Marine Peroxy Sesquiterpenoids Induce Apoptosis by Modulation of Nrf2-ARE Signaling in HCT116 Colon Cancer Cells.

Our current study demonstrated that the marine peroxy sesquiterpenoids isolated from the Okinawan soft coral Sinularia sp. have an antitumor activity in human colon cancer cell (HCT) 116 colon cancer cells with their induction of apoptosis due to H2O2 production derived from the compounds. This study clarified that peroxy sesquiterpenoids (1 and 2) inhibited anti-apoptosis proteins, such as B-cell lymphoma-extra large (Bcl-xL) and phosphoAkt (pAkt). In addition, the heme oxygenase-1 (HO-1), nuclear factor-erythroid-2-related factor (Nrf2), and phosphoNrf2 (pNrf2) proteins related to the cell survival regulation signal of Nrf2-ARE (antioxidant response element) were also suppressed in the presence of these compounds. While the cells treated with the compounds and trolox as an antioxidant expressed the inhibited proteins, such as HO-1, Nrf2, and Bcl-xL, it was suggested that the H2O2 involving free radical reactions derived from the molecule would be a trigger of apoptosis with the modulation of Nrf2-ARE signaling in the cells.

Hydrogen peroxide derived from marine peroxy sesquiterpenoids induces apoptosis in HCT116 human colon cancer cells.

In this study, the isolates of the peroxy sesquiterpenoids (1-3) from the Okinawan soft coral, Sinularia sp., indicated cytotoxicity in HCT116 colon cancer cells. The apoptotic cells with a nuclear condensation were detected in the presence of these compounds, then the caspase 3/7 activity was induced, indicating that the compounds have a potential antitumor activity by apoptosis-induction. The cells treated with these compounds were generated reactive oxygen species (ROS), indicating that the ROS is related to the induction of apoptosis. The ROS production reduced in the presence of catalase or trolox, indicating that hydrogen peroxide (H2O2) is generated through a certain free radical reaction derived from the compound. In fact, the accumulation of intracellular H2O2 was also confirmed in the presence of these compounds. Based on all the results, this study proposed the apoptosis-inducing mechanism due to the compounds that the H2O2 produced involving free radical reactions derived from cleavage of the end or hydro-peroxide in the molecule induced cell death.

New Casbane and Cembrane Diterpenoids from an Okinawan Soft Coral, Lobophytum sp.

A new rare casbane-type diterpenoid 1 and two new cembrane diterpenoids 2, 3 were isolated from an Okinawan soft coral, Lobophytum sp., together with four known cembrane diterpenoids 4-7. Their structures were elucidated by extensive analysis of spectroscopic data (1D and 2D NMR, IR, and MS) and a molecular modeling study. The new isolates showed weak anti-bacterial activity, mild cytotoxicity against HCT116 cells, and anti-inflammatory effect in LPS/IFN-γ-stimulated RAW 264.7 macrophage cells.

Dual biological functions of the apoptotic activity and anti-inflammatory effect by alcyonolide congeners from the Okinawan soft coral, Cespitularia sp.

In our current study, alcyonolide and its congeners isolated from the Okinawan soft coral, Cespitularia sp., have shown an antitumor activity in HCT116 colon cancer cells. This study investigated the biological activities of these compounds (1-12) for the apoptotic activity in the HCT116 cells and the anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. As a result, the apoptotic cells with a nuclear condensation were detected by treatment with these compounds. The apoptotic cells dependent on the caspase 3/7 activation was also induced in the low concentration range of 2.5-10 µM. While a similar concentration of the compounds inhibited the NO production in the LPS-stimulated inflammatory RAW264.7 cells, the pro-inflammatory gene expressions of the iNOS and COX-2 mRNA were also suppressed. The structurally unique alcyonolides (5, 12) having the dual biological activity of apoptotic activity and anti-inflammatory effect could be a potential development as pharmaceutical agents.

Suppression of nitric oxide production on LPS/IFN-γ-stimulated RAW264.7 macrophages by a novel catechin, pilosanol N, from Agrimonia pilosa Ledeb.

A novel catechin, pilosanol N (1), was isolated from Agrimonia pilosa Ledeb and its structure was determined by (1)H, (13)C NMR and HRESI-MS analyses. Compound 1 inhibited nitric oxide (NO) production in LPS/IFN-γ -induced RAW264.7 macrophages, and then the iNOS gene expression and its protein production with LPS/IFN-γ treatment cells were also suppressed in the presence of 1. In addition, compound 1 scavenged NO or nitrogen radicals generated from NOR3 (4-ethyl-2-hydroxyamino-5-nitro-3-hexenamide) as an NO donor. These results indicated that pilosanol N can decrease the level of NO through a mechanism that involved both a decrease in the NO production and NO scavenging.

Five new diterpenoids from an Okinawan soft coral, Cespitularia sp.

Five new diterpenoids 1-5 were isolated from an Okinawan soft coral, Cespitularia sp., together with the known diterpenoid, alcyonolide (6). New diterpenoid structures were elucidated by spectroscopic methods and by comparison of their NMR data with those of related compounds. Alcyonolide (6) was cytotoxic against HCT 116 cells (IC50 5.85 µM), while these new diterpenoids 1-5 were much less active (IC50 28.2-91.4 µM).

Recurrent brain abscess induced by pulmonary arteriovenous fistula.

Brain abscess associated with an arteriovenous fistula (AVF) is sometimes difficult to diagnose and tends to recur. We report a case of recurrent brain abscess due to a pulmonary AVF (PAVF). A 69-year-old woman with a mass in the left cerebral peduncle had taken a progressively worse and shown decorticate rigidity. After an intravenous antibiotic for fever of unknown origin was changed, her condition gradually improved. She was discharged with the help of a cane. Thirty-one months later, she suffered left hemiparesis. Magnetic resonance imaging revealed a cystic mass in the right lateral frontal lobe. At surgery, we confirmed pus in the cyst. A PAVF was detected and was treated with coil embolization. The left hemiparesis improved and the postoperative course was uneventful. Exhaustive study is absolutely necessary to detect the etiology of recurrent brain abscess and to achieve a cure.

Isolation of C11 compounds and a cyclopropane fatty acid from an Okinawan ascidian, Diplosoma sp.

Pentylphenols 1 and 2, cyclopropane fatty acid 3, and cyclopentenones 4 and 5, were isolated from an ascidian, Diplosoma sp. The structures of 1-5 were determined by spectroscopic analysis and/or synthesis. Compound 1 inhibited the division of fertilized sea urchin eggs and compound 4 showed mild cytotoxity against HCT116 cells (human colorectal cancer cell).

Isolation of C11 cyclopentenones from two didemnid species, Lissoclinum sp. and Diplosoma sp.

A series of new C(11) cyclopentenones 1-7 was isolated, together with four known metabolites 9/10, 12 and 13, from the extract of the didemnid ascidian Lissoclinum sp. The other didemnid ascidian Diplosoma sp. contained didemnenones 1, 2 and 5, and five known metabolites 8-12. The structures of 1-7 were elucidated by spectroscopic analyses. Cytotoxicity of the isolated compounds was evaluated against three human cancer cell lines (HCT116, A431 and A549).

New cytotoxic cembranolides from an Okinawan soft coral, Lobophytum sp.

Three new cembranolides (1-3) were isolated from an Okinawan soft coral, Lobophytum sp., together with the known cembranolide diterpenoids (4-9). Their structures were determined by extensive analysis of spectroscopic data (1D and 2D NMR, IR, and MS), molecular modeling, and comparison with data reported elsewhere. All compounds contain an α-methylene-γ-lactone ring adjacent to a cembrane, and some of them (1, 6-8) have an epoxide ring as well. The new metabolites were evaluated for cytotoxicity against HeLa, A459, B16-F10, and RAW 264.7 cells and anti-inflammatory effect in LPS-stimulated inflammatory RAW 264.7 macrophage cells.

Cytotoxic metabolites from the Okinawan ascidian Diplosoma virens.

The unstable isomeric compounds 5-hydroxy-7-prop-2-en-(E)-ylidene-7,7adihydro-2H-cyclopenta[b]pyran-6-one (1) and 5-hydroxy-7-prop-2-en-(Z)-ylidene-7,7adihydro-2H-cyclopenta[b]pyran-6-one (2), previously described as antimicrobial metabolites from the sponge Ulosa sp., were isolated and identified as major components of the ascidian Diplosoma virens. In this paper, full spectral data for 2 and complete 13CNMR data for 1, based on 2D NMR measurements, are provided for the first time. Compounds 1 and 2 showed cytotoxity against HCT116 cells (human colorectal cancer cells) by triggering apoptotic cell death.

Diagnostic and therapeutic considerations for sinus pericranii.

Sinus pericranii is one of the differential diagnoses which should be considered when a physician encounters a patient with a subcutaneous soft scalp mass. Sinus pericranii is a rare vascular anomaly of the venous drainage between the intracranial and extracranial systems via the diploe of the skull. We describe here a 16-year-old female with sinus pericranii following minor head trauma four years prior. CT and MRI scans revealed heterogeneous enhancement of the lesion and three-dimensional CT showed a crater-like depression and multiple honeycomb diploic holes in the skull. Angiography was normal, whereas percutaneous sinusography revealed a connection between the lesion and the superior sagittal sinus. The patient underwent surgery to disconnect her diploic veins from the lesion under general anaesthesia, and her postoperative course was uneventful after six months follow-up. To avoid profuse bleeding and air emboli and to ameliorate cosmetic problems, a specific diagnosis should be made to plan appropriate treatment.

Endoperoxy and hydroperoxy cadinane-type sesquiterpenoids from an Okinawan soft coral, Sinularia sp.

Three cadinane-type sesquiterpenoids, endoperoxide (1) and hydroperoxides (2, 3) together with three known sesquiterpenoids (4-6) were isolated from an Okinawan soft coral, Sinularia species. Structures of these isolates were elucidated by spectroscopic analyses (NMR, IR and MS) and molecular modeling. In addition, the isolates 1-3 as new compounds were examined for biological activities, resulting that they have antibacterial activity and weak cytotoxicity against HCT116 cells as well as anti-inflammatory effect on LPS/IFN-γ-stimulated RAW 264.7 macrophage cells.

Kohamaic acid A, a novel sesterterpenic acid, inhibits activities of DNA polymerases from deuterostomes.

We previously found and isolated a novel natural product, designated kohamaic acid A (KA-A), which inhibited the first cleavage of fertilized sea urchin eggs. In this paper, we report that this compound could selectively inhibit the activities of DNA polymerases (pol. alpha, beta, gamma, delta and epsilon ) only from species in the deuterostome branch in the animal kingdom, like sea urchin, fish and mammals, but not from protostomes including insects (fruit fly, Drosophila melanogaster) and mollusks (octopus and oyster). Inhibition of deuterostome DNA polymerases was dose dependent. IC(50) values for DNA polymerases of mammals and fish occurred at approximately 5.8-14.9 microM and those of sea urchin at 6.1-30.3 microM. In the sea urchin DNA polymerases, the activities of the replicative DNA polymerases such as alpha, delta and epsilon were more strongly inhibited than that of the repair-related pol. beta. KA-A is an inhibitor of replicative DNA polymerases from the deuterostome species, and subsequently, the inhibition of the first cleavage of fertilized sea urchin eggs might occur as a result of the suppression of DNA replication.

Albiziahexoside: a potential source of bioactive saponin from the leaves of Albizzia lebbeck.

Albiziahexoside (1), a new hexaglycosylated saponin, was isolated from leaves of Albizzia lebbeck. Saponin 1, which is an analog of cytotoxic albiziatrioside A (2), did not show cytotoxicity. However, 1 is a potential source of 2 and related bioactive saponins for medicinal use because leaves, which can be regenerated after collection, contain 1 in substantial quantity.

Haterumadysins A-D, sesquiterpenes from the Okinawan marine sponge Dysidea chlorea.

Haterumadysins A-D (1-4) and two known compounds, spirodysin (5) and dehydroherbadysinolide (6), were isolated from the sponge Dysidea chlorea. Their structures were successfully determined by detailed spectroscopic analysis. Compounds 1-5 all showed the ability to inhibit the division of fertilized sea urchin eggs.

Cytotoxic labdane alkaloids from an ascidian Lissoclinum sp.: isolation, structure elucidation, and structure-activity relationship.

Four labdane alkaloids, haterumaimides N-Q (1-4), were isolated from an ascidian Lissoclinum sp. and their structures were elucidated by chemical and spectral analyses. Investigation of the structure-activity relationships of haterumaimides J-K, N-Q, and 14 related compounds suggested that the presence of hydroxyl groups at C-6, C-7, C-12, and C-18, a chlorine atom at C-2, and an imido NH in ring C should be essential for cytotoxicity against P388 cells.

Leaf-closing substance in Leucaena leucocephala.

Potassium (2R,3R)-2,3,4-trihydroxy-2-methylbutanoate (1) was identified as a leaf-closing substance in the nyctinastic plant, Leucaena leucocephala. Compound 1 showed strong leaf-closing activity toward L. leucocephala and was not effective against other nyctinastic plants. The potassium ion was indispensable for the bioactivity of 1. Compound 1 gradually lost its bioactivity because of the exchange of the counter cation during isolation. A leaf-opening substance was also observed in the same plant.