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5 lipoxygenase inhibitors

Minh Anh Thu Phan, Martin Bucknall, Jayashree Arcot
The interactive effects on anti-oxidation and anti-inflammation of lutein combined with each of the six common anthocyanidin glucosides were studied in both chemical and cellular systems. The combined phytochemicals showed an antagonism in the inhibition of lipid oxidation in a liposomal membrane, but showed an additive effect on cellular antioxidant activity in Caco-2 cells. Lutein was an active lipoxygenase inhibitor at 2⁻12 μM while anthocyanins were inactive. The concentration of lutein when it was used in combination with anthocyanins was 25⁻54% higher than when lutein was used alone (i...
August 14, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Christoph Thiel, Ines Smit, Vanessa Baier, Henrik Cordes, Brigida Fabry, Lars Mathias Blank, Lars Kuepfer
A quantitative analysis of dose-response relationships is essential in preclinical and clinical drug development in order to optimize drug efficacy and safety, respectively. However, there is a lack of quantitative understanding about the dynamics of pharmacological drug-target interactions in biological systems. In this study, a quantitative systems pharmacology (QSP) approach is applied to quantify the drug efficacy of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by coupling physiologically based pharmacokinetic models, at the whole-body level, with affected biological networks, at the cellular scale...
2018: NPJ Systems Biology and Applications
Fatima Naaz, M C Preeti Pallavi, Syed Shafi, Naveen Mulakayala, M Shahar Yar, H M Sampath Kumar
To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC50 0...
July 27, 2018: Bioorganic Chemistry
Dušica Simijonović, Evangelia-Eirini Vlachou, Zorica D Petrović, Dimitra J Hadjipavlou-Litina, Κonstantinos E Litinas, Nevena Stanković, Nezrina Mihović, Milan P Mladenović
Dicoumarol derivatives were synthesized in the InCl3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC50  = 52...
July 20, 2018: Bioorganic Chemistry
Sun-Yee Cheung, Markus Werner, Lucia Esposito, Fabiana Troisi, Vincenza Cantone, Stefanie Liening, Stefanie König, Jana Gerstmeier, Andreas Koeberle, Rossella Bilancia, Roberta Rizza, Antonietta Rossi, Fiorentina Roviezzo, Veronika Temml, Daniela Schuster, Hermann Stuppner, Manfred Schubert-Zsilavecz, Oliver Werz, Thomas Hanke, Simona Pace
Leukotrienes (LTs) and prostaglandin (PG)E2 , produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC50  = 2...
July 24, 2018: European Journal of Medicinal Chemistry
Ferdinando Bruno, Suann Errico, Simona Pace, Maxim B Nawrozkij, Arthur S Mkrtchyan, Francesca Guida, Rosa Maisto, Abdurrahman Olgaç, Michele D'Amico, Sabatino Maione, Mario De Rosa, Erden Banoglu, Oliver Werz, Antonio Fiorentino, Rosanna Filosa
The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders...
July 15, 2018: European Journal of Medicinal Chemistry
Bharani Meka, Suryachandra Rao Ravada, Murali Krishna Kumar Muthyala, Purna Nagasree Kurre, Trimurtulu Golakoti
A new series of diaryl heptanones (12a-q) were synthesized and their structures were confirmed by its 1 H, 13 C NMR and Mass spectral data. These analogs were evaluated for their anti-oxidant activity and potential to inhibit 5-lipoxygenase. Compounds 12k and 12o showed potent in vitro 5-lipoxygenase enzyme inhibitory activity with IC50 values of 22.2, 21.5 μM, which are comparable to curcumin (24.4 μM). Further they also have shown significant antioxidant activity. Molecular docking studies clearly showed correlation between binding energy and potency of these compounds...
June 8, 2018: Bioorganic Chemistry
Michael Rühl, Benjamin Kühn, Jessica Roos, Thorsten J Maier, Dieter Steinhilber, Michael Karas
RATIONALE: MALDI-MS analysis of covalent 5-lipoxygenase inhibitors is challenging due to unknown amino acid specificity and low PTM-identification rates. The analysis of the amino-acid specificity and of the characteristic fragmentation of chemically modified peptides is considered to improve knowledge for the analysis of chemically modified peptides and proteins by MALDI-MS. METHODS: Various compounds were used to investigate the modification of synthetic peptides carrying reactive amino acid residues...
July 2, 2018: Rapid Communications in Mass Spectrometry: RCM
Mohamed Touaibia, Martin J G Hébert, Natalie A Levesque, Jérémie A Doiron, Marco S Doucet, Jacques Jean-François, Marc Cormier, Luc H Boudreau, Marc E Surette
Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated...
June 28, 2018: Chemical Biology & Drug Design
Geoffrey R Nunns, John R Stringham, Fabia Gamboni, Ernest E Moore, Miguel Fragoso, Gregory R Stettler, Christopher C Silliman, Anirban Banerjee
BACKGROUND: Post-traumatic lung injury following trauma and hemorrhagic shock (T/HS) is associated with significant morbidity. Leukotriene-induced inflammation has been implicated in the development of post-traumatic lung injury through a mechanism that is only partially understood. Postshock mesenteric lymph returning to the systemic circulation is rich in arachidonic acid, the substrate of 5-lipoxygenase (ALOX5). ALOX5 is the rate-limiting enzyme in leukotriene synthesis and, following T/HS, contributes to the development of lung dysfunction...
September 2018: Journal of Surgical Research
Joseph R Iacona, Nicholas J Monteleone, Carol S Lutz
Arachidonic acid (AA) can be converted into prostaglandins (PGs) or leukotrienes (LTs) by the enzymatic actions of cyclooxygenases (COX-1 and COX-2) or 5-lipoxygenase (5-LO), respectively. PGs and LTs are lipid signaling molecules that have been implicated in various diseases, including multiple cancers. 5-LO and its activating protein (FLAP) work together in the first two conversion steps of LT production. Previous work has suggested a role for LTs in cancer development and progression. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression post-transcriptionally, and have previously been shown to be involved in cancer...
June 1, 2018: Oncotarget
Sophia Carvalho, Maria Ferrini, Lou Herritt, Andrij Holian, Zeina Jaffar, Kevan Roberts
Multi-walled carbon nanotubes (MWCNT) have been reported to promote lung inflammation and fibrosis. The commercial demand for nanoparticle-based materials has expanded rapidly and as demand for nanomaterials grows, so does the urgency of establishing an appreciation of the degree of health risk associated with their increased production and exposure. In this study, we examined whether MWCNT inhalation elicited pulmonary eosinophilic inflammation and influenced the development of allergic airway inflammatory responses...
2018: Frontiers in Pharmacology
Benjamin Kühn, Camilla Brat, Jasmin Fettel, Nadine Hellmuth, Isabelle V Maucher, Ufuk Bulut, Katharina J Hock, Jennifer Grimmer, Georg Manolikakes, Michael Rühl, Alessa Kühn, Kai Zacharowski, Carmela Matrone, Anja Urbschat, Jessica Roos, Dieter Steinhilber, Thorsten J Maier
Nitro-fatty acids (NFAs) are endogenously occurring lipid mediators exerting strong anti-inflammatory effects and acting as anti-oxidants in a number of animal models of inflammation. These NFA effects are mediated by targeting important regulatory proteins involved in inflammatory processes, such as 5-lipoxygenase, soluble epoxide hydrolase, or NF-κB. In the present study, we investigated the anti-tumorigenic effects of NFAs on colorectal cancer (CRC) cells in cell culture-based experiments and in a murine xenograft model of human CRC...
June 15, 2018: Biochemical Pharmacology
Jaismy Jacob P, S L Manju, K R Ethiraj, Geetha Elias
Inflammatory mediators of the arachidonic acid cascade from cyclooxygenase (COX) and lipoxygenase (LOX) pathways are primarily responsible for many diseases in human beings. Chronic inflammation is associated with the pathogenesis and progression of cancer, arthritis, autoimmune, cardiovascular and neurological diseases. Traditional non-steroidal anti-inflammatory agents (tNSAIDs) inhibit cyclooxygenase pathway non-selectively and produce gastric mucosal damage due to COX-1 inhibition and allergic reactions and bronchospasm resulting from increased leukotriene levels...
June 5, 2018: European Journal of Pharmaceutical Sciences
Ning Wang, Artur Kuczmanski, Galyna Dubrovska, Maik Gollasch
Background: Perivascular adipose tissue (PVAT) exerts anti-contractile effects on visceral arteries by release of various perivascular relaxing factors (PVRFs) and opening voltage-gated K+ (Kv ) channels in vascular smooth muscle cells (VSMCs). Palmitic acid methyl ester (PAME) has been proposed as transferable PVRF in rat aorta. Here, we studied PVAT regulation of arterial tone of human mesenteric arteries and clarified the contribution of Kv channels and PAME in the effects. Methods: Wire myography was used to measure vasocontractions of mesenteric artery rings from patients undergoing abdominal surgery...
2018: Frontiers in Physiology
Seyyedeh Elaheh Mousavi, Pegah Saberi, Naeemeh Ghasemkhani, Nahid Fakhraei, Rezvan Mokhtari, Ahmad Reza Dehpour
PURPOSE: Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, possesses antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory properties. The aim of the present study was to investigate the effect of licofelone on lipopolysaccharide (LPS)-induced depression in a mouse model and also a possible role for nitric oxide (NO). METHODS: To elucidate the role of NO on this effect of licofelone (5 and 20 mg/kg, i.p.), L-NAME, a non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), a specific inducible NOS (iNOS) inhibitor; 7-nitroindazole (7-NI) a preferential neuronal NOS inhibitor (nNOS) and; L-arginine (L-Arg), as a NO donor, were used...
2018: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
Yanzhuo Liu, Chenfan Duan, Honglei Chen, Chenlong Wang, Xiaoxiao Liu, Miao Qiu, Honglin Tang, Feng Zhang, Xiaoyang Zhou, Jing Yang
Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal-induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5-LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2 ) and leukotriene B4 (LTB4 ) in the synovial fluid macrophages...
July 15, 2018: Toxicology and Applied Pharmacology
Rongzong Qiu, Weifeng Yao, Haocong Ji, Dongdong Yuan, Xiaofeng Gao, Weiping Sha, Fei Wang, Pinjie Huang, Ziqing Hei
BACKGROUND: Acute kidney injury occurred after sepsis, resulting in high mortality. This research aims to elucidate the mechanistic effect of DEX on the renal inflammation resolution during sepsis in rats. METHODS: The rats were randomly divided into a sham group and the other three cecal ligation and puncture (CLP) model groups, based on different treatments: placebo, DEX and 2-adrenergic receptor (AR) inhibitor atipamezole (AT) treatment (DEX + AT) groups...
July 1, 2018: Life Sciences
B Nandha, Sureshbabu A Ramareddy, Hazra Kuntal
A new series of 4-((5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)methyl)-benzoic acids 4a-o and 2-(5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)-2-methylpropanoic acids 8a-e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX) were investigated. These molecules were designed based on the combination of 5-LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5-LOX inhibitory activity. Compound 4g showed remarkable activity with IC50 values of less than 1 μM (0...
June 2018: Archiv der Pharmazie
Jessica A Martinez, Jun Yang, Betsy C Wertheim, Denise J Roe, Alexander Schriewer, Peter Lance, David S Alberts, Bruce D Hammock, Patricia A Thompson
Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes...
2018: PloS One
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