Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus grandis.

A series of chromatographic separations performed on the ethanol extracts of the peels of Citrus grandis has led to the characterization of forty compounds, including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compounds, respectively. The chemical structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric analysis. Most of the isolated compounds were examined for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18-dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 µM, and 0.43 to 4.33 µM, respectively. In addition, 7-hydroxy-8-(2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against A-mediated neurotoxicity at 50 µM.

Bioactive chemical constituents from the root bark of Morus australis.

Two new pyranoflavonoids, morustralins A (1) and B (2), a new natural benzene derivative, one benzenoid (Z)-1-hydroxy-4-(2-nitroethenyl)benzene (3), and thirty known compounds were isolated and characterized from the root bark of Morus australis. The structures of the new compounds were established from spectroscopic and spectrometric analyses. Ten isolates (1-10) were examined for inhibitory effects on adenosine diphosphate (ADP)-, arachidonic acid (AA)-, and platelet-aggregating factor (PAF)-induced platelet aggregation. Among the tested compounds, compound 3 displayed the most significant inhibition of ADP- and AA-induced platelet aggregation with IC50 values of 9.76±5.54 and 9.81±2.7µM, respectively. In addition, eight purified compounds (3-10) were examined for inhibition of nitric oxide (NO) production in RAW 264.7 cells and six compounds (3-8) displayed significant inhibitory effects with IC50 values ranging from 2.1±0.3 to 6.3±0.6µM.

Correction: Chan, Y.-Y., et al. The Constituents of Michelia compressa var. formosana and Their Bioactivities. Int. J. Mol. Sci. 2014, 15, 10926-10935.

The authors wish to make two changes to their published paper [1]. [...].

Anti-inflammatory neolignans from the roots of Magnolia officinalis.

Nine neolignan derivatives (1-9) were characterized from the roots of Magnolia officinalis, and their structures were elucidated based on spectroscopic and physicochemical analyses. Among them, houpulins E (1) and M (9) possess novel homo- and trinor-neolignan skeletons. In addition, 15 known compounds (10-24) were identified by comparison of their spectroscopic and physical data with those reported in the literature. Some of the purified constituents were examined for anti-inflammatory activity and, among the tested compounds, houpulins G (3), I (5), J (6), and 2,2'-dihydroxy-3-methoxy-5,5'-di-(2-propenylbiphenyl) (19) significantly inhibited superoxide anion generation and elastase release with IC50 values ranging from 3.54 to 5.48 µM and 2.16 to 3.39 µM, respectively. Therefore, these neolignan derivatives have tremendous potential to be explored as anti-inflammatory agents.

Total synthesis of cordatanine, structural reassignment of drymaritin, and anti-inflammatory activity of synthetic precursors.

In this study, cordatanine, with a canthin-6-one skeleton, was totally synthesized in four steps via a Pictet-Spengler reaction using tryptamine and methyl glyoxylate with a total yield of 8%. The NMR spectra of synthesized cordatanine compared well with those of drymaritin isolated by Hsieh et al., confirming the need to revise the original structural assignment. In addition, kumujian A, a synthetic intermediate, showed significant anti-inflammatory effects, inhibiting both superoxide anion generation (IC50 4.87 µg/mL) and elastase release (IC50 6.29 µg/mL).

Suppression of PI3K/Akt signaling by synthetic bichalcone analog TSWU-CD4 induces ER stress- and Bax/Bak-mediated apoptosis of cancer cells.

Suppression of the activity of pro-apoptotic Bcl-2-family proteins frequently confers chemoresistance to many human cancer cells. Using subcellular fractionation, the ER calcium (Ca(++)) channel inhibitor dantrolene and small interfering RNA (siRNA) against Bax or Bak, we show that the new synthetic bichalcone analog TSWU-CD4 induces apoptosis in human cancer cells by releasing endoplasmic reticulum (ER)-stored Ca(++) through ER/mitochondrial oligomerization of Bax/Bak. Blockade of the protein kinase RNA-like ER kinase or the unfolded protein response regulator glucose-regulated protein 78 expression by siRNA not only suppressed oligomeric Bax/Bak-mediated pro-caspase-12 cleavage and apoptosis but also resulted in an inhibition of Bcl-2 downregulation induced by TSWU-CD4. Induction of the ER oligomerization of Bax/Bak and apoptosis by TSWU-CD4 were suppressed by Bcl-2 overexpression. Inhibition of lipid raft-associated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling by TSWU-CD4 induced ER stress- and oligomeric Bax/Bak-mediated apoptosis, which were substantially reversed by overexpression of the wt PI3K p85α subunit. Taken together, these results suggest that suppression of lipid raft-associated PI3K/Akt signaling is required for the ER stress-mediated apoptotic activity of Bax/Bak, which is responsible for the ability of TSWU-CD4-treated cancer cells to exit the ER-mitochondrial apoptotic cell death pathway.

Two diterpenoids and a cyclopenta[c]pyridine derivative from roots of Salvia digitaloids.

Two new glucosides, salviadigitoside A (1) and salviatalin A-19-O-ß-glucoside (2), belonging to the salviatalin type diterpenoids, and a new cyclopenta[c]pyridine, salviadiginine A (3), were isolated from the roots of Salvia digitaloids. Structures of these compounds were determined on the basis of spectroscopic analysis. In addition, compounds 1-3 were evaluated for their anti-inflammatory activity, but the results showed a weak anti-inflammatory activity.

The constituents of Michelia compressa var. formosana and their bioactivities.

Phytochemical investigation of the heartwood of Michelia compressa afforded forty-four compounds, which were identified by comparison of experimental and literature analytical and spectroscopic data. Some compounds were evaluated for their anti-inflammatory and anticancer bioactivities. The result showed that soemerine (1) and cyathisterol (2) exhibited significant nitric oxide (NO) inhibition, with IC50 values of 8.5±0.3 and 9.6±0.5 µg/mL, respectively. In addition, liriodenine (3) and oliveroline (4) exhibited cytotoxicity to human nasopharyngeal carcinoma (NPC-TW01), non-small cell lung carcinoma (NCI-H226), T cell leukemia (Jurkat), renal carcinoma (A498), lung carcinoma (A549) and fibrosarcoma (HT1080) cell lines with IC50 values in the range of 15.7-3.68 µM.

Synthesis of analogues of gingerol and shogaol, the active pungent principles from the rhizomes of Zingiber officinale and evaluation of their anti-platelet aggregation effects.

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads.

The novel carboxamide analog ITR-284 induces caspase-dependent apoptotic cell death in human hepatocellular and colorectal cancer cells.

We have previously reported that ITR-284, a potent carboxamide-derived anticancer agent, induced apoptosis in leukemia cells. However, there are no reports showing that ITR-284 inhibits human hepatocellular and colorectal cancer cells. In this study, we investigated the antiproliferative effects and apoptotic induction of ITR-284 on various types of human hepatocellular and colorectal cancer cells in vitro. The growth inhibition effect of ITR-284 on cancer cells was evaluated by thiazolyl blue tetrazolium bromide (MTT) assay. Cell morphology was examined under a phase-contrast microscope. The activities of caspase-3, -8 and -9 were determined by caspase colorimetric assay. ITR-284 reduced the cell viability in human hepatocellular cancer cells (Hep G2, Hep 3B, SK-HEP-1 and J5) and colorectal cancer cells (HT 29, COLO 205, HCT 116 and SW 620). ITR-284 had highly selective effects on Hep 3B and COLO 205 cells. ITR-284 stimulated morphological changes of Hep 3B and COLO 205 cells. The activation of caspase-3, -8 and -9 contributed to ITR-284-induced apoptosis. ITR-284-triggered growth inhibition was significantly attenuated by the inhibitors of caspase-3, -8 and -9 in Hep 3B and COLO 205 cells. ITR-284 induced apoptosis in Hep 3B and COLO 205 cells through the caspase cascade-dependent signaling pathway.

An efficient total synthesis of a potent anti-inflammatory agent, benzocamphorin F, and its anti-inflammatory activity.

A naturally occurring enynyl-benzenoid, benzocamphorin F (1), from the edible fungus Taiwanofungus camphoratus (Antrodia camphorata) was characterized by comprehensive spectral analysis. It displays anti-inflammatory bioactivity and is valuable for further biological studies. The present study is the first total synthesis of benzocamphorin F and the developed strategy described is a more efficient procedure that allowe the large-scale production of benzocamphorin F for further research of the biological activity both in vitro and in vivo.

Physalin F induces cell apoptosis in human renal carcinoma cells by targeting NF-kappaB and generating reactive oxygen species.

BACKGROUND: The aim of this study was to determine the molecular mechanisms of physalin F, an effective purified extract of Physalis angulata L. (Solanacae), in renal carcinoma A498 cells. METHODOLOGY/PRINCIPAL FINDINGS: Physalin F was observed to significantly induce cytotoxicity of three human renal carcinoma A498, ACHN, and UO-31 cells in a concentration-dependent manner; this was especially potent in A498 cells. The physalin F-induced cell apoptosis of A498 cells was characterized by MTT assay, nuclear DNA fragmentation and chromatin condensation. Using flow cytometry analysis, physalin F induced A498 cell apoptosis as demonstrated by the accumulation of the sub-G1 phase in a concentration- and time-dependent manner. Moreover, physalin F-mediated accumulation of reactive oxygen species (ROS) caused Bcl-2 family proteins, Bcl-2, and Bcl-xL degradation, which led to disruption of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-3 and caspase-9 activity, which led to poly(ADP-ribose) polymerase cleavage. However, the antioxidant N-acetyl-(L)-cysteine (NAC) and glutathione (GSH) resulted in the inhibition of these events and reversed physalin F-induced cell apoptosis. In addition, physalin F suppressed NF-κB activity and nuclear translocation of p65 and p50, which was reversed by NAC and GSH. CONCLUSION: Physalin F induced cell apoptosis through the ROS-mediated mitochondrial pathway and suppressed NF-κB activation in human renal cancer A498 cells. Thus, physalin F appears to be a promising anti-cancer agent worthy of further clinical development.

Anti-platelet aggregation and vasorelaxing effects of the constituents of the rhizomes of Zingiber officinale.

In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty-nine compounds including one new compound, O-methyldehydrogingerol. Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol and [6]-shogaol exhibited potent anti-platelet aggregation bioactivity. In addition, [10]-gingerol inhibited the Ca²âº-dependent contractions in high K⁺ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism.

An efficient synthesis of a potent anti-inflammatory agent, viscolin, and its inducible nitric oxide synthase inhibitory activity.

A new and efficient synthetic pathway employed the aldol condensation between the acetophenone (3) and vanillin derivative (4) resulted in the precursor chalcone intermediate (14). The target compound viscolin (1) could be afforded through the hydrogenation of the chalcone and followed by deprotection. The present strategy described the development of a more efficient procedure that allowed large-scale production of viscolin for the further research of biological activity both in vitro and in vivo.

Biologically active constituents from the fruiting body of Taiwanofungus camphoratus.

Five new benzenoids, benzocamphorins A-E (1-5), and 10 recently isolated triterpenoids, camphoratins A-J (16-25), together with 23 known compounds including seven benzenoids (6-12), three lignans (13-15), and 13 triterpenoids (26-38) were isolated from the fruiting body of Taiwanofungus camphoratus. Their structures were established by spectroscopic analysis. Selected compounds were examined for cytotoxic and anti-inflammatory activities. Compounds 9 and 21 showed moderate cytotoxicity against MCF-7 and Hep2 cell lines with ED(50) values of 3.4 and 3.0µg/mL, respectively. Compounds 21, 25, 26, 29-31, 33, and 36 demonstrated potent anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) production with IC(50) values of 2.5, 1.6, 3.6, 0.6, 4.1, 4.2, 2.5, and 1.5µM, respectively, which were better than those of the nonspecific nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME) (IC(50): 25.8µM). These results may substantiate the use of T. camphoratus in traditional Chinese medicine (TCM) for the treatment of inflammation and cancer-related diseases. The newly discovered compounds deserve further development as anti-inflammatory candidates.

Cardiac glycosides from Antiaris toxicaria with potent cardiotonic activity.

An ethanolic extract of Antiaris toxicaria trunk bark showed potent in vitro cardiotonic effect on isolated guinea pig atria. Bioassay-guided fractionation of the extract led to identification of nine new cardiac glycosides (1-9, named antiarosides A-I), antiarotoxinin A (10), and 18 known compounds. Their structures were established using MS and NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The ability of these cardiotonic compounds to produce positive inotropic action and their safety indexes were examined in comparison with those of ouabain, a classical inhibitor of Na(+)/K(+)-ATPase. Malayoside (23) was nearly equipotent and had a similar safety index to ouabain in guinea pig atria. However, the maximal positive inotropic effect and safety index of 23 in papillary muscle were better than those of ouabain. An electrophysiological recording showed that 23 inhibited the sodium pump current in a concentration-dependent manner.