Dinoprost Tromethamine

Postmenopausal osteoporosis (PMOP) was caused by significant deviations in gut microbiota and metabolites. Gushudan (GSD), a small traditional Chinese medicine formula, exerted therapeutic effects including kidney-nourishing and bone-strengthening properties. The therapeutic mechanism of GSD in alleviating kidney-yang deficiency syndrome and secondary osteoporosis was systematically investigated through metabolomics and network pharmacology. However, the mechanisms and impact on gut microbiota through which GSD mitigated PMOP remained to be elucidated. In this study, fecal metabolomics was integrated with gut microbiota analysis to comprehensively investigate modification in intestinal flora and metabolic profiles in PMOP rat models from the gut-bone axis framework. Therefore, the GC-MS-based method integrating non-targeted and targeted metabolomics was established to analyze fecal metabolites. The comprehensive analysis of gut microbial communities was performed using 16S rRNA on fecal samples. In the result, 20 potential biomarkers were successfully identified in the non-targeted metabolomics analysis. Subsequently, 12 metabolites related to amino acid metabolism, energy metabolism and bile acid biosynthesis were quantitatively. Then, ten gut microorganisms with significant changes were discovered through 16S rRNA. Furthermore, alterations in fecal metabolites demonstrated a significant correlation with dysbiosis within the gut microorganisms such as [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas and Papillibacter. GSD effectively modulated abnormal levels of metabolites such as glycine, lactic acid, succinic acid, cholesterol and deoxycholic acid. Specifically, GSD improved the abundance of [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas. In conclusion, the gut-bone axis was validated as a novel framework, and gut microbiota modulation was further identified as a promising therapeutic target for the prevention of PMOP.

Exposure to individual phthalates disrupts ovarian function; however, the direct effects of phthalate mixture exposure on ovulation is unknown, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix; derived from women's urinary phthalate levels) disrupts the function of prostaglandins (PGs), which are vital mediators of ovulation. Additionally, cAMP supplementation was tested as a method to circumvent phthalate toxicity. Granulosa cells from women undergoing in vitro fertilization were acclimated in culture to regain responsiveness to human chorionic gonadotropin (hCG; clinical luteinizing hormone analogue). Granulosa cells were treated with or without hCG, with or without PHTmix (1-500 µg/ml; DMSO=vehicle control), and with or without 8-Br-cAMP (stable cAMP analogue) for 6-36 hr. Exposure to hCG+PHTmix decreased ovulatory PGE₂ and PGF_2α levels when compared to hCG. The mechanism by which the PHTmix decreased PG levels was via decreased synthesis (decreased PTGS2 and PTGES levels) and increased metabolism (increased AKR1C1, AKR1C3, and HPGD levels). Exposure to hCG+PHTmix also impaired PG function by altering levels of PG transporters (ABCC4 and SLCO2A1) and receptors (PTGER2, PTGER3, and PTGFR) when compared to hCG. Supplementation with cAMP in the hCG+PHTmix 500 µg/ml group restored PGE₂ and PGF_2α levels comparable to and beyond hCG control levels. These findings suggest that phthalates inhibit the ovulatory increase in PGs in human granulosa cells via decreased synthesis and increased metabolism. Restored PG levels with cAMP supplementation further establishes a mechanism of toxicity by providing demonstration of a potential cellular target of phthalate-induced ovulatory defects in women.