Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In LLC-PK1 cells exposed to patulin (50 microM), lipid peroxidation, abrupt calcium influx, extensive blebbing, and total LDH release appeared to be serially connected events with each representing a step in the loss of structural integrity of the plasma membrane. The aforementioned patulin-induced events were prevented by concurrent incubation with butylated hydroxytoluene, deferoxamine, and cyclopiazonic acid, a fungal metabolite. Patulin also caused depletion of nonprotein sulfhydryls, increased 86Rb+ efflux, dome collapse, and eventually the loss of cell viability. These events were not prevented by antioxidants, results consistent with the hypothesis that they were also serially connected but occurring parallel to those previously mentioned. The earliest events observed in patulin-treated cells were the decrease in nonprotein sulfhydryls and increase in 86Rb+ efflux (5 min) which occurred before statistically significant alterations in protein-bound sulfhydryls. The increased potassium efflux (86Rb+ efflux) occurred via a pathway distinct from BaCl2, quinine, or tetraethylammonium sensitive potassium channels. This is the first published report of the antioxidant activity of indole tetramic acids (cyclopiazonic acid and cyclopiazonic acid imine). The protective effect of tetramic acids in LLC-PK1 cells was restricted to indole tetramic acids, and their prevention of lipid peroxidation did not involve iron chelation. The results of this study demonstrate that cyclopiazonic acid is a potent inhibitor of azide-insensitive, ATP-dependent, a23187-sensitive calcium uptake by the lysate of LLC-PK1 cells. This result is consistent with the hypothesis that the endoplasmic reticulum calcium transport ATPase is a sensitive target for cyclopiazonic acid in LLC-PK1 cells. These findings raise the interesting possibility that the antioxidant activity of indole tetramic acids may involve multiple novel mechanisms: surface charge alterations on the cytoplasmic surface of plasma membranes, alterations in calcium permeability in the plasma and endoplasmic reticulum membrane, and inhibition of the calcium-dependent ATPase of the endoplasmic reticulum.
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PMID:The mechanism of patulin's cytotoxicity and the antioxidant activity of indole tetramic acids. 203 42

2-Ethylhexanol (70 microM), a non-genotoxic carcinogen and peroxisome proliferator, stimulated oxygen uptake in the perfused rat liver by about 10% during the first 10 min of infusion. Perfusion with a higher, hepatotoxic dose of ethylhexanol (3 mM) led to a transient increase in oxygen uptake followed by a rapid inhibition of respiration of over 50% in 10 min. Lactate dehydrogenase (LDH) release, indicative of irreversible cell death, was detected in the effluent perfusate after 20 min. After 10 min of perfusion with ethylhexanol, livers were freeze-clamped, acid extracts were prepared and adenine nucleotides were measured by high-pressure liquid chromatography. Ethylhexanol decreased the ATP/ADP ratio from 2.5 to 0.9. Thus, marked decreases in hepatic energy state due to inhibition of respiration preceded cell death. To attempt to understand this phenomenon, the effect of ethylhexanol on isolated mitochondria was studied. Similar to classical uncoupling agents, ethylhexanol stimulated state-4 rates of respiration, diminished coupled rates of respiration, and decreased the P/O ratio in a dose-dependent manner in isolated mitochondria. Ethylhexanol also decreased uptake of radiolabeled 45CaCl2 by isolated mitochondria 4- to 5-fold. Therefore, we hypothesize that ethylhexanol initially uncouples oxidative phosphorylation leading to diminished ATP synthesis and collapse of ion gradients across the mitochondrial membrane.
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PMID:2-Ethylhexanol uncouples oxidative phosphorylation in rat liver mitochondria. 204 57

The relationship between cytosolic free Ca2+, mitochondrial membrane potential, ATP depletion, pyridine nucleotide fluorescence, cell surface blebbing, and cell death was evaluated in rat hepatocytes exposed to HgCl2. In cell suspensions, 50 microM HgCl2 oxidized pyridine nucleotides between 1/2 and 2 min, caused ATP depletion between 2 and 5 min, and produced an 89% loss of cell viability after 20 min. Rates of cell killing were identical in high (1.2 mM) and low (2.6 microM) Ca2+ buffers. Cytosolic free Ca2+ was determined in 1-day cultured hepatocytes by ratio imaging of Fura-2 employing multiparameter digitized video microscopy. In high Ca2+ medium, HgCl2 caused a 3-4-fold increase of free Ca2+ beginning after 6-7 min, but free Ca2+ did not change in low Ca2+ medium. Bleb formation occurred after about 4-5 min in both buffers prior to any increase of free Ca2+. Subsequently, in high Ca2+ medium, blebs became hot spots of free Ca2+ (greater than 600 nM). After about 2 min of exposure to HgCl2, rhodamine 123 fluorescence redistributed from mitochondrial to cytosolic compartments signifying collapse of the mitochondrial membrane potential. The results taken together demonstrate that bleb formation, ATP depletion, and the onset of cell death are not dependent on an increase of cytosolic free Ca2+. HgCl2 toxicity appears to be a consequence of inhibition of oxidative phosphorylation leading to ATP depletion and cell death.
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PMID:Toxic injury from mercuric chloride in rat hepatocytes. 210 22

(1) The affinity of the F0F1-ATPase from Paracoccus denitrificans for ATP during NADH-driven oxidative phosphorylation has been analyzed under different conditions by examining the type and extent of product inhibition. (2) A limited collapse of the protonmotive force (delta p) due to partial uncoupling does not increase the affinity for ATP at the active site(s) of the enzyme; instead, a partial noncompetitive inhibition becomes apparent, compatible with the binding of ATP to a noncatalytic site (or sites) with high affinity. (3) In contrast, partial inhibition of the electron-transport chain increases the extent of pure competitive product inhibition and, therefore, the affinity for ATP at the active site(s). (4) The results are interpreted as indicative of a modulation of the rate of ATP release from the active site(s) of the F0F1-ATPase which is controlled by the activity of the electron-transport chain and not by delta p.
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PMID:Kinetics of oxidative phosphorylation in Paracoccus denitrificans. 2. Evidence for a kinetic and thermodynamic modulation of F0F1-ATPase by the activity of the respiratory chain. 214 91

We show that a synthetic peptide corresponding to the N-terminal 22 residues of the cytochrome c oxidase subunit IV presequence blocked import of pre-subunit IV into yeast mitochondria. The 22-residue peptide pL4-(1-22) did not alter the electrical potential across the mitochondrial inner membrane (the delta psi). Inhibition of import was reversible and could be overcome by the addition of increased amounts of precursor. Two other peptides, pL4-(1-16) and pL4-(1-23), which correspond to, respectively, the N-terminal 16 and 23 residues of the same presequence, also blocked import of pre-subunit IV. However, pL4-(1-16) was a much weaker inhibitor of import, while the inhibitory effect of pL4-(1-23) was due to its ability to completely collapse the delta psi. pL4-(1-22) seems to be a general inhibitor of mitochondrial import, in that it also blocked uptake of several other proteins. These included the precursors of the yeast proteins cytochrome c oxidase subunit Va, the F1-ATPase beta subunit, mitochondrial malate dehydrogenase, and the ATP/ADP carrier. In addition, uptake of two non-yeast precursor proteins (human ornithine transcarbamylase and a cytochrome oxidase subunit IV-dihydrofolate reductase fusion), was also blocked by the peptide. Subsequent studies revealed that pL4-(1-22) did not block the initial recognition or binding of proteins to mitochondria. Rather, our results suggest that the peptide acts at a subsequent translocation step which is common to the import pathways of many different precursor proteins.
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PMID:A synthetic presequence reversibly inhibits protein import into yeast mitochondria. 216 Apr 69

The effect of n-alcohols on ATP-dependent generation of delta pH and Em across the plasma membrane vesicles of the yeast Saccharomyces carlsbergensis was investigated. The alcohols were shown to collapse delta pH and Em in the order C2 less than C3 less than C4 less than C5 less than or equal to C6 greater than or equal to C7 greater than C8 greater than C11, the dissipation of Em being more pronounced. Inhibition of the plasmalemma H(+)-ATPase was insignificant; at low alcohol concentrations its activity even increased. The basic reason for the toxic effect of the alcohols on the yeast cells was suggested to be due to the increase in the anion and proton permeability of the plasma membrane. Mg2+ partially prevented the increase in the plasmalemma ion permeability by the alcohols investigated.
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PMID:Increase of the anion and proton permeability of Saccharomyces carlsbergensis plasmalemma by n-alcohols as a possible cause of its de-energization. 216 10

A gene coding for yeast 15-kDa protein, a regulatory factor of mitochondrial F1F0-ATPase, was isolated. The cloned gene was disrupted in vitro and mutant strains that did not contain the 15-kDa protein were constructed by transformation of yeast cells with the disrupted gene. The ATP-synthesizing activity of the mutant mitochondria was the same as that of wild-type cells, suggesting that the 15-kDa protein is not required for mitochondrial oxidative phosphorylation. Collapse of the membrane potential induced ATP-hydrolyzing activity of F1F0-ATPase of the mutant mitochondria but not of normal mitochondria. Activation of the enzyme was also observed during incubation of submitochondrial particles from mutant cells, but not of those from wild-type cells. Thus, it is inferred that the 15-kDa protein supports the action of an intrinsic ATPase inhibitor of the ATP-hydrolyzing activity of the enzyme upon de-energization of mitochondrial membranes.
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PMID:Isolation of a gene for a regulatory 15-kDa subunit of mitochondrial F1F0-ATPase and construction of mutant yeast lacking the protein. 216 16

The protein translocation system of Escherichia coli was solubilized and reconstituted, using the octylglucoside dilution method, into liposomes prepared from E. coli phospholipids. SecA, ATP, phospholipids and membrane proteins were found to be essential for the translocation of a model secretory protein, uncleavable OmpF-Lpp. Phospholipids were found to play roles not only in liposome formation but also in the stabilization of membrane proteins during the octylglucoside extraction. The effects of IgGs specific to five distinct regions of the SecY molecule on protein translocation into proteoliposomes were examined. IgGs specific to the amino- and carboxyl-terminal regions of the SecY molecule strongly inhibited the translocation activity, indicating the participation of SecY in the translocation. Generation of a proton motive force due to the simultaneous reconstitution of F0F1-ATPase was also observed in the presence of ATP. An ATP-generating system consisting of creatine phosphate and creatine kinase significantly enhanced the formation of the proton motive force and the protein translocation activity of the proteoliposomes. Collapse of the proton motive force thus generated partially inhibited the translocation.
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PMID:Reconstitution of translocation activity for secretory proteins from solubilized components of Escherichia coli. 217 Jan 24

Historically, increase in cell Na content during ischemic and hypoxic episodes were thought to result from impaired ATP production causing decreased Na(+)-K(+)-ATPase activity. Here we report the results of testing the alternate hypothesis that hypoxia-induced Na uptake is 1) the result of increased entry, as opposed to decreased extrusion 2) via Na-H exchange operating in a pH regulatory capacity and that cell Ca accumulation occurs via Na-Ca exchange secondary to collapse of the Na gradient. We used 23Na-, 19F-, and 31P-nuclear magnetic resonance (NMR) to measure intracellular Na content (Nai), Ca concentration [( Ca]i), pH (pHi), and high-energy phosphates in Langendorff-perfused rabbit hearts. When the Na(+)-K(+)-ATPase was inhibited by ouabain and/or K-free perfusion, hearts subjected to hypoxia gained Na at a rate greater than 10 times that of normoxic controls [during the first 12.5 min Nai increased from 7.9 +/- 5.8 to 34.9 +/- 11.0 (SD) meq/kg dry wt compared with 11.1 +/- 16.3 to 13.6 +/- 9.0 meq/kg dry wt, respectively]. When normoxic hearts were acidified using a 20 mM NH4Cl prepulse technique, pHi rapidly fell from 7.27 +/- 0.24 to 6.63 +/- 0.12 but returned to 7.07 +/- 0.10 within 20 min, while Na uptake was similar in rate and magnitude to that observed during hypoxia (24.5 +/- 13.4 to 132.1 +/- 17.7 meq/kg dry wt). During hypoxia and after NH4Cl washout, increases in [Ca]i were similar in time course to those observed for Na.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Na-H exchange in myocardium: effects of hypoxia and acidification on Na and Ca. 217 47

Fluoride inhibition of carbohydrate metabolism by the acidogenic plaque microflora is well-established, although it has not always been appreciated that oral bacteria vary considerably in their susceptibility to fluoride. Early studies demonstrated that the F-induced reduction in acid production was due, in part, to the inhibition of the glycolytic enzyme, enolase, which converts 2-P-glycerate to P-enolpyruvate. The decreased output of PEP in the presence of F, in turn, results in the inhibition of sugar transport via the PEP phosphotransferase system (PTS). Bacterial accumulation of fluoride involves the transport of HF, a process requiring a transmembrane pH difference or pH gradient, which is generated only by metabolically active cells. The uptake of HF into the more alkaline cytoplasm results in the dissociation of HF to H+ and F- and, if allowed to continue, the accumulation of protons acidifies the cytoplasm, causing a reduction in both the proton gradient and enzyme activity. Current information indicates that in addition to enolase, F- also inhibits the membrane-bound, proton-pumping H+/ATPase, which is involved in the generation of proton gradients through the efflux of protons from the cell at the expense of ATP. Thus, fluoride has the dual action of dissipating proton gradients and preventing their generation through its action on H+/ATPase. The collapse of transmembrane proton gradient, in turn, reduces the ability of cells to transport solutes via mechanisms involving proton motive force. In spite of these known effects on the bacterial cell, there is no general agreement that the anti-microbial effects of F contribute to the anti-caries effect of fluoride.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical effects of fluoride on oral bacteria. 217 27


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