BACKGROUND:Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] show high insecticide activity by acting as antagonists to the insect resistance to dieldrin (RDL) γ-aminobutyric acid (GABA) receptors. In contrast, low-level antagonist activities of meta-diamides have been demonstrated against the human GABA type A receptor (GABA R) α1β2γ2S, mammalian GABA R α1β3γ2S, and the human glycine receptor (GlyR) α1β. Glycine residue 336 in the membrane-spanning region M3 of the Drosophila RDL GABA receptor is essential for its high sensitivity to meta-diamide 7, [3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide]. RESULTS:We examined the effects of an equivalent mutation (M288G) in spontaneously opened human GABA R β3 homomers using membrane potential assay. Picrotoxin and fipronil blocked spontaneously opened human GABA Rs β3 and β3-M286G in a concentration-dependent manner. In contrast, meta-diamide 7 did not block spontaneously opened GABA R β3 homomers, although meta-diamide 7 blocked spontaneously opened GABA R β3-M286G homomers. In addition, inhibitory potency of meta-diamide 7 for GABA-induced membrane potential change in cells expressing GABA R α1β3-M286G was much higher than that in cells expressing GABA R α1β3. In the same way, the equivalent mutation (A288G) in GlyR α1 increased the inhibitory potency of meta-diamide 7 for GlyRs α1 and α1β. CONCLUSION:Studies substituting an equivalent mutation (M288G) in spontaneously opening human GABA R β3 homomers and human GABA Rs α1β3 heteromers suggest that M286 in human GABA R β3 is important for the low sensitivity to meta-diamide 7. In this study, we summarize the mechanisms underlying the selectivity of meta-diamides between insect RDL and human GABA and glycine receptors. © 2020 Society of Chemical Industry.

BACKGROUND:Immune-mediated inflammatory diseases (IMIDs) are associated with an increased risk of premature cardiovascular disease and all-cause mortality. Given lipid-lowering and anti-inflammatory properties, statins theoretically provide greater survival benefits for patients with IMIDs. OBJECTIVE:We aimed to evaluate the impact of statin on all-cause mortality and cardiovascular risk in patients with IMIDs, and examine whether the effect varies between primary prevention and secondary prevention. METHODS:We systematically searched PubMed, EMBASE and Cochrane Library to identify eligible studies evaluating the association between statin use and all-cause mortality or cardiovascular events in IMIDs. Data were pooled using fixed-effects or random-effects meta-analysis according to I and pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) were used as summary statistic. RESULTS:Our meta-analysis included 12 studies that comprised 148,722 patients with IMIDs (57,670 statin users, 91,052 statin non-users) contributing more than 840,113 patient-years. In pooled analysis, statin initiation was associated with 28 % decreased risk of all-cause mortality (random-effects: meta-HR 0.72, 95 % CI 0.65-0.80), 23 % decreased risk of major adverse cardiovascular events (fixed-effects: meta-HR 0.72, 95 % CI 0.62-0.83). Subgroup analysis of patients with rheumatoid arthritis showed similar results (fixed-effects: meta-HR 0.77, 95 % CI 0.67-0.89 for all-cause mortality; meta-HR 0.75, 95 % CI 0.63-0.88 for major adverse cardiovascular events). Furthermore, the protective role of statin in decreasing mortality was stronger in patients receiving statin for primary prevention of cardiovascular diseases than that for secondary prevention (fixed-effects: meta-HR 0.64, 95 % CI 0.59-0.70; meta-HR 0.84, 95 % CI 0.80-0.89, respectively), although both were statistically significant. Additional analysis yielded similar benefit from statin usage between females and males regarding mortality. CONCLUSION:Statin use was associated with lower risks of mortality and cardiovascular events, with greater benefits for primary prevention in those IMIDs patients without prior cardiovascular disease.