Intense browsing by sika deer (Cervus nippon) drives the genetic differentiation of hairy nettle (Urtica thunbergiana) populations.

Many studies have inferred the way in which natural selection, genetic drift and gene flow shape the population genetic structures, but very few have quantified the population differentiation under spatially and temporally varying levels of selection pressure, population fluctuation and gene flow. In Nara Park (6.6 km2), central Japan, where several hundred sika deer (Cervus nippon) have been protected for more than 1,200 years, heavily- or moderately-haired nettle (Urtica thunbergiana) populations have evolved probably in response to intense deer browsing. Here, we analysed the genetic structure of two Nara Park populations and five surrounding populations using amplified fragment length polymorphism markers. A total of 546 marker loci were genotyped from 210 individuals. A Bayesian method estimated 5.5% of these loci to be outliers, which are putatively under natural selection. Neighbour-joining, principal coordinates and Bayesian clustering analyses using all-loci, non-outlier loci and outlier loci datasets showed that the Nara Park populations formed a cluster distinct from the surroundings. These results indicate the genome-wide differentiation of the Nara Park populations from the surroundings. Moreover, these imply the following: (1) gene flow is limited between these populations and thus genetic drift is a major factor causing the differentiation; and (2) natural selection imposed by intense deer browsing has contributed to some extent to the differentiation. In conclusion, sika deer seems to have counteracted genetic drift to drive the genetic differentiation of hairy nettles in Nara Park. This study suggests that a single herbivore species could lead to genetic differentiation among plant populations.

The Novel In Vitro Method to Calculate Tissue-to-Plasma Partition Coefficient in Humans for Predicting Pharmacokinetic Profiles by Physiologically-Based Pharmacokinetic Model With High Predictability.

Proper prediction of human pharmacokinetic (PK) profiles can accelerate the compound selection in drug discovery. Recently, we reported a robust bottom-up physiologically-based pharmacokinetic (PBPK) approach (J Pharm Sci. 2019 Aug; 108(8):2718-2727), which uses the in vivo rat distribution volume at the steady state (Vss) to determine human tissue-to-plasma partition coefficients (Kptissue). Here, we report on a bottom-up PBPK approach that can simulate the PK profile with both high-throughput and high-predictive accuracy only using in vitro data. In this study, as an alternative parameter of in vivo rat Vss which was used for the correction of human Kptissue, Vss, in vitro was obtained from protein binding data in rats, and the values of Vss, in vitro for 31 reference compounds showed good correlation with the observed rat Vss (R2 = 0.859). Next, rat and human PK profiles of reference compounds were predicted by the bottom-up PBPK approach using Kptissue corrected by rat Vss, in vitro. As a result, the absolute average fold errors for pharmacokinetic parameters were almost less than 2, showing that these PK profiles could be accurately predicted using in vitro data. This method enables the screening of promising compounds with good PK profiles in humans at an early stage of drug discovery.

Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice.

The study examined whether royal jelly (RJ) can prevent obesity and ameliorate hyperglycemia in type 2 diabetes. This study utilized obese/diabetic KK-Ay mice. RJ (10 mg/kg) was administered by oral gavage. Body weight, plasma glucose and insulin levels were measured. mRNA and protein levels were determined using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. Four weeks of RJ administration improved hyperglycemia and partially suppressed body weight gain, although the latter effect did not reach statistical significance. In addition, RJ administration did not improve insulin resistance. RJ administration suppressed the mRNA expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in the liver. Simultaneously, RJ administration induced adiponectin (AdipoQ) expression in abdominal fat, adiponectin receptor-1 (AdipoR1) expression in the liver and phosphorylated AMP-activated protein kinase (pAMPK) expression, which suppressed G6Pase levels in the livers of KK-Ay mice. pAMPK levels were also increased in skeletal muscle, but glucose transporter-4 (Glut4) translocation was not increased in the RJ supplementation group. The improvement in hyperglycemia due to long-term RJ administration may be because of the suppression of G6Pase expression through the upregulation of AdipoQ and AdipoR1 mRNA and pAMPK protein expressions.