Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Endothelium-derived hyperpolarising factor (EDHF) causes vasorelaxation and may contribute to the release of the endogenous fibrinolytic factor, tissue-plasminogen activator (t-PA). Rotigaptide enhances communication via the connexin 43 gap junction subunit and may potentiate the vascular actions of EDHF. The aims of the present study were therefore to determine whether rotigaptide influences basal and stimulated endothelium-dependent vasodilatation and t-PA release in vivo in man. Using venous occlusion plethysmography, forearm blood flow was measured in 27 healthy volunteers during intra-brachial infusions of rotigaptide (0.25-25 nmol/min) alone, or co-administered with endothelium-dependent (acetylcholine [5-20 microg/min] and bradykinin [30-300 pmol/min]) and independent (sodium nitroprusside [2-8 microg/min]) vasodilators in the presence or absence of aspirin and the 'nitric oxide clamp'. The 'nitric oxide clamp' inhibits endogenous nitric oxide synthesis with L-N-monomethylarginine and restores resting blood flow with the exogenous nitric oxide donor, sodium nitroprusside. Basal blood flow was unaffected by rotigaptide (P=NS). Acetylcholine, bradykinin and sodium nitroprusside all caused dose-dependent vasodilatation in the presence and absence of aspirin and the 'nitric oxide clamp' (P< or =0.005 for all). These responses were unaffected by rotigaptide (P=NS). Bradykinin caused t-PA antigen and activity release (P=0.04, P<0.0001, respectively) that was unaffected by rotigaptide. Augmentation of connexin 43 communication has no effect on basal vascular tone and does not enhance endothelium-dependent or independent vasodilatation, or t-PA release in the forearm arterial circulation of healthy men. It remains to be established whether augmentation of connexin 43 communication improves endothelial function in patients with vascular disease.
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PMID:The vascular effects of rotigaptide in vivo in man. 1878 1

Three major cytokines, namely, tumor necrosis factor (TNF-alpha), interleukin (IL)-1, and IL-6 are produced by cultured brain cells after various stimuli such as ischemia. Neurones, astrocytes, microglia and oligodendrocytes can produce inflammatory mediators, and cytokine receptors are expressed constitutionally throughout the Central Nervous System (CNS), albeit at low levels. Cytokines are involved in virtually every facet of stroke and they have numerous pro-inflammatory and pro-coagulant effects on endothelium. TNF-alpha expression after stroke stimulates expression of tissue factor and adhesion molecules for leukocytes, release of interleukin-1 (IL-1), nitric oxide, factor VIII/von Willebrand factor, platelet-activating factor and endothelin, suppression of the thrombomodulin-protein C-protein S system, reduction of tissue-plasminogen activator and release of plasminogen activator inhibitor-1. Research into the actions of IL-1beta in the brain initially focused on its role in host defence responses to systemic disease. IL-1beta can also elicit an array of responses which could either inhibit, exacerbate or induce neuronal damage and death. IL-6 can be induced by a variety of molecules including IL-1, TNF-alpha, transforming growth factor-beta and prostaglandins (PGs), and many other mediators such as b-amyloid, interferon-g (IFNg) and IL-4 can potentiate these primary inducers, highlighting the complex nature of IL-6 modulation. Several studies reported that plasma levels of TNF-alpha and IL-6 are associated with prognosis after ischemic stroke and our group showed that plasma levels of cytokines such as TNF-alpha, IL-1beta are different in every diagnostic subtype of ischemic stroke, and how plasma levels of some immunoinflammatory markers and thrombotic-phybrinolitic markers are predictive of acute ischemic stroke diagnosis in the acute setting.
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PMID:Inflammatory cytokines in acute ischemic stroke. 1907 34

In this study we examined the effects of exogenous nitric oxide (sodium nitroprusside, SNP) and hydrogen peroxide (H2O2) on the expression level of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), and plasminogen activator inhibitor type 1 (PAI-1) in human umbilical vein endothelial cells (HUVEC). The expression of selected genes involved in fibrynolysis under the influence of oxidative stress was analyzed at the levels of mRNA, protein, and promoter activity. The results of the conducted studies revealed that oxidative stress in endothelial cells causes a significant increase in PAI-1 and u-PAR expression and a moderate increase in t-PA and u-PA expression at all of the investigated levels. We attempted to elucidate the molecular signaling mechanisms by which SNP and H2O2 regulate expression of the respective fibrinolytic factors. Therefore, we tested the protein levels of AP-1, NF-kappaB, and HIF-1 and their DNA-binding activity in endothelial cells subjected to oxidative stress. We found strong correlation between AP-1, NF-kappaB, and HIF-1 in the contribution of regulation of selected genes. In addition, we also found that the inhibition of PAI-1 synthesis by antisense oligonucleotide to PAI-1 mRNA results in markedly increased u-PAR expression and that NF-kappaB and AP-1 are involved in this regulation.
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PMID:Effect of oxidative stress on the expression of t-PA, u-PA, u-PAR, and PAI-1 in endothelial cells. 1908 96

Vascular graft surface properties significantly affect adhesion, growth and function of endothelial cells (ECs). The bulk degradation property of poly(lactic acid) (PLA) makes it possible for it to be replaced by cellular materials and PLA is desirable as a scaffold material for vascular grafts. However, PLA has an unfavorable surface property for EC adhesion and proliferation due to the lack of a selective cell adhesion motif. Photo-initiated surface-grafting polymerization is a promising method for immobilizing certain biomacromolecules on material surfaces without compromising bulk properties. N-Maleic acyl-chitosan (NMCS) is a novel biocompatible amphiphilic derivative of chitosan with double bonds and can be initiated by ultraviolet light. In this study, gelatin was complexed with NMCS via hydrophobic interaction, and gel/NMCS complex thus formed was then grafted on the PLA surface to improve EC biocompatibility. X-ray photoelectron and Fourier transform infrared spectroscopy, and water contact angle measurement confirmed immobilization of the gel/NMCS complex on PLA surface. Moreover, the gel/NMCS modified PLA enhanced human umbilical vein endothelial cell (HUVEC) spreading and flattening, and promoted the expression of more structured CD31 and vWF compared to unmodified PLA film. Compared to the unmodified PLA surface, the HUVECs on the modified PLA surface had elevated uptake of acetylated low-density lipoprotein, and maintained the ability to modulate metabolic activity upon exposure to shear stress at 5dyncm(-2) by up-regulating nitric oxide and prostacyclin production. Cell retention was 1.6 times higher on the gel/NMCS-PLA surface, demonstrating its improved potential for hemocompatibility. These results indicate that photo-initiated surface-grafting of the biomimetic gel/NMCS complex is an effective method to modify material surfaces as vascular grafts.
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PMID:Photo-initiated grafting of gelatin/N-maleic acyl-chitosan to enhance endothelial cell adhesion, proliferation and function on PLA surface. 1929 15

The role of nitric oxide (NO) in the caudal NTS (cNTS) on baseline cardiovascular and respiratory parameters and on changes in respiratory frequency (fR) and cardiovascular responses to chemoreflex activation was evaluated in awake rats. Bilateral microinjections of l-NAME (200nmoles/50nL), a non-selective NO synthase (NOS) inhibitor, into the cNTS increased baseline arterial pressure, while microinjections of N-PLA (3pmoles/50nL), a selective neuronal NOS (nNOS) inhibitor, did not. l-NAME or N-PLA microinjected into the cNTS reduced the increase in fR in response to chemoreflex activation but not cardiovascular responses. These data show that (a) NO produced by non-nNOS in the cNTS is involved in the baseline autonomic control and (b) NO produced by nNOS in the cNTS is involved in modulation of the increase in fR in response to chemoreflex activation but not in the cardiovascular responses. We conclude that NO produced by the neuronal and endothelial NOS play a different role in the cNTS neurons integral to autonomic and respiratory pathways.
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PMID:NO in the caudal NTS modulates the increase in respiratory frequency in response to chemoreflex activation in awake rats. 1937 38

Incubation of rat cortical slices in a medium that was not containing oxygen and glucose (oxygen-glucose deprivation, OGD) caused a 200% increase in the release of S100B. However, when slices were transferred to a medium containing oxygen and glucose (reoxygenation conditions, or REO), S100B release reached 500% of its control value. Neither inhibition of nitric oxide (NO) synthase by L-NAME nor addition of the NO donors sodium nitroprussid (SNP) or hydroxylamine (HA) to the medium altered basal S100B release. Similarly, the presence of SNP, HA or NO precursor L: -arginine in the medium, or inhibition of NO synthase by L-NAME also failed to alter OGD- and REO-induced S100B outputs. Moreover, individual inhibition of PKC, PLA(2) or PLC all failed to attenuate the S100B release determined under control condition or enhanced by either OGD or REO. Blockade of calcium channels with verapamil, chelating the Ca(+2) ions with BAPTA or blockade of sodium channels with tetrodotoxin (TTX) did not alter OGD- and REO-induced S100B release. In contrast to the pharmacologic manipulations mentioned above, glutamate and alpha-ketoglutarate added at high concentrations to the medium prevented both OGD- and REO-induced S100B outputs. These results indicate that neither NO nor the activation of PKC, PLA(2) or PLC seem to be involved in basal or OGD- and REO-induced S100B outputs. Additionally, calcium and sodium currents that are sensitive to verapamil and TTX, respectively, are unlikely to contribute to the enhanced S100B release observed under these conditions.
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PMID:Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions. 1982 32

Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.
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PMID:Endogenous nitric oxide contributes to bradykinin-stimulated glucose uptake but attenuates vascular tissue-type plasminogen activator release. 1984 73

The present investigations were aimed to compare the humoral and cell-mediated immune responses between recombinant hepatitis B surface antigens (HBsAg) adsorbed L-PLA microspheres (Ms) vaccine (single-shot) and marketed alum-HBsAg vaccine (two-doses). The blank cationic (cetyltrimethyammoniumbromide) microspheres were prepared by the double emulsion (w/o/w) solvent evaporation technique. The HBsAg was adsorbed onto the surface of blank cationic microspheres. These microspheres were characterized in vitro for their size, shape, adsorption-efficiency, in-process stability, and HBsAg release studies. Specific humoral immune responses (IgM and IgG) and cell-mediated immune responses (cellular-proliferation) assay including release of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and nitric oxide (NO) from host's cells stimulated with HBsAg or lipopolysaccharide (LPS)/ concanavalin A (con A) in-vitro were determined. Based on these findings, it was concluded that the single injection (using subcutaneous-route) of the polymeric microspheres produced better immune response (both humoral and cell-mediated) than two injections of a conventional alum-HBsAg vaccine. These data demonstrate high potential of polymeric microspheres for their use as a carrier adjuvant for hepatitis B vaccine.
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PMID:Humoral and cell-mediated immune-responses after administration of a single-shot recombinant hepatitis B surface antigen vaccine formulated with cationic poly(l-lactide) microspheres. 1988 3

Phospholipases A(2) (PLA(2)) participate in neuronal death signalling pathways because of their ability to release lipid mediators, although the contribution of each isoform and mechanism of neurotoxicity are still elusive. Using a novel fluorogenic method to assess changes in a PLA(2) activity by flow cytometry, here we show that the group IIA secretory phospholipase A(2) isoform (GIIA) was specifically activated in cortical neurons following stimulation of N-methyl-d-aspartate glutamate receptor subtype (NMDAR). For activation, GIIA required Ca(2+) and reactive oxygen/nitrogen species, and inhibition of its activity fully prevented NMDAR-mediated neuronal apoptotic death. Superoxide, nitric oxide or peroxynitrite donors stimulated GIIA activity, which mediated neuronal death. Intriguingly, we also found that GIIA activity induced mitochondrial superoxide production after NMDAR stimulation. These results reveal a novel role for GIIA in excitotoxicity both as target and producer of superoxide in a positive-loop of activation that may contribute to the propagation of neurodegeneration.
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PMID:Group IIA secretory phospholipase A2 (GIIA) mediates apoptotic death during NMDA receptor activation in rat primary cortical neurons. 2006 79


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