Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 µM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Copper-nickel-MOF/nickel foam catalysts grown in situ for efficient electrochemical nitrate reduction to ammonia.

Reducing nitrate (NO3-) in an aqueous solution to ammonia under ambient conditions can provide a green and sustainable NH3-synthesis technology and mitigate global energy and pollution issues. In this work, a CuNi0.75-1,3,5-benzenetricarboxylic acid/nickel foam (CuNi0.75-MOF/NF) catalyst grown in situ was prepared via a one-pot method as an efficient cathode material for electrocatalytic nitrate reduction reaction (NO3RR). The CuNi0.75-MOF/NF catalyst exhibited excellent electrocatalytic NO3RR performance at -1.0 V versus a reversible hydrogen electrode, achieving an outstanding faradaic efficiency of 95.88 % and an NH3 yield of 51.78 mg h-1 cm-2. The 15N isotope labeling experiments confirmed that the sole source of N in the electrocatalytic NO3RR was the NO3- in the electrolyte. The reaction pathway for the electrocatalytic NO3RR was derived by in situ Fourier transform infrared spectroscopy and in situ differential electrochemical mass spectrometry. Density functional theory calculations revealed that the Ni element in the CuNi0.75-MOF/NF catalyst had excellent O-H activation ability and strong *H adsorption capacity. These *H species were transferred from the Ni sites to the *NO adsorption intermediates located on the Cu sites, providing a continuous supply of *H to Cu, thereby promoting the formation of *NOH intermediates and enhancing the hydrogenation process of the electrocatalytic NO3RR.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

[Variety of differential display on gene and corresponding gene's clone following corneal alkali burns in rats].

OBJECTIVE: To study the condition of differential gene caused after corneal alkali burns in rats and clarify the molecular biological foundation of corneal denatured protein. METHODS: The animals were sacrificed on the 3rd day and the 2nd week after alkali burns. Total RNA was isolated from the excised corneas and then reverse-transcribed into cDNA. The differential gene was detected by mRNA differential display reverse transcription polymerase chain reaction (DDRT-PCR) with two kinds of anchoring primer and 12 kinds of random primers after corneal alkali burns in the rats. The differential gene fragments were cloned, and their homogeneity was compared with each other in the Gene Bank. RESULTS: Compared with the normal cornea, the cornea of alkali burns on the 2nd week produced one differential gene fragment of 630 bp in the same reaction condition, and this differential gene was homologous to the rattus norvegicus mitochondrial cytochrome oxidase subunits I, II, III gene. CONCLUSIONS: It is found that there is differential gene in the cornea of alkali burns on the 2nd week in rats, and this differential gene is homologous to the rattus norvegicus mitochondrial cytochrome oxidase subunits I, II, III gene. It can be concluded that the occurrence of this differential gene is possible to be related with the action of the superoxide free radicals caused by alkali burns.