Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. To establish a Gnmt knockout mouse model, 2 lambda phage clones containing a mouse Gnmt genome were isolated. At 11 weeks of age, the Gnmt؊/؊ mice had hepatomegaly, hypermethioninemia, and significantly higher levels of both serum alanine aminotransferase and hepatic S-adenosylmethionine. Such phenotypes mimic patients with congenital GNMT deficiencies. A real-time polymerase chain reaction analysis of 10 genes in the one-carbon metabolism pathway revealed that 5,10-methylenetetrahydrofolate reductase, S-adenosylhomocysteine hydrolase (Ahcy), and formiminotransferase cyclodeaminase (Ftcd) were significantly down-regulated in Gnmt؊/؊ mice. This report demonstrates that GNMT regulates the expression of both Ftcd and Ahcy genes. Results from pathological examinations indicated that 57.1% (8 of 14) of the Gnmt؊/؊ mice had glycogen storage disease (GSD) in their livers. Focal necrosis was observed in male Gnmt؊/؊ livers, whereas degenerative changes were found in the intermediate zones of female Gnmt؊/؊ livers. In addition, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes were observed in the Gnmt؊/؊ mice. A real-time polymerase chain reaction analysis of genes involved in the gluconeogenesis pathways revealed that the following genes were significantly down-regulated in Gnmt؊/؊ mice: fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphate transporter. Conclusion: Because Gnmt؊/؊ mice phenotypes mimic those of patients with GNMT deficiencies and share several characteristics with GSD Ib patients, we suggest that they are useful for studies of the pathogenesis of congenital GNMT deficiencies and the role of GNMT in GSD and liver tumorigenesis.

IntroductionFew population-based data are available evaluating the prevalence of lower urinary tract symptoms (LUTS) in Asia. The objective of our study was to determine LUTS prevalence in China, Taiwan, and South Korea using International Continence Society (ICS) 2002 criteria.MethodsAn Internet-based self-administered survey among individuals aged at least 40 years with the ability to use a computer and to read the local language. Survey questions included ICS symptom definitions and the international prostate symptom score (IPSS). Data analysis was based on descriptive statistics and post hoc significance testing.ResultsThere were 8284 participants, of whom 51% were women and 34% were aged at least 60 years. LUTS prevalence was slightly higher in men than women (62.8% vs. 59.6%; p = 0.004), increasing significantly with age (p = 0.001). All three ICS symptom groups (voiding, storage, and post-micturition) were present in 35% of individuals with LUTS. Symptoms with the highest overall prevalence were nocturia, frequency, incomplete emptying, and terminal dribble. The most bothersome symptoms were terminal dribble, nocturia, and urgency. According to IPSS scores, 87% of participants had at least mild symptoms; 43% of those aged over 60 years had moderate/severe symptoms. The percentage of participants with any LUTS who had visited healthcare professionals because of urinary symptoms was 26%, rising to 45% amongst individuals with all three symptom groups (p = 0.001 vs. other ICS symptom groups).ConclusionsLUTS are highly prevalent in men and women aged at least 40 years who participated in this study in China, Taiwan, and South Korea and increases with increasing age. A minority of individuals with LUTS seek healthcare and our results suggest an increased patient awareness of LUTS is required.FundingAstellas Pharma Singapore Pte. Ltd.Trial registrationClinicalTrials.gov identifier, NCT02618421.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-017-0577-9) contains supplementary material, which is available to authorized users.

Decellularization is the process by which cells are discharged from tissues/organs, but all of the essential cues for cell preservation and homeostasis are retained in a three-dimensional structure of the organ and its extracellular matrix components. During tissue decellularization, maintenance of the native ultrastructure and composition of the extracellular matrix (ECM) is extremely acceptable. For recellularization, the scaffold/matrix is seeded with cells, the final goal being to form a practical organ. In this review, we focus on the biological properties of the ECM that remains when a variety of decellularization methods are used, comparing recellularization technologies, including bioreactor expansion for perfusion-based bioartificial organs, and we discuss cell sources. In the future, decellularization-recellularization procedures may solve the problem of organ assembly on demand.

Hepatocellular carcinoma (HCC) is the fifth common cancer in the world and it mainly occurs in men. Glycine N-methyltransferase (GNMT) participates in one-carbon metabolism and affects DNA methylation by regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine. Previously, we described that the expression of GNMT was diminished in human HCC. Here, we showed that 50% (3/6) male and 100% (7/7) female Gnmt2/2 mice developed HCC, and their mean ages of HCC development were 17 and 16.5 months, respectively. In addition, 42.9% (3/7) of female Gnmt2/2 mice had hemangioma. Wnt reporter assay demonstrated that Gnmt is a negative regulator for canonical Wnt signaling pathway. Beta-catenin, cyclin D1 and c-Myc, genes related to Wnt pathway, were upregulated in the liver tissues from both 11 weeks and HCC stage of Gnmt2/2 mice. Furthermore, global DNA hypomethylation and aberrant expression of DNA methyltransferases 1 and 3b were found in the early and late stages of HCC development. Hierarchical cluster analysis of 6,023 transcripts from microarray data found that gene expression patterns of HCC tumors from male and female Gnmt2/2 mice were distinctively different. Real-time PCR confirmed that Gadd45a, Pak1, Mapk3 and Dsup3 genes of mitogen-activated protein kinase (MAPK) pathway were activated in Gnmt2/2 mice, especially in the female mice. Therefore, GNMT is a tumor suppressor gene for liver cancer, and it is associated with gender disparity in liver cancer susceptibility. '