Visible-Light-Driven Rotation of Molecular Motors in Discrete Supramolecular Metallacycles

The organization of molecular motors in supramolecular assemblies to allow the amplification and transmission of motion and collective action is an important step toward future responsive systems. Metal-coordination-driven directional self-assembly into supramolecular metallacycles provides a powerful strategy to position several motor units in larger structures with well-defined geometries. Herein, we present a pyridyl-modified molecular motor ligand (MPY) which upon coordination with geometrically distinct di-Pt(II) acceptors assembles into discrete metallacycles of different sizes and shapes. This coordination leads to a red-shift of the absorption bands of molecular motors, making these motorized metallacycles responsive to visible light. Photochemical and thermal isomerization experiments demonstrated that the light-driven rotation of the motors in the metallacycles is similar to that in free MPY in solution. CD studies show that the helicity inversions associated with each isomerization step in the rotary cycle are preserved. To explore collective motion, the trimeric motor-containing metallacycle was aggregated with heparin through multiple electrostatic interactions, to construct a multi-component hierarchical system. SEM, TEM, and DLS measurements revealed that the photo- and thermal-responsive molecular motor units enabled selective manipulation of the secondary supramolecular aggregation process without dissociating the primary metallacycle structures. These visible-light-responsive metallacycles, with intrinsic multiple rotary motors, offer prospects for cooperative operations, dynamic hierarchical self-assembled systems, and adaptive materials

Reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine

Substrate-dependent inhibition of CYP3A4 might influence the extrapolation of drug interactions from the in vitro to in vivo situation. The aim of the present study is to investigate reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine. Furthermore, in vitroin vivo extrapolation (IVIVE) was performed using in vitro parameters. The results showed that CYP3A4- mediated nifedipine oxidation activity was strongly inhibited with an IC50 of 25.7 ± 5.4 μM. Kinetic analysis showed that inhibition of CYP3A4-mediated nifedipine oxidation by noscapine was best fit to a noncompetitive manner with Ki value of 10.9 μM. IC50 shift experiment showed that IC50 was significantly decreased from 25.7 ± 5.4 μM to 0.34 ± 0.07 μM after pre-incubation with noscapine for 30 min, which indicated that time-dependent inhibition existed for inhibition of CYP3A4 by noscapine. The AUC of (R)- warfarin was predicted to increase by 0.5 % using Cmax or 0.2 % using unbound Cmax with reversible inhibition prediction equation, while the AUC of (R)-warfarin was estimated to increase by 23.1 % using Cmax or 10.4 % using unbound Cmax with TDI prediction equation. Inhibition of CYP3A4 by noscapine showed substrate-dependent inhibition behaviour. However, the results obtained from IVIVE are very similar using testosterone or nifedipine as probe substrates.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Maternal exposure to ambient air pollution and congenital heart defects in China

Background: Evidence of maternal exposure to ambient air pollution on congenital heart defects (CHD) has been mixed and are still relatively limited in developing countries. We aimed to investigate the association between maternal exposure to air pollution and CHD in China.Method: This longitudinal, population-based, case-control study consecutively recruited fetuses with CHD and healthy volunteers from 21 cities, Southern China, between January 2006 and December 2016. Residential address at delivery was linked to random forests models to estimate maternal exposure to particulate matter with an aerodynamic diameter of ≤1 µm (PM1), ≤2.5 µm, and ≤10 µm as well as nitrogen dioxides, in three trimesters. The CHD cases were evaluated by obstetrician, pediatrician, or cardiologist, and confirmed by cardia ultrasound. The CHD subtypes were coded using the International Classification Diseases. Adjusted logistic regression models were used to assess the associations between air pollutants and CHD and its subtypes.Results: A total of 7055 isolated CHD and 6423 controls were included in the current analysis. Maternal air pollution exposures were consistently higher among cases than those among controls. Logistic regression analyses showed that maternal exposure to all air pollutants during the first trimester was associated with an increased odds of CHD (e.g., an interquartile range [13.3 µg/m3] increase in PM1 was associated with 1.09-fold ([95% confidence interval, 1.01-1.18]) greater odds of CHD). No significant associations were observed for maternal air pollution exposures during the second trimester and the third trimester. The pattern of the associations between air pollutants and different CHD subtypes was mixed.Conclusions: Maternal exposure to greater levels of air pollutants during the pregnancy, especially the first trimester, is associated with higher odds of CHD in offspring. Further longitudinal well-designed studies are warranted to confirm our findings