In vitro and in silico cytotoxic activities of triterpenoids from the leaves of Aralia dasyphylla Miq. and the assessment of their ADMET properties.

From the methanol extract of the leaves of Aralia dasyphylla Miq. (Araliaceae), ten triterpenoids including five ursane-type triterpenoids, ursolic acid (1), 3-O-α-l-arabinopyranosyl ursolic acid (2), ursolic acid 28-O-ß-D-glucopyranosyl ester (3), 3-O-[ß-D-glucopyranosyl (l→3)]-α-L-arabinopyranosyl ursolic acid (4), and matesaponin 1 (5), and five oleanane-type triterpenoids, elatoside E (6), elatoside F (7), 3-O-[ß-D-glucopyranosyl (l→3)]-α-L-arabinopyranosyl oleanolic acid (8), 3-O-α-L-arabinopyranosyl oleanolic acid (9) and oleanolic acid 28-O-ß-D-glucopyranosyl ester (10) were isolated. Their structures were elucidated based on 1D-, 2D-NMR and ESI-MS spectra as well as by comparison with those reported in the literature. All isolated compounds were evaluated in vitro for their cytotoxic activities against three human cancer cell lines (HepG2, LU-1 and RD) and in silico by molecular docking studies on human glucose transporter 1 (hGLUT1) protein. The triterpenoids 2, 4, 6, 8 and 9 exhibited good growth inhibition of HepG2 and LU-1 cancer cell lines with IC50 values in the range 1.76 - 7.21 (µM). The oleanane type triterpenoid 8 was the highest cytotoxic compound to inhibit all the tested cancer cell lines with IC50 values of 2.73 ± 0.12, 1.76 ± 0.11, 2.63 ± 0.10 µM, respectively. The in silico molecular docking study results showed that compounds 4 and 6 had the highest binding affinity. Compounds 1-10 were evaluated for their in silico ADMET of absorption, distribution, metabolism, excretion and oral toxicity parameters. Compounds 6, 8, 9 and 10 from A. dasyphylla are potential hGLUT1 inhibitors and worth of further investigation for the prevention or treatment of diabetes and cancer.Communicated by Ramaswamy H. Sarma.

3-O-trans-caffeoyloleanolic acid improves acute lung injury via anti-inflammation and antioxidative stress-involved PI3K/AKT pathway.

3-O-trans-caffeoyloleanolic acid (COA) is a pentacyclic triterpenoid compound, with significant anti-inflammatory effects. In this study, we report the protective effects of COA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explored its mechanism of action. LPS was used to construct in vivo mouse ALI models to observe the effects of COA pretreatment on lung pathology, inflammation, and oxidative stress. In vitro, mouse alveolar macrophages MH-S cells were cultured and stimulated with LPS to investigate the effects of COA pretreatment on inflammation and oxidative stress. Western blotting was used to investigate the expression of iNOS, TLR4, p-p65, p-AKT, and p-PI3K from in vivo and in vitro samples. The results showed that COA significantly improved lung injury, inhibited neutrophil infiltration, prevented macrophage infiltration, inhibited the release of inflammatory factors, reduced oxidative stress, and down-regulated the expression of iNOS, TLR4, p-p65, p-AKT, and p-PI3K in ALI mice caused by LPS. In vitro, COA inhibited the release of inflammatory factors, reduced oxidative stress, and down-regulated the expression of iNOS, TLR4, p-p65, p-AKT, and p-PI3K in MH-S cells stimulated with LPS. Of interest, the protective effects of COA were significantly attenuated in MH-S cells pretreated with the PI3K phosphopeptide activator 740Y-P with no effect on TLR4 expression observed. Taken together, these findings confirm the protective effects of COA on ALI. We further demonstrate that the anti-inflammation and antioxidant effects of COA are mediated through its effects on PI3K/AKT and potentially TLR4.

Computational assessment of saikosaponins as adjuvant treatment for COVID-19: molecular docking, dynamics, and network pharmacology analysis.

Saikosaponins are major biologically active triterpenoids, usually as glucosides, isolated from Traditional Chinese Medicines (TCM) such as Bupleurum spp., Heteromorpha spp., and Scrophularia scorodonia with their antiviral and immunomodulatory potential. This investigation presents molecular docking, molecular dynamics simulation, and free energy calculation studies of saikosaponins as adjuvant therapy in the treatment for COVID19. Molecular docking studies for 23 saikosaponins on the crystal structures of the extracellular domains of human lnterleukin-6 receptor (IL6), human Janus Kinase-3 (JAK3), and dehydrogenase domain of Cylindrospermum stagnale NADPH-oxidase 5 (NOX5) were performed, and selected protein-ligand complexes were subjected to 100 ns molecular dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Molecular docking and molecular dynamics simulation studies revealed that IL6 in complex with Saikosaponin_U and Saikosaponin_V, JAK3 in complex with Saikosaponin_B4 and Saikosaponin_I, and NOX5 in complex with Saikosaponin_BK1 and Saikosaponin_C have good docking and molecular dynamics profiles. However, the Janus Kinase-3 is the best interacting partner for the saikosaponin compounds. The network pharmacology analysis suggests saikosaponins interact with the proteins CAT Gene CAT (Catalase) and Checkpoint kinase 1 (CHEK1); both of these enzymes play a major role in cell homeostasis and DNA damage during infection, suggesting a possible improvement in immune response toward COVID-19.

Triterpene acids from Euscaphis japonica and assessment of their cytotoxic and anti-NO activities.

Six new triterpenoids, euscaphic acids G-L (1-6), along with nine known triterpene acids, and two known lignans were isolated from the ethanolic extract of the twigs of Euscaphis japonica. This is the first report concerning 1α,3ß-dihydroxy-12-oleanen-28-oic acid isolated from a natural source. The structures of the new compounds were established by spectroscopic analysis. The cytotoxic and anti-NO production activities for the isolates are also evaluated and discussed; compound 1, hederagenin (11), and arjunic acid (12) showed significant cytotoxicity against NCI-H460 cells, HT-29 cells, and CEM cells (IC50 = 1.64 ± 0.87, 2.11 ± 1.54, 1.73 ± 0.64 µM, respectively). Some of the isolated triterpenoids showed marginal inhibitions on NO production induced by LPS.

A rapid LC/MS/MS method for the analysis of nonvolatile antiinflammatory agents from Mentha spp.

UNLABELLED: Mints (Mentha spp.), aromatic crops grown largely for their essential oils, also are rich sources of nonvolatile antiinflammatory agents. Identification and quantitation of the constituents responsible for their antiinflammatory activity is challenging owing to the lack of suitable chromatographic methodology. In the present research, the simultaneous quantitation of antiinflammatory constituents rosmarinic acid, oleanolic acid, and ursolic acid in mints was attained by using a unique tandem HPLC column system coupled with an electrospray ionization mass detection (MRM mode). The ion mode optimization for rosmarinic acid under negative and triterpenoid acids under positive was achieved by setting 2 time segments in a single run where the polarity mode was switched from negative (0 to 10 min) to positive (10 to 40 min). For the investigated concentration ranges of antiinflammatory agents in mints, good linearities (r² ≥ 0.998) were obtained for each calibration curve. Validation of precision and accuracy for this method showed that intra- and inter-day repeatabilities for all analytes were less than 5.51%, and the recoveries varied from 97.8% to 99.3%. The developed LC/MS/MS assay provides a suitable quality control method for the determination of antiinflammatory constituents in Mentha spp. There is a wide range of diversity in the natural product composition for these acids across the Mentha germplasm collection evaluated. The presence of these antiinflammatory acids in post-distilled mints shows that value-added nutraceutical enriched products can be developed with proper processing and recovery systems in addition to the distillation and capture of the valuable volatile essential oils. PRACTICAL APPLICATION: Results from this research would benefit both commercial farmers growing mint for essential oil and those in the food industry where value-added phytopharmaceutical enriched products can be developed with proper processing, quality control, and recovery systems during mint essential oil distillation.

S-0139 (Shionogi).

Shionogi and GlaxoSmithKline (GSK), as the joint venture company Shionogi-GlaxoSmithKline Pharmaceuticals LLC, are developing S-0139 (SB-737004), an endothelin-A (ETA) antagonist, for the potential treatment of hemorrhagic and ischemic stroke [223386], [252007], [426822], [426830]. By 1999, the compound was in phase II trials in Japan for stroke [348554]; phase II trials were ongoing in March 2002 [446957]. As of May 2000, Shionogi was preparing to develop the drug in the US and Europe [370602]. As of May 2001, a phase I European trial was in preparation [410912]; which was underway by November 2001 [429990]. In July 2001, Shionogi and GSK signed a letter of intent to create a joint venture that was initially to have exclusive rights to develop and commercialize four compounds contributed by Shionogi and one by GSK, including S-0139 14167621. The agreement wasfinalized in October 2001 [426569], [426822]. In August 1999, Lehman Brothers gave S-0139 a 10% probability of reaching the market with an expected launch in 2005. Sales were expected to peak at US $50 million in 2012 [349228].