Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant.

Epilepsy and neurodevelopmental disorders can arise from pathogenic variants of KCNQ (Kv7) channels. A patient with developmental and epileptic encephalopathy exhibited an in-frame deletion of histidine 260 on Kv7.2. Coexpression of Kv7.2 mutant (mut) subunits with Kv7.3 invoked a decrease in current density, a depolarizing shift in voltage for activation, and a decrease in membrane conductance. Biotinylation revealed an increased level of surface Kv7.2mut compared to Kv7.3 with no change in total membrane protein expression. Super-resolution and FRET imaging confirmed heteromeric channel formation and a higher expression density of Kv7.2mut. Cannabidiol (1 µM) offset the effects of Kv7.2mut by inducing a hyperpolarizing shift in voltage for activation independent of CB1 or CB2 receptors. These data reveal that the ability for cannabidiol to reduce the effects of a pathogenic Kv7.2 variant supports its use as a potential therapeutic to reduce seizure activity.

Synergism inhibition and eradication activity of silver nitrate/potassium tellurite combination against Pseudomonas aeruginosa biofilm.

OBJECTIVES: Antibiotic resistance, biofilm and persistent infection of Pseudomonas aeruginosa is a perilous challenge in the healthcare system. Hence, a vast number of novel antipseudomonas approaches are currently being pursued. Our group focuses on exploring the efficacy of metal(loid)-based antimicrobials (MBAs) towards novel infection control solutions. METHODS: Initially, nine MBAs were tested for biofilm prevention and eradication efficacy. Synergistic potentials were then screened systematically in a total of 1920 combinatorial MBA concentrations, in laboratory media [CAMHB and LB] and infection-related simulated wound fluid (SWF). The antibiofilm efficacy of the silver nitrate (AgNO3; 'Ag') with potassium tellurite (K2TeO3; 'Te') combination was examined against clinical antibiotic-resistant isolates and compared with the most used antibiotics. The in vitro resistance acquisition test, for exploring the chance of getting future resistance, and meta-analysis, for estimating Ag/Te human cell cytotoxicity, were carried out. RESULTS: The Ag/Te combination was identified as the most effective agent against P. aeruginosa biofilm. The application of the Ag/Te combination was quite effective against all clinical isolates. Comparison of clinical isolates with indicator strains showed clinical isolates are gaining resistance against the antibiotics (especially gentamicin) and Ag, while they are susceptible to Te and particularly the Ag/Te combination. The chance of getting future resistance against Ag/Te as a mixture was remarkably lower than the individual application of each metal. Te has significantly lower human cell cytotoxicity in comparison with Ag. CONCLUSIONS: Te could be an appropriate alternative against P. aeruginosa biofilms (existing or prevention thereof), especially in combination with Ag.