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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-alpha, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-alpha release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10 mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p < 0.0001; n = 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage and MG treatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation.
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PMID:Effect of methylguanidine in a model of septic shock induced by LPS. 1562 90

Semaphorin 3A (Sema3A) is a secreted disulfide-bound homodimeric molecule that induces growth cone collapse and repulsion of axon growth in the nervous system. Recently, it has been demonstrated that Sema3A is produced by endothelial cells and inhibits integrin function in an autocrine fashion. In this study, we investigated the effects of Sema3A on platelet function by using 2 distinct human Sema3A chimera proteins. We detected expression of functional Sema3A receptors in platelets and dose-dependent and saturable binding of Sema3A to platelets. Sema3A dose-dependently inhibited activation of integrin alphaIIbbeta3 by all agonists examined including adenosine diphosphate (ADP), thrombin, convulxin, phorbol 12-myristate 13-acetate, and A23187. Sema3A inhibited not only platelet aggregation induced by thrombin or collagen but also platelet adhesion and spreading on immobilized fibrinogen. Moreover, Sema3A impaired alphaIIbbeta3-independent spreading on glass coverslips and aggregation-independent granular secretion. Sema3A inhibited agonist-induced elevation of filamentous action (F-actin) contents, phosphorylation of cofilin, and Rac1 activation. In contrast, Sema3A did not affect the levels of cyclic nucleotides or agonist-induced increase of intracellular Ca2+ concentrations. Thus, the extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement.
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PMID:Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A. 1583 6

Complex I impairment with rotenone produces damage though a mechanism thought to be distinct from effects on mitochondrial respiration. The outcome of chronic rotenone on energy status in relation to toxicity, however, is unknown. To examine this, mesencephalic cultures were exposed to chronic, low-dose rotenone (5-100 nM, 8 days in vitro) or acute, high-dose rotenone (500 nM, 1-24 h), and ATP/ADP levels and toxicity were measured. Chronic exposure to 5-50 nM rotenone produced selective dopamine cell loss. High-dose rotenone produced nonselective damage at all exposure times. Chronic, low-dose rotenone (37.5 nM) decreased ATP/ADP gradually over several days to 40% of controls, whereas high-dose rotenone (500 nM, 1-6 h), collapsed ATP/ADP by 1 h of exposure. The ubiquitin proteasomal pathway, an ATP-dependent pathway, is implicated in Parkinson's disease and, thus, various rotenone exposures were examined for effects on ubiquitin proteasomal function. Chronic, low-dose rotenone (25-50 nM, 8 days), but not acute, high-dose rotenone (500 nM, 1-6 h), caused accumulation of ubiquitinated proteins, E1-ubiquitin activation, and increased proteasomal activities prior to toxicity even though both exposures increased free radical production. Findings show that selective dopamine cell loss and alterations in ubiquitin proteasomal function only occur with rotenone exposures that partially maintain ATP/ADP. High concentrations of rotenone that collapse energy status kill neurons in a nonselective manner independent of the ubiquitin proteasomal pathway.
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PMID:Energy status, ubiquitin proteasomal function, and oxidative stress during chronic and acute complex I inhibition with rotenone in mesencephalic cultures. 1589 11

The purpose of this work was to assess the effect of oligomycin on the mitochondrial membrane permeability transition. The antibiotic was found to strengthen cyclosporin A (CSA)-induced protection of non-specific permeability, which is triggered by a matrix Ca2+ load in the absence of ADP. Oligomycin also reinforced the protective effect of CSA on carboxyatractyloside-induced pore opening in the absence of ADP, but failed to do so in mitochondria incubated under anaerobic conditions or after addition of CCCP. Analyzing the efflux of matrix Ca2+, we found that mitochondrial swelling and the collapse of the transmembrane electric gradient coincided with membrane leakage. The effects of the antibiotic were observed in phosphate-containing media but not in the presence of acetate. Furthermore, N-ethylmaleimide hindered the protective effect of oligomycin-CSA. In addition, the matrix phosphate concentration increased concurrently with a diminution in the matrix-free fraction of Ca2+. We concluded that oligomycin increases phosphate uptake by stimulating the phosphate-/OH- exchange reaction.
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PMID:Oligomycin strengthens the effect of cyclosporin A on mitochondrial permeability transition by inducing phosphate uptake. 1597 5

The effect of agaric acid as inducer of mitochondrial permeability transition was studied. It was found that: (i) agaric acid (AA) promoted efflux of accumulated Ca2+, collapse of transmembrane potential, and mitochondrial swelling; (ii) these effects depend on membrane fluidity; (iii) ADP inhibited the effect of AA on Ca2+ efflux, and (iv) AA blocked binding of the sulfhydryl reagent, eosin-5-maleimide, to the adenine nucleotide translocase. It is proposed that AA induces pore opening through binding of the citrate moiety to the ADP/ATP carrier; this interaction must be stabilized by insertion of the alkyl chain in the lipid milieu of the membrane.
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PMID:Agaric acid induces mitochondrial permeability transition through its interaction with the adenine nucleotide translocase. Its dependence on membrane fluidity. 1605 Sep 90

Decreases in GSH pools detected during ischemia sensitize neurons to excitotoxic damage. Thermodynamic analysis predicts that partial GSH depletion will cause an oxidative shift in the thiol redox potential. To investigate the acute bioenergetic consequences, neurons were exposed to monochlorobimane (mBCl), which depletes GSH by forming a fluorescent conjugate. Neurons transfected with redox-sensitive green fluorescent protein showed a positive shift in thiol redox potential synchronous with the formation of the conjugate. Mitochondria within neurons treated with mBCl for 1 h failed to hyperpolarize upon addition of oligomycin to inhibit their ATP synthesis. A decreased ATP turnover was confirmed by monitoring neuronal oxygen consumption in parallel with mitochondrial membrane potential (Deltapsi(m)) and GSH-mBCl formation. mBCl progressively decreased cell respiration, with no effect on mitochondrial proton leak or maximal respiratory capacity, suggesting adequate glycolysis and a functional electron transport chain. This approach to "state 4" could be mimicked by the adenine nucleotide translocator inhibitor bongkrekic acid, which did not further decrease respiration when administered after mBCl. The cellular ATP/ADP ratio was decreased by mBCl, and consistent with mitochondrial ATP export failure, respiration could not respond to an increased cytoplasmic ATP demand by plasma membrane Na(+) cycling; instead, mitochondria depolarized. More prolonged mBCl exposure induced mitochondrial failure, with Deltapsi(m) collapse followed by cytoplasmic Ca(2+) deregulation. The initial bioenergetic consequence of neuronal GSH depletion in this model is thus an inhibition of ATP export, which precedes other forms of mitochondrial dysfunction.
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PMID:Acute glutathione depletion restricts mitochondrial ATP export in cerebellar granule neurons. 1617 17

Hypoxia leads to a collapse in mitochondrial transmembrane potential (Deltapsi(M)), a fall in the ATP/ADP ratio, and finally cell death. Since (-)deprenyl directly modulates Deltapsi(M) and production of reactive oxygen species (ROS) by altering the respiratory function of mitochondria, we were interested in the dose-response relations of these effects. The changes in JC-1 red/green signal ratios {mitochondrial transmembrane potential}, and the changes in the cerium staining (intracellular ROS) in hypoxic and normoxic PC12 cell cultures were measured following 1 h of Argon hypoxia and 24 h of re-oxygenation in the absence and in the presence of various concentrations of (-)deprenyl. Deltapsi(M) shifted to lower values following hypoxia/re-oxygenation and all cells had decreased and uniform Deltapsi(M) levels. The amount of ROS increased. Following 24 h of treatment with various concentrations of (-)deprenyl during the re-oxygenation period, survival increased, the Deltapsi(M) shift caused by oxygen deprivation was reversed and the peroxy radical levels decreased except for at 10(-3) M.
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PMID:Low dose (-)deprenyl is cytoprotective: it maintains mitochondrial membrane potential and eliminates oxygen radicals. 1624 56

Poly(ADP-ribose)polymerase-1 (PARP-1) overactivation is a key event in neurodegeneration but the underlying molecular mechanisms wait to be unequivocally identified. Energy failure, transcriptional derangement and deadly nucleus-mitochondria cross-talk have been proposed as mechanisms responsible for PARP-1 neurotoxicity. In this study, we sought to determine how these mechanisms contributes to PARP-1-dependent neuronal death. We report that the PARP-1 activating agent methyl-nitrosoguanidine (MNNG) caused poly(ADP-ribosyl)ation-dependent death of pure mouse cortical neurons in culture. Upon PARP-1 hyperactivation, NAD and ATP storages only partially decreased, neurons rapidly acquired apoptotic morphology, apoptosis inducing factor and cytochrome c were released from mitochondria and caspase activation occurred. No evidence for p53 activation was found, lactate dehydrogenase release occurred only 18h later, and JNK kinase was constitutively activated and not affected by PARP-1 activation. The PARP-1 inhibitors 6-(5)H-phenanthridinone and N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ-34) prevented nucleotide depletion and cell death, whereas the transcription inhibitor actinomycin D did not affect PARP-1-dependent neurotoxicity. Together, our findings provide the first evidence that neither energy collapse nor transcriptional changes are involved in PARP-1-dependent apoptotic neuronal death, and support the existence of a poly(ADP-ribose)-mediated death signaling targeting mitochondria.
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PMID:Neither energy collapse nor transcription underlie in vitro neurotoxicity of poly(ADP-ribose) polymerase hyper-activation. 1705

Cardiolipin peroxidation plays a critical role in mitochondrial cytochrome c release and subsequent apoptotic process. Mitochondrial pore transition (MPT) is considered as an important step in this process. In this work, the effect of peroxidized cardiolipin on MPT induction and cytochrome c release in rat heart mitochondria was investigated. Treatment of mitochondria with micromolar concentrations of cardiolipin hydroperoxide (CLOOH) resulted in a dose-dependent matrix swelling, DeltaPsi collapse, release of preaccumulated Ca2+ and release of cytochrome c. All these events were inhibited by cyclosporin A and bongkrekic acid, indicating that peroxidized cardiolipin behaves as an inducer of MPT. Ca2+ accumulation by mitochondria was required for this effect. ANT (ADP/ATP translocator) appears to be involved in the CLOOH-dependent MPT induction, as suggested by the modulation by ligands and inhibitors of adenine nucleotide translocator (ANT). Together, these results indicate that peroxidized cardiolipin lowers the threshold of Ca2+ for MPT induction and cytochrome c release. This synergistic effect of Ca2+ and peroxidized cardiolipin on MPT induction and cytochrome c release in mitochondria, might be important in regulating the initial phase of apoptosis and also may have important implications in those physiopathological situations, characterized by both Ca2+ and peroxidized cardiolipin accumulation in mitochondria, such as aging, ischemia/reperfusion and other degenerative diseases.
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PMID:Interaction of peroxidized cardiolipin with rat-heart mitochondrial membranes: induction of permeability transition and cytochrome c release. 1708 38

The interactions of Co(2+) with mitochondria have been investigated. The results indicate that Co(2+) inhibits ATP synthesis. Further investigations into ATP synthesis mechanisms indicated that inhibition is due to the opening of a transmembrane pore. The opening of this pore causes the collapse of the high-energy intermediate where, under a pH and a potential gradient, the energy is stored and subsequently utilized to form ATP from ADP.
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PMID:The interactions of cobalt(II) with mitochondria from rat liver. 1733 96


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