Sheng-An Tang

Alkaloids from Pachysandra terminalis inhibit breast cancer invasion and have potential for development as antimetastasis therapeutic agents.

The aim of the present study was to identify potentially useful natural compounds for the development of novel therapeutic agents to inhibit metastasis. A phytochemical investigation of Pachysandra terminalis resulted in the isolation of seven new pregnane alkaloids, terminamines A-G (1-7), and seven known alkaloids (8-14). The structures of 1-7 were elucidated by 1D- and 2D-NMR spectroscopic and mass spectrometric methods. Compounds 1-5 and 8-14 inhibited the migration of MB-MDA-231 breast cancer cells induced by the chemokine epithelial growth factor. In addition, compound 1 inhibited phosphorylation of integrin β(1), which plays an important role in MB-MDA-231 cell adhesion and metastasis.

IVSE, isolated from Inula japonica,suppresses LPS-induced NO production via NF-κB and MAPK inactivation in RAW264.7 cells.

AIMS Our previous study showed that the extract of Inula japonica Thunb. (I. japonica) has anti-inflammatory and anti-asthmatic activities. In an attempt to find anti-inflammatory compounds from I. japonica, we recently isolated 1,6α-dihydroxy-4αH-1,10-secoeudesma-5(10),11(13)-dien-12,8β-olide (SE), 6α-isobutyryloxy-1-hydroxy-4αH-1,10-secoeudesma-5(10),11(13)-dien-12,8β-olide (IBSE), and 6α-isovaleryloxy-1-hydroxy-4αH-1,10-secoeudesma-5(10),11(13)-dien-12,8β-olide (IVSE) from the extract of I. japonica, and investigated their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. MAIN METHODS The inhibitory effect of IVSE, SE and IBSE on NO production in LPS-induced RAW264.7 cells was examined using Griess reagent, and the effects of IVSE on the expressions of inducible nitric oxide synthase (iNOS) and its upstream signal proteins including IκB kinase (IKK)/inhibitor kappa B (IκB)-α/nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) were investigated by Western blot. KEY FINDINGS Among the 3 compounds isolated, SE, IBSE, and IVSE inhibited NO production at 2.5 μM with 5.1%, 40.4%, and 52.8%, respectively. IVSE displayed the most potent inhibition of NO production. Mechanism analysis indicated that IVSE dramatically decreased the expression of iNOS, reduced the translocation of the NF-κB subunit p65 into the nucleus by interrupting the phosphorylation and degradation of IκB-α, and inhibited the activation of the upstream mediator IKK α/β. Furthermore, our results showed that IVSE inhibited the phosphorylation of MAPKs including extracellular regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK) and p38. SIGNIFICANCE IVSE exhibited anti-inflammatory activity by inhibiting NO production, in which inactivation of NF-κB and MAPKs might be involved. Our results suggest that IVSE might become an anti-inflammatory drug candidate.

In Vitro Antitumor Activity of Stellettin B, a Triterpene from Marine Sponge Jaspis stellifera, on Human Glioblastoma Cancer SF295 Cells

Stellettin B was isolated from marine sponge Jaspis stellifera. In vitro antitumor activities were investigated on 39 human cancer cell lines. Stellettin B exhibited highly potent inhibition against the growth of a human glioblastoma cell line SF295, with a GI50 of 0.01 μM. In contrast, stellettin B showed very weak inhibitory activity on normal cell lines including HMEC, RPTEC, NHBE and PrEC, with GI50s higher than 10 μM, suggesting its relatively selective cytotoxicity against human cancer cells compared to normal human cell lines. We then focused on the antitumor activity of this compound on SF295 cells. Flow cytometric analysis indicated that stellettin B induced apoptosis in SF295 cells in a concentration-dependent manner. Further study indicated that stellettin B increased the production of ROS, the activity of caspase 3/7, as well as the cleavage of PARP, each of which is known to be involved in apoptosis. To investigate the molecular mechanism for cell proliferation inhibition and apoptosis induction, effect on the phosphorylation of several signal proteins of PI3K/Akt and RAS/MAPK pathways was examined. Stellettin B inhibited the phosphorylation of Akt potently, with no activity on p-ERK and p-p38, suggesting that inhibition of PI3K/Akt pathway might be involved in the antiproliferative and apoptosis-inducing effect. However, homogenous time-resolved fluorescence (HTRF) assay indicated that stellettin B did not inhibit PI3K activity, suggesting that the direct target might be signal protein upstream of Akt pathway other than PI3K.

Anti-inflammatory terpenes from flowers of Inula japonica

Five new terpenes (1-5) and ten known compounds (6-15) were isolated from Inula japonica, and their structures were identified by spectroscopic analysis. Compounds 3 and 14 showed positive inhibitory effects on nitric oxide production. Furthermore, compound 14 suppressed both leukotriene C4 synthesis and degranulation in c-kit ligand-induced bone marrow-derived mast cells.

Inhibitory Effects of JEUD-38, a New Sesquiterpene Lactone from Inula japonica Thunb, on LPS-Induced iNOS Expression in RAW264.7 Cells

ABSTRACTWe isolated JEUD-38, a new sesquiterpene lactone from Inula japonica Thunb. JEUD-38 dramatically attenuated lipopolysaccharide (LPS)-induced nitric oxide (NO) production. Consistent with this finding, the protein expression of inducible nitric oxide synthase (iNOS) was blocked by JEUD-38 in a concentration-dependent manner. To elucidate the mechanism, we examined the effect of JEUD-38 on LPS-stimulated nuclear factor-κB (NF-κB) nuclear translocation, inhibitory factor-κB (IκB) phosphorylation, and degradation. JEUD-38 reduced the translocation of p65, via abrogating IκB-α phosphorylation and degradation. In addition, JEUD-38 inhibited LPS-stimulated phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Since iNOS as well as the upstream NF-κB and MAPKs are known to be closely involved in inflammation, these results suggest that JEUD-38 is a promising candidate for prevention and therapy of inflammatory diseases.

Antitumor metastasis pregnane alkaloids from Pachysandra terminalis

Three new pregnane alkaloids, named terminamines H–J (1–3), together with two known alkaloids (4 and 5), were isolated from the ethanol extract of Pachysandra terminalis. The structures of isolated compounds were elucidated by spectroscopic methods, including 1H and 13C NMR, 2D NMR, and HR-ESI-MS. Compounds 1, 4, and 5 revealed significant anti-metastasis activities. In addition, compound 1 inhibited the expression of p-PKCζ in MDA-MB-231 cells, and compound 4 inhibited the expressions of p-PKCζ in MDA-MB-231 and A549 cells.

Novel polyhydroxylated steroids from the East China Sea gorgonian Echinogorgia sassapo reticulata with suppressive activity of leukotriene C4 generation and degranulation in bone marrow-derived mast cells

The gorgonian Echinogorgia sassapo reticulata contains two new bioactive polyhydroxylated steroids, sassapols A (1), B (2), and five related known compounds (3–7). Compound 6 has been encountered for the first time in natural sources. The structures of these new compounds were defined by spectroscopic analysis. All the compounds (1–7) isolated from E. sassapo reticulata were tested for anti-inflammatory activity. Compounds 1, 3, 5, and 7 inhibited both the generation of leukotriene C4 and the degranulation reaction in mouse bone marrow-derived mast cells.

Jaspiferins C–F, four new isomalabaricane-type triterpenoids from the South China Sea sponge Jaspisstellifera

A chemical investigation of marine sponge Jaspis stellifera, collected from the South China Sea, led to the isolation of four new isomalabaricane-type triterpenoids, jaspiferins C–F (1–4). The structures of those compounds were elucidated by extensive spectroscopic methods. Jaspiferin C (1), which has the six-membered carbon ring at the side chain, was discovered for the first time from the isomalabaricane-type triterpenoids. The hypothesis of a biogenetic pathway to generate jaspiferin C (1) was depicted.

A New Aurone from Smilax riparia

A phytochemical investigation of Smilax riparia A. DC. resulted in the isolation of a new aurone (1) and 13 known compounds (2–14). The structure of the new aurone was determined to be 4,5,3′,4′,5′-pentamethoxy-6-hydroxyaurone on the basis of spectroscopic methods. Compounds 3–11 were isolated from this genus for the first time. Compounds 3 and 4 significantly inhibited the migration of MDA-MB-231 breast cancer cells induced by the chemokine epithelial growth factor (EGF). In addition, compounds 3, 4, and 8 showed significant effects on enhancing GLUT4 translocation in skeletal muscle cells L6myc.

1,6- O , O -Diacetylbritannilactone Inhibits Eotaxin-1 and ALOX15 Expression Through Inactivation of STAT6 in A549 Cells

Abstract1,6-O,O-Diacetylbritannilactone (OODBL), a plant sesquiterpene lactone, was previously reported to show multiple pharmacological effects such as anti-cancer and anti-inflammatory activities. In this study, we investigated the anti-inflammatory effect of OODBL on interleukin (IL)-4-induced signal transducer and activator of transcription 6 (STAT6) signaling pathway in human lung A549 cells. We found that OODBL dramatically inhibited IL-4-induced messenger RNA (mRNA) expression of eotaxin-1 and arachidonate 15-lipoxygenase-1 (ALOX15) in a dose-dependent manner. To clarify the action mechanism of OODBL, we examined the effect of OODBL on activation of STAT6. OODBL decreased both STAT6 phosphorylation and reporter gene activity. Furthermore, OODBL suppressed phosphorylation of Janus Kinase 3 (JAK3) without affecting JAK1. Taken together, OODBL abolished IL-4-induced eotaxin-1 and ALOX15 mRNA expressions by repressing the activation of STAT6 and JAK3. These results suggest that OODBL has a potential therapeutic efficacy on inflammatory diseases especially allergic airway disease as a lead compound.