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RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3′ splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding. RNA editing and RNA splicing are involved in tumorigenesis. Here the authors report crosstalk between RNA editing and splicing by identifying ADAR1/2-dependent splicing events in esophageal squamous carcinoma cells. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is a common pathological change found in various cardiovascular diseases. Although it has long been recognized as an important risk factor responsible for heart failure, there is still a lack of effective treatments in clinic. Chrysophanol is a natural compound with multiple biological activities and protective roles in the cardiovascular system. However, its potential effect on cardiac hypertrophy remains unclear. In the current study, we found that chrysophanol could protect against isoproterenol (ISO)‐induced cardiac hypertrophy both in vitro and in vivo. Increase of cell surface and hypertrophic marker expression induced by ISO in neonatal rat cardiomyocytes was downregulated by chrysophanol. Moreover, chrysophanol ameliorated the abnormal changes of cardiac structure and function in rats subjected to ISO injection, as shown by echocardiography and morphometry measurements. Further mechanistical investigation demonstrated that chrysophanol inhibited phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) induced by ISO. Nuclear translocation of STAT3 and transcription of downstream genes promoted by ISO treatment were also remarkably suppressed by chrysophanol. Taken together, our findings revealed that chrysophanol attenuated ISO‐induced cardiac hypertrophy by inhibiting JAK2/STAT3 signaling pathway. Chrysophanol may be a potential candidate compound for the prevention and treatment of hypertrophy‐related cardiomyopathy. [ABSTRACT FROM AUTHOR]

Protocatechuic aldehyde (PCA) is a natural compound found in the Chinese herb Salvia miltiorrhiza. It has been shown to possess multiple biological activities and to protect the cardiovascular system against oxidative stress, inflammation, and atherosclerosis. However, the potential effects of PCA on cardiac hypertrophy remain to be investigated. In this study, we showed that isoproterenol treatment (ISO, 10 μM for 24 h) induced significant hypertrophy in cultured neonatal rat cardiomyocytes, as manifested by enlargement of cell surface area (1.74-fold greater than that of the control, p < 0.05) and upregulation of hypertrophic gene markers (2.44- to 2.75-fold increase in ANF and β-MHC protein expression, p < 0.05). These ISO-induced hypertrophic responses were attenuated by PCA (50-200 μM, p < 0.05). Furthermore, intragastric administration of PCA (10-100 mg/kg/day) ameliorated cardiac hypertrophy in ISO-treated rats (1.5 mg/kg/day, s.c., for 7 days). PCA inhibited the abnormal changes in echocardiographic parameters and suppressed ISO-induced increase in cardiomyocyte cross-sectional area and collagen content (p < 0.05). It also ameliorated ISO-mediated elevation of HW/BW, LVW/BW, and HW/TL ratios (p < 0.05). Mechanistically, ISO facilitated JAK2 and STAT3 phosphorylation, increased STAT3 nuclear translocation, and enhanced STAT3 transcriptional activity. All these changes were attenuated by PCA. Taken together, these findings showed that PCA could protect against cardiac hypertrophy induced by ISO possibly via inhibition of the JAK2/STAT3 signaling pathway, suggesting the potential of PCA as a therapeutic candidate for hypertrophy-associated heart diseases. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]