Natural anti-neuroinflammatory inhibitors in vitro and in vivo from Aglaia odorata.

Fifty compounds including seven undescribed (1, 13, 18-20, 30, 31) and forty-three known (2-12, 14-17, 21-29, 32-50) ones were isolated from the extract of the twigs and leaves of Aglaia odorata with anti-neuroinflammatory activities. Their structures were determined by a combination of spectral analysis and calculated spectra (ECD and NMR). Among them, compounds 13-25 were found to possess tertiary amide bonds, with compounds 16, 17, and 19-21 existing detectable cis/trans mixtures in 1H NMR spectrum measured in CDCl3. Specifically, the analysis of the cis-trans isomerization equilibrium of tertiary amides in compounds 19-24 was conducted using NMR spectroscopy and quantum chemical calculations. Bioactivity evaluation showed that the cyclopenta[b]benzofuran derivatives (2-6, 8, 10, 12) could inhibit nitric oxide production at the nanomolar concentration (IC50 values ranging from 2 to 100 nM) in lipopolysaccharide-induced BV-2 cells, which were 413-20670 times greater than that of the positive drug (minocycline, IC50 = 41.34 µM). The cyclopenta[bc]benzopyran derivatives (13-16), diterpenoids (30-35), lignan (40), and flavonoids (45, 47, 49, 50) also demonstrated significant inhibitory activities with IC50 values ranging from 1.74 to 38.44 µM. Furthermore, the in vivo anti-neuroinflammatory effect of rocaglaol (12) was evaluated via immunofluorescence, qRT-PCR, and western blot assays in the LPS-treated mice model. The results showed that rocaglaol (12) attenuated the activation of microglia and decreased the mRNA expression of iNOS, TNF-α, IL-1ß, and IL-6 in the cortex and hippocampus of mice. The mechanistic study suggested that rocaglaol might inhibit the activation of the NF-κB signaling pathway to relieve the neuroinflammatory response.

Isolation and synthesis of rocaglaol derivatives by inhibiting Wnt/ß-catenin and MAPK signaling pathways against colorectal cancer.

Eight rocaglaol derivatives with good cytotoxic activity (IC50: 0.013 âˆ¼ 5.82 µM) were isolated from Aglaia odorata. Then, a series of novel derivatives with modifications on C3 of rocaglaol were designed, synthesized, and screened for their antitumor activities against three tumor cell lines (HEL, MDA-MB-231, and HCT116). A total of 44 derivatives exhibited significant cytotoxic activity with IC50 values lower than 1 µM. In particular, four derivatives (14, 20, 22j, and 22r) exhibited the best cytotoxic activity against HCT116 cells, with an IC50 value of 70 nM. Compound 22r with relatively low toxicity against normal cells and the best cytotoxic activity against HCT116 cells was selected for further study. Subsequent cellular mechanism studies showed that compound 22r induced apoptosis and G1 cell cycle arrest in HCT116 cells. Moreover, compound 22r inhibited both the Wnt/ß-catenin and MAPK signaling pathways via key proteins, such as the phosphorylation of p38 and JNK, GSK-3ß, Axin-2, etc. Therefore, our present results suggest that compound 22r is a potential candidate for developing novel anti-colorectal cancer agents in the future.

Natural products as drugs and tools for influencing core processes of eukaryotic mRNA translation.

Eukaryotic protein synthesis is the highly conserved, complex mechanism of translating genetic information into proteins. Although this process is essential for cellular homoeostasis, dysregulations are associated with cellular malfunctions and diseases including cancer and diabetes. In the challenging and ongoing search for adequate treatment possibilities, natural products represent excellent research tools and drug leads for new interactions with the translational machinery and for influencing mRNA translation. In this review, bacterial-, marine- and plant-derived natural compounds that interact with different steps of mRNA translation, comprising ribosomal assembly, translation initiation and elongation, are highlighted. Thereby, the exact binding and interacting partners are unveiled in order to accurately understand the mode of action of each natural product. The pharmacological relevance of these compounds is furthermore assessed by evaluating the observed biological activities in the light of translational inhibition and by enlightening potential obstacles and undesired side-effects, e.g. in clinical trials. As many of the natural products presented here possess the potential to serve as drug leads for synthetic derivatives, structural motifs, which are indispensable for both mode of action and biological activities, are discussed. Evaluating the natural products emphasises the strong diversity of their points of attack. Especially the fact that selected binding partners can be set in direct relation to different diseases emphasises the indispensability of natural products in the field of drug development. Discovery of new, unique and unusual interacting partners again renders them promising tools for future research in the field of eukaryotic mRNA translation.

Discovery and synthesis of rocaglaol derivatives inducing apoptosis in HCT116 cells via suppression of MAPK signaling pathway.

Six rocaglaol derivatives were isolated from Dysoxylum gotadhora, and those compounds showed good cytotoxic activity with IC50 values ranging from 10 to 350 ng/mL against five different cancer cells. Obviously, further total synthesis of rocaglaol derivatives for medical chemistry study is of great significance. Then, twenty six rocaglaol derivatives including 25 new compounds were designed, synthesized, and evaluated for their cytotoxic activities against three human cancer cell lines: human colon cancer cells (HCT116), colorectal cancer stem cells (P6C), and human red leukocyte leukemia cells (HEL), using MTT assay. Most of derivatives showed good cytotoxic activities, with the lowest IC50 being 3.2 nM for HEL cells, which was 169 times stronger than that of the positive control (doxorubicin). Further mechanism study indicated that 11k could significantly suppress MAPK pathway in HCT116 cells, which may responsible for induction of apoptosis and cell cycle arrest.

Antiproliferative effect and mechanism of rocaglaol on HepG2 cells / 中草药

Objective: To study the effect of rocaglaol from Aglaia odorata on HepG2 proliferation and to explore the potential anti-tumor mechanism. Methods: The MTT, colony formation, EdU incorporation, and CFDA-SE assays were used to determine the anti-proliferative activity of rocaglaol in HepG2 cells. Apoptosis and cell cycle distribution effect induced by rocaglaol were carried out by flow cytometry. The effect of rocaglaol on protein involved in the G2/M checkpoint and the MAPK pathway were performed by Western blotting analysis. Results: Rocaglaol significantly inhibited the viability of HepG2 cells in a dose-dependent and time-dependent manner. Rocaglaol was more effective than doxorubicin in the growth inhibition of HepG2 cells. However, rocaglaol-induced cytotoxicity in normal human hepatic cell line L02 was lower than that of doxorubicin. Treatment with different concentrations of rocaglaol at 48 h caused G2/M cell cycle progression inhibition, rather than apoptosis in HepG2 cells. Rocaglaol can significantly reduce the expression of G2/M cell cycle-regulating proteins cdc25C, cdc2, and cyclin B1 as well as increase the expression of ERK and JNK phosphorylation levels. Further study found that U0126 can partly abrogate the anti-proliferative activity in HepG2 cells, G2/M phase arrest and the reduction in the protein expression levels of cdc2 and cdc25C induced by rocaglaol. Conclusion: Our results demonstrated that rocaglaol was superior to doxorubicin in the inhibition of HepG2 cells proliferation and the selectivity of L02 cell activity. We provided evidence that the rocaglaol had the ability to continuously over-activate the ERK signaling in HepG2 cells, leading to the inhibition of cell proliferation through G2/M phase arrest.

A Potent Phytotoxic Substance in Aglaia odorata Lour.

Aglaia odorata Lour. (Meliaceae) was found to have very strong allelopathic activity and a bioherbicide PORGANIC(™) was developed from its leaf extracts. However, the phytotoxic substances causing the strong allelopathic activity of the plants have not yet been determined. Therefore, we investigated allelopathic properties and phytotoxic substances in A. odorata. Aqueous EtOH extracts of A. odorata leaves inhibited root and shoot growth of garden cress (Lepidum sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), ryegrass (Lolium multiflorum), and Echinochloa crus-galli with the extract concentration-dependent manner. The extracts were then purified and a major phytotoxic substance with allelopathic activity was isolated and identified by spectral data as rocaglaol. Rocaglaol inhibited the growth of garden cress and E. crus-galli at concentrations > 0.3 and 0.03 µm, respectively. The concentrations required for 50% inhibition ranged from 0.09 to 2.5 µm. The inhibitory activity of rocaglaol on the weed species, E. crus-galli, was much greater than that of abscisic acid. These results suggest that rocaglaol may be a major contributor to the allelopathic effect of A. odorata and bioherbicide PORGANIC(™) .