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Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies.Methods: We used single-cell RNA sequencing to uncover PLN R14del disease mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We used both 2-dimensional and 3-dimensional functional contractility assays to evaluate the impact of modulating disease-relevant pathways in PLN R14del hiPSC-CMs.Results: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X. PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis.Conclusions: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease ( NAFLD) has become the most important chronic liver disease in China and a major cause of liver transplantation in developed countries in Europe and America. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis ( NASH) is highly likely to progress to end — stage liver disease including liver cirrhosis and liver cancer, resulting in an increase in liver — related mortality. However, there are still no therapeutic drugs for NASH at present, and many new drugs are under development in ongoing clinical trials. The research and development of new drugs for NASH require the selection of an appropriate target population and treatment outcomes depending on anti — metabolic, anti — inflammatory or anti — fibrotic effect. This article summarizes and reviews several key factors in the research and development of new drugs for NASH. [ABSTRACT FROM AUTHOR]

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185 ), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18–55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg + donepezil 5 mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1–13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n = 14) significantly reduced the area of allodynia vs placebo (n = 14; −12.83 cm 2 ; 95% confidence interval [CI] −23.14 to −2.53; P = 0.015) with supportive results for hyperalgesia (−14.04 cm 2 ; 95% CI −28.49–0.41; P = 0.057), validating the electrical hyperalgesia model. Gabapentin + donepezil (n = 30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n = 30; −11.73 cm 2 ; 95% CI −21.04 to −2.42; P = 0.014), with supportive results for allodynia (−6.62 cm 2 ; 95% CI −13.29–0.04; P = 0.052). The adverse event profile for gabapentin + donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin. [ABSTRACT FROM AUTHOR]