Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity

Guo, Hao; Verhoek, Iris; Prins, Grietje H.; Vlag, Ramon van der; Wouden, Petra E van der; Merkerk, Ronald van; Quax, Wim J.; Olinga, Peter; Hirsch, Anna K. H.

doi:10.1021/acs.jmedchem.9b00212

Cited by 16 publications

(13 citation statements)

References 45 publications

(121 reference statements)

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“…Two genes involved with SPM production were lower in expression in animals that developed BRD, relative to animals that remained healthy: ALOX15 and HPGD. The gene ALOX15 encodes arachidonate 15-lipoxygenase, an enzyme that is expressed in macrophages, neutrophils, and airway epithelial cells, and has been shown to directly regulate inflammation, innate immunity, and epithelial wound healing [68] [69] [70]. Studies of the immunological response to Mycobacterium avium sub.…”

Section: Specialized Pro-resolvin Mediator Production Genes Were Expressed Higher At Arrival In Cattle That Resist Brdmentioning

confidence: 99%

Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease

et al. 2020

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Bovine respiratory disease (BRD) is a multifactorial disease complex and the leading infectious disease in post-weaned beef cattle. Clinical manifestations of BRD are recognized in beef calves within a high-risk setting, commonly associated with weaning, shipping, and novel feeding and housing environments. However, the understanding of complex host immune interactions and genomic mechanisms involved in BRD susceptibility remain elusive. Utilizing high-throughput RNA-sequencing, we contrasted the at-arrival blood transcriptomes of 6 beef cattle that ultimately developed BRD against 5 beef cattle that remained healthy within the same herd, differentiating BRD diagnosis from production metadata and treatment records. We identified 135 differentially expressed genes (DEGs) using the differential gene expression tools edgeR and DESeq2. Thirty-six of the DEGs shared between these two analysis platforms were prioritized for investigation of their relevance to infectious disease resistance using WebGestalt, STRING, and Reactome. Biological processes related to inflammatory response, immunological defense, lipoxin metabolism, and macrophage function were identified. Production of specialized pro-resolvin mediators (SPMs) and endogenous metabolism of angiotensinogen were increased in animals that resisted BRD. Protein-protein interaction modeling of gene products with significantly higher expression in cattle that naturally acquire BRD identified molecular processes involving microbial killing. Accordingly, identification of DEGs in whole blood at arrival revealed a clear distinction between calves that went on to develop BRD and those that resisted BRD. These results provide novel insight into host immune factors that are present at the time of arrival that confer protection from BRD.

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Section: Specialized Pro-resolvin Mediator Production Genes Were Expressed Higher At Arrival In Cattle That Resist Brdmentioning

confidence: 99%

Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease

et al. 2020

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“…The relevant enzymes can be produced in large scale by micro-organisms with the help of recombinant DNA technology for instance. Recently, the use of recombinant human lipoxygenase enzymes has become increasingly common due to such sensitivities in lipoxygenase inhibition studies (35,48,53,54).…”

Section: Research Article Conclusionmentioning

confidence: 99%

Can soybean lipoxygenases be real models for mammalian lipoxygenases? A bioinformatics approach

Cengiz

Çavaş

2021

Journal of the Turkish Chemical Society Section A: Chemistry

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Soybean lipoxygenase-1 is one of well-studied enzymes because it is considered as a model enzyme for mammalian lipoxygenases. In general, the soybean lipoxygenase-1 is used in the test of inhibitory activities of various compounds. The present study provides a bioinformatics approach for comparison of various lipoxygenases in the databases. Their various physical and chemical parameters such as molecular weight, theoretical pI, amino acid composition, aliphatic index, and grand average of hydropathicity and the multiple sequence alignments of the lipoxygenases were computed by using several bioinformatics tools. In order to see phylogenetic relationships among lipoxygenases, a phylogenetic tree was constructed. The first three most abundant amino acids in soybean lipoxygenase-1 and 15-lipoxygenase (human) are L (10.3 %), S (7.4 %), A (6.7 %) and L (13.3 %), G (7.4 %), V (7.1 %), respectively. According to the phylogenetic tree, the soybean lipoxygenases are within separate clade compared to the mammalian lipoxygenases. In conclusion, soybean lipoxygenase-1 may not fully characterize the human lipoxygenase-15 since there are remarkable sequence-based differences, which are obtained by using bioinformatics tools between soybean lipoxygenase-1 and lipoxygenases from other sources especially from human. In this context, the researchers, who are aware of the problems described above and who have similar concerns, have begun to use recombinant DNA technology to produce recombinant human lipoxygenase-15 enzyme.

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“…10,11 The human 15-LOX-1 (h-15-LOX-1) is involved in the biosynthesis of anti-inflammatory and pro-inflammatory mediators such as lipoxins and eoxins and is found in both humans and animals. 12,13 This enzyme is found in high concentrations in the monocytes, bronchoalveolar epithelial cells, eosinophils, and macrophages of patients with asthma. Despite the fact that h-15-LOX-1 has been identified as a critical target in the drug discovery process for a variety of inflammatory diseases, the discovery of highly potent h-15-LOX-1 inhibitors and their potential application as a novel therapeutic strategy are still in the early stages of development.…”

Section: Introductionmentioning

confidence: 99%

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds

et al. 2022

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Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid ( a ), was consecutively transformed into benzoate ( 1 ), hydrazide ( 2 ), semicarbazide ( 3 ), and N -furfuryl 5-(4-chlorobenzyl)-4 H -1,2,4-triazole ( 4 ), which when further merged with electrophiles ( 6a–o ) resulted in end products ( 7a–o ). The structural elucidations of the newly synthesized compounds ( 7a–o ) were carried out by Fourier transform infrared, 1 H-, 13 C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds ( 7a–o ) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k , 7o , 7m , 7b, and 7i demonstrated potent activities (IC 50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

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Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity

Cited by 16 publications

References 45 publications

Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease

Whole blood transcriptomic analysis of beef cattle at arrival identifies potential predictive molecules and mechanisms that indicate animals that naturally resist bovine respiratory disease

Can soybean lipoxygenases be real models for mammalian lipoxygenases? A bioinformatics approach

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds

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