Novel and Potent Inhibitors of 5-Lipoxygenase Product Synthesis Based on the Structure of Pirinixic Acid

2008 ◽  
Vol 51 (17) ◽  
pp. 5449-5453 ◽  
Author(s):  
Oliver Werz ◽  
Christine Greiner ◽  
Andreas Koeberle ◽  
Christina Hoernig ◽  
Sven George ◽  
...  
Keyword(s):  
Lipoxygenase Product

Human Platelets Exposed to Mechanical Stresses Express a Potent Lipoxygenase Product

1992 ◽  
Vol 68 (05) ◽  
pp. 589-594 ◽  
Author(s):  
Alon Margalit ◽  
Avinoam A Livne
Keyword(s):  
Regulatory Volume Decrease ◽  
Human Platelets ◽  
Mechanical Stresses ◽  
Arterial Stenosis ◽  
Platelet Suspension ◽  
Suspension Flows ◽  
Lipoxygenase Product ◽  
Pathological Conditions ◽  
K Permeability ◽  
Volume Decrease

SummaryHuman platelets exposed to hypotonicity undergo regulatory volume decrease (RVD), controlled by a potent, yet labile, lipoxygenase product (LP). LP is synthesized and excreted during RVD affecting selectively K+ permeability. LP is assayed by its capacity to reconstitute RVD when lipoxygenase is blocked. Centrifugation for preparing washed platelets (1,550 × g, 10 min) is sufficient to express LP activity, with declining potency in repeated centrifugations, indicating that it is not readily replenish-able. When platelet suspension flows in a vinyl tubing (1 mm i.d.), at physiological velocity, controlled at 90–254 cm/s, LP formation increases as a function of velocity but declines as result of increasing the tubing length. Stirring the platelets in an aggregometer cuvette for 30 s, yields no LP unless the stirring is intermittent. No associated platelet lysis or aggregation are observed following the mechanical stress applications. These results demonstrate that although mechanical stresses result in LP production, the mode of its application plays a major role. These results may indicate that LP is synthesized under pathological conditions and could be of relevance to platelets behavior related to arterial stenosis.

Amplification of LTB4 generation in AM-PMN cocultures: transcellular 5-lipoxygenase metabolism

1991 ◽  
Vol 261 (2) ◽  
pp. L195-L203 ◽  
Author(s):  
F. Grimminger ◽  
U. Sibelius ◽  
W. Seeger
Keyword(s):  
Hydrolysis Product ◽  
Calcium Ionophore ◽  
Fold Increase ◽  
Metabolite Profile ◽  
Product Formation ◽  
Calcium Ionophore A23187 ◽  
Oxidation Products ◽  
Ionophore A23187 ◽  
Lipoxygenase Product ◽  
Isolated Cell

The generation of arachidonic acid (AA) metabolites by human polymorphonuclear leukocytes (PMN) and by rabbit alveolar macrophages (AM) was investigated and compared with that produced under conditions of coculture. Incubation of PMN with the calcium ionophore A23187 resulted in rapid generation of leukotriene (LT) B4 and its omega-oxidation products, paralleled by substantial secretion of 5-hydroxyeicosatetraenoic acid (HETE) and intact LTA4. Rapid LTA4 decay to nonenzymatic hydrolysis products in the extracellular space ensued. Exogenous AA, offered simultaneously with the ionophore, markedly increased 5-lipoxygenase product formation. Incubation of AM with A23187 evoked protracted generation of LTB4 in the absence of omega-oxidation, with concomitant liberation of 5-HETE, 15-HETE, free AA, and minor amounts of AA cyclooxygenase products. Exogenously offered LTA4 was avidly taken up and converted into LTB4 by these cells. Costimulation of AM and PMN with the ionophore resulted in an approximately 2.5-fold increase in the generation of LTB4 and its metabolites (compared with the summed amounts of the isolated cell experiments), whereas 5-HETE and nonenzymatic LTA4, hydrolysis product formation were markedly reduced. This change in metabolite profile was dependent on the AM-to-PMN ratio. Acetylsalicylic acid increased 5-lipoxygenase product formation in the coculture studies but not in the isolated cell experiments. AA prelabeling of either PMN or AM resulted in radioactivity detection in all AA lipoxygenase products except for 15-HETE.(ABSTRACT TRUNCATED AT 250 WORDS)

Eicosanoid interactions in the canine proximal colon

1989 ◽  
Vol 256 (4) ◽  
pp. G673-G679 ◽  
Author(s):  
C. M. Keenan ◽  
P. K. Rangachari
Keyword(s):  
Arachidonic Acid ◽  
Prostaglandin E2 ◽  
Metabolic Pathway ◽  
Colonic Mucosa ◽  
Short Circuit ◽  
Leukotriene B4 ◽  
Proximal Colon ◽  
Cyclooxygenase Inhibitors ◽  
Lipoxygenase Product ◽  
Short Circuit Currents

Effects of eicosanoids on the canine proximal colonic mucosa were examined. Both arachidonic acid (AA) and prostaglandin E2 (PGE2) increased short-circuit currents. Tetrodotoxin did not affect these responses, suggesting that functioning nerves are not required. Indomethacin abolished responses to AA, indicating that the cyclooxygenase pathway is the primary metabolic pathway. Indomethacin significantly potentiated responses to PGE2, suggesting that in the presence of cyclooxygenase inhibition either 1) a normally inhibitory cyclooxygenase product is not present or 2) a potentiating lipoxygenase product is being produced in greater amounts. PGE2 is produced in significant quantities, whereas leukotriene B4 (LTB4) is produced in smaller amounts. Cyclooxygenase inhibitors significantly decreased PGE2 production but had no effect on LTB4. This suggests that an inhibitory PG may be opposing the response to PGE2. Therefore, we tested the effects of several cyclooxygenase products on PGE2 responsiveness. PGD2 alone significantly reduced responses to PGE2. In the canine proximal colon the response to AA is apparently the algebraic sum of the opposing responses of PGE2 and PGD2.

Esterification of an endogenously synthesized lipoxygenase product into granulocyte cellular lipids

Biochemistry ◽  
1981 ◽  
Vol 20 (18) ◽  
pp. 5297-5301 ◽  
Author(s):  
Robert W. Bonser ◽  
Marvin I. Siegel ◽  
Sophia M. Chung ◽  
Randy T. McConnell ◽  
Pedro Cuatrecasas
Keyword(s):  
Lipoxygenase Product ◽  
Cellular Lipids

The 15-lipoxygenase product, 8R,15S-diHETE, stereospecifically sensitizes C-fiber mechanoheat nociceptors in hairy skin of rat

1990 ◽  
Vol 63 (5) ◽  
pp. 966-970 ◽  
Author(s):  
D. M. White ◽  
A. I. Basbaum ◽  
E. J. Goetzl ◽  
J. D. Levine
Keyword(s):  
Arachidonic Acid ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Thermal Stimulus ◽  
Mechanical Stimuli ◽  
Noxious Heat ◽  
Lipoxygenase Product ◽  
Hairy Skin ◽  
Mechanical Threshold ◽  
C Fiber

1. This study examined the effects of the 15-lipoxygenase product of arachidonic acid metabolism, (8R,15S)-dihydroxyicosa-(5E-9,11,13Z)tetraenoic acid (8R,15S-diHETE), on mechanical thresholds and thermal responses of saphenous nerve cutaneous C-fiber nociceptors that innervate the hairy skin of the rat hindpaw. Single C-fiber mechanoheat nociceptors (C-MH) that had von Frey hair (VFH) thresholds greater than 5 g and were activated by a noxious heat stimulus were chosen for study. We also studied the effects of prostaglandin E2 (PGE2), a cyclooxygenase product of arachidonic acid metabolism, on these nociceptors. 2. The 63 C-MHs studied had a conduction velocity of 0.82 +/- 0.03 m/s (mean +/- SE) and a mechanical threshold of 13.4 +/- 2.4 g. In a subgroup of these (n = 24), the thermal threshold was measured as (44 +/- 1 degree C) (mean +/- SE). 3. 8R,15S-diHETE produced a significant decrease in mechanical threshold of C-MHs (n = 33). The 8R,15S-diHETE-induced sensitization of C-MHs to mechanical stimuli was completely antagonized by coadministration with a stereoisomer, 8S,15S-diHETE (n = 10). 4. The mechanical threshold of C-MHs (n = 10), previously injected with the combination of 8R,15S-diHETE and 8S,15S-diHETE, was significantly reduced by a subsequent injection of PGE2. In a separate group of C-MHs (n = 7), PGE2 was co-injected with 8S,15S-diHETE, which failed to antagonize the sensitizing effect of PGE2 on mechanical threshold. 5. 8R,15S-diHETE also sensitized C-MHs (n = 9) to a thermal stimulus consisting of 37 degrees C for 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracellular signal‐regulated kinases phosphorylate 5lipoxygenase and stimulate 5‐lipoxygenase product formation in leukocytes

2002 ◽  
Vol 16 (11) ◽  
pp. 1441-1443 ◽  
Author(s):  
Oliver Werz ◽  
Eva Bürkert ◽  
Lutz Fischer ◽  
Dagmar Szellas ◽  
David Dishart ◽  
...  
Keyword(s):  
Product Formation ◽  
Lipoxygenase Product ◽  
Extracellular Signal

12-Lipoxygenase product as an inhibitor of the action of chemoattractant peptide fMet-Leu-Phe in rat neutrophils

1993 ◽  
Vol 24 (5) ◽  
pp. 1249-1251 ◽  
Author(s):  
H. Yoshino ◽  
S. Kitayama ◽  
K. Morita ◽  
H. Okamoto ◽  
A. Tsujimoto ◽  
...  
Keyword(s):  
Lipoxygenase Product ◽  
12 Lipoxygenase
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