Synthesis of 4- epi-Parviflorons A, C, and E: Structure-Activity Relationship Study of Antiproliferative Abietane Derivatives.

The first syntheses of 4- epi-parviflorons A, C, and E (4- epi-1-3) were achieved in 12-13 steps from commercially available (-)-abietic acid (5). All synthesized compounds, including intermediates and derivatives, were evaluated for antiproliferative activity against five human tumor cell lines. A structure-activity relationship study revealed no significant difference between Pf E and 4- epi-Pf E, the importance of two oxygen functional groups at C-11 and C-12 for antiproliferative activity, as well as a combination of carbomethoxy at C-4 and a benzoyl ester with electron-drawing group at C-12 or hydroxymethyl at C-4 and an appropriate oxidation state of ring-B/C for triple-negative breast cancer cell selectivity.

Comfortable Seatbelts for Pregnant Women with Twins in Japan: A Cross-Sectional Observational Study on Seatbelt Usage.

Optimal seatbelt practices for pregnant women with twins at different gestational ages remain uncertain. To offer recommendations for a comfortable seatbelt system, this cross-sectional observational study explored seatbelt usage and driving habits among women with twins across various pregnancy stages through an online survey that explored driving conditions and comfortable seatbelts at different stages of pregnancy. Women who drove daily before their pregnancy with twins decreased their driving frequency as the pregnancy progressed. Correct seatbelt usage was lower and no seatbelt usage was higher among pregnant women with twins than those with singleton pregnancies. They adapted their seatbelt-wearing techniques to minimise pressure on the chest in the first and third trimesters and the abdomen from the second trimester onwards. The comfortable seatbelts were those that could alleviate belt pressure, featuring waist belts to reduce pressure, wider belts to avoid localised pressure, and shoulder belts resembling a backpack type. When wearing a seatbelt, avoiding pressure on the thorax and abdomen is key for pregnant women with twins. This study suggests that the suitability of driving for pregnant women with twins in their last trimester and the reliability of seatbelts designed for such women should be further examined and validated.

Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists.

Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.