AU-1 from Agavaceae plants causes transient increase in p21/Cip1 expression in renal adenocarcinoma ACHN cells in an miR-34-dependent manner

Here, we show that AU-1, spirostanol saponin isolated from Agavaceae plants, causes a transient increase in cyclin-dependent kinase inhibitor (CDKI) p21/Cip1 through the upregulation of miRNAs, miR-34 and miR-21. AU-1 stimulated p21/Cip1 expression without exerting cytotoxicity against different types of carcinoma cell lines. In renal adenocarcinoma ACHN cells, AU-1 transiently elevated the expression level of p21/Cip1 protein without marked increases in p21/Cip1 mRNA levels. Rapid and transient increases in miR-34 and miR-21, both of which are known to upregulate p21/Cip1, were observed in AU-1-treated cells. Inhibitor for miR-34 and for miR-21 significantly blocked the AU-1-caused increase in p21/Cip1, indicating that elevation of p21/Cip1 protein by AU-1 is dependent on these microRNAs. We further clarified that NAD-dependent deacetylase SIRT1, a direct target of miR-34, is decreased by the treatment with AU-1. Furthermore, we found that SIRT1-knockdown increases p21/Cip1 protein levels in an miR-21-dependent manner. On the other hand, ectopic expression of p21/Cip1 resulted in the lowered expression of miR-34 and miR-21, suggesting that reciprocal regulation exists between p21/Cip1 and these miRNAs. We propose that the following feedback network composed of miR-34/SIRT1/miR-21/p21 is triggered by the treatment with AU-1: in cells treated with AU-1, transient elevation of miR-34 leads to the downregulation of SIRT1, thereby miR-21 is freed from SIRT1-dependent suppression. Then, elevated miR-21 upregulates p21/Cip1 protein, followed by the suppression of miR-34 expression.     

Identification of a Novel Titin Variant Underlying Myocardial Involvement in Neurofibromatosis Type 1

Because of the rare co-occurrence, it remains a question whether cardiomyopathy is a true association of neurofibromatosis type 1. A boy with café-au-lait spots manifested restrictive cardiomyopathy. Whole exome sequencing confirmed the genetic diagnosis of neurofibromatosis and further identified a novel titin (TTN) missense variant. The significance of the variant is supported by its de novo origin, in silico predictions, and evolutionary conservation. Modern genetics raises an intriguing explanation for the unexpected phenotype and adds to the evolving role of TTN variants in cardiomyopathy.     

Ultrasonic measurement of the effects of light irradiation and presence of water on the polymerization of self‐adhesive resin cement

Self‐adhesive resin cements are useful in restorations because they reduce the number of clinical steps involved in the restoration process. This study evaluated, using ultrasonic measurements, the influence of light irradiation and the presence of water on the polymerization behavior and elastic modulus of a self‐adhesive resin cement. A self‐adhesive resin cement (RelyX Unicem 2 Automix) or a resin cement (RelyX ARC) was inserted into a transparent mold on a sample stage, and the presence of water and effect of light‐irradiation were evaluated. The transit time of a sonic wave through the cement disk was divided by the specimen thickness to obtain the sonic velocity, and longitudinal and shear waves were used to determine the elastic modulus. When the resin cements were light‐irradiated, the sonic velocity rapidly increased and plateaued at 2,500–2,700 m s^?1. When the cements were not irradiated, the rates of increase in the sonic velocity were reduced. When water was applied to the sample stage, the sonic velocity was reduced. The elastic modulus values of the specimens ranged from 9.9 to 15.9 GPa after 24 h. The polymerization behavior of self‐adhesive resin cements is affected by the polymerization mode and the presence of water.     

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies

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