Frizzled 7 modulates goblet and Paneth cell fate, and maintains homeostasis in mouse intestine.

Intestinal homeostasis depends on interactions between the intestinal epithelium, the immune system and the microbiota. Because of these complicated connections, there are many problems that need to be solved. Current research has indicated that genes targeted by Wnt signaling are responsible for controlling intestinal stem cell fate and for modulating intestinal homeostasis. Our data show that loss of frizzled 7 (Fzd7), an important element in Wnt signaling, interrupts the differentiation of mouse intestinal stem cells into absorptive progenitors instead of secretory progenitors (precursors of goblet and Paneth cells). The alteration in canonical Wnt and Notch signaling pathways interrupts epithelial homeostasis, resulting in a decrease in physical protection in the intestine. Several phenotypes in our Fzd7-deleted model were similar to the features of enterocolitis, such as shortened intestines, decreased numbers of goblet cells and Paneth cells, and severe inflammation. Additionally, loss of Fzd7 exacerbated the defects in a chemical-induced colitis model and could initiate tumorigenesis. These findings may provide important information for the discovery of efficient therapeutic methods to treat enterocolitis and related cancers in the intestines.

Host immune response to anti-cancer camptothecin conjugated cyclodextrin-based polymers.

INTRODUCTION: Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics. METHODS: In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems. RESULTS: In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only. CONCLUSIONS: Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.

Developmental exposures to ethanol or dimethylsulfoxide at low concentrations alter locomotor activity in larval zebrafish: implications for behavioral toxicity bioassays.

Ethanol and dimethylsulfoxide (DMSO) are commonly used as carrier solvents for lipophilic chemicals in aquatic toxicity bioassays. However, very little information has been reported on the behavioral effects of these solvents. In this study, we examined the effects of ethanol and DMSO on development and locomotor activity by a zebrafish embryo-larval bioassay. The zebrafish were exposed to different concentrations (control, 0.01, 0.1, and 1%) of ethanol or DMSO from blastula stage to 144 hour-post-fertilization (hpf). Hatchability, survival, and abnormalities were monitored every 12h, and locomotor activity of the larvae was analyzed at 144 hpf. Hatchability was not affected by the ethanol or DMSO treatments. No effect on survival was observed except the 1% ethanol group suffered 89% mortality during 108-120 hpf. No developmental defects were observed in any of the solvents at the 0.01 and 0.1% concentrations, but significantly higher deformity rates occurred with 1% ethanol and DMSO groups. Hyperactivity and less tortuous swimming paths were observed in all ethanol and DMSO concentrations. Based on this study, we suggest that data of behavioral toxicity bioassays using ethanol or DMSO as carrier solvents should be interpreted cautiously, because the solvents at low concentrations could alter locomotor activity of larval zebrafish without causing any observable developmental defects.