Monoterpenoids and Triterpenoids from Pterocephalus hookeri with NF-κB inhibitory activity

In this study, we isolated two new monoterpenoids hookerinoids A and B (1 and 2; rare arranged nonglycosidic bis-iridoids) and hookerinoid C (3; a novel norursane-type triterpenoid) in addition to two known compounds, 11,12-epoxy-2,6-dihydroxy-24-norursa-1,4-dien-3-on-2-on-(28 → 13)-olide (4) and rivularicin (5), from Pterocephalus hookeri. The structures of 1–3 were established using one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionisation mass spectrometry. All compounds were isolated from this plant for the first time. Bis-iridoids isolated from P. hookeri possessed secoiridoid/iridoid subtype skeletons. Therefore, bis-iridoids can be considered chemotaxonomic markers of P. hookeri. The origins of the new compounds (1–3) were postulated and their inhibitory activities on a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway were assayed; 1 and 2 showed obvious activity in inhibiting NF-κB.     

Phenolic compounds with NF-κB inhibitory effects from the fungus Phellinus baumii

Chemical investigation of the fungus Phellinus baumii has resulted in characterization of five previously undescribed hispidin derivatives, phellibaumins A-E (1-5), as well as two pairs of new non-equivalent epimeric benzyl dihydroflavones, methylphelligrin A (9), epi-methylphelligrin A (10), methylphelligrin B (11), and epi-methylphelligrin B (12), together with five known compounds, interfungin B (6), phelligridin H (7), phelligridimer A (8), phelligrin A (13), and epi-phelligrin A (14). Phellibaumin A (1) was a novel hispidin derivative with a unique 3,4-dihydroxybenzofuran unit. These compounds exhibited NF-κB inhibitory activity with IC₅₀ values of 52.96 μM (1), 41.40 μM (2), 52.92 μM (5), 36.44 μM (9 and 10), and 22.46 μM (11 and 12), respectively.     

Paeonidanins F–H: Three new dimeric monoterpene glycosides from Paeonia lactiflora and their anti-inflammatory activity

Three new dimeric monoterpene glycosides, paeonidanins F–H (1–3) were isolated from the roots of Paeonia lactiflora. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis products. Compounds 1–3 showed inhibitory effects against nitric oxide (NO) and pro-inflammatory cytokine TNF-α release in LPS-induced RAW 246.7 macrophages.     

Vavilosides A1/A2–B1/B2, new furostane glycosides from the bulbs of Allium vavilovii with cytotoxic activity

A phytochemical analysis of the bulbs of Allium vavilovii M. Pop. & Vved. was attained for the first time extensively, affording to the isolation of four new furostanol saponins, named vavilosides A1/A2–B1/B2 (1a/b–2a/2b), as two couple of isomers in equilibrium, together with ascalonicoside A1/A2 (3a/3b) and 22-O-methyl ascalonicoside A1/A2 (4a/4b), previously isolated from shallot, Allium ascalonicum. High concentrations of kaempferol, kaempferide, and kaempferol 4^I-glucoside were also isolated. The chemical structures of the new compounds, established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses, were identified as (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-galactopyranosyl 26-O-α-l-rhamnopyranoside (vaviloside A1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-galactopyranosyl 26-O-α-l-rhamnopyranoside (vaviloside A2), (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-xylopyranosyl 26-O-α-l-rhamnopyranoside (vaviloside B1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-l-rhamnopyranosyl-(1→2)-O-β-d-xylopyranosyl 26-O-α-l-rhamnopyranoside (vaviloside B2). The isolated saponins showed cytotoxic activity on J-774, murine monocyte/macrophage, and WEHI-164, murine fibrosarcoma, cell lines with the following rank: vaviloside B1/B2 > ascalonicoside A1/A2 > vaviloside A1/A2.     

A Yersinia effector with enhanced inhibitory activity on the NF-κB pathway activates the NLRP3/ASC/caspase-1 inflammasome in macrophages

A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKβ to cause TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y. pestis KIM (YopJ^KIM) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJ^KIM causes increased apoptosis, caspase-1 activation, and secretion of IL-1β in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJ^KIM in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJ^KIM were important for enhanced apoptosis, caspase-1 activation, and IL-1β secretion. As compared to YopJ^CO92, YopJ^KIM displayed an enhanced capacity to inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in vitro. YopJ^KIM also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion occurred in IKKβ-deficient macrophages infected with Y. pestis expressing YopJ^CO92, confirming that the NF-κB pathway can negatively regulate inflammasome activation. K⁺ efflux, NLRP3 and ASC were important for secretion of IL-1β in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naïve macrophages in response to infection with a pathogen that inhibits IKKβ and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways.     

The MC159 protein from the molluscum contagiosum poxvirus inhibits NF-κB activation by interacting with the IκB kinase complex

Molluscum contagiosum virus (MCV) causes persistent neoplasms in healthy and immunocompromised people. Its ability to persist likely is due to its arsenal of viral immunoevasion proteins. For example, the MCV MC159 protein inhibits TNF-R1-induced NF-κB activation and apoptosis. The MC159 protein is a viral FLIP and, as such, possesses two tandem death effector domains (DEDs). We show in this article that, in human embryonic kidney 293 T cells, the expression of wild-type MC159 or a mutant MC159 protein containing the first DED (MC159 A) inhibited TNF-induced NF-κB, or NF-κB activated by PMA or MyD88 overexpression, whereas a mutant protein lacking the first DED (MC159 B) did not. We hypothesized that the MC159 protein targeted the IκB kinase (IKK) complex to inhibit these diverse signaling events. Indeed, the MC159 protein, but not MC159 B, coimmunoprecipitated with IKKγ. MC159 coimmunoprecipitated with IKKγ when using mouse embryonic fibroblasts that lack either IKKα or IKKβ, suggesting that the MC159 protein interacted directly with IKKγ. MC159-IKKγ coimmunoprecipitations were detected during infection of cells with either MCV isolated from human lesions or with a recombinant MC159-expressing vaccinia virus. MC159 also interacts with TRAF2, a signaling molecule involved in NF-κB activation. However, mutational analysis of MC159 failed to reveal a correlation between MC159-TRAF2 interactions and MC159's inhibitory function. We propose that MC159-IKK interactions, but not MC159-TRAF2 interactions, are responsible for inhibiting NF-κB activation.     

Daphnodorin dimers from Edgeworthia chrysantha with α-glucosidase inhibitory activity

Four daphnodorin dimers named herein as edgechrins A–D (1–4) were isolated from the stems and twigs of Edgeworthia chrysantha Lindl. along with four known compounds identified as daphnodorin A (5), B (6), C (7) and I (8). Their structures were established by spectroscopic methods, including IR, HR-MS, and 1D- and 2D NMR. All of these compounds showed potent in vitro α-glucosidase inhibitory activity with IC₅₀ values in the range of 0.4–20 μM.     

Three new phenylpropanoyl amides from the leaves of Piper sarmentosum and their α-glucosidase inhibitory activities

Piper sarmentosum is pungent climber that is a widely used vegetable in Southeast Asia. In screening for α-glucosidase inhibitors from edible plants, an inhibitory activity in the leaf extract of P. sarmentosum was observed. Bioassay-guided fractionation resulted in the isolation of three new phenylpropanoyl amides, named chaplupyrrolidones A (1) and B (2) and deacetylsarmentamide B (7). Chaplupyrrolidones A and B contained a 5-oxygenated-Δ³-2-pyrrolidone moiety, which is the first report of their natural encounter. Of these all isolated compounds, 2 revealed most potent inhibition against α-glucosidase, which is 18-fold more active than its demethylated congener, 1. Kinetic evaluation of 2 indicated that it acts as a noncompetitive inhibitor.