronal damage in the CA1 and CA2 areas after ischemia. Neuronal damage in mice was significantly decreased by pioglitazone treatment, compared with vehicle-treated mice. Pioglitazone also inhibited TdT-mediated dUTP nick end labeling staining in CA1 and CA2 areas. Pioglitazone, a PPARgamma agonist, reduces delayed neuronal damage induced by global ischemia through inhibition of MMP-9 activity.
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PMID:PPARgamma agonist pioglitazone reduces [corrected] neuronal cell damage after transient global cerebral ischemia through matrix metalloproteinase inhibition. 1821 32

Previous studies have demonstrated that (-)-epigallocatechin gallate (EGCG), a green tea polyphenol, protects against ischemia and reperfusion-induced injury in many organ systems. Here, we test the hypothesis that part of EGCG's neuroprotective effects may involve a modulation of matrix metalloproteinases (MMPs) after cerebral ischemia. C57BL/6 mice were subjected to 20 min of transient global cerebral ischemia. EGCG (50 mg/kg) or vehicle (saline) was administered i.p. immediately after ischemia. Brains were examined 3 days after ischemia. The effects of EGCG on MMP (gelatinase) activity and neuronal damage in the hippocampus were assessed. Gelatin gel zymography showed induction of active forms of MMP-9 protein after transient global cerebral ischemia. In situ zymography showed that ischemic gelatinase activity occurred primarily in pyramidal neuronal areas after brain ischemia. Mice treated with EGCG showed significantly reduced gelatinase levels. Neuronal damage was evident in CA1 and CA2 pyramidal sectors, corresponding to TUNEL-positive signals. In EGCG-treated mice, delayed neuronal damage was significantly reduced compared with vehicle-treated mice. These results demonstrate that the green tea polyphenol EGCG suppresses MMP-9 activation and reduces the development of delayed neuronal death after transient global cerebral ischemia in mouse brain.
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PMID:Green tea polyphenol (-)-epigallocatechin gallate reduces neuronal cell damage and up-regulation of MMP-9 activity in hippocampal CA1 and CA2 areas following transient global cerebral ischemia. 2104 62

Doxycycline, a tetracycline antibiotic inhibits matrix metalloproteinase (MMP) and reduces neuronal damage in focal brain ischemia. This study was undertaken to assess if doxycycline reduces delayed neuronal damage following transient global cerebral ischemia through MMP inhibition. C57BL/6 mice were subjected to 20 min global cerebral ischemia. Doxycycline was administered to mice 30 min before and 2 h after ischemia. In TUNEL assay, damaged neurons were also apparent in the CA1 and CA2 areas and doxycycline reduced TUNEL-positive neurons. Gelatin gel and in situ zymography showed upregulation of gelatinase activity after ischemia. Doxycycline significantly inhibited MMP-9 activity in gel zymography and also suppressed in situ gelatinase activity. Laminin degradation was remarkable in CA1 and CA2 areas after ischemia and doxycycline reduced the laminin degradation and neuronal loss. Our data suggest that doxycycline may provide a neuroprotection against global cerebral ischemia since it reduces perineuronal laminin degradation by inhibiting MMP-9 activity.
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PMID:Doxycycline inhibits matrix metalloproteinase-9 and laminin degradation after transient global cerebral ischemia. 1920 Aug 54

Perinatal hypoxia-ischemia (H-I) often manifests as cognitive and/or motor disturbances that appear early in development. Growing evidence indicates that neuroinflammation may exacerbate H-I injury. Resident microglia release proinflammatory cytokines and proteases in response to ischemia. Matrix metalloproteinases (MMPs), in particular, activate cytokines and degrade basement membrane proteins. These actions ultimately permit entry of peripheral leukocytes into the CNS neuropil, enhancing neuroinflammation and cell death. Currently, the relative contributions of resident and peripheral immune cells to ischemic brain injury are unclear. The present study employed an ex vivo model of H-I through oxygen glucose deprivation (OGD) to identify the cellular localization of MMP-9 in organotypic hippocampal slices from rat, and to determine whether inhibiting gelatin-degrading MMPs affords neuroprotection in the absence of peripheral immune cells. Immunohistochemistry revealed ubiquitous neuronal MMP-9 expression in both normoxic and hypoxic slices. Increased MMP-9 expression was detected in CD11b-positive microglia after 48 h exposure to OGD relative to normoxic controls. Consistent with these data, in situ zymography showed increased gelatinolytic activity after OGD. Gelatin-cleaved fluorescence localized to astrocytic processes and somata of various cellular morphologies. Treatment with either the MMP inhibitor AG3340 (prinomastat) or minocycline dampened OGD-induced gelatinolytic activity and neural injury, as measured by Fluoro-Jade staining, relative to vehicle controls. These results show that resident microglia, in the absence of peripheral immune cells, were sufficient to enhance neural injury after OGD in the organotypic hippocampal slice. Additionally, these effects were associated with upregulation or secretion of MMP-9, and were blocked after treatment with either the gelatinase-selective compound AG3340 or the anti-inflammatory compound minocycline. These data, coupled with the effectiveness of these compounds previously shown in vivo, support the selective targeting of gelatin-degrading MMPs and activated microglia as potential therapeutic approaches to combat neonatal H-I injury.
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PMID:Inhibition of gelatinase activity reduces neural injury in an ex vivo model of hypoxia-ischemia. 1927 21

Green tea polyphenol (-)-epigallocatechin gallate (EGCG) has been reported to reduce neuronal damage after cerebral ischemic insult. EGCG is known to reduce matrix metalloproteinase (MMP) activity. MMP can play an important role in the pathophysiology of neurological disorders including cerebral ischemia. The purpose of the current study was to investigate whether EGCG shows an inhibitory effect on MMP activity and neural tissue damage following transient focal cerebral ischemia. In the present study, C57BL/6 mice were subjected to 80 min of focal ischemia induced by middle cerebral artery occlusion (MCAO). Animals were killed 24 h after ischemia. EGCG (50 mg/kg) was administered intraperitoneally immediately after ischemia. Gelatin gel zymography showed an increase in the active form of MMP-9 after ischemia. EGCG reduced ischemia-induced up-regulation of the active form of MMP-9. In in situ zymography, EGCG reduced up-regulation of gelatinase activity induced by cerebral ischemia. Co-incubation with EGCG reduced gelatinase activity directly in postischemic brain section. In 2,3,5-triphenyltetrazolium chloride (TTC) assay, brain infarction was remarkable in the middle cerebral artery territory after focal cerebral ischemia. In EGCG-treated mice, infarct volume was significantly reduced compared with vehicle-treated mice. These results demonstrate that EGCG, a green tea polyphenol, may reduce up-regulation of MMP-9 activity and neuronal damage following transient focal cerebral ischemia. In addition to its antioxidant effect, MMP-9 inhibition might be a possible mechanism potentially involved in the neuroprotective effect of a green tea polyphenol, EGCG.
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PMID:Green tea polyphenol (-)-epigallocatechin gallate reduces matrix metalloproteinase-9 activity following transient focal cerebral ischemia. 1996 94

Remote ischemic preconditioning (RIPC) can be induced by transient occlusion of blood flow to a limb with a blood pressure cuff and exerts multiorgan protection from ischemia/reperfusion injury. Ischemia/reperfusion injury in the intestinal tract leads to intestinal barrier dysfunction and can result in multiple organ failure. Here we used an intestinal cell line (CaCo-2) to evaluate the effects of RIPC-conditioned patient sera on hypoxia-induced cell damage in vitro and to identify serum factors that mediate RIPC effects. Patient sera (n = 10) derived before RIPC (T0), directly after RIPC (T1) and 1 h after RIPC (T2) were added to the culture medium at the onset of hypoxia until 48 h after hypoxia. Reverse transcription-polymerase chain reaction, lactate dehydrogenase (LDH) assays, caspase-3/7 assays, silver staining, gelatin zymography and Western blotting were performed. Hypoxia led to morphological signs of cell damage and increased the release of LDH in cultures containing sera T0 (P < 0.01) and T1 (P < 0.05), but not sera T2, which reduced the hypoxia-mediated LDH release compared with sera T0 (P < 0.05). Gelatin zymography revealed a significant reduction of activities of the matrixmetalloproteinase (MMP)-2 and MMP-9 in the protective sera T2 compared with the nonprotective sera T0 (MMP-2: P < 0.01; MMP-9: P < 0.05). Addition of human recombinant MMP-2 and MMP-9 to MMP-deficient culture media increased the sensitivity of CaCo-2 cells to hypoxia-induced cell damage (P < 0.05), but did not result in a reduced phosphorylation of prosurvival kinases p42/44 and protein kinase B (Akt) or increased activity of caspase-3/7. Our results suggest MMP-2 and MMP-9 as currently unknown humoral factors that may be involved in RIPC-mediated cytoprotection in the intestine.
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PMID:Serum from patients undergoing remote ischemic preconditioning protects cultured human intestinal cells from hypoxia-induced damage: involvement of matrixmetalloproteinase-2 and -9. 2200 79


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