Naja sputatrix Venom Preconditioning Attenuates Neuroinflammation in a Rat Model of Surgical Brain Injury via PLA2/5-LOX/LTB4 Cascade Activation.

Inflammatory preconditioning is a mechanism in which exposure to small doses of inflammatory stimuli prepares the body against future massive insult by activating endogenous protective responses. Phospholipase A2/5-lipoxygenase/leukotriene-B4 (PLA2/5-LOX/LTB4) axis is an important inflammatory signaling pathway. Naja sputatrix (Malayan spitting cobra) venom contains 15% secretory PLA2 of its dry weight. We investigated if Naja sputatrix venom preconditioning (VPC) reduces surgical brain injury (SBI)-induced neuroinflammation via activating PLA2/5-LOX/LTB4 cascade using a partial frontal lobe resection SBI rat model. Naja sputatrix venom sublethal dose was injected subcutaneously for 3 consecutive days prior to SBI. We observed that VPC reduced brain edema and improved neurological function 24 h and 72 h after SBI. The expression of pro-inflammatory mediators in peri-resection brain tissue was reduced with VPC. Administration of Manoalide, a PLA2 inhibitor or Zileuton, a 5-LOX inhibitor with VPC reversed the protective effects of VPC against neuroinflammation. The current VPC regime induced local skin inflammatory reaction limited to subcutaneous injection site and elicited no other toxic effects. Our findings suggest that VPC reduces neuroinflammation and improves outcomes after SBI by activating PLA2/5-LOX/LTB4 cascade. VPC may be beneficial to reduce post-operative neuroinflammatory complications after brain surgeries.

Polyphenols from aerial parts of Polygonum bellardii and their biological activities.

CONTEXT: Polygonum species have been used in the treatment of several types of inflammatory disorders and cancer. Nevertheless, there are no reports related to the anti-inflammatory and anti-proliferative activities of Polygonum bellardii All. (Polygonaceae). OBJECTIVE: This study investigated the chemical composition of the methanol extract of P. bellardii. The anti-inflammatory and cytotoxic activities of methanol, n-butanol, ethyl acetate extracts and isolated polyphenols were determined. MATERIALS AND METHODS: The chemical structure of the isolated compounds was elucidated using different spectral techniques. MTT assay was used to evaluate the anti-proliferative activity in HeLa, MCF-7 and HepG-2 cells. Inhibition of 5-lipoxygenase (5-LOX) activity and prostaglandin E2 (PGE2) production in stimulated HepG-2 cells were used to assess the anti-inflammatory activity. RESULTS: The present study resulted in isolation of five compounds (new for the species). They were identified as gallic acid (1), quercetin (2), myricetin (3), quercetin-3-O-ß-D-glucopyranoside (5) and myricetin-3-O-α-arabinofuranoside (7). Additionally, a couple of previously isolated compounds such as quercetin-3-O-(5″-acetyl-α-arabinofuranoside) (4) and myricetin-3-O-(5″-acetyl-α-arabinofuranoside) (6) were detected. The n-butanol extract has the highest cytotoxicity in HeLa, MCF-7 and HepG-2 cells, with IC50 values of 15.26, 50.66 and 30.09 µg/ml, respectively. Compound 6 exhibited a marked cytotoxicity in HeLa (IC50 75.04 µg/ml) and HepG-2 (IC50 41.03 µg/ml) cells. Crude extracts and pure compounds inhibited the 5-LOX activity and PGE2 production in a dose-dependent manner (0.1-250 µg/ml). DISCUSSION AND CONCLUSION: These results explain the traditional uses of P. bellardii and indicate that polyphenols, despite structural similarity, have different cytotoxic and anti-inflammatory effects.

The antioxidant effect of ß-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation.

Plant-based whole foods provide thousands of bioactive metabolites to the human diet that reduce the risk of developing chronic diseases. ß-Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. Here, we report the antioxidant activity of CAR, its protective effect on liver fibrosis and its inhibitory capacity on hepatic stellate cell (HSC) activation. CAR was tested for the inhibition of lipid peroxidation and as a free radical scavenger. CAR had higher inhibitory capacity on lipid peroxidation than probucol, α-humulene and α-tocopherol. Also, CAR showed high scavenging activities against hydroxyl radical and superoxide anion. The activity of 5-lipoxygenase, an enzyme that actively participates in fibrogenesis, was significantly inhibited by CAR. Carbon tetrachloride-treated rats received CAR at 2, 20 and 200 mg/kg. CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 µm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation.

Effects of the rhizomes of Atractylodes japonica and atractylenolide I on allergic response and experimental atopic dermatitis.

Although some anti-allergic activities of the rhizome of Atractylodes japonica have been previously reported, the active principle(s) for anti-allergic action is not fully elucidated and the effect of this plant material on atopic dermatitis (AD) is not known. In this study, the 70% ethanol extract of the rhizome of A. japonica was found to significantly inhibit 5-lipoxygenase (5-LOX)-catalyzed leukotrienes (LT) production from rat basophilic leukemia (RBL)-1 cells. From the extract of A. japonica, three major sesquiterpene derivatives including atractylenolide I, atractylenolide III and eudesma-4,7-dien-8-one were successfully isolated. Among these compounds, only atractylenolide I was shown to strongly inhibit 5-LOX from RBL-1 cells (IC(50) = 18.6 µM). To evaluate the effects of experimental AD, the ethanol extract of A. japonica (200 mg/day) was administered orally to hapten-treated NC/Nga mice which is an animal model of AD. It was firstly found that the extract significantly inhibited AD-like symptoms in mice, as judged by severity score and scratching behavior. Taken together, it is concluded that A. japonica possesses the inhibitory activity on 5-LOX and an animal model of AD, and atractylenolide I may contribute, at least in part, to these anti-allergic actions of A. japonica.

Myrtucommulone from Myrtus communis: metabolism, permeability, and systemic exposure in rats.

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 ·â€Š10⁻6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol.

Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.

Inhibition of 5-lipoxygenase and skin inflammation by the aerial parts of Artemisia capillaris and its constituents.

The aerial parts of Artemisia capillaris Thunberg (Compositae) have been used in Chinese medicine as a liver protective agent, diuretic, and for amelioration of skin inflammatory conditions. This study was conducted to establish the scientific rationale for treating skin inflammation and to find active principles from A. capillaris. To accomplish these goals, the 70% ethanol extract of the aerial parts of A. capillaris (AR) was prepared and its 5-lipoxygenase (5-LOX) inhibitory action was studied since 5-LOX products are known to be involved in several allergic and skin inflammatory disorders. AR showed potent inhibitory activity against 5-LOX-catalyzed leukotriene production by ionophore-induced rat basophilic leukemia-1 cells, with an IC(50) of < 1.0 µg/mL. Nine major compounds, scopoletin, scopolin, scoparone, esculetin, quercetin, capillarisin, isorhamnetin, 3-O-robinobioside, isorhamnetin 3-O-galactoside and chlorogenic acid, were isolated from A. capillaris, and their effects were examined to identify the active principle(s). Several coumarin and flavonoid derivatives were found to be 5-LOX inhibitors. In particular, esculetin and quercetin were potent inhibitors, with IC(50) values of 6.6 and 0.7 µM, respectively. Against arachidonic acid-induced ear edema in mice, AR, and esculetin strongly inhibited edematic response. AR and esculetin also inhibited delayed-type hypersensitivity response in mice. In conclusion, AR and some of their major constituents are 5-LOX inhibitors, and these in vitro and in vivo activities may contribute to the therapeutic potential of AR in skin inflammatory disorders in traditional medicine.

Inhibition of 5-lipoxygenase product synthesis by natural compounds of plant origin.

The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA (4) by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA (4) yields LTB (4) and the cysteinyl-LTs C (4), D (4) and E (4). LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structure-activity relationships are discussed.

Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme.

12(S)-Lipoxygenase (LOX) is regarded as a pro-tumorigenic enzyme and as a potential target for therapy and prevention of cancer so that the search for specific 12(S)-LOX inhibitors is part of drug development strategies. To facilitate the identification of specific 12(S)-LOX inhibitors we have created an assay cell line by introducing a12(S)-LOX expression vector into SW480 colorectal cancer cells. When arachidonic acid was supplied in the medium both transiently and stably overexpressing cells produced 12(S)-hydroxytetraenic acid (HETE) originating from the transfected gene at 4-5-fold the amount obtained from control transfectants. 12(S)-HETE production was 1913.7+/-17.2pg/ml and reached a steady state level 24h after addition of arachidonic acid. To demonstrate the models suitability of 12(S)-LOX overexpressing SW480 cells they were used to measure the inhibitory activity of the plant phenols baicalein, kaempferol, quercetin, nordihydroguaretic acid and resveratrol which are known for their chemopreventive as well as LOX-inhibitory activity in different tumour models. All 5 compounds inhibited 12(S)-HETE production at concentrations below those necessary for growth inhibition.

In vitro 5-lipoxygenase and anti-oxidant activities of South African medicinal plants commonly used topically for skin diseases.

An investigation was undertaken to determine the possible mechanisms of action of medicinal plants used for dermatological pathologies. A total of 14 plant species were selected from the readily available ethnobotanical literature. 5-Lipoxygenase and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays were used to determine the anti-inflammatory activity and the anti-oxidant activity of selected medicinal plants, respectively. Both aqueous and methanol extracts were tested. Among the plants screened, four species (Croton sylvaticus, Warburgia salutaris, Pentanisia prunelloides, and Melianthus comosus) displayed promising 5-lipoxygenase inhibitory activity with IC(50) values <61 ppm. A large number of plants exhibited significant anti-oxidant activities with IC(50) values between 5.27 and 83.36 ppm. Aqueous extracts of M. comosus exhibited the most potent anti-inflammatory and anti-oxidant activity.

Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro.

Lipoxygenases (LOXs) have been implicated in carcinogenesis in various cancer types. In the current study, three structurally different lichen metabolites, protolichesterinic acid (1), lobaric acid (2) and baeomycesic acid (3) were tested for anti-proliferative effects against 12 different human cancer cell lines. All compounds have known in vitro 5-LOX inhibitory activity, and 1 and 2 also inhibit 12-LOX. The activity of the lichen metabolites was compared to that of a specific 5-LOX inhibitor, zileuton (4). The following cancer cell lines were tested: Capan-1, Capan-2 and PANC-1 (all from pancreas), T47-D (breast), PC-3 (prostate), NCI-H1417 (small cell lung), NIH:OVCAR-3 (ovary), AGS (stomach), WiDr (colorectal), HL-60, K-562 and JURKAT (acute promyelocytic, erythro- and T-cell leukemia, respectively). Compound 1 showed the greatest inhibitory effect against all cell lines, with EC50 ranging from 2.4-18.1 microg mL(-1) (7.4-55.8 microM), followed by 2, with EC50 of 15.2 - 65.5 microg mL(-1) (33.2-143.6 microM). The effects of 3 and 4 were of similar orders of magnitude, with EC50 of 28.7 - >80 microg mL(-1) (76.8 - > 213.9 microM) and 12.9 - > 80 microg mL(-1) (50.4 - > 313.7 microM). The dual 5- and 12-LOX inhibitors 1 and to some extent 2 thus exert significant anti-proliferative effects against a variety of human cancer cell lines, while the selective 5-LOX inhibitors 3 and 4 are considerably less active.

A new anti-inflammatory glucoside from Ficus racemosa L.

Bioassay-guided fractionation of the ethanol extract of Ficus racemosa resulted in the identification of a new compound (rel)-4,6-dihydroxy-5-[3-methyl-(E)-propenoic acid-3-yl]-7-beta-glucopyranosyl-[2alpha,3beta-dihydrobenzofuran]-(3,2: b)-[4alpha,5beta-dihydroxy-6alpha-hydroxymethyltetrahydropyran] (racemosic acid). Racemosic acid showed potent inhibitory activity against COX-1 and 5-LOX in vitro with IC50 values of 90 and 18 microM, respectively. Racemosic acid also demonstrated a strong antioxidant activity to scavenge ABTS free radical cations with an IC50 value of 19 microM. In addition, cytotoxic effects of the extracts of F. racemosa were investigated in vitro using the ATP-based luminescence assay and results showed no cytotoxicity on the cell lines skin fibroblasts (1BR3), human Caucasian hepatocyte carcinoma (Hep G2) and human Caucasian promyelocytic leukaemia (HL-60). Bergenin was also isolated from the same active fraction.

Inhibitory activity of Juniperus communis on 12(S)-HETE production in human platelets.

Extracts of Juniperus communis L. (Cupressaceae) have been evaluated for their inhibitory activity on human platelet-type 12(S)-lipoxygenase [12(S)-LOX]. The methylene chloride extracts of Juniperi lignum, Juniperi pseudo-fructus and the ethyl acetate extract of Juniperi pseudo-fructus showed a significant inhibition on the production of 12(S)-HETE [12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid] at 100 microg/mL (54.0 +/- 6.73, 66.2 +/- 4.03 and 76.2 +/- 3.36%, respectively). From the methylene chloride extract of the wood, cryptojaponol and beta-sitosterol were isolated as compounds with inhibitory activity (inhibition at 100 microg/mL = 55.4 +/- 2.80% [IC50 = 257.5 microM] and 25.0 +/- 2.15%, respectively). In addition, a lipid fraction containing unsaturated fatty acids contributed to the in vitro activity of the crude extract.

Lipoxygenase inhibition by anadanthoflavone, a new flavonoid from the aerial parts of Anadenanthera colubrina.

Chemical investigation of the aerial parts of Anadenanthera colubrina led to the isolation of a new flavonoid named anadanthoflavone ( 1), along with 11 known compounds: alnusenol, lupenone, lupeol, betulinic acid, alpha-amyrin, beta-amyrin, beta-sitosterol, stigmasterol, apigenin, 4-hydroxybenzoic acid and cinnamic acid. The isolated compounds were evaluated for their inhibitory activity on human platelet 12-lipoxygenase (12-hLO), human reticulocyte 15-lipoxygenase (15-hLO) and soybean lipoxygenase-1 (15-sLO). Compound 1 was found to be active against 12-hLO and 15-hLO with IC50 values of 13 +/- 3 microM and 17 +/- 3 microM, respectively. Apigenin selectively inhibited the activity of 15-hLO (IC50 : 4.0 +/- 1 microM), while lupenone, lupeol and alpha-amyrin were found active against 15-sLO (IC50 : 22 +/- 3 microM, 35 +/- 9 microM and 15 +/- 3 microM, respectively).

Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells.

Plant-derived lignans caused cell loss by apoptosis in colorectal adenoma and carcinoma cells. Nordihydroguaiaretic acid (NDGA), commonly used for the inhibition of lipoxygenase isoenzymes, showed the strongest growth inhibition with an IC50 of 1.9+/-0.5 microg followed by epiashantin (IC50=9.8+/-4.5 microM) and arctigenin (IC50=16.5+/-8.5 microM). The lignans caused a time- and dose-dependent loss of mitochondrial membrane potential (MMP), down regulation of the anti-apoptotic protein bcl(xl) and an increase of the apoptotic index. The time interval until loss of MMP and down modulation of bcl(xl) became evident correlated with the efficiency of growth inhibition by NDGA, epiashantin and yangambin. Bcl2 and caspase 3 were not involved. NDGA also induced a shift of the culture population to the G2/M phase of the cell cycle. With respect to these results, naturally occurring lignans could be useful in the therapy and chemoprevention of colorectal tumors.

Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol).

A lipid-rich extract, prepared by supercritical fluid (CO2) extraction of freeze-dried stabilized NZ green-lipped mussel powder (Lyprinol) has shown significant anti-inflammatory (AI) activity when given to animals and humans. When treated p.o. with Lyprinol, Wistar and Dark Agouti rats developed neither adjuvant-induced polyarthritis or collagen(II)-induced auto-allergic arthritis. This was achieved with doses < NSAIDs, and 200 times < of other seed or fish oils. Lyprinol subfractions inhibited LTB4 biosynthesis by PMN in vitro, and PGE2 production by activated macrophages. Much of this AI activity was associated with omega-3 PUFAs and natural antioxidants [e.g. carotenoids]. In contrast to NSAIDs, Lyprinol is non-gastro toxic in disease-stressed rats at 300 mg/kg p.o., and does not affect platelet aggregation [human, rat]. Clinical studies, either controlled or randomized, have demonstrated very significant AI activity in patients with osteoarthritis (OA), rheumatoid arthritis (RA), asthma, and other inflammatory conditions. Lyprinol is a reproducible, stable source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.

Mast cell stabilizing and lipoxygenase inhibitory activity of Cedrus deodara (Roxb.) Loud. wood oil.

Volatile oil of C. deodara, administered orally at the doses of 50, 100 and 200 mg/kg body weight, significantly inhibited the pedal edema induced by compound 48/80 in rats. The oil significantly inhibited compound 48/80 induced degranulation of isolated rat peritoneal mast cells at concentrations ranging from 25-200 micrograms/ml. C. deodara wood oil also significantly inhibited the enzyme lipoxygenase at a concentration of 200 micrograms/ml. Thus, the anti-inflammatory activity of C. deodara wood oil could be attributed to its mast cell stabilizing activity and the inhibition of leukotriene synthesis.

A practical guide to the management of distal ulcerative colitis.

This article reviews the role of corticosteroids, sulfasalazine and mesalazine (5-aminosalicylic acid, mesalamine), immunosuppressive agents and alternative novel drugs for the treatment of distal ulcerative colitis. Short cycles of traditional, rectally administered corticosteroids (methylprednisolone, betamethasone, hydrocortisone) are effective for the treatment of mild to moderately active distal ulcerative colitis. In this context, their systemic administration is limited to patients who are refractory to either oral 5-amino-salicylates, topical mesalazine or topical corticosteroids. Of no value in maintaining remission, the long term use of either or topical corticosteroids may be hazardous. A new class of topically acting corticosteroids [budesonide, fluticasone, beclomethasone dipropionate, prednisolone-21-methasulphobenzoate, tixocortol (tixocortol pivalate)] represents a valid alternative for the treatment of active ulcerative colitis, and may be useful in the treatment of refractory distal ulcerative colitis. Although there is controversy concerning dosage or duration of therapy, oral and topical mesalazine is effective in the treatment of mild to moderately active distal ulcerative colitis. Sulfasalazine and mesalazine remain the first-choice drugs for the maintenance therapy of distal ulcerative colitis. Evidence exists showing a trend to a higher remission rate with higher doses of oral mesalazine. Topical mesalazine (suppositories or enemas) also is effective in maintenance treatment. For patients with chronically active or corticosteroid-dependent disease, azathioprine and mercaptopurine are effective in reducing either the need for corticosteroids or clinical relapses. Moreover, they are effective for long term maintenance remission. Cyclosporin may be useful in inducing remission in patients with acutely severe disease who do not achieve remission with an intensive intravenous regimen. Existing data suggest that azathioprine and mercaptopurine may be effective in prolonging remission in these patients. The role of alternative drugs for the treatment of distal ulcerative colitis and its different forms is reviewed. In particular data are reported concerning the effectiveness of 5-lipoxygenase inhibitors, topical use of short chain fatty acids, nicotine, local anaesthetics, bismuth subsalicylate enema, sucralfate, clonidine, free radical scavengers, heparin and hydroxychloroquine.

Dietary fish oil or lofrin, a 5-lipoxygenase inhibitor, decrease the growth-suppressing effects of coccidiosis in broiler chicks.

Broiler chicks were fed a diet containing 4% of either corn oil or fish oil from 3 to 14 d of age. From Days 15 to 23, half of the chicks in each dietary treatment were fed Lofrin (an experimental 5-lipoxygenase inhibitor) at 33 micrograms/kg feed. The remaining chicks within each dietary treatment were the untreated controls. At 24 d of age, half of the chicks within each diet-Lofrin treatment group were each infected with 4.6 x 10(4) sporulated Eimeria tenella oocysts, resulting in a 2 x 2 x 2 factorial arrangement of treatments. Body weight gain, feed consumption, and feed conversion efficiency were determined throughout the study. At 27 d of age, blood, liver, and ceca were sampled. Plasma tumor necrosis factor and hemopexin, hepatic fatty acid composition, and cecal inflammatory cell infiltration were determined. Liver fatty acid composition tended to reflect that of the diet. Chicks fed fish oil had livers that were enriched in (n-3) polyunsaturated fatty acids (PUFA) at the expense of (n-6) PUFA. Chicks fed fish oil gained body weight more rapidly than those fed corn oil. Infection of chicks with Eimeria decreased body weight gain of chicks fed corn oil, but not of chicks fed fish oil. The addition of Lofrin to the corn oil diets abrogated the growth-suppressing effects of infection, although there was no Lofrin effect among chicks fed fish oil. There was a diet by Lofrin interaction in which Lofrin treatment of birds fed corn oil decreased feed consumption and increased feed conversion efficiency, but had no effect on chicks fed diets containing fish oil. Plasma hemopexin was greater, but tumor necrosis factor was lower, in chicks fed fish oil than in chicks fed corn oil. Eimeria infection significantly increased cecal inflammatory cell infiltration across all dietary treatments. There were no clear relationships between growth rate or efficiency and the severity of the inflammatory response to Eimeria infection, as indicated by hemopexin levels and cecal inflammatory scores. These results indicate that Lofrin or fish oil, both of which modify eicosanoid metabolism, attenuate the growth-depressing effects of an Eimeria tenella infection.

Effects of single-dose zileuton on bronchial hyperresponsiveness in asthmatic patients treated with inhaled corticosteroids.

The aim of the study was to determine whether zileuton, an inhibitor of 5-lipoxygenase, attenuated bronchial hyperresponsiveness (BHR) in asthmatic subjects who had marked BHR during maintenance treatment with inhaled corticosteroids (ICS). In a randomized, double-blind, placebo-controlled, cross-over study, a challenge test with histamine (provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20,Hist)) and with ultrasonically nebulized distilled water (UNDW) (provocative dose of UNDW producing a 20% fall in FEV1 (PD20,UNDW)) was performed in seven patients with asthma after intake of either 400 mg zileuton or placebo. All patients (mean age 33 yrs, mean FEV1 111% of predicted) had marked BHR, as indicated by a mean PD20,UNDW of 4.74 mL under treatment for at least 6 months with up to 800 microg ICS (mean 536 microg daily). On four different occasions, separated by at least 5 days, two UNDW and two histamine challenge tests were performed in random order 3 h after a morning dose of either zileuton or placebo. Neither zileuton nor placebo changed baseline airway calibre prior to provocation. Zileuton increased PC20,Hist from 0.99 to 5.64 mg x mL(-1) (2.1 doubling doses; p<0.03 compared to placebo), and increased PD20,UNDW from 3.10 to 9.31 mL (1.3 doubling doses; p<0.05 compared to placebo). In conclusion, a single dose of 400 mg zileuton attenuates bronchial hyperresponsiveness to histamine and ultrasonically nebulized distilled water in asthmatic patients with marked bronchial hyperresponsiveness during treatment with inhaled corticosteroids.