Won Keun Oh

Publications of Won Keun Oh

• Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase.

  Authors: Rehman Gauhar, Seung-Lark Hwang, Si-Sung Jeong, Ji-Eun Kim, Hebok Song, Dong Chan Park, Kyung-Sik Song, Tae Young Kim, Won Keun Oh, Tae-Lin Huh

  Biotechnology letters. 05/2012;

  Gynostemma pentaphyllum is widely used in Asian countries as a herbal medicine to treat dyslipidemia, type 2 diabetes and inflammation. An ethanol extract of G. pentaphyllum lessened obesity byGynostemma pentaphyllum is widely used in Asian countries as a herbal medicine to treat dyslipidemia, type 2 diabetes and inflammation. An ethanol extract of G. pentaphyllum lessened obesity by activating AMP-activated protein kinase (AMPK). The levels of damulins A and B, components responsible for AMPK activation in the extract, were increased by autoclaving in a time-dependent manner. Heat-processed G. pentaphyllum extract, actiponin containing damulins A (0.93 %, w/w) and B (0.68 %, w/w), significantly stimulated fat oxidation and glucose uptake via AMPK activation in L6 myotube cells. Oral administration of actiponin to ob/ob mice for 8 weeks decreased body weight gain, liver weight, and blood cholesterol levels with AMPK activation in the soleus muscle. Our results demonstrate the beneficial effect of G. pentaphyllum on improving obesity and have elucidated the underlying molecular mechanisms.

• Xanthones from Polygala karensium inhibit neuraminidases from influenza A viruses.

  Authors: Trong Tuan Dao, Thai Trung Dang, Phi Hung Nguyen, Eunhee Kim, Phuong Thien Thuong, Won Keun Oh

  Bioorganic & medicinal chemistry letters. 04/2012;

  The emergence of the H1N1 swine flu pandemic has the possibility to develop the occurrence of disaster- or drug-resistant viruses by additional reassortments in novel influenza A virus. In the courseThe emergence of the H1N1 swine flu pandemic has the possibility to develop the occurrence of disaster- or drug-resistant viruses by additional reassortments in novel influenza A virus. In the course of an anti-influenza screening program for natural products, 10 xanthone derivatives (1-10) were isolated by bioassay-guided fractionation from the EtOAc-soluble extract of Polygala karensium. Compounds 1, 3, 5, 7, and 9 with a hydroxy group at C-1 showed strong inhibitory effects on neuraminidases from various influenza viral strains, H1N1, H9N2, novel H1N1 (WT), and oseltamivir-resistant novel H1N1 (H274Y) expressed in 293T cells. In addition, these compounds reduced the cytopathic effect of H1N1 swine influenza virus in MDCK cells. Our results suggest that xanthones from P. karensium may be useful in the prevention and treatment of disease by influenza viruses.

• Symmetric dimers of ent-kaurane diterpenoids with cytotoxic activity from Croton tonkinensis.

  Authors: Phuong Thien Thuong, Thi Hong Minh Pham, Thi Van Thu Le, Trong Tuan Dao, Thai Trung Dang, Quyet Tien Nguyen, Won Keun Oh

  Bioorganic & medicinal chemistry letters. 12/2011; 22(2):1122-4.

  Breast cancer is the most common malignant tumor in women these days accounting for approximately 24% of all cancer. During our screening program searching for cytotoxic materials from naturalBreast cancer is the most common malignant tumor in women these days accounting for approximately 24% of all cancer. During our screening program searching for cytotoxic materials from natural products, two new symmetric dimers of ent-kaurane diterpenoid, crotonkinensins C (1) and D (2), with connectivity at C-17 were isolated from the leaves of the Vietnamese endemic medicinal plant Croton tonkinensis. Their structures were determined on the basis of physicochemical and spectroscopic data. Compound 2 showed a potent cytotoxic activity against MCF-7, tamoxifen-resistant MCF-7 (MCF-7/TAMR), adriamycin-resistant MCF-7 (MCF-7/ADR), and MDA-MB-231 breast cancer cell lines.

• ent-Kaurane diterpenoids from Croton tonkinensis stimulate osteoblast differentiation.

  Authors: Trong-Tuan Dao, Kwang-Youl Lee, Hyung-Min Jeong, Phi-Hung Nguyen, Tien Lam Tran, Phuong-Thien Thuong, Bich-Thu Nguyen, Won-Keun Oh

  Journal of natural products. 11/2011; 74(12):2526-31.

  Four new ent-kaurane diterpenoids (1-4) were isolated from the leaves of Croton tonkinensis by bioactivity-guided fractionation using an in vitro osteoblast differentiation assay. Their structuresFour new ent-kaurane diterpenoids (1-4) were isolated from the leaves of Croton tonkinensis by bioactivity-guided fractionation using an in vitro osteoblast differentiation assay. Their structures were identified as ent-11β-acetoxykaur-16-en-18-ol (1), ent-11α-hydroxy-18-acetoxykaur-16-ene (2), ent-14β-hydroxy-18-acetoxykaur-16-ene (3), and ent-7α-hydroxy-18-acetoxykaur-16-ene (4). Compounds 1-4 significantly increased alkaline phosphatase activity and osteoblastic gene promoter activity. Compounds 1-3 also increased the levels of ALP and collagen type I alpha mRNA in C2C12 cells in a dose-dependent manner. These results suggest that ent-kaurane diterpenoids from C. tonkinensis have a direct stimulatory effect on osteoblast differentiation and may be potential therapeutic molecules against bone diseases such as osteoporosis.

• New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum.

  Authors: Phi Hung Nguyen, Rehman Gauhar, Seung Lark Hwang, Trong Tuan Dao, Dong Chan Park, Ji Eun Kim, Hebok Song, Tae Lin Huh, Won Keun Oh

  Bioorganic & medicinal chemistry. 11/2011; 19(21):6254-60.

  AMP-activated protein kinase (AMPK) is a key sensor and regulator of glucose, lipid, and energy metabolism throughout the body. Activation of AMPK improves metabolic abnormalities associated withAMP-activated protein kinase (AMPK) is a key sensor and regulator of glucose, lipid, and energy metabolism throughout the body. Activation of AMPK improves metabolic abnormalities associated with metabolic diseases including obesity and type-2 diabetes. The oriental traditional medicinal herbal plant, Gynostemma pentaphyllum, has shown a wide range of beneficial effects on glucose and lipid metabolism. In this study, we found that G. pentaphyllum contains two novel dammarane-type saponins designated as damulin A (1), 2α,3β,12β-trihydroxydammar-20(22)-E,24-diene-3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside], and damulin B (2), 2α,3β,12β-trihydroxydammar-20,24-diene-3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside], that strongly activate AMPK in cultured L6 myotube cells. Damulins A and B also increased β-oxidation and glucose uptake with increasing GluT4 translocation to the plasma membrane in L6 myotube cells. Taken together our results indicate that activation of AMPK by damulins A and B may contribute to beneficial effect of G. pentaphyllum on glucose and lipid metabolism.

• Nectandrin B activates endothelial nitric-oxide synthase phosphorylation in endothelial cells: role of the AMP-activated protein kinase/estrogen receptor α/phosphatidylinositol 3-kinase/Akt pathway.

  Authors: Tran Thi Hien, Won Keun Oh, Phi Hung Nguyen, Seok Jeong Oh, Moo Yeol Lee, Keon Wook Kang

  Molecular pharmacology. 09/2011; 80(6):1166-78.

  We revealed previously that nectandrin B isolated from Myristica fragrans (nutmeg, Myristicaceae) functions as a potent AMP-activated protein kinase (AMPK) activator and showed its antiobesityWe revealed previously that nectandrin B isolated from Myristica fragrans (nutmeg, Myristicaceae) functions as a potent AMP-activated protein kinase (AMPK) activator and showed its antiobesity effect. In this study, we investigated whether nectandrin B affects phosphorylation of endothelial nitric-oxide synthase (eNOS) in human endothelial cells. Nectandrin B increased the phosphorylation of eNOS and nitric oxide (NO) production in a concentration-dependent manner and maximal effect was found at 10 μg/ml. Nectandrin B activates AMPK, presumably via Ca(2+)/calmodulin kinase II activation and nectandrin B-stimulated eNOS phosphorylation was reversed by AMPK inhibition. Both the enzyme activity of phosphatidylinositol 3-kinase (PI3K) and the estrogen receptor (ER)-dependent reporter gene transcription were enhanced by nectandrin B. ERα inhibition by specific antagonist or small interfering siRNA (siRNA) suppressed nectandrin B-mediated eNOS phosphorylation. Moreover, AMPK inhibition significantly reversed the activation of ER-dependent transcription and PI3K activation in response to nectandrin B. Nectandrin B evoked endothelium-dependent relaxation in rat aortic rings, and this was blocked by inhibition of AMPK, ER, or PI3K. These results suggest that potent AMPK activator nectandrin B enhances NO production via eNOS phosphorylation in endothelial cells and ERα-dependent PI3K activity is required.

• New 5-deoxyflavonoids and their inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) activity.

  Authors: Phi Hung Nguyen, Trong Tuan Dao, Jayeon Kim, Do Tuan Phong, Derek Tantoh Ndinteh, Joseph Tanyi Mbafor, Won Keun Oh

  Bioorganic & medicinal chemistry. 06/2011; 19(11):3378-83.

  In the course of our program to search for protein tyrosine phosphatase 1B (PTPB) inhibitors, five new 5-deoxyflavonoids along with eight known derivatives were isolated from EtOAc layer of the rootIn the course of our program to search for protein tyrosine phosphatase 1B (PTPB) inhibitors, five new 5-deoxyflavonoids along with eight known derivatives were isolated from EtOAc layer of the root bark of Erythrina abyssinica. Their structures were elucidated on the basis of spectroscopic (IR, UV, MS, CD, 1D- and 2D-NMR) and physicochemical analyses. All isolates exhibited moderate inhibitory effects on the enzyme assay with IC₅₀ values ranging from 14.9 ± 1.6 to 98.1 ± 11.3 μM. Compounds with prenyl and methoxy groups in the B ring (1, 2, 4, 8, and 13) possessed strong activity (IC(50) 14.9 ± 1.6 to 19.2 ± 1.1 μM), while compounds (3, 5, and 9) with 2,2-dimethylpyrano ring showed less inhibitory effect (IC₅₀ 22.6 ± 2.3 to 72.9 ± 9.7 μM). These results suggest that prenyl and methoxy groups may be responsible for the increase on the activity of 5-deoxyflavonoids against PTP1B, but the presence of 2,2-dimethylpyrano ring on the B ring may be induced the decrease of PTP1B inhibitory activity.

• Hepatoprotective effects of chestnut (Castanea crenata) inner shell extract against chronic ethanol-induced oxidative stress in C57BL/6 mice.

  Authors: Jung-Ran Noh, Yong-Hoon Kim, Gil-Tae Gang, Jung Hwan Hwang, Hyun-Sun Lee, Sun-Yung Ly, Won-Keun Oh, Kyung-Sik Song, Chul-Ho Lee

  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 03/2011; 49(7):1537-43.

  This study was carried out to evaluate the protective effects of chestnut inner shell extract (CISE) on chronic ethanol-induced oxidative stress in liver. Mice were fed a control liquid dietThis study was carried out to evaluate the protective effects of chestnut inner shell extract (CISE) on chronic ethanol-induced oxidative stress in liver. Mice were fed a control liquid diet (Normal-control), liquid diet containing ethanol alone (EtOH+Vehicle), or were administered CISE and ethanol (EtOH+CISE) for 6 weeks. Administration of ethanol induced liver damage with significant increase of plasma GOT, GPT, hepatic triglyceride (TG) and thiobarbituric acid reactive substance (TBARS) levels. By contrast, co-treatment of CISE with ethanol significantly decreased the activities of GOT and GPT in the plasma, and hepatic TG and TBARS levels. Histological observations were consistent with the result obtained from hepatic lipid quantification. Moreover, CISE treatment with ethanol decreased CYP2E1 expression and increased activities of catalase and superoxide dismutase, which were significantly inhibited by treatment with ethanol alone. To determine the active compound of CISE, fractionation of CISE was conducted and scoparone and scopoletin were identified as main compounds. These compounds were also shown to inhibit the ethanol-induced reduction in antioxidant enzyme activity in an in vitro model system. These results suggest that CISE has protective effects against ethanol-induced oxidative damage, possibly by inhibition of lipid accumulation, peroxidation and increase of antioxidant defense system in the liver.

• Chalcones as novel influenza A (H1N1) neuraminidase inhibitors from Glycyrrhiza inflata.

  Authors: Trong Tuan Dao, Phi Hung Nguyen, Hong Sik Lee, Eunhee Kim, Junsoo Park, Seong Il Lim, Won Keun Oh

  Bioorganic & medicinal chemistry letters. 01/2011; 21(1):294-8.

  The emergence of highly pathogenic influenza A virus strains, such as the new H1N1 swine influenza (novel influenza), represents a serious threat to global human health. During our course of anThe emergence of highly pathogenic influenza A virus strains, such as the new H1N1 swine influenza (novel influenza), represents a serious threat to global human health. During our course of an anti-influenza screening program on natural products, one new licochalcone G (1) and seven known (2-8) chalcones were isolated as active principles from the acetone extract of Glycyrrhiza inflata. Compounds 3 and 6 without prenyl group showed strong inhibitory effects on various neuraminidases from influenza viral strains, H1N1, H9N2, novel H1N1 (WT), and oseltamivir-resistant novel H1N1 (H274Y) expressed in 293T cells. In addition, the efficacy of oseltamivir with the presence of compound 3 (5 μM) was increased against H274Y neuraminidase. This evidence of synergistic effect makes this inhibitor to have a potential possibility for control of pandemic infection by oseltamivir-resistant influenza virus.

• p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP-activated protein kinase to inhibit carcinogenesis.

  Authors: Prem Khanal, Won-Keun Oh, Hyo Jeong Yun, Gwang Mo Namgoong, Sang-Gun Ahn, Seong-Min Kwon, Hoo-Kyun Choi, Hong Seok Choi

  Carcinogenesis. 01/2011; 32(4):545-53.

  Phenolic constituents of virgin olive oil are reported to have antitumor activity. However, the underlying molecular mechanisms and specific target proteins of virgin olive oil remain to bePhenolic constituents of virgin olive oil are reported to have antitumor activity. However, the underlying molecular mechanisms and specific target proteins of virgin olive oil remain to be elucidated. Here, we report that dialdehydic form of decarboxymethyl ligstroside aglycone (p-HPEA-EDA), a phenolic compound of virgin olive oil, inhibits tumor promoter-induced cell transformation in JB6 Cl41 cells and suppress cyclooxygenase-2 (COX-2) and tumorigenicity by adenosine monophosphate-activated protein kinase (AMPK) activation in HT-29 cells. p-HPEA-EDA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation of extracellular signal-regulated kinases 1/2 and p90RSK in JB6 Cl41 cells, resulting in the inhibition of cell proliferation, activator protein-1 transactivation and cell transformation promoted by TPA. Moreover, p-HPEA-EDA strongly inhibited the cell viability and COX-2 expression by activation of AMPK activity in HT-29 cells, resulted from depletion of intracellular adenosine triphosphate. p-HPEA-EDA-induced activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase, phosphorylation of p53 (Ser15) and DNA fragmentation in HT-29 cells, leading to apoptosis. Importantly, p-HPEA-EDA suppressed the colony formation of HT-29 cells in soft agar. In contrast, Compound C, an AMPK inhibitor, and Z-DEVD-FMK, a caspase-3 inhibitor, blocked the p-HPEA-EDA-inhibited colony formation in HT-29 cells. In vivo chorioallantoic membrane assay also showed that p-HPEA-EDA-inhibited tumorigenicity of HT-29 cells. These findings revealed that targeted activation of AMPK and inhibition of COX-2 expression by p-HPEA-EDA contribute to the chemopreventive and chemotherapeutic potential of virgin olive oil against colon cancer cells.

• Alpinumisoflavone induces apoptosis and suppresses extracellular signal-regulated kinases/mitogen activated protein kinase and nuclear factor-κB pathways in lung tumor cells.

  Authors: Sim Namkoong, Tack-Joong Kim, Ik-Soon Jang, Keon-Wook Kang, Won-Keun Oh, Junsoo Park

  Biological & pharmaceutical bulletin. 01/2011; 34(2):203-8.

  The extracellular signal-regulated kinases/mitogen activated protein kinase (ERK/MAPK) and nuclear factor-κB (NF-κB) pathways are critical for cell survival and proliferation. AlpinumisoflavoneThe extracellular signal-regulated kinases/mitogen activated protein kinase (ERK/MAPK) and nuclear factor-κB (NF-κB) pathways are critical for cell survival and proliferation. Alpinumisoflavone (AIF), isolated from the African medicinal plant Erythrina lysistemon, is a member of the isoflavone group. In this report, we demonstrated that AIF treatment induces cell death of human lung tumor cells. Incubation of lung tumor cells with AIF increased the sub-G1 population and caspase 3/7 activity, suggesting that the cell death is caused by apoptosis. To identify the signaling pathway involved in the tumor cell death, we examined the modulation of transcriptional activity using various reporter constructs and found that AIF significantly deregulated both the ERK/MAPK and NF-κB pathways. Western blot analysis with antibodies to MAP/ERK kinase (MEK) and ERK showed that AIF dephosphorylates both MEK and ERK. Alpinumisoflavone also repressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells by inhibiting NF-κB-dependent transcription. Therefore, the cell death induced by AIF may be via repressing both the ERK/MAPK and NF-κB pathways.

• Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1.

  Authors: Won Keun Oh, Kyoung Bin Cho, Tran Thi Hien, Tae Hyung Kim, Hyung Sik Kim, Trong Tuan Dao, Hyo-Kyung Han, Seong-Min Kwon, Sang-Gun Ahn, Jung-Hoon Yoon, Tae Hyun Kim, Yoon Gyoon Kim, Keon Wook Kang

  Molecular pharmacology. 11/2010; 78(5):855-64.

  The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an importantThe transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many anticancer agents. We recently showed that a Forkhead box-containing protein of the O subfamily 1 (FoxO1) is a key regulator of MDR1 gene transcription. Because nuclear localization of FoxO1 is regulated by silent information regulator two ortholog 1 (SIRT1) deacetylase, we wondered whether SIRT1 dominates MDR1 gene expression in breast cancer cells. Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. In addition, SIRT1 inhibition reduced both nuclear FoxO1 levels and MDR1 expression in doxorubicin-resistant breast cancer cells (MCF-7/ADR) cells. A potent SIRT1 inhibitor, amurensin G (from Vitis amurensis), was identified by screening plant extracts and bioassay-guided fractionation. The compound suppressed FoxO1 activity and MDR1 expression in MCF-7/ADR cells. Moreover, pretreatment of MCF-7/ADR cells with 1 μg/ml amurensin G for 24 h increased cellular uptake of doxorubicin and restored the responsiveness of MCF-7/ADR cells to doxorubicin. In xenograft studies, injection of 10 mg/kg i.p. amurensin G substantially restored the ability of doxorubicin to inhibit MCF-7/ADR-induced tumor growth. These results suggest that SIRT1 is a potential therapeutic target of MDR1-mediated chemoresistance and that it may be possible to develop amurensin G as a useful agent for chemoresistance reversal.

• Antioxidant effects of the chestnut (Castanea crenata) inner shell extract in t-BHP-treated HepG2 cells, and CCl4- and high-fat diet-treated mice.

  Authors: Jung-Ran Noh, Gil-Tae Gang, Yong-Hoon Kim, Keum-Jin Yang, Jung-Hwan Hwang, Hyun-Sun Lee, Won-Keun Oh, Kyung-Sik Song, Chul-Ho Lee

  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 11/2010; 48(11):3177-83.

  The antioxidant effects of chestnut inner shell extract (CISE) were investigated in a tert-butylhydroperoxide (t-BHP)-treated HepG2 cells, and in mice that were administered carbon tetrachlorideThe antioxidant effects of chestnut inner shell extract (CISE) were investigated in a tert-butylhydroperoxide (t-BHP)-treated HepG2 cells, and in mice that were administered carbon tetrachloride (CCl(4)) and fed a high-fat diet (HFD). Pre-incubation with CISE significantly blocked the oxidative stress induced by t-BHP treatment in HepG2 cells (P<0.05) and preserved the activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase compared to group treated with t-BHP only. Similarly, the CCl(4)- and HFD-induced reduction of antioxidant enzymes activities in liver was prevented by CISE treatment compared to control groups. Furthermore, hepatic lipid peroxidation were remarkably lower (P<0.05) in the CISE-treated groups with t-BHP or HFD. To determine the active compound of CISE, the fractionation of CISE has been conducted and scoparone and scopoletin were identified as main compounds. These compounds were also shown to inhibit the t-BHP-induced ROS generation and reduction in antioxidant enzyme activity in an in vitro model system. From these results, it was demonstrated that CISE has the ability to protect against damage from oxidative stressors such as t-BHP, CCl(4) and HFD in in vitro and in vivo models. The CISE might be useful for the prevention of oxidative damage in liver cells and tissues.

• C-Methylated Flavonoids from Cleistocalyx operculatus and Their Inhibitory Effects on Novel Influenza A (H1N1) Neuraminidase.

  Authors: Trong-Tuan Dao, Bui-Thanh Tung, Phi-Hung Nguyen, Phuong-Thien Thuong, Sung-Sik Yoo, Eun-Hee Kim, Sang-Kyum Kim, Won-Keun Oh

  Journal of natural products. 10/2010;

  As part of an ongoing study focused on the discovery of anti-influenza agents from plants, four new (1-4) and 10 known (5-14) C-methylated flavonoids were isolated from a methanol extract ofAs part of an ongoing study focused on the discovery of anti-influenza agents from plants, four new (1-4) and 10 known (5-14) C-methylated flavonoids were isolated from a methanol extract of Cleistocalyx operculatus buds using an influenza H1N1 neuraminidase inhibition assay. Compounds 4, 7, 8, and 14, with a chalcone skeleton, showed significant inhibitory effects on the viral neuraminidases from two influenza viral strains, H1N1 and H9N2. Compound 4 showed the strongest inhibitory activity against the neuraminidases from novel influenza H1N1 (WT) and oseltamivir-resistant novel H1N1 (H274Y mutant) expressed in 293T cells with IC(50) values of 8.15 ± 1.05 and 3.31 ± 1.34 μM, respectively. Compounds 4, 7, 8, and 14 behaved as noncompetitive inhibitors in the kinetic studies. These results indicate that C-methylated flavonoids from C. operculatus have the potential to be developed as neuraminidase inhibitors for novel influenza H1N1.

• Inhibition of neointimal formation by trans-resveratrol: role of phosphatidyl inositol 3-kinase-dependent Nrf2 activation in heme oxygenase-1 induction.

  Authors: Jung Woo Kim, Sung Chul Lim, Moo Yeol Lee, Jeong Woon Lee, Won Keun Oh, Sang Kyum Kim, Keon Wook Kang

  Molecular nutrition & food research. 10/2010; 54(10):1497-505.

  Neointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitoryNeointima, defined as abnormal growth of the intimal layer of blood vessels, is believed to be a critical event in the development of vascular occlusive disease. Although resveratrol's inhibitory effects on proliferation and migration of vascular smooth muscle cells has been reported, its activity on neointimal formation is still unclear. Oral administration of trans-resveratrol significantly suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. In cultured vascular smooth muscle cells, trans-resveratrol inhibited platelet-derived growth factor-stimulated DNA synthesis and cell proliferation with down-regulation of cyclin D and pRB. Moreover, platelet-derived growth factor-induced production of reactive oxygen species was inhibited by trans-resveratrol and the compound induced heme oxygenase-1 (HO-1). The anti-proliferative activity of trans-resveratrol was reversed by an HO-1 inhibitor, ZnPPIX. Subcellular fractionation and reporter gene analyses revealed that trans-resveratrol increased the level of nuclear Nrf2 and antioxidant response element reporter activity, and that these were essential for the induction of HO-1. Trans-resveratrol also enhanced the activities of phosphatidyl inositol 3-kinase and extracellular signal regulated kinase, and phosphatidyl inositol 3-kinase was required for Nrf2/antioxidant response element-dependent HO-1 induction. These data have significant implications for the elucidation of the pharmacological mechanism by which trans-resveratrol prevents vascular occlusive diseases.

• Selected compounds derived from Moutan Cortex stimulated glucose uptake and glycogen synthesis via AMPK activation in human HepG2 cells.

  Authors: Do Thi Ha, Trinh Nam Trung, Tran Thi Hien, Trong Tuan Dao, Namhui Yim, Tran Minh Ngoc, Won Keun Oh, KihWan Bae

  Journal of ethnopharmacology. 09/2010; 131(2):417-24.

  To evaluate the effect of selected compounds derived from Moutan Cortex on glucose uptake and glycogen synthesis associated with AMPK activation in insulin-resistant human HepG2 cell. The effect ofTo evaluate the effect of selected compounds derived from Moutan Cortex on glucose uptake and glycogen synthesis associated with AMPK activation in insulin-resistant human HepG2 cell. The effect of isolated compounds (1-16) on glucose uptake and glycogen synthesis was performed using HepG2 cells. The western blot was used to determine the expression of AMPK and its downstream substrates, ACC, p-ACC, and p-GSK-3beta. The effects of the 16 compounds from Moutan Cortex on glucose metabolism in HepG2 cells under high glucose conditions were evaluated. Compounds 2, 3, and 6 displayed highly potent effects on the stimulation of glucose uptake and glycogen synthesis in human HepG2 cells under high glucose conditions. Compounds 2, 3, and 6 phosphorylate AMPK (AMP-activated protein kinase), and resulted in increased phosphorylation of GSK-3beta and suppression of lipogenic expression (ACC and FAS) in a dose-dependent manner. Compounds 2, 3, and 6 also demonstrated interesting, strong eNOS phosphorylation in human umbilical vein endothelial cells (HUVECs). Compounds 1, 4, 5-12, and 14 displayed considerable effects on hepatic glucose production, AMPK activation, and phosphorylation of GSK-3beta in HepG2 cells under high glucose conditions. These effects may indicate that the activation of AMPK by the active compounds from Moutan Cortex has considerable potential for reversing the metabolic abnormalities associated with type-2 diabetes.

• Resveratrol modulates RTX toxin-induced cytotoxicity through interference in adhesion and toxin production.

  Authors: Jong Ro Kim, Mi Hye Cha, Dool-Ri Oh, Won Keun Oh, Joon Haeng Rhee, Young Ran Kim

  European journal of pharmacology. 09/2010; 642(1-3):163-8.

  Host-parasite contact is a prerequisite for the acute cytotoxicity of Vibrio vulnificus, which is mediated primarily by RtxA1, a repeat in toxin (RTX) toxin. We found that resveratrol (at 10 or 30Host-parasite contact is a prerequisite for the acute cytotoxicity of Vibrio vulnificus, which is mediated primarily by RtxA1, a repeat in toxin (RTX) toxin. We found that resveratrol (at 10 or 30 microM), a natural polyphenol, protected HeLa cells from V. vulnificus cytotoxicity. To further characterize the underlying mechanism, the effect of resveratrol was investigated at the level of the host-microbe interactions. We studied the effects of resveratrol on adhesion, motility, cytotoxicity, and RtxA1 toxin expression of V. vulnificus. In addition, the effect of resveratrol on mouse mortality caused by V. vulnificus was investigated. Resveratrol inhibited V. vulnificus motility and the microbe adhesion to host cells, critical virulence traits for many bacteria. Resveratrol also down-regulated the expression of RtxA1 toxin at the transcriptional level and thereby protected the host cells from becoming rounded and damaged. In addition, resveratrol (20mg/kg) protected CD-1 mice from V. vulnificus infection. Taken together, these results suggest that resveratrol, a modulator of host-microbe interactions, has potential for development as a new paradigm drug to treat infectious diseases.

• New stilbenoid with inhibitory activity on viral neuraminidases from Erythrina addisoniae.

  Authors: Phi Hung Nguyen, MinKyun Na, Trong Tuan Dao, Derek Tantoh Ndinteh, Joseph Tanyi Mbafor, Jaeyoung Park, Hyeonsook Cheong, Won Keun Oh

  Bioorganic & medicinal chemistry letters. 09/2010; 20(22):6430-4.

  Influenza occurs with seasonal variations and reaches the peak prevalence in winter causing the death of many people worldwide. A few inhibitors of viral neuraminidase, including amantadine,Influenza occurs with seasonal variations and reaches the peak prevalence in winter causing the death of many people worldwide. A few inhibitors of viral neuraminidase, including amantadine, rimantadine, zanamivir, and oseltamivir, have been used as influenza therapy. However, as drug-resistant influenza viruses are generated rapidly, there is a need to identify new agents for chemotherapy against influenza. Therefore, research on more effective drugs has been given high priority. During the course of an anti-influenza screening program on natural products, two new compounds (1 and 2) along with seven known flavonoid derivatives (3-9) were isolated as active principles from an EtOAc-soluble extract of the root bark of Erythrina addisoniae. The stilbenoid (2) and chalcone (3, 4, and 6) compounds of the isolates exhibited stronger activity than the isoflavone ones. Compound 2, which is a formylated stilbenoid derivative, exhibited strong inhibition of both influenza H1N1 and H9N2 neuraminidases with IC(50) values of 8.80±0.34 μg/mL and 7.19±0.40 μg/mL, respectively.

• AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect.

  Authors: Phi Hung Nguyen, Thi Van Thu Le, Hu Won Kang, Jooyoung Chae, Sang Kyum Kim, Kwang-iI Kwon, Dae Bang Seo, Sang Jun Lee, Won Keun Oh

  Bioorganic & medicinal chemistry letters. 07/2010; 20(14):4128-31.

  AMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPKAMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPK activators from plants, this study found that the total extract of Myristica fragrans (nutmeg) activated the AMPK enzyme in differentiated C2C12 cells. As active constituents, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C(1) (6), and galbacin (7) were isolated from this extract. Among the isolates, compounds 1, 4, and 5 at 5 microM produced strong AMPK stimulation in differentiated C2C12 cells. In addition, the preventive effect of a tetrahydrofuran mixture (THF) on weight gain in a diet-induced animal model was further examined. These results suggest that nutmeg and its active constituents can be used not only for the development of agents to treat obesity and possibly type-2 diabetes but may also be beneficial for other metabolic disorders.

• Fatty acid synthase inhibitory activity of dibenzocyclooctadiene lignans isolated from Schisandra chinensis.

  Authors: MinKyun Na, Tran Manh Hung, Won Keun Oh, Byung Sun Min, Seung Ho Lee, KiHwan Bae

  Phytotherapy research : PTR. 06/2010; 24 Suppl 2:S225-8.

  Inhibition of fatty acid synthase (FAS) has been proposed to be a new therapeutic target for the treatment of cancer and obesity. In our preliminary screening study on the FAS inhibitory activity, aInhibition of fatty acid synthase (FAS) has been proposed to be a new therapeutic target for the treatment of cancer and obesity. In our preliminary screening study on the FAS inhibitory activity, a n-hexane soluble fraction prepared from the fruit of Schisandra chinensis (Schisandraceae) was found to inhibit FAS activity at 100 microg/mL. Nine dibenzocyclooctadiene lignans were isolated from the active fraction and were evaluated for their inhibitory effect on FAS for the first time. The compounds possessing a benzoyl or tigloyl group in the dibenzocyclooctadiene skeleton entirely inhibited the FAS activity in a dose dependent manner. The findings may be partially related to the anticancer effect of the medicinal plant, suggesting a further study on the anticancer potential of dibenzocyclooctadiene derivatives.