No abstract

Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has been known to reduce cholesterol biosynthesis. However, recent studies demonstrate that simvastatin shows diverse cholesterol-independent functions including cellular differentiation. In this study, we investigated the stimulatory effect of simvastatin on the osteogenic differentiation of mouse embryonic stem cells (ESCs). The osteogenic effect of simvastatin was observed at relatively low doses (ranging from 1 nM to 200 nM). Incubation of ESCs in simvastatin-supplemented osteogenic medium significantly increased alkaline phosphatase (ALP) activity at day 7. The matrix mineralization was also augmented and demonstrated pivotal levels after 14 days incubation of simvastatin. Osteogenic differentiation of ESCs by simvastatin was determined by upregulation of the mRNA expression of runtrelated gene 2 (Runx2), osterix (OSX), and osteocalcin (OCN) as osteogenic transcription factors. Moreover, the increased protein expression of OCN, osteopontin (OPN), and collagen type I (Coll I) was assessed using Western blot analysis and immunocytochemistry. However, the blockage of canonical Wnt signaling by DKK-1 downregulated simvastatin-induced ALP activity and the mRNA expression of each osteogenic transcription factor. Furthermore, the β-catenin specific siRNA transfection decreased the protein levels of OCN, OPN, and Coll I. Collectively, these findings suggest that simvastatin enhances the differentiation of ESCs toward osteogenic lineage through activation of canonical Wnt/β-catenin signaling.

Lung cancer, especially lung adenocarcinoma (LUAD), is one of the most common neoplasms worldwide. However, the mechanisms underlying its initiation, development, and metastasis are still poorly understood. Destrin (DSTN) is a member of ADF/cofilin family. Its detailed biological function remains unknown, although it is reported that DSTN is involved in cytoskeleton remodeling and regulation of actin filament turnover. Recent evidence has shown that high expression of cofilin-1 is associated with invasion and poor prognosis of several types of human tumors, but the detailed mechanism is still entirely unclear, particularly in lung cancer tumorigenesis and malignancy. Here, we report that DSTN was highly expressed in a mouse lung cancer model induced by urethane and in clinical LUAD tissue samples. Its expression level was positively correlated with cancer development, as well as metastasis to the liver and lymph nodes. Consistently, it was directly associated with the poor prognosis of LUAD patients. Furthermore, we also found that DSTN promotes cell proliferation, invasion and migration in vitro, and facilitates subcutaneous tumor formation and lung metastasis via intravenous injection in vivo. Mechanically, DSTN associates with and facilitates nuclear translocation of β-catenin, which promotes epithelial-mesenchymal transition (EMT). Taken together, our results indicated that DSTN enhances lung cancer malignancy through facilitating β-catenin nuclear translocation and inducing EMT. Combined with multivariate analyses, DSTN might potentially serve as a therapeutic target and an independent prognostic marker of LUAD. Implications: This finding indicated DSTN facilitates β-catenin nuclear translocation and promotes malignancy in lung adenocarcinoma. Research.

Proteasome dysregulation is a common feature of cancer and a critical risk for tumorigenesis. However, the characteristics of proteasome components in tumor development and metastasis are poorly understood. PSMA5, an α5 subunit of the 20S core proteasome, is associated with the degradation of intracellular proteins. Increasing evidence indicated it is involved in tumor development, but the underlying mechanism has remained unknown. Here, we show that PSMA5 is up-regulated in lung adenocarcinoma (LUAD) cells and clinical LUAD tissues. Moreover, its up-regulation is positively associated with lymph node metastasis and the poor prognosis of LUAD patients. PSMA5 knockdown inhibited the proliferation, invasion and metastasis of LUAD cells in vitro and in vivo, induced apoptosis of LUAD cells and sensitized LUAD cells to cisplatin. Further investigations revealed that PSMA5 overexpression inhibited cell apoptosis by activating the janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway in LUAD cells. In total, our results demonstrate that PSMA5 may function as a prognostic factor in LUAD. In addition, PSMA5 is a promising therapeutic target for LUAD, as its depletion induces cell apoptosis by inhibiting the JAK/STAT pathway.

Objective: The objective of this study is to further explore the difference between elevated blood pressure (EBP), elevated pulse pressure (EPP), and elevated mean arterial pressure (EMAP) and obesity in Chinese school-age children by sex.Methods: We performed a cross-sectional study of 935 children between 7 and 12 years old. Overweight and obesity were defined by body mass index and body composition. The multivariate logistic regression and the adjusted population attributable risk were used to assess the effects of obesity on pre-EBP/EBP, EPP, and EMAP. The interactions were used to identify the modification of obese on the relationship between related indicators of blood pressure and height or age.Results: The average age of the children included in the study was 10. Boys with overweight and obesity had higher pre-EBP/EBP, EPP, and EMAP (p < 0.05). The multivariate logistic regression analysis showed that overweight and obesity had a greater impact on BP and MAP than PP, especially in boys [odds ratio (OR) > 1]. Pre-EBP/EBP in 79% of boys and 76% of girls could be attributable to the visceral fat level. The interaction between BP, PP, MAP, and height or age was modestly increased in children with overweight and obesity, especially in boys.Conclusions: Independent of age and height, obesity not only increases blood pressure, it also increases mean arterial pressure and pulse pressure, and this effect is more pronounced in boys.