Introduction. Phospholipase A 2 (PLA 2 ) is a group of lipolytic enzymes that catalyze the hydrolysis of fatty acid ester bonds at the sn-2 position of phospholipids. This enzyme is thought to play an important role in the biosynthesis of eicosanoids via the release of arachidonic acid from biomembranes. Another product from biomembranes, a lysophospholipid, is converted to plateletactivating factor (PAF) known as an inflammatory mediator. PLA 2 s have been generally classified into secretory PLA 2 (sPLA 2 ), cytosolic PLA 2 (cPLA 2 ), and Ca 2+ -independent PLA 2 (iPLA 2 ) by their molecular weights, amino acid sequences, and calcium requirements. 1 cPLA 2 comprises three distinct types of enzymes: R, β, and γ. 2 cPLA 2 R, an 85-kDa protein, contains a calcium-dependent lipid binding domain and a catalytic domain, requires micromolar levels of Ca 2+ for membrane translocation, and has a specificity for arachidonic acid bound to the sn-2 position of phospholipids 3 in contrast with sPLA 2 and iPLA 2 which have broad substrate specificities, suggesting that cPLA 2 R is involved in the production of eicosanoids.

BackgroundCOPD is a major global cause of mortality and morbidity. PINNACLE-4 evaluated the efficacy and safety of GFF MDI (glycopyrrolate/formoterol fumarate metered dose inhaler) in patients from Asia, Europe, and the USA with moderate-to-very severe COPD.MethodsIn this double-blind, placebo-controlled, Phase III study, patients were randomized to treatment with GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI (all twice daily) for 24 weeks. Lung function, patient-reported outcomes (symptoms and health-related quality of life), and safety were assessed.ResultsOf the 1,756 patients randomized, 1,740 patients were included in the intent-to-treat population (mean age 64.2 years, 74.1% male, and 40.2% Asian). GFF MDI significantly improved morning predose trough FEV1 at Week 24 (primary endpoint) vs placebo MDI, GP MDI, and FF MDI (least squares mean differences: 165, 59, and 72 mL, respectively; all P<0.0001). GFF MDI also significantly improved other lung function endpoints vs placebo MDI, GP MDI, and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI. A larger proportion of patients treated with GFF MDI achieved the minimum clinically important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George’s Respiratory Questionnaire score vs placebo MDI. Adverse event rates were similar across treatment groups.ConclusionThese results demonstrated the efficacy of GFF MDI in patients with moderate-to-very severe COPD. GFF MDI was well tolerated, with a safety profile commensurate with long-acting bronchodilators.

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

No abstract

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.