Treatment of 5-[2-(4-hydroxyphenyl)vinyl]benzene-1,3-diol (resveratrol) with an equimolar amount of silver(I) acetate in dry MeOH at 50 degrees C for 1 h followed by chromatographic purification with a short silica gel column allowed the isolation of its (E)-dehydrodimer, 5-[5-[2-(3,5-dihydroxyphenyl)vinyl]-2-(4-hydroxyphenyl)-2,3-dihydrobenzofuran-3-yl]benzene-1,3-diol, as a racemic mixture in high yield. The present method was applicable to the oxidative dimerization of 4-hydroxystilbenes such as trans-styrylphenol and 5-[6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)vinyl]-2,3-dihydrobenzofuran-3-yl]benzene-1,3-diol (epsilon-viniferin) leading to the corresponding 2-(4-hydroxyphenyl)-2,3-dihydrobenzofurans possessing various types of biological activities.
O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2␣ and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.
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