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

Our previous report has showed that the treatment of 48 h with 22 mM glucose prevents hypoxia-induced cardiac cell death. In the present study, we investigated whether high glucose affects the mitochondrial death pathway during hypoxia, and if it does, what relates to the high glucose induced cardioprotection. Heart-derived H9c2 cells were incubated in low (5.5 mM) or high (22 mM) glucose medium for 48 h, then transferred to a normoxic or hypoxic condition. The hypoxia-induced reduction of mitochondrial redox potential, assessed by MTT assay, was inhibited in high glucose treated cells. The mitochondrial membrane potential was significantly decreased by hypoxia in low glucose treated cells, but not in high glucose treated cells. The hypoxia-induced cytoplasmic accumulation of cytochrome c, released from the mitochondria, was blocked by a treatment of high glucose. High glucose did not induce the expression of an antiapoptotic protein Bcl-2, nor did it reduce a proapoptotic protein Bax, but it did inhibit a hypoxia-induced downregulation of Bcl-2. The cellular ATP contents were not changed by the treatment of high glucose for 48 h, and the hypoxia-induced decline of intracellular ATP level was observed in high glucose treated cells and in low glucose. A glycolytic inhibitor, 2-deoxyglucose, did not reverse the high glucose induced reduction of LDH release. The elevation of [ROS](i) induced by hypoxia was inhibited in high glucose treated cells. These results suggest that high glucose induced cardioprotection may be accounted for in part by the preservation of MMP and the maintenance of a basal level of [ROS](i) during hypoxia.
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PMID:High-glucose induced protective effect against hypoxic injury is associated with maintenance of mitochondrial membrane potential. 1503 43

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on osteosarcoama cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of a HDAC inhibitor Trichostatin A (TSA)-induced apoptosis in a osteosarcoma cell line HOS. We observed that TSA treatment decreased the viability of the cells and prominently increased acetylation of histone H3. Evidence was obtained indicating that TSA induced apoptosis of HOS cells as follows: (1) Generation of DNA fragmentation; (2) activation of procaspase-3; (3) cleavage of PARP; and (4) increase of DNA hypoploidy. The reduction of MMP and the release of cytochrome c to cytosol were also shown, indicating that TSA induces apoptosis in HOS cells in a histone acetylation- and mitochondria-dependent fashions. We also examined whether TSA can sensitize HOS cells to the action of an antitumor agent genistein. The combination therapy of TSA and genistein showed synergistic anticancer effect indicating that TSA can be considered as a novel therapeutic strategy for osteosarcoma not only from its direct apoptosis-inducing activity but also from the possibility of sensitization to other antitumor agents.
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PMID:Mechanism of histone deacetylase inhibitor Trichostatin A induced apoptosis in human osteosarcoma cells. 1531 86

Microperoxidases are small heme-peptides obtained by proteolytic digestion of cytochrome c, exhibiting peroxidase activity. They consist of a short- or medium-length polypeptide chain, covalently linked to an iron protoporphyrin IX moiety via two thioether bonds involving Cys residues at the c-porphyrin A and B pyrrole rings. These small molecules are interesting for a wide range of possible applications. We have structurally characterized, by means of electrospray ionization (ESI) mass and tandem mass spectrometric experiments, a novel microperoxidase called MMP-5 (Marinobacter MicroPeroxidase-5), obtained by proteolytic digestion of cytochrome c552, a monoheminic electron-transfer protein isolated from Marinobacter hydrocarbonoclasticus. This microperoxidase, which still maintains the functional peptide moieties for peroxidase activity, is devoid of the two amino acids intercalating the Cys residues linked to the c-porphyrin, thus increasing its water solubility. Once submitted to the ESI source potential, MMP-5 showed an interesting tendency for the reduction of the iron protoporphyrin substructure. This behaviour was clearly evidenced by the mass shift exhibited by the reduced form.
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PMID:Characterization of a novel microperoxidase from Marinobacter hydrocarbonoclasticus by electrospray ionization tandem mass spectrometry. 1567 61

The preparation and characterization of a new microperoxidase obtained from proteinase K-treated cytochrome c(552) from Marinobacter hydrocarbonoclasticus (previously known as Pseudomonas nautica) are presented. This microperoxidase (MMP-5) has novel structural properties relative to previously reported microperoxidases, as the two intervening amino acid (X) residues within the consensual CXXCH c-type heme binding motif are missing, yielding a heme-pentapeptide with increased solubility in aqueous solvents and a 1-2 order of magnitude higher stability of the monomeric state relative to canonical microperoxidases. The electronic spectra in the near-UV and visible regions have been studied as a function of MMP-5 concentration and pH. The spectroscopic properties of MMP-5 are typical of microperoxidases with high-spin hexa- or pentacoordinate heme species dominant in the 1-8 pH range and low-spin states prevailing at higher pH values. In the presence of hydrogen peroxide, MMP-5 displays peroxidatic activities towards several compounds.
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PMID:A new microperoxidase from Marinobacter hydrocarbonoclasticus. 1598 63

C2-ceramide, a cell permeable analogue of ceramide [CER] markedly reduced mitochondrial membrane potential [MMP] in insulin-secreting INS cells, which was followed by a significant accumulation of cytochrome c [Cyt c] into the cytosolic compartment. In a manner akin to CER, exposure of these cells to interleukin-1beta [IL-1beta] also resulted in reduction in MMP and cytosolic accumulation of Cyt c. Further, long-term exposure of these cells to either CER [but not its inactive analogue] or IL-1beta caused a marked reduction in their metabolic viability. However, unlike IL-1beta, which increased nitric oxide [NO] release, CER-treatment of INS cells had no effects of CER on NO release were demonstrable. Together, these findings suggest that CER-induced mitochondrial effects may not be mediated via iNOS gene expression and NO production. CER also activated an okadaic acid -sensitive protein phosphatase [CAPP] in the purified mitochondrial fraction, suggesting that CAPP might represent one of the target proteins for CER in the beta cell mitochondria. Together, our findings suggest direct detrimental effects of CER on mitochondrial function in beta cells leading to their dysfunction and demise via apoptosis. Moreover, our findings provide evidence for a potential difference in the mechanisms underlying CER- and IL-1beta-induced mitochondrial defects and apoptotic demise of the effete beta cell.
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PMID:Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: potential mechanisms underlying ceramide-mediated metabolic dysfunction of the beta cell. 1613 74

We investigated the action of tissue inhibitor of metalloproteinase-1 (TIMP-1) on apoptosis and differentiation of mouse bone marrow stromal cell line MBA-1. TIMP-1 did not affect alkaline phosphatase (ALP) activity, suggesting that it is not involved in osteoblastic differentiation in MBA-1 cells. However, TIMP-1 inhibited MBA-1 apoptosis induced by serum deprivation in a dose-dependent manner. Our study also showed increased Bcl-2 protein expression and decreased Bax protein expression with TIMP-1 treatment. TIMP-1 decreased cytochrome c release and caspase-3 activation in MBA-1 cells. TIMP-1 activated phosphatidylinositol 3-kinase (PI3-kinase) and c-Jun N-terminal kinase (JNK), and the PI3-kinase inhibitor LY294002 or the JNK inhibitor SP600125 abolished its antiapoptotic activity. To investigate whether antiapoptotic action of TIMP-1 was mediated through its inhibition on MMP activities, we constructed mutant TIMP-1 by side-directed mutagenesis, which abolished the inhibitory activity of MMPs by deletion of Cys1 to Ala4. Wild-type TIMP-1 and mutant TIMP-1 expression plasmids were transfected in MBA-1 cells, and results showed that mutant TIMP-1 still protected the induced MBA-1 cell against apoptosis. These data suggest that TIMP-1 antiapoptotic actions are mediated via the PI3-kinase and JNK signaling pathways and independent of TIMP-1 inhibition of MMP activities.
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PMID:Tissue inhibitor of matrix metalloproteinase-1 suppresses apoptosis of mouse bone marrow stromal cell line MBA-1. 1669 94

Ginsenoside-Rg1, the pharmacologically active component isolated from ginseng, demonstrated neuroprotective effects on primary cultured rat nigral neurons against rotenone toxicity. Rotenone, a common household pesticide known for its specific and irreversible mitochondria complex I inhibition, has been suggested to be the causal agent of Parkinson's disease (PD) by inducing degeneration of cells in the substantial nigra. The present study demonstrated that co-treatment of rotenone and Rg1 could reduce rotenone-induced cell death by 58% (SEM=+/-5.60; N=3). Rotenone-induced mitochondria membrane potential (MMP, DeltaPsim) depletion was restored and elevated by at least 38% (SEM=+/-2.15; N=3) by Rg1. In addition, Rg1 prevented cytochrome c release from the mitochrondrial membrane and increased the phosphorylation inhibition of the pro-apoptotic protein Bad through activation of the PI3K/Akt pathway. The protective effects of Rg1 was blocked by glucocorticoid receptor antagonist RU486, indicating that the action of Rg1 is mediated through glucocorticoid receptor (GR). In conclusion, Rg1 inhibits the mitochondrial apoptotic pathway and increases the survival chance of the primary cultured nigral neurons against rotenone toxicity. Thus, Rg1 and its related compounds may be developed as protective agents against neurodegenerative diseases induced by mitochondrial toxins.
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PMID:Neuroprotective effects of ginsenoside-Rg1 in primary nigral neurons against rotenone toxicity. 1712 56

Flavonoids exist extensively in plants, and several biological effects of them have been demonstrated. Wogonin is an important flavonoid compound. In this study, wogonin showed obvious growth inhibition on Bel-7402 cells. The major mechanisms of inhibition included cell apoptosis and cytotoxic effects. Wogonin-induced cell death showed characteristics of apoptosis including DNA fragmentation, chromatin condensation, appearance of apoptotic bodies, and an increase in hypodiploid cells. However, the percentage of necrosis cells also increased with the increase of wogonin concentration. Furthermore, treatment with wogonin caused changes of reactive oxygen species (ROS) and mitochondrial membrane potentials (DeltaPsim, MMP), the decrease of the ratio of reduced and oxidized glutathione (GSH/GSSG), cytochrome c release and activation of caspase-9.
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PMID:Changes in mitochondrial membrane potential and reactive oxygen species during wogonin-induced cell death in human hepatoma cells. 1730 Jul

The mycotoxin CTN (citrinin), a natural contaminant in foodstuffs and animal feeds, has cytotoxic and genotoxic effects on various mammalian cells. CTN is known to cause cell injury, including apoptosis, but the precise regulatory mechanisms of CTN action, particularly in stem cells and embryos, are currently unclear. In the present paper, I report that CTN has cytotoxic effects on mouse embryonic stem cells and blastocysts, and is associated with defects in their subsequent development, both in vitro and in vivo. Experiments in embryonic stem cells (ESC-B5) showed that CTN induces apoptosis via ROS (reactive oxygen species) generation, increased Bax/Bcl-2 ratio, loss of MMP (mitochondrial membrane potential), induction of cytochrome c release, and activation of caspase 3. In this model, CTN triggers cell death via inactivation of the HSP90 [a 90 kDa isoform of the HSP (heat-shock protein) family proteins]/multichaperone complex and subsequent degradation of Ras and Raf-1, further inhibiting anti-apoptotic processes, such as the Ras-->ERK (extracellular-signal-regulated kinase) signal transduction pathway. In addition, CTN causes early developmental injury in mouse ESCs and blastocysts in vitro. Lastly, using an in vivo mouse model, I show that consumption of drinking water containing 10 muM CTN results in blastocyst apoptosis and early embryonic developmental injury. Collectively, these findings show for the first time that CTN induces ROS and mitochondria-dependent apoptotic processes, inhibits Ras-->ERK survival signalling via inactivation of the HSP90/multichaperone complex, and causes developmental injury in vivo.
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PMID:Citrinin induces apoptosis via a mitochondria-dependent pathway and inhibition of survival signals in embryonic stem cells, and causes developmental injury in blastocysts. 1733 Oct 71

tert-Butylhydroperoxide has been reported to inhibit growth and induce apoptosis in number of cell types, but little is known about the molecular mechanism mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with t-BOOH. The cells were exposed to different concentrations of t-BOOH (100-750 microM) for 1-4 h and various parameters such as cytotoxicity, ROS (reactive oxygen species) generation, MMP (mitochondrial membrane potential), intracellular Ca++ levels and expression of various proteins involved in apoptosis were determined. Exposure of U-937 cells to t-BOOH induced cytotoxicity in a time dependent manner with about 50% toxicity at 400 microM t-BOOH in 4h. t-BOOH treatment resulted in a time dependent increase in reactive oxygen species levels, Ca++ influx and annexin V positive cells. There was a significant fall in MMP following exposure to t-BOOH with time. t-BOOH treatment of U-937 cells leads to apoptosis, which is accompanied by activation of caspase-3. The caspase-3 inhibitor (Ac-DEVD-CHO) inhibits the cytotoxicity induced by t-BOOH, indicating a direct link between caspase-3 activation and cell death. This activation of apoptosis is accompanied by release of cytochrome c, down regulation of anti-apoptotic protein Bcl-2 levels with concurrent increase in pro-apoptotic proteins Bax and Bad levels. These observations indicate that t-BOOH induces cell death in U-937 macrophages by apoptosis, which is mediated through mitochondrial pathway.
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PMID:Mechanism of tert-butylhydroperoxide induced cytotoxicity in U-937 macrophages by alteration of mitochondrial function and generation of ROS. 1741


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