Search PubMed⌕ Search

Biomedical subjects

J R Hoult

Publications and source records attributed to J R Hoult.

At least 37 records · Page 2Linked to original sources
PubMed1996

A novel diterpenoid labdane from Sideritis javalambrensis inhibits eicosanoid generation from stimulated macrophages but enhances arachidonate release.

The diterpenoid ent-8alpha-hydroxy-labda-13(16),14-dien ("labdane F2") was obtained from an anti-inflammatory extract of Sideritis javalambrensis. Labdane F2 inhibited prostaglandin E2 generation in cultured mouse peritoneal macrophages, treated with zymosan, ionophore A23187, or arachidonic acid itself, and in J774 macrophage-like cells activated by bacterial lipopolysaccharide (LPS). The mechanism was investigated by prelabelling the macrophages with radiolabelled arachidonic acid or oleic acid, followed by cell activation in the presence or absence of nontoxic concentrations of labdane F2. Surprisingly, under those conditions in which reduced PGE2 generation was observed, labdane F2 consistently enhanced the release of labelled fatty acid, in a manner similar to that displayed by thimerosal a known acyl-CoA: lysolecithin transferase inhibitor. Labdane E2 therefore appears to possess 2 mutually opposing actions on the eicosanoid system in macrophages: potentiation of delivery of substrate following cell activation, followed by inhibition of conversion of substrate to product. It was also found that nontoxic concentrations of labdane F2 reduced the expression of the inducible isoforms of cyclooxygenase and nitric oxide synthase in LPS-treated J774 cells. Thus, this anti-inflammatory diterpenoid labdane possesses a diverse array of effects impinging on enzyme pathways involved in eicosanoid generation and other inflammatory pathways in macrophages.

Animals↗
PubMed1996

Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential.

1. More than 300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (< 5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronidation. It may, therefore, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5,7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

Animals↗
PubMed1996

The in vitro effects of 6-methoxy-2-naphthylacetic acid, the active metabolite of nabumetone, on rat gastric mucosal eicosanoid synthesis and metabolism.

Nabumetone is a neutral non-steroidal anti-inflammatory drug with a low propensity to cause gastrointestinal (GI) damage. Previous studies, in vivo, have shown that the drug has weak effects on gastric mucosal cyclooxygenase activity, which may help to explain its favourable GI profile. The present study set out to determine whether the observed effects of nabumetone on cyclooxygenase, in vivo, parallel those of its active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA), in vitro. We have also studied nabumetone and 6MNA on two other systems, namely 15-prostaglandin dehydrogenase (15-PGDH) and 5-lipoxy-genase (5-LO), which when inhibited may confer mucosal protection. The results showed that 6MNA had variable effects on cyclooxygenase activity, depending on the concentration and was less potent and less effective than indomethacin. Cyclooxygenase activity was not inhibited by the reversible inhibitor, aminopyrine, but at low concentrations stimulation was observed. Sulphasalazine inhibited 15-PGDH in a concentration-dependent manner whereas 6MNA inhibited it only at high concentrations. Nabumetone was devoid of activity. Basal 5-LO activity was attenuated by phenidone and unaltered by 6MNA but increased by nabumetone at the highest concentration. In the presence of arachidonic acid, to raise 5-LO activity, nabumetone, 6MNA, BW755C and phenidone apparently inhibited this activity. However, it was possible that both nabumetone and 6MNA inhibited a prostanoid-mediated stimulatory effect on 5-LO rather than effecting enzyme inhibition per se. Nabumetone's favourable GI profile may, therefore, relate to 6MNA having weak effects on mucosal cyclooxygenase and is unlikely to involve inhibition of prostanoid metabolism or 5-LO.

Animals↗
PubMed1995

A biologically active lipophilic flavonol from Tanacetum parthenium.

A new lipophilic flavonol, 6-hydroxykaempferol 3,7,4'-trimethyl ether, called tanetin, has been characterized in the leaf, flower and seed of feverfew, Tanacetum parthenium. It co-occurs with the known 6-hydroxykaempferol 3,7-dimethyl ether, quercetagetin 3,7-dimethyl ether and quercetagetin 3,7,3'-trimethyl ether. Pharmacological tests indicate that tanetin could contribute to the anti-inflammatory properties of feverfew by inhibiting the generation of pro-inflammatory eicosanoids, although it is unlikely to be the only biologically active compound within the plant. Water soluble flavone glycosides were detected in the leaves and identified as apigenin 7-glucuronide, luteolin 7-glucuronide, luteolin 7-glucoside and chrysoeriol 7-glucuronide.

Chromatography, High Pressure Liquid↗
PubMed1995

Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation.

Samples of the expressed fixed oil from different sources of Nigella sativa seeds were examined by thin-layer and gas chromatography for content of fixed oils and thymoquinone, and these substances were tested as possible inhibitors of eicosanoid generation and membrane lipid peroxidation. The crude fixed oil and pure thymoquinone both inhibited the cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism in rat peritoneal leukocytes stimulated with calcium ionophore A23187, as shown by dose-dependent inhibition of thromboxane B2 and leukotriene B4, respectively. Thymoquinone was very potent, with approximate IC50 values against 5-lipoxygenase and cyclo-oxygenase of < 1 microgram/ml and 3.5 micrograms/ml, respectively. Both substances also inhibited non-enzymatic peroxidation in ox brain phospholipid liposomes, but thymoquinone was about ten times more potent. However, the inhibition of eicosanoid generation and lipid peroxidation by the fixed oil of N. sativa is greater than is expected from its content of thymoquinone (ca. 0.2% w/v), and it is possible that other components such as the unusual C20:2 unsaturated fatty acids may contribute also to its anti-eicosanoid and antioxidant activity. These pharmacological properties of the oil support the traditional use of N. sativa and its derived products as a treatment for rheumatism and related inflammatory diseases.

Animals↗
PubMed1994

Superoxide scavenging activity in leukocytes and absence of cellular toxicity of a series of coumarins.

Sixteen synthetic or plant-derived coumarins of dietary importance with different patterns of substitution were tested for their capacity to scavenge superoxide and for their cytotoxicity. Superoxide was generated by human polymorphonuclear leukocytes stimulated by phorbol myristate acetate and was measured using the reduction of ferricytochrome c or of nitrobule tetrazolium (NBT). Eleven of the coumarins, all lacking dihydroxy substitution, did not scavenge superoxide. Of the remaining five, the most potent scavenger was fraxetin (7,8-dihydroxy-6-methoxycoumarin) with an IC50 (concentration producing 50% inhibition) of 2.3 microM in the cytochrome assay and 5.8 microM using NBT. The other four coumarins (all containing ortho-dihydroxy catechol functions, and found previously to be pro-oxidant in cell-free systems by virtue of reduction of ferric to ferrous ions), themselves rapidly reduced cytochrome c. Therefore their effects on superoxide were measured using NBT, yielding IC50 values in the range 8.5 to 82.0 microM. Fraxetin and the other active and inactive coumarins were not directly cytotoxic at 100 microM to leukocytes or to erythrocytes, as shown by their failure to cause release of cytosolic lactate dehydrogenase or to cause haemolysis, respectively. However, all five dihydroxylated pro-oxidant coumarins were toxic to NS20Y neuroblastoma cells in 24 hr culture, whereas the other eleven coumarins were nontoxic. We conclude that 7,8-dihydroxylated coumarins such as fraxetin are agents which are not themselves directly cytotoxic and are capable of direct scavenging of superoxide anion radicals, an action which might be protective at sites of leukocyte activation during inflammation. However, in the presence of free ferric ions they may exert potentially damaging pro-oxidant actions, including cytotoxicity. This series of compounds provides a useful basis for structure-activity studies designed to achieve separation or combination of these properties.

Animals↗
PubMed1994

Calcium overload toxicity and functional impairment in peritoneal leukocytes elicited by glycogen or interleukin-1 beta.

Although calcium plays an important role in the activation of leukocytes for such processes as eicosanoid biosynthesis, secretion of granular constituents and superoxide generation, sustained high levels of intracellular calcium ions may be toxic. We have previously found that high concentrations of calcium ionophores induce a rapid-onset "calcium overload" toxicity in rat peritoneal leukocytes, in which functional responses such as beta-glucuronidase secretion, superoxide generation and leukotriene B4 synthesis are greatly attenuated, and some leakage of cytoplasmic LDH occurs. We have now compared this phenomenon in peritoneal leukocytes elicited from animals pretreated in three ways: glycogen, interleukin-1 beta (IL-1 beta) alone or glycogen plus IL-1 beta. Peritoneal administration of IL-1 beta caused elicitation of cells which were enriched in eosinophils; however, the functional responses of the cells in all three groups were broadly similar in terms of the ability of the agonists FMLP, PMA and A23187 to initiate superoxide generation, beta-glucuronidase secretion and leukotriene generation. Cells from all three treatment groups showed diminished responsiveness at 10(-5) M A23187, indicative of calcium overload toxicity. This was most evident for the superoxide and beta-glucuronidase responses. Some quantitative differences observed between treatment groups may reflect the different sensitivities of the various cells contained in the mixed leukocyte preparations. We conclude that IL-1 beta induces leukocyte emigration into the peritoneal cavity but that the cell population is different from that induced by glycogen. However, the cells retain susceptibility to calcium overload toxicity.

Animals↗
PubMed1994

Groups I, II and III extracellular phospholipases A2: selective inhibition of group II enzymes by indomethacin but not other NSAIDs.

The three types (groups I, II and III) of stable extracellular 14 kDa phospholipase A2 enzymes differ in their primary amino acid sequences and their properties. It may thus be possible to design low-molecular weight inhibitors targeted to the secretory form of mammalian PLA2. This enzyme has been implicated in inflammatory disorders. We have studied the inhibition of four distinct PLA2 enzymes by a range of NSAIDs, using 3H-oleate release from prelabelled membranes of E. coli for assay. The enzymes used were cobra venom PLA2 (Naja naja, a group I enzyme), bee venom PLA2 (Apis mellifera, group III), recombinant human synovial PLA2 (group II) and rat peritoneal PLA2 (group II). Under the conditions of the 3H-oleate E. coli assay, 1 mM concentrations of aspirin, sodium salicylate, paracetamol (acetaminophen), oxphenbutazone, ibuprofen, flurbiprofen and nabumetone failed to inhibit significantly any of the four enzymes. However, indomethacin inhibited all four enzymes, although effects were greatest on the two group II enzymes (rat peritoneal and human synovial PLA2). Approximate IC50 values were 28 and 35 microM, respectively. Inhibition by indomethacin was not time dependent and was greater at micromolar rather than millimolar levels of calcium. We conclude that indomethacin but not the other tested classes of NSAID inhibits the group II PLA2 enzyme in a selective manner and suggest that this may be relevant both to its clinical spectrum and to the design of novel pharmaceutical leads.

Acetophenones↗
PubMed1994

Novel anti-inflammatory plant labdanes: comparison of in vitro properties with aspirin and indomethacin.

Two purified plant products were obtained from anti-inflammatory extracts of the Spanish herb Sideritis javalambrensis: ent-13-epi-12 alpha-acetoxy-manoyl oxide (= "manoyl oxide F1") and ent-8 alpha-hydroxy-lambda-13(16),14-dien (= "labdane F2"). They were evaluated for possible anti-inflammatory actions in vitro, and were compared with aspirin, sodium salicylate and indomethacin. Neither of the natural products affected superoxide generation or scavenging and they did not affect granular enzyme secretion from activated human and rat neurotrophils. The compounds were not toxic to the cells at up to 10(-4) M. However, both F1 and F2 inhibited thromboxane B2 and leukotriene B4 generation by A23187-treated rat peritoneal leukocytes, suppressing leukotriene generation at 10(-5) to 10(-4) M and thromboxane B2 at 10(-4) M. Labdane F2 also inhibited human secretory synovial phospholipase A2 activity at 10(-3) M, a property not shared by manoyl oxide F1. We conclude that these two natural products interact with the eicosanoid system, perhaps at the phospholipase level, but do not interfere with the other tested leukocyte functions or with reactive oxygen species, and are essentially non-toxic at the doses used.

Animals↗
PubMed1994

Inhibitory activity of a series of coumarins on leukocyte eicosanoid generation.

Sixteen plant-derived or synthetic coumarins with different patterns of substitution were tested for their capacity to modify A23187-induced synthesis of leukotriene B4 and thromboxane B2 via the 5-lipoxygenase and cyclooxygenase pathways of arachidonate metabolism in rat peritoneal exudate leukocytes. Five of the 16 coumarins inhibited LTB4 production: all contain orthodihydroxy substitutions (approximate IC50 values 8-100 microM). The mechanism is likely to depend upon a combination of the coumarins' iron-chelating and iron ion-reducing abilities, properties which also confer beneficial activities of these compounds as scavengers of reactive oxygen species (Payá et al., Biochem. Pharmacol. 44, 205-214 (1992)). Inhibition of the cyclooxygenase pathway was only demonstrated by one compound, 5,7-dihydroxy-4-methylcoumarin, which did not inhibit 5-lipoxygenase, indicating that the cyclooxygenase inhibitory mechanism is different. Similar effects of the active coumarins were obtained using arachidonic acid as substrate for rat leukocyte eicosanoid generation, confirming that they act at the 5-lipoxygenase/cyclooxygenase level. The same profile of activity was also shown when the coumarins were tested against 5-lipoxygenase in human polymorphonuclear neutrophils. Taken together, these antioxidant and anti-eicosanoid properties of coumarins could be exploited for the design of potentially valuable non-toxic anti-inflammatory agents for treating diseases in which eicosanoid generation and the production of reactive oxygen species are involved.

Animals↗
PubMed1994

Non-cytotoxic inhibition of macrophage eicosanoid biosynthesis and effects on leukocyte functions and reactive oxygen species of two novel anti-inflammatory plant diterpenoids.

Two diterpenoids were prepared from hexane anti-inflammatory extracts of the Spanish herb Sideritis javalambrensis: ent-13-epi-12 alpha-acetoxymanoyl oxide (= "manoyl oxide F1") and ent-8 alpha-hydroxy-labda-13(16), 14-diene (= "labdane F2"). They were evaluated for possible anti-inflammatory actions in vitro in the concentration range 10(-7)M to 10(-4)M, and were compared with aspirin, sodium salicylate, and indomethacin. Neither compound affected superoxide generation or scavenging and they did not inhibit non-enzymatic lipid peroxidation. Neither compound affected azurophil granular enzyme secretion from activated human and rat neutrophils. The diterpenoids were not toxic to the leukocytes or to washed human erythrocytes up to 3 x 10(-5)M but at 10(-4)M some leakage of LDH or haemolysis was observed. However, both F1 and F2 inhibited prostaglandin E2 generation in cultured mouse peritoneal macrophages stimulated by zymosan, ionophore A23187, melittin, and PMA. Labdane F2 was more potent (approximate IC50 = 3 microM in zymosan-activated macrophages). We conclude that these two natural products interact with the eicosanoid system, but do not interfere with the other tested leukocyte functions or with reactive oxygen species, and are essentially non-toxic at submaximal doses. This biochemical profile distinguishes these diterpenoids from the anti-inflammatory polyphenolics such as flavonoids obtained from the genus Sideritis, and suggests that medicinal decoctions of these plants are likely to owe any anti-inflammatory activity to more than one bioactive ingredient.

Adult↗
PubMed1994

Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive alpha-methylenebutyrolactone functions.

1. Previous studies have shown that extracts of feverfew (Tanacetum parthenium) and parthenolide, a sesquiterpene alpha-methylenebutyrolactone obtained from it, inhibit smooth muscle contractility in a time-dependent, non-specific and irreversible manner. 2. The hypothesis that this toxic effect is due specifically to the presence in the sesquiterpene lactone of the potentially reactive alpha-methylene function was tested on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant-derived sesquiterpene lactones purified from yellow star thistle (Centaurea solstitialis): cynaropicrin (an alpha-methylenebutyrolactone) and solstitialin 13-acetate (lacking the alpha-methylene function), and (b) by chemically inactivating the alpha-methylene functions in cynaropicrin and parthenolide by reaction with cysteine. 3. The results show that the characteristic smooth muscle inhibitory profile is demonstrated by the two alpha-methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound lacking this functional group (solstitialin 13-acetate), or by those previously active compounds in which it has been inactivated with cysteine. 4. Thus the alpha-methylene function is critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones, which are natural products widely distributed in the Compositae family of flowering plants.

Animals↗
PubMed1993

The modification of low density lipoprotein by the flavonoids myricetin and gossypetin.

Myricetin and gossypetin, two hexahydroxylated flavonoids, are capable of modifying low density lipoprotein (LDL) to increase greatly its uptake by macrophages. When human 125I-labelled LDL was incubated with 100-1000 microM myricetin or gossypetin, it was subsequently endocytosed much faster by mouse peritoneal macrophages. This modification did not occur at a concentration of 10 microM. Nine other flavonoids containing up to five hydroxyl substituents did not modify LDL to any great extent at 100 microM. The modification of LDL by 100 microM myricetin was time-dependent and complete by 6 hr. Flavonoids can sometimes act as pro-oxidants but myricetin did not act by oxidizing the LDL, as the LDL lipid hydroperoxide content was not increased by myricetin, nor did it promote the depletion of the endogenous antioxidant alpha-tocopherol in the LDL. High concentrations of myricetin caused the aggregation of LDL particles, as judged by light microscopy, agarose gel electrophoresis, retention by a membrane filter and sedimentability by centrifugation. SDS-PAGE indicated that the apolipoprotein B-100 molecules of LDL particles were covalently crosslinked. The uptake and degradation by macrophages of myricetin-modified 125I-labelled LDL reached saturation at about 10 micrograms protein/mL, suggesting the existence of a high affinity uptake process for the modified LDL. The uptake of myricetin-modified 125I-labelled LDL was not competed for by a large excess of non-labelled native LDL or acetylated LDL. We conclude that myricetin and gossypetin at high concentrations are capable of modifying LDL by a novel non-oxidative mechanism to a form taken up by macrophages by a high affinity process.

Animals↗
PubMed1993

Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content.

Preparations of fresh or dried feverfew (Chrysanthemum parthenium) are widely consumed in the U.K. as a remedy for arthritis and migraine, but the pharmacological basis for this has not been established. We have, therefore, compared the properties of extracts of fresh plants with those of dried powdered leaves available commercially from health food shops. The two extracts differed radically in their content of alpha-methylbutyrolactones and in their pharmacological profile when tested in vitro on the rabbit aortic ring and rat anococcygeus preparations. Extracts of fresh leaves caused does- and time-dependent inhibition of the contractile responses of aortic rings to all receptor-acting agonists so far tested; the effects were irreversible and may represent a toxic modification of post-receptor contractile function in the smooth muscle. The presence of potentially -SH reactive parthenolide and other sesquiterpene alphamethylenebutyrolactones in these extracts, and the close parallelism of the actions of pure parthenolide, suggest that the inhibitory effects are due to these compounds. In contrast , chloroform extracts of dried powdered leaves were not inhibitory but themselves elicited potent and sustained contractions of aortic smooth muscle that were not antagonised by ketanserin (5-HT2 receptor antagonist). These extracts did not contain parthenolide or butyrolactones according to a chemical-HPLC assay, We conclude that there are marked differences in the pharmacological potency and profiles between preparations from fresh and dried feverfew and that this may relate to their lactone content. As the effects of the lactones are potentially toxic, it will be necessary to compare the clinical profiles and side effects of preparations obtained from the two sources.

Animals↗
PubMed1992

Interactions of a series of coumarins with reactive oxygen species. Scavenging of superoxide, hypochlorous acid and hydroxyl radicals.

Sixteen plant-derived or synthetic coumarins with various hydroxyl and other substitutions were tested for their ability to inhibit lipid peroxidation and to scavenge hydroxyl radicals, superoxide radicals and hypochlorous acid. Seven unsubstituted or monosubstituted coumarins were essentially inactive in all tests except for ability to scavenge OH with rate constants approximately greater than 1 x 10(9) M-1. sec-1. Of the remaining nine, six containing dihydroxy substitutions were effective inhibitors of Fe3+-ascorbate-dependent microsomal lipid peroxidation (IC50 less than 20 microM), with ortho-dihydroxy + one additional substitution optimal (IC50 less than 10 microM). ortho-Dihydroxylated coumarins were pro-oxidant (enhanced OH generation) in the Fe3+-EDTA-H2O2 deoxyribose system but decreased OH' generation in the Fe3+-ascorbate-H2O2 deoxyribose system, indicating that these compounds can both chelate iron ions and also readily donate electrons for redox cycling of Fe3+. The meta-dihydroxycoumarin did not show this behaviour, but was an effective scavenger of hypochlorous acid, a property shared by only one other compound. Several other coumarins with one or more hydroxyl substituents were also capable of effectively removing superoxide anions (IC50 3.7-72 microM), although some could not be quantified due to direct rapid reduction of cytochrome c. We conclude that several compounds, notably 5,7-dihydroxy-4-methylcoumarin, possess beneficial biochemical profiles of interest in relation to pathophysiological processes dependent upon reactive oxygen species.

Animals↗
PubMed1992

Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components.

Leaves or infusions of feverfew, Tanacetum parthenium, have long been used as a folk remedy for fever, arthritis and migraine, and derived products are widely available in U.K. health food shops. Previous reports have suggested interactions with arachidonate metabolism. Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Isolated lactones (parthenolide, epoxyartemorin) treated with cysteine (to neutralize reactive alpha-methylene butyrolactone functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not time-dependent. We conclude that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb.

Animals↗
PubMed1992

Eicosanoid synthesis and Helicobacter pylori associated gastritis: increase in leukotriene C4 generation associated with H. pylori colonization.

The importance of pro-inflammatory leukotriene C4 in Helicobacter pylori (H. pylori) associated gastritis in man is unknown. Fresh gastric biopsy specimens from 28 dyspeptic patients were obtained: 10 showed normal antral histology with no evidence of H. pylori, the remaining 18 patients exhibited histological gastritis and were H. pylori positive as assessed by histology, culture and urease test. Twelve of these 18 patients received 240 mg twice daily colloidal bismuth subcitrate for four weeks before re-endoscopy. Gastric biopsies from H. pylori positive patients were incubated under basal and Ca(2+)-ionophore mediated conditions: Radioimmunoassay analysis of the supernatant showed basal release of prostaglandin E2 and leukotriene C4 was slightly but not significantly elevated in H. pylori positive mucosa. However in H. pylori positive mucosa there was an 85% increase in leukotriene C4 synthesis when biopsies were incubated with ionophore, compared to only 13% increase in H. pylori negative mucosa (p less than 0.02). After eradication of H. pylori by colloidal bismuth subcitrate, there was a clearance of inflammatory cell infiltrate as assessed by histology and a significant reduction in ionophore-mediated leukotriene C4 formation compared with before treatment (p less than 0.02). These results suggest that H. pylori gastritis is associated with increased capacity to generate leukotriene C4, which may amplify the damaging effects of the bacteria on gastric mucosa.

Adult↗