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Objective: Treatment experiment was conducted to investigate the effectiveness and mechanism of the action of zileuton in corticosteroid-induced depressive mice model through neuroinflammation. Methods: The mice were randomly separated into four groups: (Veh+Veh), (Corticosteroid+Veh), (Corticosteroid+ZIL50), and (Corticosteroid+ZIL100). Intraperitoneal injection of corticosterone (CORT) (20 mg/kg for 6 weeks) was used in the mice to induce depression and neuroinflammation diverse from the Veh+Veh group, which was injected only physiological saline. The drug-treated groups (Corticosteroid+ZIL50 and Corticosteroid+ZIL100) were orally administered with the mentioned doses of zileuton. After confirming the effectiveness of zileuton through the behavioral tests, the mechanism of the action of the drug was explored through a set of biochemical assays. Results: Zileuton (50/100 mg/kg) administration improved the performance of the mice in the behavioral experiments (p

Objective: The experiment aimed to find out the effectiveness of Zileuton, a 5-LOX inhibitor on depressive behavior and neuroinflammation in vivo. Method: Male ICR mice (25-30g) randomly distributed Veh+Veh, CRS+Vehicle, CRS+ZIL50, and CRS+ZIL100. Zileuton was orally given in the treatment groups for 21 days after 3 weeks of stress induce CRS model. Starting from the day 1, in CRS model, mice were immobilized 8 hr/day for consecutive 21 days to induce stress. After completing the drug administration, subjected the mice for behavioral tests, and then performed histopathological & Western Blotting. Result: Stress induces CRS model guide to the significant depressive-like behavior of the mice in behavioral tests which was united by adverse changes at the cellular/molecular level responsible for regulation of inflammatory and apoptotic processes. CRS triggered Microglial over activation in the DG of the hippocampus, which was successfully inhibited by Zileuton post-treatment at the dose of 100mg/kg than 50mg/kg. Level of TNF-α, IL- 1β, nuclear NF-κB p65, Bax, and cleaved Caspase-3 was high and Bcl-2 expression was low in the stress induce CRS -treated mice which were found to be opposite in the Zileuton (100mg/kg). However, the dose of 50mg/kg less to mimic the effects as exhibited more by the 100mg/kg dose of Zileuton. Conclusion: It can be concluded that selective 5-lipoxygenase inhibitor Zileuton can efficiently inhibit the depressive-like behavior/activity in CRS-induced depressive mouse model. The study is the first to show the role of 5-lipoxygenase enzyme in and Chronic Restraint Stress (CRS)-induced mice models of stress, anxiety or depression.

Background: This study aims to evaluate the effects of zileuton on myocardial ischemia/reperfusion injury and ischemia-induced ventricular arrhythmias and to investigate the role of 5-lipoxygenase pathway in the pathogenesis of myocardial ischemia/reperfusion injury. Methods: In anesthetized rats, myocardial ischemia was induced by the ligation of the left main coronary artery for 30 min before 120-min reperfusion period. Zileuton was given both at the doses of 3 and 10 mg/kg 15 min before the ligation. During the experiment, electrocardiography, blood pressure, and heart rate were recorded. The duration of arrhythmia types were determined during the ischemic period. To evaluate the ischemia/reperfusion injury in the myocardial tissue, histopathological examination was performed and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Results: Zileuton at a dose of 3 mg/kg significantly decreased the infarct size and the tissue injury score obtained using histopathological examinations (infarct size [% of the area at risk]: zileuton 3 mg/kg 36±7% versus control 66±6%, p < 0.05). Zileuton 10 mg/kg was found to be ineffective. Both 3 and 10 mg/kg doses of zileuton did not shorten the duration of arrhythmias during the ischemic period. Conclusion: Our study results showed that 3 mg/kg dose of zileuton protected the heart against myocardial ischemia/ reperfusion injury. However, it was ineffective to reduce the ischemia-induced ventricular arrhythmias. Based on these results, zileuton may be a promising drug for the treatment of myocardial ischemia/reperfusion injury. © 2017. Turkish Society of Cardiovascular Surgery.

Tenidap is a derivative of Flavonoids which are actually plant derivatives, it shows inhibition activity of 5-lipoxygenase. Molecular models were directed to discover molecular docking mode, also to help explain molecular tool behind its inhibitory action

Cyperus rotundus L. (Suada, Sueda, family: Cyperaceae) is vastly spread in several world's subtropical and tropical regions. It had variable traditional uses and bioactivities. A new flavonol derivative: cyperaflavoside (myricetin 3,3′,5′-trimethyl ether 7-O-β-d-glucopyranoside) and five flavonoids: vitexin, orientin, cinaroside, quercetin 3-O-β-d-glucopyranoside, and myrcetin 3-O-β-d-glucopyranoside were separated from the methanolic extract of C. rotundus aerial parts. Their structures were verified based on UV, IR, NMR (1D and 2D), HRESIMS, and comparison with literature. All metabolites were assessed for their 5-lipoxygenase inhibitory potential. All compounds possessed 5-lipoxygenase inhibitory potentials with IC50s 5.1, 4.5, 5.9, 4.0, 3.7, and 2.3 μM, respectively, in comparison to indomethacin (IC50 0.98 μM). These results supported the traditional uses of C. rotundus in treating inflammation and its related symptoms. Keywords: Cyperaceae, Flavonols, Myricetin derivative, 5-Lipoxygenase inhibitor, Inflammation, Structural activity relationship

Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies.

A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 is described using as the key step a stereoselective anomeric oxygen to carbon rearrangement of an alkynyl stannane tetrahydrofuranyl ether derivative mediated by boron trifluoride etherate.

Background—Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor.Methods and Results—In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291–treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291–treated groups in the 34 of these 60 patients in whom this end point was analyzable (PConclusions—VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.

The association between inflammation and atherosclerosis has been well described in the literature. There is now also mounting evidence in support of adipose tissue as a repertoire for inflammatory markers. Epicardial adipose tissue (EAT) has been shown to associate with coronary atherosclerosis and

We previously showed that, in vitro, hyperforin from St. John's wort (Hypericum perforatum) inhibits 5-lipoxygenase (5-LO), the key enzyme in leukotriene biosynthesis. Here, we demonstrate that hyperforin possesses a novel and unique molecular pharmacological profile as a 5-LO inhibitor with remarkable efficacy in vivo. Hyperforin (4 mg/kg, i.p.) significantly suppressed leukotriene B(4) formation in pleural exudates of carrageenan-treated rats associated with potent anti-inflammatory effectiveness. Inhibition of 5-LO by hyperforin, but not by the iron-ligand type 5-LO inhibitor BWA4C or the nonredox-type inhibitor ZM230487, was abolished in the presence of phosphatidylcholine and strongly reduced by mutation (W13A-W75A-W102A) of the 5-LO C2-like domain. Moreover, hyperforin impaired the interaction of 5-LO with coactosin-like protein and abrogated 5-LO nuclear membrane translocation in ionomycin-stimulated neutrophils, processes that are typically mediated via the regulatory 5-LO C2-like domain. Together, hyperforin is a novel type of 5-LO inhibitor apparently acting by interference with the C2-like domain, with high effectiveness in vivo.

We evaluated the anti-asthmatic effects and mechanism of action of TMK-688, a potent 5-lipoxygenase inhibitor, on the dual-phase asthmatic response and on airway inflammation in conscious guinea pigs sensitized with ovalbumin (OA). TMK-688 inhibited both the immediate and the late asthmatic response (LAR) after administration of a single oral dose of 3.2 or 10 mg/kg 2 h before OA challenge. Pretreatment with TMK-688 also inhibited airway hyperresponsiveness to acetylcholine. The increase in eosinophils in bronchoalveolar lavage fluid and the production of reactive oxygen, an index of cell activation during LAR, was also suppressed by TMK-688. These findings suggest the following inhibitory mechanism of LAR by TMK-688: (i) a reduction of eosinophil accumulation in airways; (ii) the inhibition of the immediate asthmatic response; (iii) the inhibition of airway hyperresponsiveness; and (iv) the suppression of the generation of reactive oxygen from bronchoalveolar lavage cells.

Summary Chronic obstructive pulmonary disease (COPD) is associated with neutrophil-mediated inflammation, a potential target for treatment in COPD. We evaluated MK-0633, a 5-lipoxygenase inhibitor in patients with COPD. This was a 12 week, randomized, double-blind, multicenter study comparing MK-0633 100 mg and placebo in patients 40–75 years of age ( N = 266) with COPD, post-β-agonist forced expiratory volume in 1 s (FEV 1 ) 25%–75% predicted, and an FEV 1 /forced vital capacity ratio (FVC) ≤70%. Long-acting inhaled bronchodilators were permitted for approximately 50% of patients. The primary efficacy endpoint was the change from baseline in pre-dose (trough) FEV 1 measured over the last 2 weeks of the 12 week treatment period. The change in FEV 1 over the last 2 weeks of the 12 weeks treatment period compared to baseline was 0.015 L for MK-0633 and 0.0002 for placebo ( p = 0.556). For COPD Global Evaluation, 75.4% of patients receiving MK-0633 reported feeling better vs. 59.8% of patients receiving placebo ( p = 0.032). There were no other significant differences between treatments. MK-0633 was well-tolerated and comparable to placebo. The 5-LO inhibitor MK-0633 was not significantly more effective than placebo in improving FEV 1 from baseline in patients with COPD, although more patients reported feeling improved with MK-0633. Clinicaltrials.gov identifier: NCT00418613.

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

The structure of the title compound (alternative IU-PAC name: α-[1-(tricyclo[3.3.1.1 3,7 ]dec-1-yl)ethylamino-carbonyl]benzyl acetate}, C 22 H 29 NO 3 , a de novo designed non-acidic anti-inflammatory agent, has been determined. Data collection was performed utilizing methods common in macromolecular crystallography (rotation method and an imaging plate area detector) and provided data of good quality.

Bronchial asthma is an inflammatory condition. The inflammatory actions of leukotrienes (LT) B4, C4, D4, and E4 have been shown experimentally to play a role in inflammatory mechanisms, producing asthma. Antileukotrienes (ALT) or leukotrienes antagonists (LA) is a new class of anti-asthma drugs with anti-inflammatory role. LT modifiers from the groups of 5 lipoxygenase inhibitor and Cys LT1 receptor antagonists, are found useful in asthma therapy. LAs are of main use in young infants and toddler with recurrent wheezing, children with moderate to severe chronic asthma on steroid therapy and in allergic rhinitis. In chronic asthma they are required to be used for prolonged periods with other anti-asthma agents. Except for Montelukast and Zafirlukast, which can be used in children above two and six years of age respectively, the paediatric use of other agents is yet to be established. However, these agents are essentially safe. The cost of LAs is reasonably high. At present, with available evidence, these drugs are considered promising in management of asthma in children. However, there is need to do more long term clinical trials for ascertaining their effectivity in different types of asthma to compare their effects with long acting B2 agnoists and chromones, so as to optimally explore their utility.

Summary The antiallergic effects of ardisiaquinone A, a potent 5-lipoxygenase inhibitor, were examined. Pretreatment with ardisiaquinone A (0.1–10 μM) significantly inhibited compound 48/80-induced production of cysteinyl-leukotrienes (cys-LTs; LTC 4 , LTD 4 and LTE 4 ) in rat peritoneal mast cells, but not histamine release. The IC 50 value was 5.56 μM. Pre-administration with ardisiaquinone A (0.1–1 mg/kg, s.c.) dose-dependently inhibited rat homologous passive cutaneous anaphylaxis (PCA) and the maximal inhibitory ratio was 22.3 ± 3.9% at the dose of 1 mg/kg. Ardisiaquinone A (1–5 mg/kg, s.c.) dose-dependently prevented the allergen-induced increase of tracheal pressure in ovalbumin-sensitized guinea pigs, especially during the late phase. In conclusion, the findings of this study show that 5-lipoxygenase inhibitor ardisiaquinone A partially attenuates the allergen-induced increases of vascular permeability and tracheal pressure via the inhibition of cys-LTs production in mast cells.

Introduction 5-Loxin® is a novel Boswellia serrata extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid (AKBA), which exhibits potential anti-inflammatory properties by inhibiting the 5-lipoxygenase enzyme. A 90-day, double-blind, randomized, placebo-controlled study was conducted to evaluate the efficacy and safety of 5-Loxin® in the treatment of osteoarthritis (OA) of the knee. Methods Seventy-five OA patients were included in the study. The patients received either 100 mg (n = 25) or 250 mg (n = 25) of 5-Loxin® daily or a placebo (n = 25) for 90 days. Each patient was evaluated for pain and physical functions by using the standard tools (visual analog scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index) at the baseline (day 0), and at days 7, 30, 60 and 90. Additionally, the cartilage degrading enzyme matrix metalloproteinase-3 was also evaluated in synovial fluid from OA patients. Measurement of a battery of biochemical parameters in serum and haematological parameters, and urine analysis were performed to evaluate the safety of 5-Loxin® in OA patients. Results Seventy patients completed the study. At the end of the study, both doses of 5-Loxin® conferred clinically and statistically significant improvements in pain scores and physical function scores in OA patients. Interestingly, significant improvements in pain score and functional ability were recorded in the treatment group supplemented with 250 mg 5-Loxin® as early as 7 days after the start of treatment. Corroborating the improvements in pain scores in treatment groups, we also noted significant reduction in synovial fluid matrix metalloproteinase-3. In comparison with placebo, the safety parameters were almost unchanged in the treatment groups. Conclusion 5-Loxin® reduces pain and improves physical functioning significantly in OA patients; and it is safe for human consumption. 5-Loxin® may exert its beneficial effects by controlling inflammatory responses through reducing proinflammatory modulators, and it may improve joint health by reducing the enzymatic degradation of cartilage in OA patients. Trail Registration (Clinical trial registration number: ISRCTN05212803.)

Several inhibitors of the arachidonic acid-metabolizing enzyme, 5-lipoxygenase reduce proliferation of hematopoietic and non-hematopoietic cells and cell lines and some cells undergo limited differentiation. Cells were cultured from patients with chronic myelogenous leukemia in "blast" crisis with the selective inhibitor of 5-lipoxygenase,SC41661A[3-{3,5-bis(1,1-dimethyl)-4-hydroxyphenyl}hiol]-N-methyl-N-[2-(2-phridinyl-propanamide)]. Cells cultured for 3 to 5 days with 40 μM SC41661A exhibited reduced cellular numbers along with ultrastructural changes and DNA laddering characteristic of apoptosis. Similar culture conditions reduced proliferation of U937 monoblastoid cells. In U937 cells, the ultrastructural features of apoptosis were not observed at 72 hours, when DNA laddering was present and cell numbers were reduced, but was present after 144 hours of culture. Dissociation between certain morphologic and biochemical sequelae of apoptosis has been described in other systems. These observations are of interest since the induction of apoptosis in dividing chronic myelogenous leukemia (CML) cells by a noncytotoxic agent suggests paradigmatically new sites for therapeutic intervention.

Terphenyl compounds, tentatively named Bl-I (1), Bl-II (2), Bl-III (3), Bl-IV (4) and Bl-V (5), showing 5-lipoxygenase inhibitory activity have been isolated from the mushroom Boletopsis leucomelas (Pers.) Fayod. On the basis of physico-chemical and spectral evidence, they were concluded to be a series of cycloleucomelone-leucoacetates.

The carba-analogs of 5-HPETE and leukotriene A4, unstable intermediates of slow-reacting substance (SRS), were synthesized. These carbaanalogs inhibited the 5-lipoxygenase. The carba-analog of leukotriene A4 was a particularly potent specific inhibitor of the 5-lipoxygenase.

SummaryBackgroundInhalation of swine house dust induces acute airway inflammation and increased bronchial responsiveness in healthy subjects.ObjectiveThe aim of the study was to investigate whether 5-lipoxygenase products such as leukotrienes may have a role in this reaction.MethodsTwenty-three healthy subjects were randomised into two groups receiving treatment with either zileuton (600mg) or placebo four times a day. After 5 days of treatment, all subjects were exposed for 3h in a swine barn. Bronchial responsiveness, exhaled nitric oxide (NO), and mediators in nasal lavage (NAL), blood and urine were measured before and after the exposure.ResultsThe exposure induced an increased bronchial responsiveness to methacholine in both groups with 2–3 doubling concentration steps, no significant difference between treatments. Leukotriene E4 in urine increased significantly following exposure in the placebo group from 37.3 (29.1–45.6) (mean (95% confidence interval)) ng/mmol creatinine to 47.7 (36.3–59.0) ng/mmol creatinine (P