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At least 775 records · Page 43Linked to original sources
PubMed1996

Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine.

The levels of N-arachidonoylethanolamine (anandamide), an endogenous cannabinoid-receptor ligand, and a relevant molecule, N-arachidonoylphosphatidylethanolamine (N-arachidonoylPtdEtn), in rat brain were investigated using a newly developed sensitive analytical method. We found that rat brain contains small but significant amounts of these two types of N-arachidonoyl lipids (4.3 pmol/g tissue and 50.2 pmol/g tissue, respectively). Then, we investigated how N-arachidonoylethanolamine (anandamide) is produced in the brain. We found that anandamide can be formed enzymatically via two separate synthetic pathways in the brain: enzymatic condensation of free arachidonic acid and ethanolamine; and formation of N-arachidonoylPtdEtn from PtdEtn and arachidonic acid esterified at the 1-position of phosphatidyl-choline (PtdCho), and subsequent release of anandamide from N-arachidonoylPtdEtn through the action of a phosphodiesterase. We confirmed that rat brain contains both the enzyme activities and lipid substrates involved in these reactions. Several lines of evidence strongly suggest that the second pathway, rather than the first one, meets the requirements and conditions for the synthesis of various species of N-acylethanolamine including anandamide in the brain.

Acyltransferases↗
PubMed1998

Nitric oxide suppresses bFGF- and IL-1-alpha-mediated but not VEGF165-mediated angiogenesis in natively vascularized mammalian tissue.

Using the rat mesenteric window angiogenesis assay, we studied the systemic effect of the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester, L-NAME, on angiogenesis induced by basic fibroblast growth factor (bFGF), interleukin-1-alpha (IL-1) or vascular endothelial growth factor (VEGF165). Using technically independent morphometric and image analysis methods, the angiogenic response was quantified in variables related to (i) microvascular spatial extension and (ii) microvascular density. The test tissue, which is natively vascularized and lacks significant angiogenesis physiologically, was unaffected by surgical intervention. Two daily intraperitoneal injections of bFGF (2.20 nmole), IL-1 (1.18 nmole) and VEGF165 (480 pmole) for 5 days elicited significant angiogenesis in the mesenteric windows. L-NAME (0.5 g/L in drinking water) caused further enhancement of the angiogenic response produced by human recombinant bFGF (p<0.001), bovine purified bFGF (p<0.05) or murine recombinant IL-1 (p<0.05). In contrast, the L-NAME treatment did not affect the angiogenic response produced by human and murine recombinant VEGF165. These data suggest that nitric oxide can act as an endogenous suppressor of mammalian de novo angiogenesis, which is a new finding, and, moreover, that angiogenesis induced by VEGF165 on the one hand and by bFGF and IL-1 on the other in the rat mesenteric window depends on different pathways.

Animals↗
PubMed2006

Cilostazol suppresses superoxide production and expression of adhesion molecules in human endothelial cells via mediation of cAMP-dependent protein kinase-mediated maxi-K channel activation.

This study shows whether increased intracellular cAMP level by cilostazol is directly coupled to its maxi-K channel activation in human endothelial cells. Cilostazol (1 microM) increased the K+ currents in the human endothelial cells by activating maxi-K channels, which was abolished by iberiotoxin (100 nM), a maxi-K channel blocker. On incubation of human coronary artery endothelial cells with tumor necrosis factor-alpha (TNF-alpha) (50 ng/ml), monocyte adhesion significantly increased with increased superoxide generation and expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) accompanied by increased degradation of inhibitory kappaBalpha in cytoplasm and activation of nuclear factor-kappaB p65 in nucleus. All these variables were significantly suppressed by cilostazol (10 microM), which was antagonized by iberiotoxin (1 microM) and (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-l] [1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) (300 nM, cAMP-dependent protein kinase inhibitor), but not by (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindo-lo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT 5823) (300 nM, cGMP-dependent protein kinase inhibitor). In the human endothelial cells transfected with siRNA-targeting maxi-K channels, cilostazol did not suppress the superoxide generation, VCAM-1 and MCP-1 expressions, and monocyte adhesion as contrasted with the wild-type cells. These findings were similarly evident with (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one (BMS-204352), a maxi-K channel opener, and forskolin and dibutyryl cAMP. In conclusion, increased cAMP level by cilostazol is directly coupled to its maxi-K channel opening action via protein kinase activation in human endothelial cells, thereby suppressing TNF-alpha-stimulated superoxide production and expression of adhesion molecules.

Cell Adhesion↗
PubMed1996

Potent CD14-mediated signalling of human leukocytes by Escherichia coli can be mediated by interaction of whole bacteria and host cells without extensive prior release of endotoxin.

How invading microorganisms are detected by the host has not been well defined. We have compared the abilities of Escherichia coli and lipopolysaccharides (LPS) purified from these bacteria to prime isolated neutrophils for phorbol myristate acetate-stimulated arachidonate release, to trigger respiratory burst in 1% blood, and to increase steady-state levels of tumor necrosis factor alpha mRNA in whole blood. In all three assays, bacteria were > or = 10-fold more potent than equivalent amounts of LPS and could trigger maximal cellular responses at ratios as low as one bacterium per 20 to 200 leukocytes. Both E. coli and LPS-triggered responses were enhanced by LPS-binding protein and inhibited by an anti-CD14 monoclonal antibody and the bactericidal/permeability-increasing protein (BPI). However, whereas O polysaccharide did not affect the potency of isolated LPS, intact E. coli carrying long-chain LPS (O111:B4) was less potent than rough E. coli (J5). Furthermore, material collected by filtration or centrifugation of bacteria incubated under conditions used to trigger arachidonate release or chemiluminescence was 5- or 30-fold less active, respectively, than whole bacterial suspensions. Extracellular BPI (not bound to bacteria) inhibited bacterial signalling, but BPI bound to bacteria was much more potent. Taken together, these findings indicate that E. coli cells can strongly signal their presence to human leukocytes not only by shedding LPS into surrounding fluids but also by exposing endotoxin at or near their surface during direct interaction with host cells.

Acute-Phase Proteins↗
PubMed1987

Alterations of humoral, cell mediated and antibody dependent cell mediated cytotoxic responses during the course of amoebic infection in guinea pigs.

The cellular and antibody dependent cellular cytotoxic (ADCC) responses of splenic lymphocytes and peritoneal macrophages obtained from animals at variable intervals after inoculation were studied against trophozoites of axenic E histolytica (NIH:200). Cytotoxic responses of effector cells from infected animals were compared with those of effector cells from vaccine stimulated and unstimulated uninfected control animals. Cellular and antibody-dependent cellular cytotoxic responses of the effector cells from animals during the establishment and acute phase of infection were significantly suppressed, compared with unstimulated uninfected and vaccinated (FI amoebic proteins stimulated) effector cells. The effector cells from animals recovered from infection showed enhanced cytotoxic responses against trophozoites of E histolytica. The suppressed cytotoxic response was accompanied by impairment of cytotoxic cell activities and lack, or very low level of anti-FI antibodies in the sera of animals during the establishment phase of infection. With the rise in anti-FI antibodies in the sera of animals ADCC could be induced effectively against trophozoites of E histolytica, which seem to result in clearance of amoebic infection.

Amebiasis↗
PubMed1988

Experimental studies of immunologically mediated enteropathy. Development of cell mediated immunity and intestinal pathology during a graft-versus-host reaction in irradiated mice.

The intestinal component of a graft-versus-host reaction (GvHR) provides a useful experimental model to elucidate the pathogenesis of clinical enteropathies which cause villus atrophy and crypt hyperplasia and which are associated with a local immune response. One to three days after induction of GvHR in heavily irradiated (CBAxBALB/c)F1 mice, a proliferative form of enteropathy developed. Compared with controls, these mice had increased counts of jejunal intraepithelial lymphocytes and had a four-fold increase in crypt cell production rate as well as an increase in crypt length. These changes were accompanied by a marked enhancement of splenic natural killer cell activity. After day three, the crypt cell production rate fell to zero and cytotoxic T lymphocytes (CTL) which could lyse targets of host origin appeared. In parallel, mice with GvHR developed significant villus shortening and their clinical condition deteriorated. Further experiments showed that increased counts of intraepithelial lymphocytes, villus atrophy and crypt hyperplasia also occurred in grafts of fetal CBA intestine implanted under the kidney capsule of (CBAxBALB/c)F1 mice with GvHR. As these grafts are syngeneic to the injected CBA spleen cells, they should not be attacked by anti-host cytotoxic T lymphocytes. We suggest that the proliferative and destructive components of enteropathy in GvHR are caused by lymphokines released by an anti-host delayed type hypersensitivity reaction.

Animals↗
PubMed1985

Unusual potassium channels mediate nonadrenergic noncholinergic nerve-mediated inhibition in opossum esophagus.

Field stimulation of the circular muscle of the opossum esophagus produces a transient hyperpolarization (inhibitory junction potential, IJP) followed by an "off" depolarization. A similar nonadrenergic, noncholinergic (NANC) response in guinea pig taenia caecum has been shown to be due to an increase in the potassium ion permeability of the smooth muscle cell membrane. Double sucrose gap studies showed a decrease in resistance during the IJP, and a reversal at an estimated membrane potential of about -90 mV (4 mM K+). The reversal potential was dependent on the extracellular potassium concentration, shifting to -75 mV when the potassium in the superfusion medium was increased to 10 mM. The IJP in the opossum esophageal circular smooth muscle is therefore like the IJP of the guinea pig taenia caecum in that it is probably due to a selective increase in potassium ion permeability. Potassium conductance blocking agents, tetraethylammonium chloride (TEA, 20 mM) and 4-aminopyridine (4-AP, 5 mM) both caused a depolarization of the smooth muscle cell membrane, but TEA increased the membrane resistance, whereas 4-AP did not affect the membrane conductance in a consistent way. A decrease in IJP amplitude owing to these agents was not apparent. Apamin (10 microM) did not affect the membrane potential, the membrane resistance, or the IJP. Quinine (0.1 mM) produced effects quantitatively similar to those of TEA. Quinine (1 mM) did abolish the IJP, however, this was likely due to a blockade of impulse transmission of the intramural nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed2002

Lyn- and ERK-mediated vs. Ca2+ -mediated neutrophil O responses with thermal injury.

We evaluated the dependency of neutrophil O production on PTK-Lyn and MAPK-ERK1/2 in rats after thermal injury. Activation of PTK-Lyn was assessed by immunoprecipitation. Phosphorylation of ERK1/2 was assessed by Western blot analysis. O production was measured by isoluminol-enhanced luminometry. Imaging technique was employed to measure neutrophil [Ca2+](i) in individual cells. Thermal injury caused marked upregulation of Lyn and ERK1/2 accompanying enhanced neutrophil O production. Treatment of rats with PTK blocker (AG556) or MAPK blocker (AG1478) before burn injury caused complete inhibition of the respective kinase activation. Both AG556 and AG1478 produced an ~66% inhibition in O production. Treatment with diltiazem (DZ) produced an ~37% inhibition of O production without affecting Lyn or ERK1/2 activation with burn injury. Ca2+ mobilization was upregulated with burn injury but not affected by treatment of burn rats with AG556. Unlike the partial inhibition of burn-induced O production by AG556, AG1478, or DZ, platelet-activating factor antagonist (PAFa) treatment of burn rats produced near complete inhibition of O production. PAFa treatment also blocked activation of Lyn. The findings suggest that the near complete inhibition of O production by PAFa was a result of blockade of PTK as well as Ca2+ signaling. Overall, our studies show that enhanced neutrophil O production after thermal injury is a result of potentiation of Ca2+ -linked and -independent signaling triggered by inflammatory agents such as PAF.

Animals↗
PubMed2005

Neutrophil-mediated accumulation of 2-ClHDA during myocardial infarction: 2-ClHDA-mediated myocardial injury.

The pathophysiological sequelae of myocardial infarction include neutrophil infiltration into the infarct zone that contributes to additional damage to viable tissue and removal of cellular debris from necrosed tissue. Reactive chlorinating species produced by myeloperoxidase amplify the oxidant capacity of activated neutrophils. Plasmalogens are a major phospholipid subclass of both endothelial cells and cardiac myocytes. Recent studies have shown that plasmalogens are targeted by neutrophil-derived reactive chlorinating species that lead to the production of alpha-chloro fatty aldehydes. Results herein demonstrate that the alpha-chloro fatty aldehyde 2-chlorohexadecanal (2-ClHDA) accumulates in rat hearts subjected to left anterior descending coronary artery occlusion. Myocardia from rats subjected to surgical infarction had increased 2-ClHDA and neutrophil infiltration levels compared with myocardia from rats subjected to sham surgery. Additionally, infarcted myocardia from rats rendered neutropenic by treatments with an anti-neutrophil antibody had diminished 2-ClHDA and neutrophil infiltration levels compared with infarcted myocardia from normopenic rats; 2-ClHDA was shown to elicit myocardial damage as determined by lactate dehydrogenase release in isolated perfused rat hearts. Additionally, 2-ClHDA treatment of hearts resulted in decreased heart rate and ventricular performance. Taken together, the present results demonstrate a novel neutrophil-dependent myeloperoxidase-based mechanism that results in 2-ClHDA production in response to regional myocardial infarction that may also contribute to cardiac dysfunction.

Aldehydes↗
PubMed1995

Catecholamine affects acetylcholine release in trachea: alpha 2-mediated inhibition and beta 2-mediated augmentation.

We investigated the effects of catecholamines on acetylcholine (ACh) release from equine airway parasympathetic nerves. Trachealis strips were suspended in 2-ml tissue baths with Krebs-Henseleit solution containing atropine (10(-7) M), neostigmine (10(-6) M), and guanethidine (10(-5) M). Electrical field stimulation (20 V, 0.5 ms, 0.5 Hz, for 15 min) was applied, and ACh was measured by high-performance liquid chromatography with electrochemical detection. Epinephrine (Epi) and norepinephrine (NE) inhibited ACh release in a concentration-dependent manner. Inhibition was attenuated by the alpha 2-adrenoceptor antagonist idazoxan (10(-6) M) but not by the alpha 1-antagonist prazosin (10(-6) M). After alpha 2-blockade with idazoxan (10(-5) to 10(-4) M), Epi but not NE augmented ACh release. Isoproterenol (10(-7) to 10(-5) M) increased ACh release, an effect that was reversed by the beta 2-adrenoceptor antagonist ICI-118,551 (10(-5) M) but not by the beta 1-adrenoceptor antagonist atenolol (10(-5) M). Our results indicate that horse airway cholinergic nerves are modulated by both alpha 2-inhibitory and beta 2-excitatory adrenoceptors, with the former being predominant.

Acetylcholine↗