Molecular insights into the structure destabilization effects of ECG and EC on the Aß protofilament: An all-atom molecular dynamics simulation study.

The formation of Aß into amyloid fibrils was closely connected to AD, therefore, the Aß aggregates were the primary therapeutic targets against AD. Previous studies demonstrated that epicatechin-3-gallate (ECG), which possessed a gallate moiety, exhibited a greater ability to disrupt the preformed Aß amyloid fibrils than epicatechin (EC), indicating that the gallate moiety was crucial. In the present study, the molecular mechanisms were investigated. Our results demonstrated that ECG had more potent disruptive impacts on the ß-sheet structure and K28-A42 salt bridges than EC. We found that ECG significantly interfered the interactions between Peptide-4 and Peptide-5. However, EC could not. The disruption of K28-A42 salt bridges by ECG was mainly due to the interactions between ECG and the hydrophobic residues located at C-terminus. Interestingly, EC disrupted the K28-A42 salt bridges by the interactions with C-terminal hydrophobic residues and the cation-π interactions with K28. Moreover, our results indicated that hydrophobic interactions, H-bonds, π-π interactions and cation-π interactions between ECG and the bend of L-shaped region caused the disaggregation of interactions between Peptide-4 and Peptide-5. Significantly, gallate moiety in ECG had contributed tremendously to the disaggregation. We believed that our findings could be useful for designing prospective drug candidates targeting AD.

Exposure to amitriptyline induces persistent gut damages and dysbiosis of the gut microbiota in zebrafish (Danio rerio).

Amitriptyline (AMI), the most commonly prescribed tricyclic antidepressant, is widely detected in water environments. Exposure to AMI may lead to diverse adverse effects on aquatic organisms, but little is known about the effect of short-term exposure to AMI on the gut microbiota of aquatic organisms and their recovery characteristics. In the present study, adult zebrafish (Danio rerio) were exposed to AMI (0, 2.5, 10, and 40 µg/L) for seven days, and then allowed to recover in AMI-free culture water for 21 days. The exposure caused gut damages in all the AMI treated groups of zebrafish, which became more severe after recovery compared to the control group. AMI exposure also disturbed the microbiota of zebrafish guts and rearing water even after the 21-day recovery period. Furthermore, AMI exposure affected microbes involved in the substance and energy metabolic functions in zebrafish guts and tended to increase the abundance of microbial genera associated with opportunistic pathogens. In addition, the microbial predicted metabolic functions in AMI-exposed guts of zebrafish were significantly altered after the 21-day recovery period, explaining the persistent effects of short-term exposure to AMI. The results of this study suggest that acute exposure to AMI may have persistent impacts on the gut histomorphology and the gut microbiota in aquatic organisms.