Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity

Importance of “meal first” strategy and effective situations of supplement use in elite athletes: Japan high performance sport center position stand

The “meal first” strategy is traditionally recommended for athletes' conditioning. However, the importance of the “meal first” principle has not been detailly well documented in athletes' lives. Supplement use has recently become a common part of athletes' diets, but unmonitored supplement use can cause negative consequences, such as anti-doping violations and health issues. Therefore, this review summarizes how the “meal first” strategy and planned supplement use are important for enhancing athletes’ health and performance. We believe that the “meal first” strategy is beneficial in terms of the following aspects: (1) consumption of multi-nutrients and other functional components simultaneously; (2) positive effects on psychological well-being; (3) contribution to athletes' health by way of mastication; and (4) less risk for anti-doping violations. Before supplement use, we recommend that athletes first verify their basic factors (e.g., diet, training, and sleep), given that the benefits of supplements are examined and demonstrated with the control of those factors. Otherwise, athletes cannot obtain maximal benefits from the supplements. In contrast, there are situations in which supplements in athletes' lives can be advantageous, such as (1) nutrient deficiency due to ongoing dietary characteristics; (2) interruption of meals due to disease; (3) inaccessibility of quality food during athletic travel; (4) difficulty preparing food due to societal restrictions associated with disasters or infection outbreaks; (5) having a meal before, during, or after exercise is difficult; and (6) achieving targeted intake of performance-enhancing ingredients is not practical. In summary, we emphasize that the “meal first” strategy is recommended for athletes' conditioning, but there are several contexts when supplement use can be more useful in athletes' lives

Clinical trials for drug approval : a pilot study of the view of doctors at Tokushima University Hospital

The development of new and useful pharmaceutical drugs is essential in order to improve the quality of drug therapeutics. Clinical trials play a central role in drug development. Over time, the clinical trial infrastructure has improved and is now integrating the contribution of clinical research coordinators (CRC). Nevertheless, the attitude of doctors towards clinical trials still favors conventional/historical methodologies. In the present study, we explored the view of doctors towards clinical trials for drug development, in order to improve communication among participants, sponsors, and investigators. A questionnaire was designed for this pilot study. The questionnaire included general attitudes, difficult points, the benefit of doctors in participating as investigators, special attention requirements, and the expected role of CRC in clinical trials for drug approval. In addition, the appropriate use of the outpatient clinic was examined. The questionnaire was provided to doctors in each department of Tokushima University Hospital in 2000 and 2004. Because of the small number of subjects included in this pilot study, no statistical analysis is presented. A total of 89 (81%) and62 (56%) doctors among 110 responded to the survey in 2000 and 2004, respectively. Inquiries about the familiarity of the physicians with clinical trials for drug approval revealed that 84% in 2000 and 66% in 2004 were aware of such trials. The attitude towards participating as investigators in the clinical trials was favorable, with a response of 66% in 2000 and 58% in 2004. Patients’ refusal and the informed consent process were considered difficult areas by many doctors. Expected roles of CRC included activities based on the nurse’s specialty. Although many doctors agreed to take care of the study participants separately from the clinical practice, they lacked the time to do so. In spite of the doctors’ workload reduction by introduction of the CRC concept, their views regarding clinical trials for drug approval remain conventional. Further refinement in the support process by CRC should be considered in our hospital, and the views of the doctors should be investigated in a larger study, in order to promote clinical trials for drug approval in Japan

Rhenium-Catalyzed Regioselective Synthesis of Multisubstituted Pyridines from β-Enamino Ketones and Alkynes via C–C Bond Cleavage

A new method is described for the regioselective synthesis of multisubstituted pyridine derivatives. Treatment of <i>N</i>-acetyl β-enamino ketones with alkynes in the presence of the rhenium catalyst, Re₂(CO)₁₀, gives multisubstituted pyridines regioselectively. In this reaction, the <i>N</i>-acetyl moieties are important for the selective formation of the multisubstituted pyridines. This reaction proceeds via insertion of alkynes into a carbon–carbon single bond of β-enamino ketones, intramolecular nucleophilic cyclization, and elimination of acetic acid

Mast cell chymase expression and mast cell phenotypes in human rejected kidneys

Mast cell chymase expression and mast cell phenotypes in human rejected kidneys.BackgroundMast cells (MCs) are known to participate in various types of chronic disease, but their role in chronic renal rejection is poorly understood. Recently, distinct phenotypes of MCs have been described in humans by the demonstration of one protease, chymase. Hence, we questioned whether chymase in MCs could play a role in the pathogenesis of renal rejection in humans.MethodsWe investigated MC chymase expression and MC phenotypes, using immunohistochemical single- and double-staining techniques, in nephrectomy (N = 13) and biopsy (N = 8) specimens of human rejected kidneys. Tissue chymase levels were determined by enzymatic assay for chymase activity. We also examined the association between MC chymase expression and the degree of interstitial fibrosis in these renal allografts.ResultsBased on chymase positivity, rejected kidneys were divided into two groups, a chymase-negative [Chy(-)] group and a chymase-positive [Chy(+)] group. Quantitative analysis showed that the number of chymase-positive MCs and tissue chymase levels were significantly higher in the Chy(+) group than in the Chy(-) group. Furthermore, the interstitial fibrotic area in the Chy(+) group was significantly larger than that in the Chy(-) group. Immunodouble staining analysis also demonstrated that a new MC phenotype, positive for chymase but negative for tryptase, was present in the human rejected kidney.ConclusionsThese results show that increased expression of chymase in MCs is related to the severity of interstitial fibrosis in human rejected kidneys

Epigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood

The nutritional environment to which animals are exposed in early life can lead to epigenetic changes in the genome that influence the risk of obesity in later life. Here, we demonstrate that the fibroblast growth factor-21 gene (Fgf21) is subject to peroxisome proliferator-activated receptor (PPAR) α–dependent DNA demethylation in the liver during the postnatal period. Reductions in Fgf21 methylation can be enhanced via pharmacologic activation of PPARα during the suckling period. We also reveal that the DNA methylation status of Fgf21, once established in early life, is relatively stable and persists into adulthood. Reduced DNA methylation is associated with enhanced induction of hepatic FGF21 expression after PPARα activation, which may partly explain the attenuation of diet-induced obesity in adulthood. We propose that Fgf21 methylation represents a form of epigenetic memory that persists into adulthood, and it may have a role in the developmental programming of obesity