Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
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PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

The present study is undertaken to investigate whether the phospholipase A(2) (PLA(2)) influences mRNA nucleocytoplasmic transport evaluated by nucleoside triphosphatase (NTPase) activity and mRNA export in isolated hepatic nuclear envelope. Isolated hepatic nuclei from rat liver were exposed to PLA(2) (10(-5) approximately 10(-2)/ml) with or without incorporation of nuclei with phosphatidylcholine (PC) liposome. Messenger RNA exports and NTPase activities of nuclear membrane were assayed using ATP and GTP as substrates. We found that the RNA efflux, evaluated by [3H] uridine, was potently decreased in a concentration-dependent manner, by incubation of hepatic nuclei with PLA(2), regardless using ATP or GTP as substrates. The PC content in nuclear membrane was also decreased by PLA(2)-treatment. The PC was incorporated into the nuclear membrane by addition of phospholipid liposomes into the incubation mixture. PC incorporation into the nuclear membrane did not alter mRNA export. However this resulted in a significant increase in mRNA export rate in PLA(2)-treated group. Messenger RNA export rate in PLA(2) (10(-3) unit/mL)- treated nuclear membrane was positively correlated with level of PC incorporation, both using ATP and GTP as substrates. The activity of nucleoside triphosphatase, a nuclear membrane-associated enzyme, showed parallel variations with mRNA transport. It is concluded that nuclear PLA(2) plays a regulatory role in RNA transport, which can be antagonized by exogenous PC. These might be pathophysiologically significance, although the mechanisms by which this effect takes place remain to be clarified.
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PMID:Phospholipase A2 inhibits nuclear nucleoside triphosphatase activity and mRNA export in isolated nuclei from rat liver. 1281 50

Secretory phospholipase A(2) (sPLA(2)), abundantly expressed in various cells including fibroblasts, is able to promote proliferation and migration. Degradation of collagenous extracellular matrix by matrix metalloproteinase (MMP) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, tumor invasion, and metastasis. Here we show that group IB PLA(2) increased pro-MMP-2 activation in NIH3T3 fibroblasts. MMP-2 activity was stimulated by group IB PLA(2) in a dose- and time-dependent manner. Consistent with MMP-2 activation, sPLA(2) decreased expression of type IV collagen. These effects are due to the reduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) and the activation of the membrane type1-MMP (MT1-MMP). The decrease of TIMP-2 levels in conditioned media and the increase of MT1-MMP levels in plasma membrane were observed. In addition, treatment of cells with decanoyl Arg-Val-Lys-Arg-chloromethyl ketone, an inhibitor of pro-MT1-MMP, suppressed sPLA(2)-mediated MMP-2 activation, whereas treatment with bafilomycin A1, an inhibitor of H(+)-ATPase, sustained MMP-2 activation by sPLA(2). The involvement of phosphatidylinositol 3-kinase (PI3K) and Akt in the regulation of MMP-2 activity was further suggested by the findings that PI3K and Akt were phosphorylated by sPLA(2). Expression of p85alpha and Akt mutants, or pretreatment of cells with LY294002, a PI3K inhibitor, attenuated sPLA(2)-induced MMP-2 activation and migration. Taken together, these results suggest that sPLA(2) increases the pro-MMP-2 activation and migration of fibroblasts via the PI3K and Akt-dependent pathway. Because MMP-2 is an important factor directly involved in the control of cell migration and the turnover of extracellular matrix, our study may provide a mechanism for sPLA(2)-promoted fibroblasts migration.
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PMID:Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migration via the phosphatidylinositol 3-kinase and Akt pathway. 1522 Mar 45

Macrophage fusion leading to formation of multinucleated giant cells during chronic inflammation is poorly understood in mechanism and physiological significance. To address this, we developed a system of human macrophage fusion that utilizes IL-4, IL-13, or alpha-tocopherol to generate large foreign body-type giant cells (FBGC). Extending our previously demonstrated requirements for F-actin and mannose receptor (MR) activity, we find that macrophage fusion exhibits further features of a phagocytic process. Pharmacological inhibition of IL-4-induced FBGC formation indicates critical roles for vacuolar-type ATPase, microtubules, the endoplasmic reticulum (ER), and calcium-independent phospholipase A(2) (iPLA(2)), but not calcium-dependent PLA(2) (cPLA(2)), secretory PLA(2) (sPLA(2)), cyclooxygenase, or lipoxygenase. Immunocytochemistry confirms iPLA(2) expression and absence of cPLA(2) or sPLA(2) expression in macrophages/FBGC. As markers of ER-mediated phagocytosis, calnexin and calregulin are detectable on non-permeabilized fusing macrophages and also concentrated at fusion interfaces where they co-localize with actin in permeabilized macrophages/FBGC. Furthermore, ER markers co-localize with concanavalin A reactivity on non-permeabilized fusing macrophages, suggesting that the ER may present MR ligand during fusion events. These data demonstrate for the first time that the mechanism of macrophage fusion leading to formation of multinucleated giant cells exhibits multiple features of phagocytosis with potential participation of the ER.
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PMID:Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum. 1610 4

Intracellular calcium overload plays a key role in severe acute pancreatitis. Resveratrol can decrease the severity of pancreatitis; however, the mechanism of action of resveratrol has not been determined. The aim of our study was to examine the relationship between calcium overload and the effects of resveratrol in severe acute pancreatitis. Animals were randomly divided into 3 groups: control group (sham operation), model group (0.1 ml/100 g of 3.5% sodium taurocholate used to induce severe acute pancreatitis), and treated group (treated with resveratrol, 10 mg/kg). In model group, the severity of pancreatitis was aggravated; this was evaluated by pancreatic weight/body weight and lung weight/body weight ratios, serum amylase activities, and pancreatic histopathological scoring; the Ca(2+)-Mg(2+)-ATPase and Ca(2+)-ATPase activities decreased while PLA(2) activity and [Ca(2+)](i) increased gradually with time. Compared to the control group, in the model group, these changes were observed in the pancreatic tissue at the 3 h time point and in the lung tissue at the 6 h time point. Resveratrol ameliorated the changes in the laboratory parameters and significantly reduced the pathological damage in the tissues at the corresponding time points. In conclusion, intracellular calcium overload leads to tissue damage in severe acute pancreatitis, and the beneficial effects of resveratrol appear to be mediated by reducing the intracellular calcium overload; this not only limits pancreatic cellular injury but also secondary lung injury.
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PMID:Effects of resveratrol on calcium regulation in rats with severe acute pancreatitis. 1803 30

In snake venoms, non-covalent protein-protein interaction leads to protein complexes with synergistic and, at times, distinct pharmacological activities. Here we describe a new protein complex containing phospholipaseA(2) (PLA(2)), protease, and a trypsin inhibitor. It is isolated from the venom of Daboia russelii by gel permeation chromatography, on a Sephadex G-75 column. This 44.6 kDa complex exhibits only phospholipase A(2) activity. In the presence of 8M urea it is well resolved into protease (29.1 kDa), PLA(2) (13 kDa), and trypsin inhibitor (6.5 kDa) peaks. The complex showed an LD(50) of 5.06 mg/kg body weight in mice. It inhibited the frequency of spontaneous release of neurotransmitter in hippocampal neurons. It also caused peritoneal bleeding, and edema in the mouse foot pads. Interestingly, the complex caused degeneration of both the germ cells and the mouse Leydig cells of mouse testis. A significant reduction in both the diameter of the seminiferous tubules and height of the seminiferous epithelia were observed following intraperitoneal injection of the sub-lethal dose (3 mg/kg body weight). This effect of the toxin is supported by the increase in the activities of acid and alkaline phosphatases and the nitric oxide content in the testes, and a decrease in the ATPase activity. Because of its potent organ atrophic effects on the reproductive organs, the toxin is named "Reprotoxin". This is the first report demonstrating toxicity to the reproductive system by a toxin isolated from snake venom.
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PMID:Isolation and characterization of "Reprotoxin", a novel protein complex from Daboia russelii snake venom. 1857 7

This paper explores the effects of hydroxysafflor yellow A (HSYA) on traumatic brain injury (TBI). Rats were divided into four groups: control, TBI, TBI combined with HSYA, and TBI combined with nimodipine. Saline, HSYA, or nimodipine was i.v. injected at 30 min before and 6 h after the onset of TBI. The contusion volume of brain, mitochondrial ATPase activity, brain malondialdehyde (MDA) content, and the concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in the blood plasma were investigated. The results showed that the inhibitory rate of HSYA at a dose of 4 mg/kg was 59.2% compared with the TBI group. After the insult by TBI for 48 h, the activity of Na(+), K(+)-ATPase, Ca(2+)-ATPase, and Mg(2+)-ATPase decreased to 31, 35, and 38% of control group. HSYA increased these ATPase activities by 162, 96, and 131% of TBI group. HSYA also increased superoxide dismutase activity and decreased MDA content in the right parietal lobe adjacent to contusion foci in TBI rats. HSYA enhanced the t-PA activity by 64.64%, decreased the PAI-1 activity by 71.88%, and decreased the MMP-9 expression to 49.11% in the hippocampus of the TBI group at 12 h. In conclusion, HSYA may exert a potential therapeutic strategy to improve the outcome following TBI injury.
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PMID:Effects of hydroxysafflor yellow A on the experimental traumatic brain injury in rats. 2039 Jul 72

Rat brain membranes were incubated with bee venom phospholipase A(2) (PLA(2)) or phospholipase C (PLC) from Clostridium perfringens. PLA(2) caused a significant increase in free polyunsaturated fatty acids concomitant with membrane phospholipid degradation as monitored by HPLC and by gas chromatography. Equal concentrations of PLC had a much lesser effect than PLA(2). Divergent and differential effects were shown on deacylation and incorporation of [(3)H]arachidonic acid in membrane phospholipids. The incorporation of [(3)H]arachidonic acid into various phospholipids was greatly reduced by PLA(2) (0.018 units/ml) whereas PLC at identical concentration was not effective. PLA(2) inhibited (Na(+) + K(+))-ATPase but was not effective on p-nitrophenyl-phosphatase activity whereas PLC stimulated both enzymes. PLA(2) induced swelling of cortical brain slices whereas PLC was not effective. Thus, the severity of the perturbation of membrane integrity, and the inhibition of (Na(+) + K(+))-ATPase in brain membranes may play an important role in cellular swelling of brain slices induced by PLA(2).
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PMID:Effects of exogenous phospholipases on brain membrane phospholipid perturbation, (Na(+) + K(+))-ATPase activity and cellular swelling of brain slices. 2050 Nov

Understanding the processes involved in the cellular uptake of nanoparticles is critical for developing effective nano drug delivery systems. In this paper we found that PEG-b-PLA polymeric micelles firstly interacted with cell membrane using atomic force microscopy (AFM) and then released their core-loaded agents into the cell membrane by fluorescence resonance energy transfer (FRET). The released agents were internalized into the cells via lipid raft/caveolae-mediated endocytosis using total internal reflection fluorescence microscopy (TIRFM) and endocytic inhibitors. Further studies revealed that paclitaxel (PTX)-loaded PEG-b-PLA micelles (M-PTX) increased the cellular accumulation of PTX in PTX-resistant human ovarian cell line A2780/T which resulted in more apoptosis as measured by flow cytometry and the cleavage of poly (ADP-ribose) polymerase (PARP) compared with free PTX. PEG-b-PLA micelles inhibited P-glycoprotein (Pgp) function and Pgp ATPase activity but had no effect on Pgp protein expression. The membrane microenvironment studies showed that PEG-b-PLA micelles induced cell membrane depolarization and enhanced membrane microviscosity. These results suggested that PEG-b-PLA micelles might inhibit Pgp function to reverse multidrug resistance (MDR) via interaction with cell membrane to affect the membrane microenvironment. This study provides a foundation for understanding the mechanism of reversing MDR by nanoparticles better and designing more effective nano drug carriers.
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PMID:Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA polymeric micelles. 2218 40

The effects of the anti-proliferative, phospholipase A(2) (PLA(2))-activating riminophenazine agents, clofazimine and B669, on the Na+, K+-adenosine triphosphatase activity of the FaDu human pharynx squamous carcinoma cell line have been investigated in vitro. At concentrations of 1.25-10 mu g/ml both agents caused dose-related enhancement of PLA(2), as measured by increased release of lysophosphatidylcholine (LPC), and inhibition of Na+, K+-ATPase in intact cells and isolated membrane preparations. The inhibitory effects of both riminophenazines on the Na+, K+-ATPase activity of FaDu cells were mimicked by reagent LPC and prevented by treatment of the cells with the lysophospholipid-neutralizing agents alpha-tocopherol and lysophospholipase. Riminophenazine-mediated inhibition of Na+, K+-ATPase activity was also observed with the HeLa (human cervix epitheloid carcinoma) and T24 (human transitional cell bladder carcinoma) cell lines. The anti-proliferative activity of clofazimine and B669 is therefore probably achieved by lysophospholipid-mediated inactivation of Na+, K+-ATPase.
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PMID:The antiproliferative riminophenazine agents clofazimine and b669 promote lysophospholipid-mediated inhibition of na+, k+-adenosine triphosphatase-activity in cancer cell-lines in-vitro. 2156 28


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