Rational Design of a Cocktail of Inhibitors against Aß Aggregation.

It has been reported that many molecules could inhibit the aggregation of Aß (amyloid-ß) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aß aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp-glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co-inhibition of various fibrillar species and avoid unwanted interference.

Differential Modulation of the Aggregation of N-Terminal Truncated Aß using Cucurbiturils.

Modulating the aggregation of Aß has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aß species, including N-terminal truncated or/and modified Aß, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aß species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aß4-40 and Aß1-40 through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aß4-40 than Aß1-40 , which was possibly due to the N-terminal phenylalanine residue of Aß4-40 . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aß species.

A kinetics mechanism of NOX formation and reduction based on density functional theory.

NOX are serious pollutants emitted during combustion, which are greatly harmful to human health and the environment. However, previous studies have not accurately elucidated the NOX conversion mechanism in complicated combustion reactions. To reveal the micro-chemical mechanism of NOX conversion and obtain accurate kinetics data, advanced quantum chemistry methods are employed in this study to systematically explore the pathways of NOX formation and reduction, and determine the new rate coefficients. An energy barrier analysis revealed that during NOX formation (N2 → N2O → NO→NO2), NO is primarily produced by a sequence of reactions (N2 + O → N2O → NO) rather than the traditional reaction (O + N2 → NO+N). Meanwhile, NO2 formation (NO→NO2) largely depends on the O and HO2 radicals, while the active O atom can promote both the formation and destruction of NO2. During NOX reduction (NO2 → NO→N2O → N2), NO2 reduction (NO2 → NO) is closely related to H, CO, and O, whereas CO plays a critical role in NO2 destruction. However, NO reduction (NO→N2O) is unfavourable because of a high energy barrier, while N2O reduction (N2O → N2) is strongly affected by the O atom instead of CO. HONO is mainly formed when NO2 reacts with the HO2 and H radicals, and when NO reacts with OH radicals; thus, HONO consumption largely depends on OH and H radicals. Based on the transition state theory, we obtained new kinetic parameters for NOX conversion, which supplement and correct critical kinetics data obtained from the current NOX model. Performance assessment of the proposed NOX kinetic mechanism reveals that it can improve the existing NOX kinetic mode, which is in good agreement with experimental data.