LncRNA Kcnq1ot1 renders cardiomyocytes apoptosis in acute myocardial infarction model by up-regulating Tead1.

Acute myocardial infarction (AMI) is a major cardiovascular disease with high mortality worldwide. Hypoxia is a key inducing factor for AMI. We aimed to examine the expression and functions of Kcnq1ot1 (KCNQ1 overlapping transcript 1) in hypoxia-induced cardiomyocytes in the process of AMI. The left anterior descending coronary artery ligation (LAD) was used for inducing in-vivo AMI model and the primary cardiomyocytes were extracted; in-vitro H9c2 cell model was simulated by hypoxia treatment. TUNEL, flow cytometry and JC-1 assay were carried out to evaluate cell apoptosis. Mechanism assays including luciferase reporter assay and RIP assay revealed interplays between RNAs. To begin with, Kcnq1ot1 was revealed to be conspicuously upregulated in myocardium infracted zone and border zone within 2 days since establishment of the model. Moreover, inhibition of Kcnq1ot1 protected cardiomyocytes against hypoxia-triggered cell apoptosis during the process of AMI. Then, miR-466k and miR-466i-5p were proved to bind with Kcnq1ot1 and participated in Kcnq1ot1-mediated cardiomyocyte injury under hypoxia. Subsequently, Kcnq1ot1 was found to elevate Tead1 (TEA domain transcription factor 1) expression via sponging miR-466k and miR-466i-5p. Finally, it was verified that Kcnq1ot1 regulated hypoxia-induced cardiomyocyte injury dependent on Tead1. In conclusion, Kcnq1ot1 sponged miR-466k and miR-466i-5p to up-regulate Tead1, thus triggering cardiomyocyte injury in the process of AMI.

2,4,6-Tribromophenol Disposition and Kinetics in Rodents: Effects of Dose, Route, Sex, and Species.

2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%-94% in 24 h; 5% was recovered in feces; and 1%-2% in blood/tissues. TBP administered to female SD rats (0.1-1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%-27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.

Inhibition of the transcriptional repressor complex Bcl-6/BCoR induces endothelial sprouting but does not promote tumor growth.

The oncogenic potential of the transcriptional repressor Bcl-6 (B-cell lymphoma 6) was originally discovered in non-Hodgkin patients and the soluble Bcl-6 inhibitor 79-6 was developed to treat diffuse large B-cell lymphomas with aberrant Bcl-6 expression. Since we found Bcl-6 and its co-repressor BCoR (Bcl-6 interacting co-repressor) to be regulated in human microvascular endothelium by colorectal cancer cells, we investigated their function in sprouting angiogenesis which is central to tumor growth. Based on Bcl-6/BCoR gene silencing we found that the transcriptional repressor complex in fact constitutes an endogenous inhibitor of vascular sprouting by supporting the stalk cell phenotype: control of Notch target genes (HES1, HEY1, DLL4) and cell cycle regulators (cyclin A and B1). Thus, when endothelial cells were transiently transfected with Bcl-6 and/or BCoR siRNA, vascular sprouting was prominently induced. Comparably, when the soluble Bcl-6 inhibitor 79-6 was applied in the mouse retina model of physiological angiogenesis, endothelial sprouting and branching were significantly enhanced. To address the question whether clinical treatment with 79-6 might therefore have detrimental therapeutic effects by promoting tumor angiogenesis, mouse xenograft models of colorectal cancer and diffuse large B-cell lymphoma were tested. Despite a tendency to increased tumor vessel density, 79-6 therapy did not enhance tumor expansion. In contrast, growth of colorectal carcinomas was significantly reduced which is likely due to a combined 79-6 effect on cancer cells and tumor stroma. These findings may provide valuable information regarding the future clinical development of Bcl-6 inhibitors.