Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Banana resistant starch and its effects on constipation model mice.

Banana resistant starch (BRS) was extracted to investigate the structural properties of BRS, its effects on the gastrointestinal transit, and dejecta of normal and experimentally constipated mice. The mouse constipation model was induced by diphenoxylate administration. The BRS administered mice were divided into three groups and gavaged with 1.0, 2.0, or 4.0 g/kg body weight BRS per day. The small intestinal movement, time of the first black dejecta, dejecta granules, weight and their moisture content, body weight, and food intake of mice were studied. Results showed that the BRS particles were oval and spindly and some light cracks and pits were in the surface. The degree of crystallinity of BRS was 23.13%; the main diffraction peaks were at 2(θ) 15.14, 17.38, 20.08, and 22.51. The degree of polymerization of BRS was 81.16 and the number-average molecular weight was 13147.92 Da, as determined by the reducing terminal method. In animal experiments, BRS at the dose of 4.0 g/kg body weight per day was able to increase the gastrointestinal propulsive rate, and BRS at the doses of 2.0 and 4.0 g/kg body weight per day was found to shorten the start time of defecation by observing the first black dejecta exhaust. However, there were no influences of BRS on the dejecta moisture content, the dejecta granules and their weight, body weight, or daily food intake in mice. BRS was effective in accelerating the movement of the small intestine and in shortening the start time of defecation, but did not impact body weight and food intake. Therefore, BRS had the potential to be useful for improving intestinal motility during constipation.

Structure analysis and laxative effects of oligosaccharides isolated from bananas.

Banana oligosaccharides (BOS) were extracted with water, and then separated and purified using column chromatography. Gel penetration chromatography was used to determine the molecular weights. Thin layer chromatogram and capillary electrophoresis were employed to analyze the monosaccharide composition. The indican bond and structure of the BOS molecule were determined using Fourier transform infrared spectroscopy and nuclear magnetic resonance. Results showed that BOS were probably composed of eight ß-D-pyran glucose units linked with 1→6 indican bonds. The laxative effects of BOS were investigated in mice using the method described in "Handbook of Technical Standards for Testing and Assessment of Health Food in China." The length of the small intestine over which a carbon suspension solution advanced in mice treated with low-, middle-, and high-dose BOS was significantly greater than that in the model group, suggesting that BOS are effective in accelerating the movement of the small intestine.