The rescuable function and mechanism of resveratrol on As2O3-induced hERG K⁺ channel deficiency.

Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity.

Ginkgo biloba extract and ginkgolide antiarrhythmic potential by targeting hERG and ICa-L channel.

We investigated the effects of Ginkgo biloba extract (GBE) and ginkgolide (GLD) on human ether-a-go-go-related gene (hERG)-encoded K(+) channels and its underlying mechanisms in the hERG-HEK293 cell line by determining GBE- and GLD-induced changes in action potential duration (APD), L-type calcium currents (ICa-L), and the intracellular calcium concentration ([Ca(2+)]i) in guinea-pig ventricular myocytes. hERG currents, APD and ICa-L were recorded using the whole-cell patch clamp technique, the [Ca(2+)]i was examined by an immunofluorescence experiment. In the present study, we found that a low concentration of GBE (0.005 mg/ml) increased hERG currents, but the high concentration of GBE (from 0.05 to 0.25 mg/ml) reduced hERG currents. GLD reduced hERG currents in a concentration-dependent manner (from 0.005 to 0.25 mg/ml). Both GBE and GLD altered kinetics of the hERG channel. GBE accelerated the activation of hERG channels without changing the inactivation curve, but reduced the time constant of inactivation; GLD did not shift the activation or the inactivation curve, but only reduced the time constant of inactivation. Both GBE and GLD shortened the APD, inhibited the ICa-L currents, and decreased the [Ca(2+)]i in isolated guinea-pig ventricular myocytes. The results indicate that GBE and GLD can prevent ischemic arrhythmias and have an antiarrhythmic effect potential via inhibition of IKr and ICa-L currents.

Controllable Mono-/Dialkenylation of Benzyl Thioethers through Rh-Catalyzed Aryl C-H Activation.

Under solvent control: Benzyl thioethers were alkenylated in excellent yields with broad substrate scope and the selectivity (mono- vs. disubstituted product) was controlled by the solvent and ratio of reactants. Sequential alkenylation with two different alkenes was also carried out in a one-pot process. In addition, the thioether directing group was removed in a one-pot process with simultaneous hydrogenation of the double bond to give the toluene derivatives.

Direct lactonization of 2-arylacetic acids through Pd(II)-catalyzed C-H activation/C-O formation.

Palladium-catalyzed direct lactonization of 2-arylacetic acids through a reaction sequence that includes C-H activation/C-O formation is reported. This method provides a concise and efficient pathway to synthesize fully functionalized benzofuranone derivatives, which are highly relevant to bioactive natural and synthetic products.

Olefinic C-H bond addition to aryl aldehyde and its N-sulfonylimine via Rh catalysis.

The first example of olefinic C-H addition to N-sulfonylaldimines and aryl aldehydes is reported. This strategy offered a concise and high atom-economic approach to vinyl amines and vinyl alcohols.

Rhodium/copper-catalyzed annulation of benzimides with internal alkynes: indenone synthesis through sequential C-H and C-N cleavage.

Doubled up: a rhodium(III)/copper(II) system co-catalyzes the annulation of benzimides with internal alkynes for the synthesis of indenones (see scheme; Cp*=C(5) Me(5)). The reaction involves an uncommon nucleophilic addition of a transition-metal-carbon bond to an imide moiety. This novel reaction provides a facile route to synthesize indenones from readily available benzimides and internal alkynes.