Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine.

Voltage-gated sodium (Nav) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Nav channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Nav1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Nav1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Nav channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Nav channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.

Determination and Chemotaxonomic Analysis of Lanostane Triterpenoids in the Mycelia of Ganoderma spp. Using Ultra-performance Liquid Chromatography-Tandem Mass Spectrometry (I).

A comprehensive and sensitive method combining ultra-performance liquid chromatography with tandem mass spectrometry was developed for the quantification of characteristic triterpenoids in Ganoderma mycelia. Eight ganoderic acids previously isolated from the mycelia of Ganoderma lingzhi were separated with a binary mobile phase on a reversed-phase C18 column. A triple quadrupole mass spectrometer equipped with an electrospray ionization source was used as the detector in the negative ion mode. Identification and quantitation of target ganoderic acids were accomplished using the dynamic multiple reaction monitoring mode. The developed method was validated in terms of linearity, precision, accuracy, stability, and recovery. The method was first applied to quantify the contents of eight ganoderic acids in the mycelia of G. lingzhi at different times to determine the optimum fermentation conditions. Subsequently, the distribution of triterpenoids and the contents of eight ganoderic acids in sixteen different Ganoderma species were investigated. The results indicated that UV chromatography combined with dynamic multiple reaction monitoring quantification was an effective chemotaxonomy method for Ganoderma species identification. This study also provided a helpful analytical methodology for both scientific and industrial applications in the quality control of Ganoderma triterpenoids.

Lanostane triterpenoids from mycelia-associated Ganoderma sinense and their anti-inflammatory activity.

Seven previously undescribed lanostane triterpenoids, ganoderic acid M1 (1), M2 (2), M3 (3), M4 (4), M5 (5), M6 (6), and M7 (7), together with eight known compounds, were isolated from mycelia of the basidiomycete Ganoderma sinense (Ganodermataceae). The structures of all compounds were elucidated by spectroscopic analysis. The possible biosynthetic pathway of these fifteen triterpenoids was proposed. Some of the compounds were evaluated for their anti-inflammatory activity by measuring the production of nitric oxide (NO), TNF-α, and IL-6 in RAW264.7 macrophage cells induced by lipopolysaccharide. Lanosta-7,9(11),24-trien-3ß,15α,22ß-triacetoxy-26-oic acid (14) exhibited the strongest inhibition of NO production with an IC50 of 0.6 ± 0.1 µM and completely inhibited the secretion of TNF-α and IL-6 at 10 µM. The structure-activity relationship of the anti-inflammatory activity is discussed.

Self-calibrated optical thermometer based on luminescence from SrLu2O4:Bi3+,Eu3+ phosphors.

Bi3+,Eu3+ co-doped SrLu2O4 phosphors were synthesized by a solid state reaction method. Their structural, luminescent and temperature sensing properties have been systematically investigated. The color-tunable emissions from violet to red were detected with the increase of Eu3+ concentration. Relying on energy transfer process from Bi3+ to Eu3+ and thermal quenching behaviour, the fluorescence intensity ratio (FIR) presents excellent temperature sensing performance. The maximum absolute and relative sensitivities reach 1.10% K-1 and 0.87% K-1, respectively. These meaningful results indicate that SrLu2O4:Bi3+,Eu3+ is a promising material for optical temperature sensing.