Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug—quinidine—has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single‐cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC‐CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD‐prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC‐CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine‐induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.

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Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O–H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O–H bond insertion reactions between water and α-alkyl- and α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- and [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.

Aims Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. Conclusion Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.

BackgroundAmong rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking.ObjectivesWe sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)–derived cardiomyocytes (hiPSC-CMs).Methods and ResultsA BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (INa) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced INa led to a reduction of amplitude (APA) and upstroke velocity (Vmax) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS.ConclusionOur hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants.

Collectively, our data indicate that HOXC9 is an oncogene in glioblastoma. We have revealed its role in the control of autophagy, and we suggest that HOXC9 is a novel and promising therapeutic target.

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually fatal lung disease that is characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung’s architecture and the formation of focal fibrous hyperplasia. The molecular mechanism by which pulmonary fibrosis develops is not fully understood, and no satisfactory treatment currently exists. However, many studies consider that aberrant activation of TGF-β1 frequently promotes epithelial-mesenchymal transition (EMT) and fibroblast activation in pulmonary fibrosis. Cinobufagin (CBG), a traditional Chinese medicine, has been widely used for long-term pain relief, cardiac stimulation, and anti-inflammatory and local anesthetic treatments. However, its role in pulmonary fibrosis has not yet been established. We investigated the hypothesis that cinobufagin plays an inhibitory role on TGF-β1 signaling using a luciferase-reporter assay. We further explored the effect of cinobufagin on pulmonary fibrosis both in vitro and in vivo. The in vitro experiments showed that cinobufagin suppresses TGF-β1/Smad3 signaling in a dose-dependent manner, attenuates the activation and differentiation of lung fibroblasts and inhibits EMT induced by TGF-β1 in alveolar epithelial cells. The in vivo experiments indicated that cinobufagin significantly alleviates bleomycin-induced collagen deposition and improves pulmonary function. Further study showed that cinobufagin could attenuate bleomycin-induced inflammation and inhibit fibroblast activation and the EMT process in vivo. In summary, cinobufagin attenuates bleomycin-induced pulmonary fibrosis in mice via suppressing inflammation, fibroblast activation and epithelial–mesenchymal transition.

Organophosphate (OP) and pyrethroid (PYR) pesticides are widely used in China. However, few studies have investigated the neurobehavioral outcomes of Chinese children exposed to low levels of OP and PYR. We investigated urinary metabolite levels and their association with exposure characteristics and the neurobehavior of children. For all children, biomarker measurements were made in the same interval relative to neurobehavioral testing. We analyzed the morning urine samples of 406 children aged 3-6 years from Nanjing, China. The Kruskal-Wallis and Wilcoxon rank sum tests were used to identify the associations between urinary metabolite levels and exposure characteristics. Multiple linear regression models were used to test the associations between urinary metabolite levels and neurobehavioral test scores after adjusting for covariates (e.g., sex, age, and education expense). The detection of 3,5,6-trichloropyridinol (TCP) and 3-phenoxybenzoic acid (3-PBA) in the urine was positively associated with living areas adjacent to agricultural fields and using indoor mosquito repellent incense. These two metabolites were negatively associated with the soaking time of fruits and vegetables. When treated as dichotomous variables, TCP was significantly associated with arithmetic test scores in adjusted models, and 3-PBA was significantly associated with the scores on the Chinese Binet and arithmetic tests. When treated as a continuous variable, higher urinary 3-PBA levels were significantly associated with lower cancellation test scores. Our findings suggest that exposure to organophosphate and pyrethroid pesticides may have a significant impact on children's working memory and verbal comprehension.