FGF19 Regulates Cell Proliferation, Glucose and Bile Acid Metabolism via FGFR4-Dependent and Independent Pathways

Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation

スイッチOTC候補成分に関する模擬添付文書作成演習の実施とその効果

A training program was conducted at our pharmacy school concerning the necessity of over-thecounter (OTC) drug sales and counselling tasks undertaken by community pharmacists. In this study, we evaluated the changes in their awareness of pharmacy studies regarding self-medication and the professional practice of community pharmacists, as well as their satisfaction with the training. The training program involved the preparation of simulated OTC package inserts for potential prescription (Rx)-to-OTC switch candidates and a presentation about the details of these inserts. A questionnaire was distributed to 67 students who participated in the program in 2011, and responses from completed questionnaires were analysed (n = 61). Before training, 75.4% and 65.5% of the respondents selected `agree\u27 or `slightly agree\u27 respectively, as their responses to the statements `increase in Rx-to-OTC switch is useful for self-medication\u27 and `increase in Rx-to-OTC switch widens pharmacists\u27 appeal\u27. After training, the response rates were 96.7% and 85.2%, respectively. Furthermore, 98.3% of the respondents indicated that they were satisfied with the training. These findings suggest that the training program was useful for increasing students\u27 awareness about the importance of OTC sales, patient counselling and the professional practice of community pharmacists under the current sales system for OTC medicines

Drosophila Brain Tumor is a translational repressor

The Drosophila brain tumor (brat) gene encodes a member of the conserved NHL family of proteins, which appear to regulate differentiation and growth in a variety of organisms. One of the founding family members, Caenorhabditis elegans LIN-41, is thought to control posttranscriptional gene expression. However, the mechanism by which LIN-41, or any other NHL protein, acts has not been clear. Using a yeast “four-hybrid” interaction assay, we show that Brain Tumor is recruited to hunchback (hb) mRNA through interactions with Nanos and Pumilio, which bind to the RNA to repress its translation. Interaction with the Nanos/Pumilio/RNA complex is mediated by the Brat NHL domain; single amino acid substitutions in this domain compromise quaternary complex assembly in vitro and hb regulation in vivo. Thus, recruitment of Brat is necessary for translational repression and the normal development of posterior embryonic pattern. In addition to regulating abdominal segmentation, previous genetic analysis has shown that Brat, Nanos, and Pumilio govern a variety of developmental processes. We examined the role of Brat in two of these processes—regulation of maternal Cyclin B mRNA in the embryo and regulation of imaginal disc development. The results of these experiments suggest that NHL domain proteins are recruited to various mRNAs by combinatorial protein–protein interactions

Nuclear receptors: Decoding metabolic disease

AbstractNuclear receptors (NR) are a superfamily of ligand-activated transcription factors that regulate development, reproduction, and metabolism of lipids, drugs and energy. The importance of this family of proteins in metabolic disease is exemplified by NR ligands used in the clinic or under exploratory development for the treatment of diabetes mellitus, dyslipidemia, hypercholesterolemia, or other metabolic abnormalities. Genetic studies in humans and rodents support the notion that NRs control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters and other proteins involved in metabolic homeostasis. Current knowledge of complex NR metabolic networks is summarized here

Green Tea Polyphenols Induce Apoptosis in vitro in Peripheral Blood T Lymphocytes of Adult T‐Cell Leukemia Patients

Green tea polyphenols (TEA) are known to exhibit antioxidative activity as well as tumor‐suppressing activity. In order to examine the tumor‐suppressing activity of TEA against adult T‐cell leukemia (ATL), we cultivated peripheral blood T lymphocytes of ATL patients (ATL PBLs), an HTLV‐I‐infected T‐cell line (KODV) and healthy controls (normal PBLs) for 3 days in the presence of TEA and its main constituent, epigallocatechin‐3‐gallate (EGCg), to measure cell proliferation and apoptosis, and to quantitate mRNAs of HTLV‐I pX and β‐actin genes of the cultured cells. Growth of ATL PBLs was significantly inhibited by 9–27 μg/ml of TEA and EGCg, in contrast to minimal growth inhibition of T cells of normal PBLs. Inhibition of KODV was intermediate between ATL PBLs and normal PBLs. The ATL PBLs and KODV treated with 27 μg/ml of either TEA or EGCg induced apoptotic DNA fragmentation, producing terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling (TUNEL)‐positive cells, while the normal PBLs treated with the same concentration of TEA or EGCg produced a negligibly small number of TUNEL‐positive cells, in which apoptotic DNA fragmentation was not detectable. Expression of HTLV‐I pX mRNA was suppressed more than 90% in ATL PBLs by treatment with 3–27 μg/ml of either TEA or EGCg, while expression of β‐actin mRNA was much less suppressed by treatment with the same concentration of TEA or EGCg. These results indicate that TEA and EGCg inhibit growth of ATL PBLs, as well as HTLV‐I‐infected T‐cells, by suppressing HTLV‐I pX gene expression and inducing apoptotic cell death