ABSTRACT
While inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, due to compliance, drug safety, and resistance issues, new medications to replace ICSs are in high demand. Inotodiol, a fungal triterpenoid, showed a unique immunosuppressive property with a preference for mast cells. It exerted a mast cell-stabilizing activity equally potent to dexamethasone in mouse anaphylaxis models when orally administered in a lipid-based formulation, upgrading bioavailability. However, it was four to over ten times less effective in suppressing other immune cell subsets, depending on the subsets, than dexamethasone showing invariably potent inhibition. Accordingly, inotodiol affected the membrane-proximal signaling for activating mast cell functions more profoundly than other subsets. Inotodiol also effectively prevented asthma exacerbation. Importantly, considering the no-observed-adverse-effect level of inotodiol was over 15 times higher than dexamethasone, its therapeutic index would be at least eight times better,implying that inotodiol is a viable option for replacing CSs in treating asthma.
Subject(s)
Anti-Asthmatic Agents , Asthma , Animals , Mice , Mast Cells , Anti-Asthmatic Agents/pharmacology , Anti-Asthmatic Agents/therapeutic use , Disease Models, Animal , Asthma/drug therapy , Dexamethasone/pharmacology , Dexamethasone/therapeutic useABSTRACT
Chromatography of the ethanol extract of the medicinal fruit Stauntonia hexaphylla resulted in the purification of 26 compounds (1-26), including two undescribed triterpene saponins 1 and 2 (hexaphylosides A and B). Their structures were confirmed by spectroscopic data, including IR, HR QTOF MS, 1H, 13C NMR, COSY, HMQC, HMBC, and TOCSY, and HPLC sugar analysis after acid hydrolysis. The anti-inflammatory effects of the high-purity constituents (1-26) on lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells were investigated by screening nitric oxide production. The NO inhibitory activity of compounds 6 and 10 with the IC50 values of 1.33 and 1.10⯵M, respectively. The structure-activity relationships (SAR) of the isolated compounds were also analyzed. Furthermore, compounds 6 and 10 inhibited the protein expression inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 via Western blotting analysis. This showed that compounds 6 and 10 contributed to the anti-inflammatory effects of S. hexaphylla fruit, which could be developed as a natural nutraceutical and functional food ingredient.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Saponins/pharmacology , Triterpenes/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/isolation & purification , Cyclooxygenase 2 Inhibitors/pharmacology , Fruit/chemistry , Mice , Molecular Structure , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/antagonists & inhibitors , RAW 264.7 Cells , Ranunculales/chemistry , Saponins/chemistry , Saponins/isolation & purification , Structure-Activity Relationship , Triterpenes/chemistry , Triterpenes/isolation & purificationABSTRACT
Eight compounds were isolated from the leaves of Clerodendrum inerme, including one new rearranged abietane diterpene, crolerodendrum B (1). Their structures were determined by means of spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance (1-D and 2-DNMR), high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) and circular dichroism (CD). The DPPH radical scavenging and cytotoxic activities of isolated compounds against MCF7 (breast), HCT116 (colon) and B16F10 (melanoma) cancer cell lines were evaluated. Compounds 1, 3 and 4 exhibited strong DPPH radical-scavenging effects (ED50 values of 17.6 ± 2.1, 10.1 ± 0.8 and 11.3 ± 0.3 µM, respectively) and 4 showed strong cytotoxicity against the HCT116 cell line (IC50 = 3.46 ± 0.01 µM).
