Tumor suppression by resistant maltodextrin, Fibersol-2.

Resistant maltodextrin Fibersol-2 is a soluble and fermentable dietary fiber that is Generally Recognized As Safe (GRAS) in the United States. We tested whether Fibersol-2 contains anti-tumor activity. Human colorectal cancer cell line, HCT116, and its isogenic cells were treated with FIbersol-2. Tumor growth and tumorigenesis were studied in vitro and in vivo. Apoptotic pathway and generation of reactive oxygen species (ROS) were investigated. We discovered that Fibersol-2 significantly inhibits tumor growth of HCT116 cells by inducing apoptosis. Fibersol-2 strongly induces mitochondrial ROS and Bax-dependent cleavage of caspase 3 and 9, which is shown by isogenic HCT116 variants. Fibersol-2 induces phosphorylation of Akt, mTOR in parental HCT116 cells, but not in HCT116 deficient for Bax or p53. It prevents growth of tumor xenograft without any apparent signs of toxicity in vivo. These results identify Fibersol-2 as a mechanism-based dietary supplement agent that could prevent colorectal cancer development.

Historical control data on developmental toxicity studies in rodents.

Historical control data on rodent developmental toxicity studies, performed between 1994 and 2010, were obtained from 19 laboratories in Japan, including 10 pharmaceutical and chemical companies and nine contract research organizations. Rats, mice, and hamsters were used for developmental toxicity studies. Data included maternal reproductive findings at terminal cesarean sections and fetal findings including the spontaneous incidences of external, visceral, and skeletal anomalies. No noticeable differences were observed in maternal reproductive data between laboratories. Inter-laboratory variations in the incidences of fetuses with anomalies appeared to be due to differences in the selection of observation parameters, observation criteria, classification of the findings, and terminology of fetal alterations. Historical control data are useful for the appropriate interpretation of experimental results and evaluation of the effects of chemical on reproductive and developmental toxicities.

The value of juvenile animal studies: a Japanese industry perspective.

Pharmaceuticals have been used on adults and children; however, they were previously investigated only by adult human clinical studies and adult animal nonclinical studies. The US FDA finalized the guidance of juvenile animal toxicity studies in 2006, and EMEA was finalized in 2008. At that point, juvenile animal toxicity studies were encouraged to investigate the safety of the pediatric population. In Japan, the awareness of the development of pediatric drugs is increasing, and many scientific meetings about juvenile animal studies are being held. A Japanese guideline for juvenile animal toxicity studies has been long awaited by many Japanese pharmaceutical companies because concrete directionality has not been available in Japan thus far. The Ministry of Health, Labour, and Welfare started to prepare the guideline for nonclinical safety studies in juvenile animals since October 2010. After completion of the Japanese guideline, guidelines would exist in the three regions: Japan, US, and Europe. Then, global development of pediatric pharmaceuticals would be accelerated effectively.

Testicular toxicity induced by a triple neurokinin receptor antagonist in male dogs.

Mechanism mediating the testicular toxicity induced by CS-003, a triple neurokinin receptor antagonist, was investigated in male dogs. Daily CS-003 administrations showed testicular toxicity, such as a decrease in the sperm number, motility and prostate weight; and an increase in sperm abnormality, accompanying histopathological changes in the testis, epididymis and prostate. A single CS-003 administration suppressed plasma testosterone and LH levels in intact and castrated males. The suppressed LH release was restored by GnRH agonist injection, suggesting that pituitary sensitivity to GnRH is not impaired by CS-003. Treatment with SB223412, a neurokinin 3 receptor antagonist, caused a similar effect to CS-003, such as toxicity in the testis, prostate and epididymis and decreased plasma level of LH and testosterone. In conclusion, CS-003-induced testicular toxicity is caused by the inhibition of neurokinin B/neurokinin 3 receptor signaling probably at the hypothalamic level in male dogs.

Genomewide association analysis in diverse inbred mice: power and population structure.

The discovery of quantitative trait loci (QTL) in model organisms has relied heavily on the ability to perform controlled breeding to generate genotypic and phenotypic diversity. Recently, we and others have demonstrated the use of an existing set of diverse inbred mice (referred to here as the mouse diversity panel, MDP) as a QTL mapping population. The use of the MDP population has many advantages relative to traditional F(2) mapping populations, including increased phenotypic diversity, a higher recombination frequency, and the ability to collect genotype and phenotype data in community databases. However, these methods are complicated by population structure inherent in the MDP and the lack of an analytical framework to assess statistical power. To address these issues, we measured gene expression levels in hypothalamus across the MDP. We then mapped these phenotypes as quantitative traits with our association algorithm, resulting in a large set of expression QTL (eQTL). We utilized these eQTL, and specifically cis-eQTL, to develop a novel nonparametric method for association analysis in structured populations like the MDP. These eQTL data confirmed that the MDP is a suitable mapping population for QTL discovery and that eQTL results can serve as a gold standard for relative measures of statistical power.