The effective compounds and mechanisms of Cang-Fu-Dao-Tan Formula in treating polycystic ovary syndrome based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments.

BACKGROUND: Polycystic ovary syndrome (PCOS), as a common endocrine disease in reproductive-age women, which is characterized by both reproductive and metabolic disorders. Cang-Fu-Dao-Tan Formula (CFDTF) is an effective and relatively safe treatment for PCOS. However, the underlying mechanism is poorly understood. PURPOSE: To explore the effective compounds and mechanisms of CFDTF in treating PCOS based on UPLC/Q-TOF-MS/MS, network pharmacology and molecular experiments. METHODS: The UPLC/Q-TOF-MS/MS and TCMSP, SwissTargetPrediction databases were used to identify the active ingredients of CFDTF. Then GeneCards, Disgenet, Drugbank databases were used to obtain the PCOS related targets. Based above, the Drug-component-target (D-C-T) network and protein-protein-interaction (PPI) network were built to analysis the key targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were performed to find the potential mechanisms. Finally, molecular docking analysis, molecular dynamics (MD) simulations and molecular experiments were used to confirm the interactions among the active compounds, targets and explore the potential mechanisms. RESULTS: A total of 20 compounds were identified by UPLC/Q-TOF-MS/MS, and 136 active compounds by TCMSP from CFDTF. After removing the duplicate results, there were 370 targets related to both CFDTF and PCOS, among which, MAPK3, AKT1, RELA, EGF, TP53 and MYC were proved to have high interactions with the components. The mechanisms of CFDTF against PCOS were related to PI3K-Akt, mTOR, MAPK signaling pathways, and the in vitro experiments proved that the CFDTF positively regulated the cell proliferation and inhibited the apoptosis levels in PCOS cell model. CONCLUSIONS: The combination of UPLC/Q-TOF-MS/MS, systematic network pharmacology and molecular experiments identified that the quercetin, hesperidin, and glycyrrhizin disaccharide are the TOP 3 effective compounds of CFDTF in treating PCOS and the potential mechanisms may involve in regulating proliferation and apoptosis of granulosa cells.

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

Synergistic Chemo-thermal Therapy of Cancer by DNA-Templated Silver Nanoclusters and Polydopamine Nanoparticles.

Herein, we develop a novel and effective combination nanoplatform for cancer theranostics. Folic acid (FA) is first modified on the photothermal agent of polydopamine (PDA), which possesses excellent near-infrared (NIR) absorbance and thermal conversion features. Temperature-sensitive silver nanoclusters (AgNCs) are then synthesized on the DNA template that also loads the anticancer drug doxorubicin (Dox). After accumulation in cancer cells, PDA generates cytotoxic heat upon excitation of NIR light for photothermal therapy. On the other hand, the temperature increment is able to destroy the template of AgNCs, leading to the fluorescence variation and controlled release of Dox for chemotherapy. The combined nanosystem exhibits outstanding fluorescence tracing, NIR photothermal transduction, as well as chemo drug delivery capabilities. Both in vitro and in vivo results demonstrate excellent tumor growth suppression phenomena and no apparent adverse effects. This research provides a powerful targeted nanoplatform for cancer theranostics, which may have great potential value for future clinical applications.