Fitoterapia

Hosimosines A-E, structurally diverse cytisine derivatives from the seeds of Ormosia hosiei Hemsl. et Wils

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1-4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6-18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1-4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells.

Kopetdaghinanes, pro-apoptotic hemiacetialic cyclomyrsinanes from Euphorbia kopetdaghi

Euphorbia kopetdaghi grows wild in the Northeast parts of Iran. Phytochemical study of its aerial parts led to the isolation of two undescribed cyclomyrsinol macrocyclic diterpenes with a new tetrahydrofuran oxidation pattern containing a hemiacetal group named: kopetdaghinane A and B. The structure of the isolated compounds was elucidated by extensive spectroscopic methods. Cytotoxic activity of kopetdaghinane A was evaluated using standard MTT assay against MCF-7 breast cancer and OVCAR-3 ovary cells. HUVEC cells were used as a normal cell line for calculation of the selectivity index. The MTT showed cyclomyrsinol diterpene has a significant cytotoxic effect with good selectivity indexes against both cell lines but with more selectivity against MCF-7 cells. Apoptosis induction by cyclomyrsinol treatment was confirmed by annexin V-FITC/PI staining, and caspase-6 activation. Western blot analysis showed that the expression of Bcl-2 was noticeably decreased in response to kopetdaghinane A treatment, while the expression of Bax protein was increased. Moreover, the apoptotic effect of cyclomyrsinol was shown to be related to ROS production, and loss of mitochondrial membrane potential (ΔΨm). Taken together, these results showed that kopetdaghinane A inhibits the growth of MCF-7 breast cancer cells through the activation of the mitochondrial apoptotic pathway and may be considered as an investigational compound in breast cancer preclinical study.

α-Tomatine, a novel early-stage autophagy inhibitor, inhibits autophagy to enhance apoptosis via Beclin-1 in Skov3 cells

Targeting the autophagy process is considered to be a promising new strategy for drug treatment of ovarian cancer. α-Tomatine, a steroidal alkaloid extracted, is mainly isolated from leaves, roots and immature green tomatoes. α-Tomatine has biological activities such as anticancer, antioxidative and anti-inflammatory. The study aimed to explore the effects of α-tomatine on proliferation, apoptosis and autophagy and the underlying mechanisms in ovarian cancer Skov3 cells. After treatment with different concentrations of α-tomatine (0, 0.75, 1 and 1.5 μM) in Skov3 cells for 24 h, proliferation was determined by the CCK-8 assay, and apoptosis was detected by flow cytometric analysis. Autophagy in cells was determined by the number of fluorescent spots using confocal fluorescence microscopy after mRFP-GFP-LC3 transfection. The relationship between autophagy and apoptosis was proved by Beclin-1 overexpression. The protein expression levels were tested by western blotting. The results demonstrated that α-tomatine effectively repressed proliferation, exerted a proapoptotic effect and inhibited early-stage autophagy in Skov3 cells in a dose- and time-dependent manner. Additionally, Beclin-1 overexpression significantly suppressed α-tomatine-treated apoptosis in Skov3 cells, indicating that α-tomatine inhibits autophagy to induce apoptosis. We also found α-tomatine inhibited the protein expression levels of PI3K/Akt/mTOR signaling pathway. However, the autophagy inhibition of α-tomatine could be reversed obviously by Beclin-1 overexpression. Taken together, α-tomatine inhibited autophagy through Beclin-1. Our study suggests that α-tomatine, as a novel early-stage autophagy inhibitor, might be a potential drug for further treatment of ovarian cancer by inhibiting proliferation and promoting apoptosis.

Unraveling the active ingredients and molecular mechanisms of Buyi Xiaozheng decoction against ovarian cancer: An integrative approach combining UHPLC-QE-MS, network pharmacology, molecular docking, dynamics simulations, and experimental verification

Buyi Xiaozheng decoction (BYXZD) is widely used as an adjunct therapy for ovarian cancer (OC) chemotherapy, effectively inhibiting OC progression. However, its targets and mechanisms remain unclear. This study aimed to identify the active components and clarify the molecular mechanisms of BYXZD in OC treatment using an integrated approach combining UHPLC-QE-MS, network pharmacology, molecular docking, dynamics simulations, and experimental validation METHODS: UHPLC-QE-MS was employed to identify the main components of BYXZD. Targets of BYXZD were predicted using PharmMapper and Swiss target prediction, while OC-related targets were retrieved from GeneCards, OMIM, TTD, and CTD databases. The intersection of these targets was analyzed to identify potential therapeutic targets of BYXZD. An "herb-compound-target" network was constructed using Cytoscape, and protein-protein interactions (PPI) were analyzed via the string database. Functional enrichment analysis (GO and KEGG) was performed using the DAVID database. Molecular docking and dynamics simulations were conducted to evaluate the binding affinity and stability of core components with key targets. In vitro experiments were performed to validate the effects of BYXZD on OC cell migration, invasion, and signaling pathways RESULTS: The main components of BYXZD were identified as atractylenolide II, lithospermic acid, baicalein, and scutellarein. PPI, GO, and KEGG analyses identified AKT1, MAPK1, MAPK3, and PIK3CA as key targets, with the PI3K/AKT and MAPK pathways serving as the primary mechanisms. Molecular docking showed high binding affinity between core components and key targets, and molecular dynamics simulations indicated stable interactions between baicalein/lithospermic acid and MAPK1/PI3CA. In vitro experiments confirmed that BYXZD dose-dependently inhibited OC cell migration and invasion by regulating the PI3K/AKT and MAPK pathways CONCLUSIONS: The integrative approach revealed that BYXZD exerts therapeutic effects on OC through multiple components, multiple targets, and multiple pathways, highlighting its potential as a valuable adjuvant therapy for OC.

Curcumae Rhizoma and Sparganii Rhizoma component compatibility exerts an inhibitory effect on endometrial cancer by regulating HDAC8/PTEN/Akt axis

Sparganii Rhizoma (SR) and Curcumae Rhizoma (CR) are Chinese botanical medicines with potential anti-tumor properties yet to be fully characterized. This study aimed to clarify the influence of total flavonoids of SR (FSR), essential oil from CR (OCR), and the combination of FSR and OCR (FO) on endometrial cancer and to determine the possible molecular mechanism MATERIALS AND METHODS: LC-MS/MS and GC-MS were employed for the chemical characterization of FSR and OCR, respectively. The viability, apoptosis, migration, and invasion in Ishikawa cells were assessed by cell counting kit-8 (CCK8), flow cytometry, scratch assay, and Transwell assay, respectively. In addition, Western blot and RT-qPCR experiments were used to verify the mechanism of action. In the mouse xenograft model experiment, we utilized immunofluorescence staining to detect tumor proliferation-related indexes to evaluate tumor growth RESULTS: In vitro, FO inhibited the proliferation, migration and invasion of Ishikawa cells in a dose- and time-dependent manner, but facilitated their apoptosis as compared to FSR or OCR. The above phenomena were accompanied by an increase in PTEN expression as well as a decline in HDAC8 expression and Akt phosphorylation. Silencing PTEN reversed FO-induced protein changes in PCNA, Bax, and Bcl-2. In vivo, FO suppressed tumor growth even greater than medroxyprogesterone acetate (MPA) CONCLUSIONS AND IMPLICATIONS: Taken together, our study demonstrates for the first time that FO could curb the malignant biological behavior of EC cells in vivo and in vitro, and mechanistically discloses that this effect may be achieved by modulating the HDAC8/PTEN/Akt signaling axis.

Synthesis, biological evaluation and mechanism studies of C-3 substituted nitrogenous heterocyclic 23-Hydroxybetulinic acid derivatives as anticancer agents

A series of novel nitrogenous heterocycle substituted 23-Hydroxybetulinic acid (23-HBA) derivatives with amide linkages at the C-3 position were designed, synthesized and evaluated for their antitumor activities. The biological screening results showed that most of the derivatives exhibited more potent antiproliferative activities than 23-HBA. In particular compound II-9 exhibited the most potent activities with IC

Terpenoids mediated cell apoptotsis in cervical cancer: Mechanisms, advances and prospects

Cervical cancer remains one of the most common malignancies among women globally, causing hundreds of thousands of deaths annually. Despite widespread vaccination and screening programs, the incidence of cervical cancer remains high in developing countries. This review aims to systematically summarize the existing terpenoids effective in preventing cervical cancer, elucidate their potential mechanisms in the prophylaxis and treatment of cervical cancer, and assess the limitations of current studies. Studies have shown that terpenoids can decrease the incidence of cervical cancer and promote apoptosis of cancer cells through various signaling pathways, including the PI3K/AKT pathway, the endoplasmic reticulum stress (ERS) pathway, and the mitochondria- and caspase-dependent cell death pathways. Furthermore, some terpenoids have been found to enhance the sensitivity to chemotherapy drugs, thus improving patients' quality of life. Terpenoids play a significant role in inhibiting the progression of cervical cancer. However, due to their diversity and complex mechanisms of action, further research is necessary to investigate their specific targets and bioactivities to advance their clinical trials and applications.