OBJECTIVES: To assess the efficacy and safety of Tiaozhou Ziyin (TZZY) recipe for treatment of premature ovarian insufficiency (POI) and explore the possible mechanisms. METHODS: We used bioinformatics analyses and network pharmacology to identify the main active ingredients in TZZY recipe and their core targets, which were verified by Western blotting. We tested the efficacy and safety of the recipe in 60 POI patients, who were randomized into control group (n=30) with Femoston treatment and TZZY group (n=30) with additional TZZY recipe treatment for 3 menstrual cycles. RESULTS: The core active ingredients of TZZY recipe included kaempferol, β-sitosterol, luteolin, and quercetin. The core targets included SRC, TP53, STAT3, PIK3CA, and MAPK3, which were involved in positive regulation of cell movement and protein phosphorylation, the cancer pathways and the PI3K-Akt signaling pathway. Molecular docking showed that the core active ingredients had good binding ability with the core targets. In female rat models of POI, TZZY recipe treatment significantly up-regulated ovarian expressions of p-PI3K and p-Akt proteins. In the clinical trial, treatment with Femoston and Femoston plus TZZY recipe both significantly increased E₂ levels and reduced FSH and LH levels and Kupperman scores of the patients, and the combined treatment produced significantly stronger effects. Both treatments increased the number of antral follicles of the patients, but the combined treatment also significantly increased the levels of AMH. CONCLUSIONS The therapeutic mechanism of TZZY recipe for POI involves multiple active ingredients, multiple therapeutic targets and multiple pathways, and activating the PI3K /Akt pathway is one of its main mechanisms of action, to improve ovarian reserve function, alleviate clinical symptoms, and enhance clinical efficacy in POI patients.
Female ; Primary Ovarian Insufficiency/drug therapy* ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Rats ; Molecular Docking Simulation ; Signal Transduction ; Sitosterols/therapeutic use* ; Kaempferols/therapeutic use*

A new γ-alkylated-γ-butyrolactone, named melongenolide A (1), along with nine known compounds were obtained from the roots of Solanum melongena, and their structures were identified as melongenolide A (1), (+)-syringaresinol (2), (+)-lyoniresinol (3), 5,5'-dimethoxy lariciresinol (4), (+)-(7R,8R)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7, 9-diol-7'-aldehyde (5), kaempferol-3-O-(2″,6″-di-O-p-trans-coumaroyl)-β-glucoside (6), arjunolic acid (7), vanillic acid (8), scoparone (9), and β-sitosterol (10). Compounds 2, 6, and 7 showed potent inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages, with IC50 values being 5.62 ± 0.86, 11.47 ± 0.98, and 27.75 ± 1.26 μmol·L(-1), respectively.
4-Butyrolactone ; analogs & derivatives ; isolation & purification ; Animals ; Furans ; isolation & purification ; pharmacology ; Inflammation ; drug therapy ; metabolism ; Inhibitory Concentration 50 ; Kaempferols ; isolation & purification ; pharmacology ; Lignans ; isolation & purification ; pharmacology ; Macrophages ; drug effects ; metabolism ; Mice ; Nitric Oxide ; metabolism ; Plant Extracts ; chemistry ; pharmacology ; therapeutic use ; Plant Roots ; chemistry ; RAW 264.7 Cells ; Solanum melongena ; chemistry ; Triterpenes ; isolation & purification ; pharmacology

AIM: The fruits of Lagenaria siceraria (Molina) Standl. (Cucurbitaceae), a commonly used vegetable, are reported to possess various medicinal properties. In previous studies, the fibrinolytic potential of an ethanolic extract of fruits of Lagenaria siceraria was investigated in comparison with kaempferol isolated from it. The aim of the present study was to explore its mechanistic antithrombotic potential and antiplatelet activity using a wide dose range in different in vitro and in vivo models, and to quantify the total phenolic, flavonoid, and kaempferol contents using a colorimetric method. METHOD: The antithrombotic potential was investigated using tail bleeding time in mice, a plasma recalcification assay, and pulmonary thromboembolism in mice. The antiplatelet activity was studied using an in vitro model to investigate IC50 value. RESULTS: A significant amount of total phenols, flavonoids, and kaempferol was quantified in L. siceraria ethanolic extract. An ethanolic extract of the fruits of L. siceraria showed a significant increase in tail bleeding time and plasma recalcification time, significant protection against ADP induced pulmonary thromboembolism in mice, and also inhibited the platelet aggregation induced by ADP in vitro. The study suggested that the fruits of L. siceraria exhibit significant antithrombotic potential due to inhibition of ADP-mediated platelet aggregation and the involvement of various non-cellular chemical mediators of blood. CONCLUSION This finding may be helpful in treating the serious consequences of the thrombus formed in blood vessels which include atherothrombotic diseases, such as myocardial or cerebral infarction. So, further investigation should be done for revealing exact mechanism of action behind these types of activities.
Adenosine Diphosphate ; Animals ; Calcium ; blood ; Cucurbitaceae ; chemistry ; Female ; Fibrinolytic Agents ; analysis ; pharmacology ; therapeutic use ; Fruit ; Goats ; Kaempferols ; analysis ; pharmacology ; therapeutic use ; Male ; Mice ; Phytotherapy ; Plant Extracts ; chemistry ; pharmacology ; therapeutic use ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; analysis ; pharmacology ; therapeutic use ; Polyphenols ; analysis ; pharmacology ; therapeutic use ; Pulmonary Embolism ; blood ; chemically induced ; drug therapy ; Rats, Wistar ; Thrombosis ; prevention & control

Thyroid carcinogenesis is accompanied by loss of thyroid-specific functions and refractory to radioiodine and thyroid stimulating hormone (TSH) suppression therapy. Redifferentiating agents have been shown to inhibit tumor growth and improve the response to conventional therapy. Polyphenol phytochemicals (PPs) in fruits and vegetables have been reported to inhibit cancer initiation, promotion, progression and induce redifferentiation in selected types. In this study we examined PPs induce redifferentiation in thyroid cancer cell lines. We investigated the effects of genistein, resveratrol, quercetin, kaempferol, and resorcinol on the F9 embryonal carcinoma cell differentiation model. The thyroid cancer cell lines, TPC-1, FTC-133, NPA, FRO, and ARO, displayed growth inhibition in response to genistein, resveratrol, quercetin. We further demonstrated that genistein decreased the dedifferention marker CD97 in NPA cells and resveratrol decreased CD97 in FTC-133, NPA, FRO cells and quercetin decreased CD97 in all cell lines. We observed increased expression of differentiation marker NIS in FTC-133 cells in response to genistein, and resveratrol but no change in NPA, FRO, ARO cells. Quercetin increased or induced NIS in FTC-133, NPA, FRO cells. These findings suggest that PPs may provide a useful therapeutic intervention in thyroid cancer redifferentiation therapy.
Antigens, CD/metabolism ; Antineoplastic Agents/*pharmacology/therapeutic use ; Carcinoma, Embryonal/*drug therapy/metabolism ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Flavonoids/*pharmacology/therapeutic use ; Gene Expression Regulation, Neoplastic ; Genistein/pharmacology/therapeutic use ; Humans ; Kaempferols/pharmacology/therapeutic use ; Models, Biological ; Phenols/*pharmacology/therapeutic use ; Quercetin/pharmacology/therapeutic use ; Resorcinols/pharmacology/therapeutic use ; Stilbenes/pharmacology/therapeutic use ; Symporters/metabolism ; Thyroid Neoplasms/*drug therapy/metabolism