LTA4H

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals...

Leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4 ). Preclinical studies have provided strong evidence that LTA4H is an attractive drug target for the treatment of chronic inflammatory diseases. Here, we describe the transformation of compound 2 , a fragment-like hit, into the potent inhibitor of LTA4H 3 . Our strategy involved two key steps. First, we aimed to increase the polarity of fragment 2 to improve its drug-likeness, particularly its solubility, while preserving both its promising potency and low molecular weight...

LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b...

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260)...

Invasive fungal infections are life-threatening, and neutrophils are vital cells of the innate immune system that defend against them. The role of LTA4H-LTB4 -BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood. Here, we demonstrated that the LTA4H-LTB4 -BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus, but not Cryptococcus neoformans infection, by regulating the antifungal activity of neutrophils. Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils...

BACKGROUND: Cancer-derived exosomes contribute significantly in intracellular communication, particularly during tumorigenesis. Here, we aimed to identify two immune-related ovarian cancer-derived exosomes (IOCEs) subgroups in ovarian cancer (OC) and establish a prognostic model for OC patients based on immune-related IOCEs. METHODS: The Cancer Genome Atlas (TCGA) database was used to obtain RNA-seq data, as well as clinical and prognostic information. Consensus clustering analysis was performed to identify two IOCEs-associated subgroups...

BACKGROUND: Early diagnosis remains difficult because the early symptoms of thymoma are atypical. OBJECTIVE: This study aimed to analyze the changes of serum proteins in the early stage of thymoma (stage I/II) by proteomics method and to screen and validate candidate biomarkers. METHODS: Proteins were extracted from 8 sera patients with stage I/II thymoma and 9 healthy controls. The levels of serum proteins were detected by data-independent acquisition (DIA) quantitative proteomics techniques, and the differential proteins were identified...

The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective O -phosphorylation of the ( R )-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the ( S )-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo...

Leukotriene A4 hydrolase (LTA4H) functions as a mono-zinc bifunctional enzyme with aminopeptidase and epoxidase activities. While the aminopeptidase mechanism is well understood, the epoxidase mechanism remains less clear. In continuation of our prior research, we undertook an in-depth exploration of the LTA4H catalytic role as an epoxidase, employing a combined SCC-DFTB/CHARMM method. In the current work, we found that the conversion of LTA4 to leukotriene B4 (LTB4) involves three successive steps: epoxy ring opening (RO), nucleophilic attack (NA), and proton transfer (PT) reactions at the epoxy oxygen atom...

Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function...

INTRODUCTION: Ganshu Nuodan is a liver-protecting dietary supplement composed of Ganoderma lucidum ( G. lucidum ) spore powder, Pueraria montana (Lour.) Merr. ( P. montana ), Salvia miltiorrhiza Bunge ( S. miltiorrhiza ) and Astragalus membranaceus (Fisch.) Bunge. ( A. membranaceus ). However, its pharmacodynamic material basis and mechanism of action remain unknown. METHODS: A mouse model of acute alcohol liver disease (ALD) induced by intragastric administration of 50% alcohol was used to evaluate the hepatoprotective effect of Ganshu Nuodan...

Epidermal growth factor receptor inhibitors (EGFRIs) are widely used to treat various types of malignancies. One of the common adverse reactions is cutaneous toxicity, mostly presenting as acneiform eruptions, paronychia and xerosis. Erosive pustular dermatosis of the scalp (EPDS) is a rare cutaneous adverse reaction that develops during treatment with EGFRIs. The pathogenesis of EGFRI-induced EPDS is poorly understood. Here we present three cases of EPDS induced by EGFRIs. The proteins LTA4H (leukotriene A-4 hydrolase), METAP1 (methionine aminopeptidase 1), BID (BH3-interacting domain death agonist), SMAD1 (mothers against decapentaplegic homologue), PRKRA (interferon-inducible double-stranded RNA-dependent protein kinase activator A), YES1 (tyrosine-protein kinase Yes) and EGFL7 (epidermal growth factor-like protein 7) were significantly upregulated in EGFRI-stimulated peripheral blood mononuclear cell cultures, and validated in the lesions...

BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disorder, and sublingual immunotherapy (SLIT) is an important therapy. However, SLIT exhibits a wide range of fluctuations and lacks objective monitoring indicators. Therefore, exploring biomarkers for early prediction of the efficacy of SLIT is urgently needed. METHODS: We recruited two independent cohorts. In the discovery cohort, house dust mite (HDM) -induced AR patients underwent SLIT for at least 1 year, and were categorized into response and no response groups based on early efficacy...

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS: β-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation...

BACKGROUND: Immune checkpoint blockade (ICB) induces durable immune responses across a spectrum of advanced cancers and revolutionizes the oncology field. However, only a subset of patients achieves long-lasting clinical benefits. Tumor-associated macrophages (TAMs) usually secrete immunosuppressive cytokines and contribute to the failure of ICB therapy. Therefore, it is crucial to mechanically manipulate the abundance and function of TAMs in the tumor microenvironment (TME), which can offer a promising molecular basis to improve the clinical response efficacy of ICB in cancer patients...

The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumor (SI-NET) is a rare disease, but its incidence has increased over the past 4 decades. Understanding the genetic risk factors underlying SI-NETs can help in disease prevention and may provide clinically beneficial markers for diagnosis. Here the results of the largest genome-wide association study of SI-NETs performed to date with 405 cases and 614,666 controls are reported. METHODS: Samples from 307 patients with SI-NETs and 287,137 controls in the FinnGen study were used for the identification of SI-NET risk-associated genetic variants...

Airway diseases can disrupt tight junction proteins, compromising the epithelial barrier and making it more permeable to pathogens. In people with pulmonary disease who are prone to infection with Pseudomonas aeruginosa, pro-inflammatory leukotrienes are increased and anti-inflammatory lipoxins are decreased. Upregulation of lipoxins is effective in counteracting inflammation and infection. However, whether combining a lipoxin receptor agonist with a specific leukotriene A4 hydrolase (LTA4H) inhibitor could enhance these protective effects has not to our knowledge been investigated...

Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein-ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs...

INTRODUCTION: Acute respiratory distress syndrome and acute lung injury (ARDS/ALI) still lack a recognized diagnostic test and pharmacologic treatments that target the underlying pathology. METHODS: To explore the sensitive non-invasive biomarkers associated with pathological changes in the lung of direct ARDS/ALI, we performed an integrative proteomic analysis of lung and blood samples from lipopolysaccharide (LPS)-induced ARDS mice and COVID-19-related ARDS patients...