Effects of chimeric decoy oligodeoxynucleotide in the regulation of transcription factors NF-κB and Sp1 in an animal model of atherosclerosis.

Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-κB and Sp1-binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.

Compounds from the heartwood of Caesalpinia sappan and their anti-inflammatory activity.

Two new phenolics, (3S,4R)-3,7,2',3'-tetrahydroxy-3,4-dihydro-9H-indeno[6,5-c]chromene (caesalpiniaphenol E, 1), and (3R,4S)-3,7-dihydroxy-3-(3'-methoxy-4'-hydroxyphenyl)-4-methoxychroman (caesalpiniaphenol F, 2), together with eleven known compounds (3-13), were isolated from the heartwood of Caesalpinia sappan. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW264.7 cells. Among them, compounds 10 and 13 showed strong inhibitory activities toward the LPS-induced NO production in macrophage RAW264.7 cells, with IC(50) values of 12.5 and 8.1 µm, respectively. In addition, compounds 10 and 13 inhibited the inductions of iNOS mRNA in dose-dependent manners, indicating that these compounds attenuated the synthesis of these transcripts at the transcriptional level.

Apamin inhibits THP-1-derived macrophage apoptosis via mitochondria-related apoptotic pathway.

The development of atherosclerotic lesions is mainly due to macrophage death. The oxidative stresses of monocytes/macrophages play a vital role in the initiation and amplification of atherosclerosis. Apamin, a component of bee venom, exerts an anti-inflammatory effect, and selectively inhibits the Ca(2+)-activated K(+) channels. The mechanisms involved in the inhibition of macrophage apoptosis have been fully elucidated. We induced oxidized low-density lipoprotein (oxLDL) in THP-1-derived macrophage and studied the effect of apamin on intercellular lipid levels, mitochondria-related apoptotic pathway and numbers of apoptotic cells. Oil-red O staining indicates that the inhibition of apamin in the condition significantly prevents intracellular lipid deposition. Treatment with apamin significantly decreased the apoptotic macrophages by decreasing the expression of pro-apoptotic genes Bax, caspase-3 and PARP protein levels, as well as through increasing expression of anti-apoptotic genes Bcl-2 and Bcl-xL protein levels in the absence and presence of oxLDL. In vivo, with apamin treatment reduced apoptotic cells death by TUNEL staining. These results indicate that apamin plays an important role in monocyte/macrophage apoptotic processing, which may provide a potential drug for preventing atherosclerosis.

A new cytotoxic coumarin, 7-[(E)-3',7'-dimethyl-6'-oxo-2',7'-octadienyl] oxy coumarin, from the leaves of Zanthoxylum schinifolium.

A new coumarin, 7-[(E)-3',7'-dimethyl-6'-oxo-2',7'-octadienyl]oxy coumarin (1), together with three known compounds, schinilenol (2), schinindiol (3) and 7-[(E)-7'-hydroxy-3',7'-dimethylocta-2',5'-dienyloxy]-coumarin (4) were isolated from the methylene chloride fraction of Z. schinifolium by normal and reverse phase column chromatographies. Their structures were determined on the basis of physical and spectroscopic evidences. Compound 1 (IC(50) 8.10 µM) showed potent cytotoxicity compared to auraptene (IC(50) 55.36 µM) against Jurkat T cells. The other isolated compounds 2 and 4 exhibited weak cytotoxicities.

Monoterpenoids from the aerial parts of Aruncus dioicus var. kamtschaticus and their antioxidant and cytotoxic activities.

The aerial parts of Aruncus dioicus var. kamtschaticus afforded five new monoterpenoids (1-5): 4-(erythro-6,7-dihydroxy-9-methylpent-8-enyl)furan-2(5H)-one (1, aruncin A), 2-(8-ethoxy-8-methylpropylidene)-5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylic acid (2, aruncin B), 4-(hydroxymethyl)-6-(8-methylprop-7-enyl)-5,6-dihydro-2H-pyran-2-one-11-O-ß-D-glucopyranoside (3, aruncide A), (3S,4S,5R,10R)-3-(10-ethoxy-11-hydroxyethyl)-4-(5-hydroxy-7-methylbut-6-enyl)oxetan-2-one-11-O-ß-D-glucopyranoside (4, aruncide B), and (3S,4S,5R,7R)-5-(9-methylprop-8-enyl)-1,6-dioxabicyclo[3,2,0]heptan-2-one-7-(hydroxymethyl)-12-O-ß-D-glucopyranoside (5, aruncide C). Compound 2 showed potent cytotoxicity against Jurkat T cells with an IC(50) value of 17.15 µg/mL. In addition, compounds 7 and 10 exhibited moderate antioxidant activity with IC(50) values of 46.3 and 11.7 µM, respectively.

Anti-inflammatory action of legume isoflavonoid sophoricoside through inhibition on cyclooxygenase-2 activity.

Soy is a main source of isoflavonoids which are of high dietary intake for the oriental population. In this study, the anti-inflammatory action of sophoricoside, an isoflavone glycoside isolated from immature fruits of Sophora japonica L. (Leguminosae), has been demonstrated. When administered orally at > 100 mg/kg or injected intravenously at > 10 mg/kg, sophoricoside showed significant reduction of carrageenin-induced paw edema in mice. Sophoricoside has been identified as a selective inhibitor of cyclooxygenase (COX)-2 activity with an IC50 value of 3.3 microM.