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Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from Alnus japonica has shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of β-catenin through β-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked β-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the leading causes of cancer, and it has the lowest 5-year survival rates. It is necessary to develop more potent anti-pancreatic cancer drugs to overcome the fast metastasis and resistance to surgery, radiotherapy, chemotherapy, and combinations of these. We have identified several diarylheptanoids as anti-pancreatic cancer agents from Alpinia officinarum (lesser galangal) and Alnus japonica. These diarylheptanoids suppressed cell proliferation and induced the cell cycle arrest of pancreatic cancer cells (PANC-1). Among them, the most potent compounds 1 and 7 inhibited the shh-Gli-FoxM1 pathway and their target gene expression in PANC-1 cells. Furthermore, they suppressed the expression of the cell cycle associated genes that were rescued by the overexpression of exogenous FoxM1. Taken together, (E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one ( 1) from Alpinia officinarum (lesser galangal) and platyphyllenone ( 7) from Alnus japonica inhibit PANC-1 cell proliferation by suppressing the shh-Gli-FoxM1 pathway, and they can be potential candidates for anti-pancreatic cancer drug development. [ABSTRACT FROM AUTHOR]

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic ( Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence. [ABSTRACT FROM AUTHOR]

The DataChip is a universal platform for three-dimensional (3D) cell cultures on a micropillar chip, which can be applicable to a variety of human cells to simulate organ-specific toxicity. In addition, the MetaChip is developed for various combinations of drug metabolizing enzymes that can be spotted into the microwell chip and incubated with 3D human cells to simulate systematic compound metabolism in the human liver on a microscale format. Ajoenes have been known for various therapeutics activities, including anticancer effects, but there was limited information available in regard to their metabolism and cytotoxicity. In the present work, the metabolism-mediated toxicity of ajoenes was evaluated on a DataChip/MetaChip platform. In detail, we tested cytotoxicity of E- and Z-ajoene on 3D cultured Hep3B human hepatoma cells coupled with mixtures of drug metabolizing enzymes. Metabolic profiles of ajoenes were assessed with 23 representative drug metabolizing enzymes on the MetaChip. As a result, cytotoxicity of E-ajoene was significantly augmented in the presence of cytochrome P450 (CYP) isoforms, such as CYP2E1 and CYP3A5. Both E- and Z-ajoene were drastically detoxified in the presence of Phase II enzymes, including major UGTs, SULTs, NATs, and GSTs. Interestingly, All Mix, an artificial human liver microsome containing representative P450 mixture and phase II enzyme mixture, attenuated P450-induced cytotoxicity of ajoenes. Conclusively, we were able to confirm the metabolism-medicated toxicity of ajoenes on the chip. [ABSTRACT FROM AUTHOR]

We have designed the cyclopropane analog of stilbene as subtype-selective ligands for estrogen receptor based on the bioisosterism that cyclopropane could act as alkene bioisoster. Three cyclopropane analogs were prepared efficiently starting from 4-benzyloxybenzaldehyde, and evaluated for their binding to estrogen receptors ERα and ERβ. These cyclopropane analogs were also found to be full agonists in estrogen receptor-mediated gene transcription assay. Compared to the stilbene analogs such as tamoxifen and raloxifene, the three cyclopropane analogs showed lower binding affinity for estrogen receptor, but higher subtype selectivity for ERα. The structure-activity relationship revealed from this study might provide clues for improving subtype selectivity for ERα. [ABSTRACT FROM AUTHOR]

The incidence of breast cancer in Korea has been increasing for the last two decades (1983–2005), and now, breast cancer is ranked the leading cause of cancer in Korean women. Along with other endocrine disrupting chemicals (EDCs), bisphenol A (BPA) has been suspected as a potential risk factor for breast cancer. We studied potential associations between BPA exposure and breast cancer risks in Korean women by performing biomonitoring of BPA among breast cancer patients and controls ( N = 167). Blood samples were collected between 1994 and 1997 and kept over 10 years in a freezer under well controlled conditions. The blood BPA levels determined by HPLC/FD, ranged between LOD (0.012 µg/L) and 13.87 µg/L (mean ± SD, 1.69 ± 2.57 µg/L; median, 0.043 µg/L). In age-matched subjects ( N = 152), there were some associations between BPA levels and risks of breast cancer, such as age at first birth and null parity. However, there were no significant differences in blood BPA levels between the cases and the controls ( P = 0.42). Considering interactions between BPA exposure and risks of breast cancer, we suggest further enlarged biomonitoring studies of BPA to provide effective prevention against breast cancer. [ABSTRACT FROM AUTHOR]

Activated microglia produce diverse neurotoxic factors such as nitric oxide (NO) and prostaglandin E2 (PGE2) that may cause neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. From the EtOAc soluble fraction of Farfarae flos ( Tussilago farfara), we purified tussilagone as a bioactive compound by monitoring the inhibitory potential of NO production in activated microglia through the purification procedures. Tussilagone showed dose-dependent inhibition of NO and PGE2 production in LPS-activated microglia with IC50 values of 8.67 μM and 14.1 μM, respectively. It suppressed the expression of protein and mRNA of inducible nitric oxide synthase and cyclooxygenase-2 through the inhibition of 1-κBα degradation and nuclear translocation of p65 subunit of NF-κB. Therefore tussilagone from Farfarae flos may have therapeutic potential in the treatment of neuro-inflammatory diseases through the inhibition of overproduction of NO and PGE2. [ABSTRACT FROM AUTHOR]

Benzothiazole derivatives of thiazolidinediones (TZD) were synthesized using a modified Mitsunobu reaction of 2-(benzothiazol-2-ylmethylamino)ethanol ( 2) with 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione and assayed for activity on peroxisome proliferator-activated receptor (PPAR) subtypes and inhibitory activity of NO production in lipopolysaccharide-activated macrophages. Most of the tested compounds were identified as potent PPARγ agonists, indicating their potential as drug candidates for diabetes. [ABSTRACT FROM AUTHOR]

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) is known to be responsible for vasodilation and hypotension observed in septic shock and inflammation. Inhibitors of iNOS, thus, may be useful candidates for the treatment of inflammatory diseases accompanied by overproduction of NO. In the course of screening oriental anti-inflammatory herbs for the inhibitory activity of NO synthesis, a crude methanolic extract of Curcuma zedoaria exhibited significant activity. The activity-guided fractionation and repetitive chromatographic procedures with the EtOAc soluble fraction allowed us to isolate three active compounds. They were identified as 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one ( 1), procurcumenol ( 2) and epiprocurcumenol ( 3) by spectral data analyses. Their concentrations for the 50% inhibition of NO production (IC50) in lipopolysaccharide (LPS)-activated macrophages were 8, 75, 77 μM, respectively. Compound 1 showed the most potent inhibitory activity for NO production in LPS-activated macrophages, while the epimeric isomers, compound 2 and 3 snowed weak and similar potency. Inhibition of NO synthesis by compound 1 was very weak when activated macrophages were treated with 1 after iNOS induction. In the immunoblot analysis, compound 1 suppressed the expression of iNOS in a dose-dependent manner. In summary, 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one from Curcuma zedoaria inhibited NO production in LPS-activated macrophages through suppression of iNOS expression. These results imply that the traditional use of C. zedoaria rhizome as anti-inflammatory drug may be explained at least in part, by inhibition of NO production. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is an important bioactive agent that mediates a wide variety of physiological and pathophysiological events. NO overproduction by inducible nitric oxide synthase (iNOS) results in severe hypotension and inflammation. This investigation is part of a study to dis-cover new iNOS inhibitors from medicinal plants using a macrophage cell culture system. Two sesquiterpenes (1 and 2) were isolated from Artemisia iwayomogi (Compositae) and were found to inhibit NO synthesis (IC50 3.64 μg/mL and 2.81 ng/mL, respectively) in lipopolysac-charide (LPS)-activated RAW 264.7 cells. Their structures were identified as 3-O-methyl-iso-secotanapartholide (1) and iso-secotanapartholide (2). Compounds 1 and 2 inhibited the LPS-induced expression of the iNOS enzyme in the RAW 264.7 cells. The inhibition of NO produc-tion via the down regulation of iNOS expression may substantially modulate the inflammatory responses. [ABSTRACT FROM AUTHOR]

A new guaiane type sesquiterpene was isolated from the fruit of Torilis japonica (Umbelliferae). Based on NMR, IR and mass spectroscopy its structure was confirmed as deangeloyloxy torilin, 1ß, 7α, 10αH-11 -acetoxy-guaia-4-en-3-one ( 1). This is the first report showing that this compound can be isolated from Torilis japonica. [ABSTRACT FROM AUTHOR]

In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (yomogin) isolated from medicinal plant Artemisia princeps Pampan inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing i-NOS enzyme expression. Thus, yomogin may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO. [ABSTRACT FROM AUTHOR]

A new celastraceae alkaloid, euojaponine C has been isolated from the methanol extract of the root bark of Euonymus japonica. With the relative stereochemistry of euojaponine C established by NOESY data, the absolute stereochemistry has been determined by circular dichroism (CD) exciton chirality method. The CD of the 2, 5-bis-phenyl benzoate of triacetonide derived from the LiAlH4 hydrolysate, euonyminol shows that the configuration of C-2 and C-5 are both R. [ABSTRACT FROM AUTHOR]

Protein X is one of the subunits of pyruvate dehydrogenase complex. The biological role of this protein has not been fully elucidated, mainly because of the difficulty in its dissociation from the tightly bound dihydrolipoamide acetyltransferase-protein X subcomplex. We have found that the detachment of protein X from acetyltransferase subunit can be easily accomplished by the cycles of freezing and thawing process. Several lines of evidence including sodium dodecyl sulfate-polyacrylamide gel electrophoresis, N-terminal amino acid sequence analysis and acetylation with [2-C] pyruvate confirmed that the purified protein is protein X. The purified intact form of protein X was acetylated by [2-C] pyruvate in the presence of pyruvate dehydrogenase subunit. The acetylation efficiency of this protein was lower than that of acetyltransferase and was not affected by the presence of acetyltransferase. [ABSTRACT FROM AUTHOR]

A genuine dammarane glycoside, named ginsenoside Rg, has been isolated by repeated column chromatography and preparative HPLC from the MeOH extract of Korean red ginseng ( Panax ginseng C.A. Meyer). The chemical structure of ginsenoside Rg was determined as 3-O-[β-D-glucopyranosyl (1→2)-β-D-glucopyranosyl] dammar-20(22),24-diene-3β,12β-diol by spectral and chemical methods. The stereostructure of a double bond at C-20(22) of ginsenoside Rg was characterized as (E) from the chemical shift of C-21 in theC-NMR and a NOESY experiment in theH-NMR. [ABSTRACT FROM AUTHOR]

Colon cancer is one of the most common cancers. In this study, we isolated a lignan [(−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica (Betulaceae) and investigated its biological activity and mechanism of action on colon cancer. DFS reduced the viability of colon cancer cells and induced cell cycle arrest. DFS also suppressed β-catenin nuclear translocation and β-catenin target gene expression through a reduction in FoxM1 protein. To assess the mechanism of the action of DFS, we investigated the effect of DFS on endogenous and exogenous FoxM1 protein degradation in colon cancer cells. DFS-induced FoxM1 protein degradation was suppressed by lysosomal inhibitors, chloroquine and bafilomycin A1, but not by knock-down of proteasomal proteins. The mechanism of DFS for FoxM1 degradation is lysosomal dependent, which was not reported before. Furthermore, we found that FoxM1 degradation was partially lysosomal-dependent under normal conditions. These observations indicate that DFS from A. japonica suppresses colon cancer cell proliferation by reducing β-catenin nuclear translocation. DFS induces lysosomal-dependent FoxM1 protein degradation. This is the first report on the lysosomal degradation of FoxM1 by a small molecule. DFS may be useful in treating cancers that feature the elevated expression of FoxM1. [ABSTRACT FROM AUTHOR]