Apolipoprotein E (APOE) plays a significant role in determining the risk of Alzheimer's disease (AD). Three mutations-APOE3-R136S, APOE3-V236E, and APOE4-R251G-have been reported to reduce the risk of Show more
Apolipoprotein E (APOE) plays a significant role in determining the risk of Alzheimer's disease (AD). Three mutations-APOE3-R136S, APOE3-V236E, and APOE4-R251G-have been reported to reduce the risk of AD. Unveiling the molecular mechanism behind this reduction could lay a foundation for developing therapeutics for AD. To shed light on this subject, we investigate the mutation-induced variation in structural and dynamic properties of APOE3-R136S, APOE3-V236E, and APOE4-R251G in explicit solvent using molecular dynamics simulations. The APOE2, APOE3, and APOE4 were used as the reference. The analysis unveiled that the three protective mutations may exert protection through different mechanisms. The R215G mutation makes the flexibility of APOE4 proteins more similar to that of APOE2 and APOE3. In addition, this mutation reduced the exposure area of the oligomerization region by 5-16%. Such a reduction could alleviate the aggregation tendencies of the APOE proteins with amyloid-forming peptides. On the other hand, the R136S and V236 mutations alter the exposure area of the hydrophobic amino acid residues in the lipidation region. Their protective mechanisms may be due to the alteration in the lipidation capability of the APOE3 protein. Show less
To evaluate the effect of pioglitazone, a member of the thiazolidinedione family of drugs known for its antihyperglycemic properties, on lipoprotein (a) [Lp(a)]. Pioglitazone is recognized for enhanci Show more
To evaluate the effect of pioglitazone, a member of the thiazolidinedione family of drugs known for its antihyperglycemic properties, on lipoprotein (a) [Lp(a)]. Pioglitazone is recognized for enhancing insulin sensitivity and β-cell function, and it also has a positive influence on the overall lipid profile. Meta-analysis of 7 studies (4 RCTs and three non-RCTs) including 254 patients showed a significant decrease of circulating Lp(a) levels after treatment with pioglitazone (SMD: -0.373, 95% CI: -0.642, -0.104, p = 0.007). The reduction in circulating Lp(a) was robust in the leave-one-out sensitivity analysis. The presented results were obtained following a comprehensive literature search conducted in PubMed, Scopus, Embase, and Web of Science, covering studies from their inception up to March 1, 2025. Pioglitazone significantly decreases circulating Lp(a) concentrations. This decrease might have a beneficial effect on atherosclerotic cardiovascular disease (ASCVD) in high-risk patients. Show less