Effect on 5-lipoxygenase

A significant advance in the understanding of the anti-inflammatory properties of Bupleurum fruticescens has been provided by Prieto et al. (36). The showed that a methanol extract from the aerial parts had a significant effect on 5-lipoxygenase activity, inhibiting both LTB4 and 5(S)-HETE production, with IC50 values of 112 and 95 (xg/mL, respectively. At concentrations of 200 (Xg/mL, the extract inhibited COX-1 (90%) and elastase activities (54%). What are the principles involved here, saponin ... 

As a further example of the promising properties of / terphenyl metabolites, we wish to mention here the benzofuranoid compounds isolated from the fruiting bodies of Poliporus leucomelas, and in particular Bl-III (69), displaying an inhibitory effect on 5-lipoxygenase comparable to that of a therapeutic drug for asthma. 

All eight natural prenyl-flavones evaluated by Reddy et al. showed potent inhibitory effects on 5-lipoxygenase with IC50 from 0.36 to 4.3 pM. Artonin E isolated from the bark of Artocarpus communis Forst. (Moraceae) was the most potent dual LOX and COX inhibitor with IC50 values of 0.36 pM and 2.5 pM, respectively. It also inhibited leukocyte and platelet 12-... 

Phenylethanoid glycosides from Forsythia fruits were assayed for their inhibitory effect on 5-lipoxygenase from rat peritoneal cells [54], Forsythiaside (27), suspensaside (28), acteoside (1) and p-hydroxyacteoside (29) showed a high inhibitory effect with IC50 of 2.50 x 10 M, 7.97 x 10 M, 5..27 x 10 M and 19.3 x 10 M, respectively. 

Tornhamre S, Schmidt TJ, Nasman-Glaser B, Ericsson I, Ake L. Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells. Biochem Pharmacol 2001 62 903-911. 

The effects of berbamine, oxyacanthine, and berberine on 5-lipoxygenase lipid peroxidation in phospholipid liposomes induced by 2,2 -azo-(bis-2-amidinopropane)(AAPH), deoxyribose degradation, and their reactivities against the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) were studied. None of the alkaloids showed any appreciable effects in the inhibition of 5-lipoxygenase. Reactivity against DPPH increased in the following order berberine < oxyacanthine < berbamine. Pro-oxidant effects of the alkaloids were excluded, since deoxyribose degradation was not influenced as determined by the release of malondialdehyde [200],... 

Low concentrations of calcium ion (1-2 pM) are required for maximal activity of purified 5-LO, but the major role of calcium appears to be that of increasing lipophilicity of 5-LO through a C-2-like domain in order to translocate to the nuclear envelope. ATP has a stimulatory effect on 5-LO at 20 nM and lipid hydroperoxides are important to initiate the 5-LO catalytic cycle since they readily form Fe(III) from inactive 5-LO with Fe(II) by the pseudoperoxidase mechanism. Microsomal membranes as well as phosphatidylcholine vesicles can stimulate purified 5-LO activity since 5-LO performs the oxidation of AA at the interface between the membrane and cytosol in a manner similar to that of cPLAja. Calcium ions increase the association of 5-LO with phosphatidylcholine vesicles that likely recapitulate events within the cell where 5-LO becomes associated with the nuclear membrane which is rich in phosphatidylcholine [25]. At the nuclear membrane AA is thought to be presented by a protein which has been termed 5-lipoxygenase activating protein (FLAP) [24]. In cells, such as the neutrophil and mast cells where 5-LO is found in the cytosol, 5-LO is catalytically active only when bound to a membrane, typically the nuclear membrane. In fact, in some cells 5-LO is found to be constitutively associated with the nuclear membrane, likely a result of a process of cellular activation while 5-LO is found in the alveolar macrophage within the nucleus itself [25]. 

Neichi, T., Koshihara, Y.. and Murota, S. (1983) Inhibitory Effect of Esculetin on 5-Lipoxygenase and Leukotriene Biosynthesis, Biochim.Biophyr.Ac/a 753,130-132. 

Specific 15-lipoxygenase inhibitors are not yet available, but several drugs that inhibit 12-lipoxygenase and 5-lipoxygenase activities (e.g., NDGA) exert a similar inhibitory effect on 15-lipoxygenase. 

Hui, P.H., Taylor, I.K., Taylor, G.W., Rubin, P., Kesterton, J., Barnes, N.C. and Barnes, P.J. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax 46, 184-189. 

Payne, A.N., Garland, L.G., Lees, I.W. and Salmon, J.A. (1988). Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids effects on bronchial anaphylaxis in anaesthetised guinea-pigs. Br. J. Pharmacol. 94, 540-546. 

Anderson W, Kalberg C, Edwards L et al. Effects of polymorphisms in the promoter region of 5-lipoxygenase and LTC4 synthase on the clinical response to Za-firlukast and Fluticasone. Eur Respir J 2000 16 183s. 

Lopez-Nicolas JM, Bru-Martinez R and Garcia-Carmona F. 2000. Effect of calcium on the oxidation of linoleic acid by potato (Solarium tuberosum var. Desiree) tuber 5-lipoxygenase. J Agric Food Chem 48(2) 292-296. 

An intravenous infusion of PAF causes rapid (within 60 s) intravascular platelet aggregation, thrombocytopenia and platelet factor 4 release, as well as a profound and reversible neutropenia, due to enhanced aggregation and adherence of these cells. In vitro, PAF effects on neutrophils are dependent upon extracellular Ca2+ and Mg2+ and occur within 60 s of addition. The addition of inhibitors of 5-lipoxygenase activity (e.g. ETYA, 5,8,11,14-eicosatetraenoic acid and NDGA, nordihydroguaiaretic acid) - but not those... 

CSOll Sekine, T., Y. Arai, F. Ikegami, Y. Fujii, S. Shindo, T. Yanagisawa, Y. Ishida, S. Okonogi and 1. Murakoshi. Isolation of camelliaside C from tea seed cake and inhibitory effects of its derivatives on arachidonate 5-lipoxygenase. Chem Pharm Bull 1993 41(6) 1185-1187. 

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