Mining Therapeutic Efficacy from Treasure Chest of Biodiversity and Chemodiversity: Pharmacophylogeny of Ranunculales Medicinal Plants.

Ranunculales, comprising of 7 families that are rich in medicinal species frequently utilized by traditional medicine and ethnomedicine, represents a treasure chest of biodiversity and chemodiversity. The phylogenetically related species often have similar chemical profile, which makes them often possess similar therapeutic spectrum. This has been validated by both ethnomedicinal experiences and pharmacological investigations. This paper summarizes molecular phylogeny, chemical constituents, and therapeutic applications of Ranunculales, i.e., a pharmacophylogeny study of this representative medicinal order. The phytochemistry/metabolome, ethnomedicine and bioactivity/pharmacology data are incorporated within the phylogenetic framework of Ranunculales. The most studied compounds of this order include benzylisoquinoline alkaloid, flavonoid, terpenoid, saponin and lignan, etc. Bisbenzylisoquinoline alkaloids are especially abundant in Berberidaceae and Menispermaceae. The most frequent ethnomedicinal uses are arthritis, heat-clearing and detoxification, carbuncle-abscess and sore-toxin. The most studied bioactivities are anticancer/cytotoxic, antimicrobial, and anti-inflammatory activities, etc. The pharmacophylogeny analysis, integrated with both traditional and modern medicinal uses, agrees with the molecular phylogeny based on chloroplast and nuclear DNA sequences, in which Ranunculales is divided into Ranunculaceae, Berberidaceae, Menispermaceae, Lardizabalaceae, Circaeasteraceae, Papaveraceae, and Eupteleaceae families. Chemical constituents and therapeutic efficacy of each taxonomic group are reviewed and the underlying connection between phylogeny, chemodiversity and clinical uses is revealed, which facilitate the conservation and sustainable utilization of Ranunculales pharmaceutical resources, as well as developing novel plant-based pharmacotherapy.

Novel cycloartane triterpenoid from Cimicifuga foetida (Sheng ma) induces mitochondrial apoptosis via inhibiting Raf/MEK/ERK pathway and Akt phosphorylation in human breast carcinoma MCF-7 cells.

BACKGROUND: Cycloartane triterpenoids exhibited anticancer effects. This study aims to identify any potential novel anticancer cycloartane triterpenoids from Cimicifuga foetida L. rhizome (Sheng ma) and the mode of actions. METHODS: Cycloartane triterpenoids were isolated from the C. foetida rhizome by a series of column chromatography and identified by IR, MS and NMR. Their anticancer effects on several human cancer cell lines, MCF-7, HepG2, HepG2/ADM, HeLa, and PC3, and normal human mammary epithelial cells MCF10A were investigated by colony formation and MTT assays. Morphological analysis of apoptosis induction was performed by acridine orange/ethidium bromide dual-staining and Hoechst 33258 nuclear staining. The cell-cycle profile and annexin V staining were evaluated by flow cytometry. Apoptosis were investigated by measuring changes in mitochondrial membrane potential and analyzing expression of cell cycle- and apoptosis-related proteins in MCF-7 cells by Western blotting. RESULTS: A novel cycloartane triterpenoid, 25-O-acetyl-7,8-didehydrocimigenol-3-O-ß-d-(2-acetyl)xylopyranoside (ADHC-AXpn), together with the known 7,8-didehydrocimigenol-3-O-ß-d-xylopyranoside (DHC-Xpn) were isolated. MCF-7 growth was significantly inhibited by ADHC-AXpn in a dose- and time-dependent manner (IC50: 27.81 µM at 48 h; P = 0.004 vs. control at 25 µM for 48 h treatment), and ADHC-AXpn was selectively cytotoxic for cancerous cells (MCF-7, HepG2/ADM, HepG2 and HELA cells) based on its higher IC50 values for normal cells MCF10A (IC50: 78.63 µM at 48 h) than for tumor cells. In MCF-7 cells, ADHC-AXpn induced G2/M cell cycle arrest by mediating cyclin-B1, and CDK1 and its phosphorylation; and induced apoptosis through the mitochondrial-mediated apoptotic pathway, with inhibition of Akt activation. As ADHC-AXpn suppressed phosphorylation of ERK1/2, Raf and Akt proteins in MCF-7 cells, its apoptotic effect might be associated with Raf/MEK/ERK signaling and Akt activation. CONCLUSIONS: ADHC-AXpn significantly suppressed the growth of MCF-7 cells, induced mitochondrial apoptosis and cell-cycle arrest, and inhibited Raf/MEK/ERK signaling pathway and Akt phosphorylation.

Minocycline inhibits ICAD degradation and the NF-κB activation induced by 6-OHDA in PC12 cells.

6-Hydroxydopamine (6-OHDA) is a neurotoxin that is commonly employed to induce lesions of the dopaminergic pathways to generating experimental models of Parkinson's disease (PD) in rodents. Antioxidant and anti-inflammatory therapy approaches have been the focus of attention in the treatment of neurodegenerative. PD and Alzheimer's diseases, and oxidative stress have been implicated in these diseases. In this study, we investigated the neuroprotective effects of minocycline and the signalling pathway that is possibly involved in a PC12 cell model of PD. The results indicated that 6-OHDA cytotoxicity was accompanied by an increment in lactate dehydrogenase (LDH) release, an increase in caspase-3 protein activity, an increase in ROS generation, MDA content and decrease in the SOD, CAT activities and cell viability. Moreover, treatment with 6-OHDA alone for 24h resulted in ICAD degradation, increased nuclear translocation of NF-κB, and increased p53 expression. However, pretreatment with minocycline (5, 10, 20 µM) for 24h significantly reduced LDH release, reduced caspase-3 protein production, reduced ROS production, MDA content and attenuated the decrease in SOD, CAT activities and cell viability. Additionally, minocycline (20 µM) markedly decreased the levels of cleaved ICAD protein, down-regulated p53 activity and inhibited the nuclear translocation of NF-κB. The neuroprotective effects of minocycline were attributable to its potent antioxidant activities, which prevented the nuclear translocation of NF-κB and the subsequent promotion of cell death. Therefore, the present study supports the notion that minocycline may be a promising neuroprotective agent for the treatment of Parkinson's disease.

Bioactive triterpenoids from Kadsura heteroclita.

A phytochemical study of Kadsura heteroclita led to the isolation of eight triterpenoids, including two new compounds, named kadheterilactone A (1) and kadheterilactone B (2), as well as six known compounds, longipedlactone H (3), longipedlactone A (4), longipedlactone F (5), kadsuranic acid A (6), nigranoic acid (7), and schisandronic acid (8). Their structures were elucidated on the basis of spectroscopic methods, including 2D NMR techniques. The cytotoxic activities of 1-8 were tested against several tumor cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide (MTT) assay in vitro. As a result, 4 and 5 turned out to be significantly cytotoxic against Hep-G2 and Bel-7402 tumor cell lines. All compounds were also tested for inhibition on HIV-1 protease (PR) and reverse transcriptase (RT). Compounds 6 and 7 showed strong inhibition on HIV-1 PR, while 8 exhibited moderate activity, others were only weakly active. No compounds were active against HIV-1 RT.

Cytotoxic polyprenylated xanthones from the resin of Garcinia hanburyi.

Thirteen xanthones (1-13) were isolated from the resin of Garcinia hanburyi. Among them, two new compounds (namely gaudichaudic acid, and isogambogenic acid, 1, 2), and one new natural product (deoxygaudichaudione A, 3) were identified on the basis of extensive spectral evidence including detailed 2D NMR data. Ten of these xanthones were tested for their cytotoxicities against human leukemia K562 (K562/S) and doxorubicin-resistant K562 (K562/R) cell lines, and showed similar inhibitory effects on both cell lines, suggesting that this group of polyprenylated xanthones might not be multidrug resistance (MDR) substrates.

New lignans and cytotoxic constituents from Schisandra propinqua.

The CHCl (3) extract from the stems of Schisandra propinqua (Wall.) Baill exhibited significant cytotoxic activity against cancer cell lines. Subsequent fractionation procedures led to the isolation of four new dibenzocyclooctadiene lignans, propinquanins A - D, along with two known lignans, schisantherin I and heteroclitin A, and three known triterpenoids, isoschisandrolic acid, schisandrolic acid and schisandronic acid. Their structures, including absolute stereochemistry, were elucidated through analyses of NMR data and CD spectra. The isolated compounds were tested for their cytotoxic activity in several tumor cell lines with the MTT assay. Propinquanin B ( 2) was significantly cytotoxic (IC (50) values < 10 microM) in HL-60 and Hep-G2 tumor cell lines. Cell cycle analysis and Hoechst 33 258 staining assay suggested that one possible mechanism of cytotoxic activity by 2 might be related to the induction of apoptosis.