RESUMO
Membrane Bound O-Acyltransferase Domain-Containing 4 (MBOAT4) protein catalyzes ghrelin acylation, leading to prominent ghrelin activity, hence characterizing its role as an anti-obesity target. We extracted 625 exonic SNPs from the ENSEMBL database and one phenotype-based missense mutation associated with obesity (A46T) from the HGMD (Human Gene Mutation Database). These were differentiated on deleterious missense SNPs of the MBOAT4 gene through MAF (minor allele frequency: <0.01) cut-off criteria in relation to some bioinformatics-based supervised machine learning tools. We found 8 rare-coding and harmful missense SNPs. The consensus classifier (PredictSNP) tool predicted that the SNP (G57S, C: rs561065025) was the most pathogenic. Several trained in silico algorithms have predicted decreased protein stability [ΔΔG (kcal/mol)] function in the presence of these rare-coding pathogenic mutations in the MBOAT4 gene. Then, a stereochemical quality check (i.e. validation and assessment) of the 3D model was performed, followed by a blind cavity docking approach, used to search for druggable cavities and molecular interactions with citrus flavonoids of the Rutaceae family, ranked with energetic estimations. Significant interactions with Phloretin 3',5'-Di-C-Glucoside were also observed at R304, W306, N307, A311, L314 and H338 with (iGEMDOCK: -95.82 kcal/mol and AutoDock: -7.80 kcal/mol). The RMSD values and other variables of MD simulation analyses on this protein further validated its significant interactions with the above flavonoids. The MBOAT4 gene and its molecular interactions could serve as an interventional future anti-obesity target. The current study's findings will benefit future prospects for large population-based studies and drug development, particularly for generating personalized medicine.Communicated by Ramaswamy H. Sarma.
RESUMO
BACKGROUND: Both mineralocorticoid receptor antagonists (MRAs) and sodium-glucose co-transporter type 2 inhibitors (SGLT2is) have demonstrated beneficial reductions in cardiovascular outcomes. However, the risk of precipitating hyperkalemia with their concomitant usage remains unclear. METHODS: MEDLINE and Cochrane were searched from inception through March 2022. Randomized controlled trials on patients with heart failure (HF) evaluating the effect of SGLT2is on clinical outcomes between MRA users and non-users were considered for inclusion. Outcomes of interest were mild and moderate/severe hyperkalemia, for which hazard ratios (HR) were pooled using a random effects model. RESULTS: From the 972 articles retrieved from the initial search, three RCTs (n = 14,462 patients) were included in our meta-analysis. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR 0.82 [0.70-0.97]) and non-users (HR 0.95 [0.77-1.17]) (P-interaction = 0.28). The risk of severe hyperkalemia was significantly decreased in MRA users (HR 0.59 [0.44-0.78]; p = 0.0002; I2 = 0%) but not in non-users (HR 0.76 [0.56-1.02]; p = 0.07; I2 = 0%) (P-interaction = 0.22). Sensitivity analysis including patients with HF with reduced ejection fraction (HFrEF) revealed similar results across all subgroups, but no significant reduction in the incidence of mild hyperkalemia (HR 0.89 [0.76-1.04] was noted in MRA users with HFrEF. CONCLUSION: MRAs reduced the risk of mild or moderate/severe hyperkalemia, when added to SGLT2is. Future clinical trials should target scrupulous assessment of the risk of mild and moderate/severe hyperkalemia when used concomitantly with MRAs.
RESUMO
The effect of Sodium-glucose cotransporter-2 (SGLT2) inhibitors on the occurrence of AF and stroke remains unclear due to underpowered individual studies. We aim to conduct a meta-analysis including all studies that have evaluated the effects of SGLT2 inhibitors on the occurrence of AF and stroke. We queried electronic databases (PubMed, Cochrane CENTRAL and ClinicalTrials.gov) for randomized controlled trials assessing the effect of SGLT2 inhibitors. Trials were selected if they reported 1 or both of the pre-specified outcomes of stroke and AF. Results were pooled using a random-effects model. Subgroup analysis was conducted to study patients with T2DM, HF, CVD and CKD. 56 trials comprising 111,773 patients were included. SGLT2 inhibitors significantly reduced the incidence of AF across all studies (RR:0.87; 95%CI, [0.76-0.99], P=0.03, I^2=0%) especially when used as monotherapy (RR:0.87; 95%CI, [0.77-0.99], P=0.04, I^2=0%) and among T2DM patients (RR:0.83; 95%CI, [0.72-0.97], P=0.02, I^2=0%). The risk of stroke was not reduced after treatment with SGLT2 inhibitors (RR:0.97; 95%CI, [0.89-1.07], P=0.56, I^2=0%) and this was consistent when given as monotherapy (RR:0.98; 95%CI, [0.89-1.07], P=0.62, I^2=0%) or combination therapy (RR:0.58; 95%CI, [0.17-1.95], P=0.38, I^2=0%). This result was consistent among the 3 subpopulations: T2DM, CVD and HF, however benefit was seen in patients with CKD (eGFR<90) (RR:0.85; 95%CI, [0.75-0.97], P=0.02, I^2=0%). SGLT2 inhibitors significantly reduce the incidence of atrial fibrillation, and this effect is primarily seen when given as monotherapy and in patients with T2DM. However, they have no significant effect on the incidence of stroke, except for in patients with Stage 2 CKD and beyond (eGFR<90).
