Hyo-Jung Lee

Publications of Hyo-Jung Lee

• Comparison Between Bioactive Fluoride Modified and Bioinert Anodically Oxidized Implant Surfaces in Early Bone Response Using Rabbit Tibia Model.

  Authors: Jung-Yoo Choi, Hyo-Jung Lee, Jae-Up Jang, In-Sung Yeo

  Implant dentistry. 02/2012; 21(2):124-128.

  PURPOSE:: The aim of this study was to investigate whether bioactive surfaces were more favorable to bone than bioinert surfaces by evaluating bone responses around two commercial dental implants.PURPOSE:: The aim of this study was to investigate whether bioactive surfaces were more favorable to bone than bioinert surfaces by evaluating bone responses around two commercial dental implants. MATERIALS AND METHODS:: Bioactive fluoride-modified implants (Osseospeed) were compared with bioinert oxidized implants (TiUnite). Field emission scanning electron microscopy, energy dispersive spectroscopy, and confocal laser scanning microscopy analyzed the implant surface characteristics. Five New Zealand white rabbits were used to evaluate the bone response. Each rabbit received two implants: a fluoride-modified implant in one tibia and an oxidized implant in the other. Drilling was performed bicortically, and a gap defect was created in the upper cortexonly. Bone-to-implant contact and bone area were measured on the histological specimens 2 weeks after implant insertion. RESULTS:: No significant differences were found in surface roughness (P > 0.05). The gap defects were almost filled with new bone within a period of 2 weeks. The histomorphometry revealed no significant differences in bone-to-implant contact and bone area (P > 0.05). CONCLUSIONS:: Within the limitation of this study, the bioactive fluoride-modified surface may show no superiority to the bioinert anodized surface in early bone response.

• Essential Oil of Pinus koraiensis Leaves Exerts Antihyperlipidemic Effects via Up-regulation of Low-density Lipoprotein Receptor and Inhibition of Acyl-coenzyme A: Cholesterol Acyltransferase.

  Authors: Ji-Hyun Kim, Hyo-Jung Lee, Soo-Jin Jeong, Min-Ho Lee, Sung-Hoon Kim

  Phytotherapy research : PTR. 01/2012;

  Hyperlipidemia is an important factor to induce metabolic syndrome such as obesity, diabetes and cardiovascular diseases. Recently, some antihyperlipidemic agents from herbal medicines have been inHyperlipidemia is an important factor to induce metabolic syndrome such as obesity, diabetes and cardiovascular diseases. Recently, some antihyperlipidemic agents from herbal medicines have been in the spotlight in the medical science field. Thus, the present study evaluated the antihyperlipidemic activities of the essential oil from the leaves of Pinus koraiensis SIEB (EOPK) that has been used as a folk remedy for heart disease. The reverse transcription polymerase chain reaction (RT-PCR) revealed that EOPK up-regulated low density lipoprotein receptor (LDLR) at the mRNA level as well as negatively suppressed the expression of sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), fatty acid synthase (FAS) and glycerol-3-phosphate acyltransferase (GPAT) involved in lipid metabolism in HepG2 cells. Also, western blotting showed that EOPK activated LDLR and attenuated the expression of FAS at the protein level in the cells. Consistently, EOPK significantly inhibited the level of human acylcoenzyme A: cholesterol acyltransferase (hACAT)1 and 2 and reduced the low-density lipoprotein (LDL) oxidation activity. Furthermore, chromatography-mass spectrometry (GC-MS) analysis showed that EOPK, an essential oil mixture, contained camphene (21.11%), d-limonene (21.01%), α-pinene (16.74%) and borneol (11.52%). Overall, the findings suggest that EOPK can be a potent pharmaceutical agent for the prevention and treatment of hyperlipidemia. Copyright © 2012 John Wiley & Sons, Ltd.

• Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells.

  Authors: Yun-Hee Rhee, Soo-Jin Jeong, Hyo-Jeong Lee, Hyo-Jung Lee, Wonil Koh, Ji Hoon Jung, Sun-Hee Kim, Kim Sung-Hoon

  BMC cancer. 01/2012; 12:28.

  ABSTRACT: Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP wasABSTRACT: Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.

• Gallotannin suppresses calcium oxalate crystal binding and oxalate-induced oxidative stress in renal epithelial cells.

  Authors: Hyo-Jung Lee, Soo-Jin Jeong, Moon Nyeo Park, Michael Linnes, Hee Jeoung Han, Jin Hyoung Kim, John Charles Lieske, Sung-Hoon Kim

  Biological & pharmaceutical bulletin. 01/2012; 35(4):539-44.

  Calcium oxalate monohydrate (COM) crystals bind avidly to the surface of proliferating and migrating renal endothelial cells, perhaps a key event in kidney stone formation. Oxalate-inducedCalcium oxalate monohydrate (COM) crystals bind avidly to the surface of proliferating and migrating renal endothelial cells, perhaps a key event in kidney stone formation. Oxalate-induced pre-oxidative stress can further promote crystal attachment cells. Natural products including gallotannins found in green teas have been studied as potentially novel treatments to prevent crystal retention and kidney stone formation. Gallotannin significantly inhibited COM crystal growth and binding to Madin-Darby Canine Kidney Cells type I (MDCK I) renal epithelial cells at non-toxic concentrations. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that gallotannin significantly attenuated oxalate-induced mRNA and protein expressions of monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22(phox) and p47(phox) in human primary renal epithelial cells (HRCs). Gallotannin also reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as enhanced antioxidant enzyme superoxide dismutase (SOD) activity in oxalate treated HRCs. Taken together, our findings suggest that gallotannin can contribute to nephrolithiasis prevention via direct effects on renal epithelial cells including suppression of COM binding and MCP-1 and OPN expression, along with augmenting antioxidant activity.

• Penta-O-galloyl-β-D-glucose attenuates cisplatin-induced nephrotoxicity via reactive oxygen species reduction in renal epithelial cells and enhances antitumor activity in Caki-2 renal cancer cells.

  Authors: Ho-Geon Ryu, Soo-Jin Jeong, Hee-Young Kwon, Hyo-Jung Lee, Eun-Ok Lee, Min-Ho Lee, Seung Hoon Choi, Kyoo Seok Ahn, Sung-Hoon Kim

  Toxicology in vitro : an international journal published in association with BIBRA. 12/2011; 26(2):206-14.

  Cisplatin shows limited therapeutic efficacy due to serious side effects such as nephrotoxicity and hepatotoxicity. In the present study, we demonstrate that 1,2,3,4,6-penta-O-galloyl-β-d-glucoseCisplatin shows limited therapeutic efficacy due to serious side effects such as nephrotoxicity and hepatotoxicity. In the present study, we demonstrate that 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) has protective effects against cisplatin-induced cytotoxicity and apoptosis in normal human primary renal epithelial cells (HRCs) while showing synergistic effect against cisplatin-induced cell death in human Caki-2 renal cancer cells. PGG significantly blocked cisplatin-mediated cytotoxicity and reduced cisplatin-induced sub-G1 accumulation in HRCs. Consistently, PGG reduced the number of apoptotic cell populations by TdT-mediated dUTP nick end labeling (TUNEL) and Live/Dead assays in cisplatin-treated HRCs. Furthermore, PGG suppressed PARP cleavage and caspase-3 activation, cytochrome c release, up-regulation of bax and p53 in cisplatin-treated HRCs. Moreover, PGG attenuated reactive oxygen species (ROS) production mediated by cisplatin treatment, suggesting that PGG prevented cisplatin-induced apoptosis by inhibiting ROS generation in HRCs. Notably, PGG significantly enhanced cytotoxicity and PARP cleavage in cisplatin-treated Caki-2 renal cancer cells. Combination Index (CI) revealed synergism between PGG and cisplatin in Caki-2 cells. Taken together, our findings suggest the dual effects of PGG as a protective supplement against cisplatin-induced toxicity in normal renal cells and a combination chemotherapeutic drug with cisplatin in renal cancer cells.

• Proteomic analysis of mesenchymal stem-like cells derived from ovarian teratoma: Potential role of glutathione S-transferase M2 in ovarian teratoma.

  Authors: Ihn Han, Soo-Jin Jeong, Hyo-Jung Lee, Wonil Koh, Hyo-Jeong Lee, Eun-Ok Lee, Hyun Seok Kim, Soo Jin Lee, Chang-Yan Chen, Min-Hyung Jung, Sung-Hoon Kim

  Proteomics. Clinical applications. 08/2011; 5(7-8):472.

• Cryptotanshinone enhances TNF-α-induced apoptosis in chronic myeloid leukemia KBM-5 cells.

  Authors: Ji-Hyun Kim, Soo-Jin Jeong, Tae-Rin Kwon, Sun-Mi Yun, Ji Hoon Jung, Minseok Kim, Hyo-Jung Lee, Min-Ho Lee, Seong Gyu Ko, Chang-Yan Chen, Sung-Hoon Kim

  Apoptosis : an international journal on programmed cell death. 07/2011; 16(7):696-707.

  Cryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy withCryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy with tumor necrosis factor-alpha (TNF-α) for the induction of apoptosis in human chronic myeloid leukemia (CML) KBM-5 cells. The co-treatment of cryptotanshinone with TNF-α reduced the viability of the cells [combination index (CI) < 1]. Concomitantly, the co-treatment of cryptotanshinone and TNF-α elicited apoptosis, manifested by enhanced the number of terminal deoxynucleotide transferase-mediated dUTP-nick-end labeling (TUNEL)-positive cells, the sub-G1 cell populations, and the activation of caspase-8 and -3, in comparison with the treatment with either drug alone. The treatment with cryptotanshinone further suppressed TNF-α-mediated expression of c-FLIP(L), Bcl-x(L), but the increased level of tBid (a caspase-8 substrate). Furthermore, cryptotanshinone activated p38 but not NF-κB in TNF-α-treated KBM-5 cells. The addition of a specific p38 MAPK inhibitor SB203580 significantly attenuated cryptotanshinone/TNF-α-induced apoptosis. The combination treatment of cryptotanshinone and TNF-α also stimulated the reactive oxygen species (ROS) generation. N-acetyl-L-cysteine (NAC, a ROS scavenger) was not only able to block cryptotanshinone/TNF-α-induced ROS production but also the activation of caspase-8 and p38 MAPK. Overall, our findings suggest that cryptotanshinone can sensitize TNF-α-induced apoptosis in human myeloid leukemia KBM-5 cells, which appears through ROS-dependent activation of caspase-8 and p38.

• Analgesic and anti-inflammatory effects of ethyl acetate fraction of Polygonum cuspidatum in experimental animals.

  Authors: Jong-Hyun Han, Wonil Koh, Hyo-Jung Lee, Hyo-Jeong Lee, Eun-Ok Lee, Soo Jin Lee, Jae-Ho Khil, Jung Tae Kim, Soo-Jin Jeong, Sung-Hoon Kim

  Immunopharmacology and immunotoxicology. 06/2011; 34(2):191-5.

  Polygonum cuspidatum (PC) has been used for the treatment of arthritis and urinary diseases in traditional medicine. Despite recent evidence that PC has anti-oxidant, anti-tumoral, andPolygonum cuspidatum (PC) has been used for the treatment of arthritis and urinary diseases in traditional medicine. Despite recent evidence that PC has anti-oxidant, anti-tumoral, and anti-inflammatory effects, analgesic and anti-inflammatory effects of PC have not been elucidated yet in vivo. Thus, in the present study, analgesic and anti-inflammatory effects of ethyl acetate extract of PC (EAPC) were investigated in vivo for the first time. Hot plate test and tail-flick test revealed that EAPC at 200 mg/kg exerts analgesic effect (p < 0.05). In contrast, EAPC did not show significant analgesic effect in acetic acid-induced writhing test. Serotonin-induced paw edema model and Freund's complete adjuvant (FCA)-induced adjuvant arthritis model were used to examine anti-inflammatory effect of EAPC in vivo. In serotonin-induced paw edema model, EAPC suppressed swelling inflammatory response within 12 min after serotonin injection, at both 100- and 200-mg/kg dose (p < 0.05). Consistently, in FCA-induced adjuvant arthritis model, FCA at 200 mg/kg significantly suppressed FCA-induced joint swelling within 3 days (p < 0.05), whereas FCA at 100 mg/kg showed the similar result within 5 days (p < 0.05). Furthermore, EAPC effectively inhibited positive responses of c-reactive protein and rheumatoid factor compared to untreated control. Taken together, our findings suggest that EAPC can be a potent candidate for rheumatoid arthritis treatment.

• The genome-wide expression profile of 1,2,3,4,6-penta-O-galloyl-β-D-glucose-treated MDA-MB-231 breast cancer cells: molecular target on cancer metabolism.

  Authors: Woo Sik Yu, Soo-Jin Jeong, Ji-Hyun Kim, Hyo-Jung Lee, Hyo Sook Song, Min-Seok Kim, Eunjung Ko, Hyo-Jeong Lee, Jae-Ho Khil, Hyeung-Jin Jang, Young Chul Kim, Hyunsu Bae, Chang Yan Chen, Sung-Hoon Kim

  Molecules and cells. 05/2011; 32(2):123-32.

  1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a polyphenolic compound isolated from Rhus chinensis Mill. PGG has been known to have anti-tumor, anti-angiogenic and anti-diabetic activities. The1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a polyphenolic compound isolated from Rhus chinensis Mill. PGG has been known to have anti-tumor, anti-angiogenic and anti-diabetic activities. The present study revealed another underlying molecular target of PGG in MDA-MB-231 breast cancer cells by using Illumina Human Ref-8 expression BeadChip assay. Through the Beadstudio v3 micro assay program to compare the identified genes expressed in PGG-treated MDA-MB-231 cells with untreated control, we found several unique genes that are closely associated with pyruvate metabolism, glycolysis/gluconeogenesis and tyrosine metabolism, including PC, ACSS2, ACACA, ACYP2, ALDH3B1, FBP1, PRMT2 and COMT. Consistent with microarray data, real-time RT-PCR confirmed the significant down-regulation of these genes at mRNA level in PGG-treated MDA-MB-231 cells. Our findings suggest the potential of PGG as anticancer agent for breast cancer cells by targeting cancer metabolism genes.

• Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells.

  Authors: Sora Park, Hyo-Jung Lee, Soo-Jin Jeong, Hyo Sook Song, Minseok Kim, Hyo-Jeong Lee, Eun-Ok Lee, Dong-Hyun Kim, Kyoo Seok Ahn, Sung-Hoon Kim

  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 03/2011; 49(6):1367-72.

  Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, the role of STAT3 pathway in the antitumor activity of an activeSignal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, the role of STAT3 pathway in the antitumor activity of an active ginseng saponin metabolite compound K (CK) was investigated in human multiple myeloma U266 cells. CK increased the cytotoxicity, accumulated the sub-G1 DNA population, cleaved poly (ADP-ribose) polymerase (PARP) and activated caspase-3 in U266 cells. Interestingly, CK inhibited phosphorylation of STAT3 and its upstream activators, the Janus activated kinase 1 (JAK1), but not JAK2. Furthermore, CK enhanced the expression of protein tyrosine phosphatase (PTP) SHP-1, but not PTEN. Additionally, CK down-regulated STAT3 target genes bcl-x(L), bcl-2, survivin, cyclin E and cyclin D1. Conversely, PTP inhibitor pervanadate reversed CK-mediated STAT3 inactivation and cleavages of caspase-3 and PARP. Overall, our findings demonstrate that JAK1/STAT3 signaling mediates CK-induced apoptosis in U266 cells and also suggest the chemopreventive potential of CK for treatment of multiple myeloma.

• JAK2/STAT5 signaling pathway mediates Bojungbangdocktang enhanced hematopoiesis.

  Authors: Jeonghan Lim, Soo-Jin Jeong, Wonil Koh, Ihn Han, Hyo-Jung Lee, Tae-Rin Kwon, Ji Hoon Jung, Jung Hyo Kim, Hyo-Jeong Lee, Eun-Ok Lee, Sun-Hyung Kim, Min-Ho Lee, Sung-Hoon Kim

  Phytotherapy research : PTR. 03/2011; 25(3):329-37.

  Bojungbangdocktang (BJBDT) is a medicinal herbal cocktail that has been used for cancer prevention and treatment in traditional Korean medicine. In the current study, BJBDT was demonstrated toBojungbangdocktang (BJBDT) is a medicinal herbal cocktail that has been used for cancer prevention and treatment in traditional Korean medicine. In the current study, BJBDT was demonstrated to regulate hematopoiesis. BJBDT significantly increased the expression of hematopoietic cytokines interleukin (IL)-3, stem cell factor (SCF), granulocyte-macrophage-colony stimulating factor (GM-CSF), thrombopoietin (TPO) and erythropoietin (EPO) at the level of mRNA and secretion in hematopoietic stem cells (HSCs). Additionally, BJBDT enhanced the phosphorylation of Janus activated kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) and STAT binding to gamma interferon activated sites (GAS) in HSCs. Furthermore, BJBDT significantly enhanced the growth rate of granulocyte erythrocyte monocyte macrophage colony-forming units (CFU-GEMM) and erythroid burst forming units (BFU-E) in vitro. Moreover, BJBDT increased the level of EPO at mRNA in kidney and plasma, and the numbers of erythroid-specific antigen Ter-119(+) erythroid cells in mice with aplastic anemia induced by 20% benzene. Consistently, histochemical staining revealed BJBDT increased the bone marrow and stromal cells as well as decreased macrophages and adipocytes in bone marrow tissues of mice with aplastic anemia. Taken together, the results suggest that BJBDT can enhance hematopoiesis via hematopoietic cytokine-mediated JAK2/STAT5 pathway as a potent hematopoietic candidate. Copyright © 2010 John Wiley & Sons, Ltd.

• Proteomic analysis of mesenchymal stem-like cells derived from ovarian teratoma: potential role of glutathione S-transferase M2 in ovarian teratoma.

  Authors: Ihn Han, Soo-Jin Jeong, Hyo-Jung Lee, Wonil Koh, Hyo-Jeong Lee, Eun-Ok Lee, Hyun Seok Kim, Soo Jin Lee, Chang-Yan Chen, Min-Hyung Jung, Sung-Hoon Kim

  Proteomics. 02/2011; 11(3):352-60.

  Ovarian teratoma is a dermoid cyst in the ovary that contains mature tissues such as hair, teeth, bone, thyroid, etc. To understand the molecular mechanisms of ovarian teratoma growth, a comparativeOvarian teratoma is a dermoid cyst in the ovary that contains mature tissues such as hair, teeth, bone, thyroid, etc. To understand the molecular mechanisms of ovarian teratoma growth, a comparative proteomic analysis was undertaken using mesenchymal stem cell-like cells (MSCLCs) isolated from normal human ovarian or teratoma tissues. Both normal ovarian and teratoma MSCLCs expressed stem cell markers OCT4 and NANOG, and were negatively staining with the senescence-associated (SA) β-galactosidase. Furthermore, teratoma MSCLCs had higher proliferation and colony formation rates, with more angiogenic property than that of normal MSCLCs. Proteomic study revealed that 17 proteins had the expression changes over eightfold in ovarian teratoma MSCLCs compared with normal control. Interestingly, among them, GSTM2 was strongly expressed in teratoma MSCLCs. Moreover, overexpressed GSTM2 in the teratoma was associated with downregulation of p38 MAPK and activation of AKT and survivin. Taken together, these findings suggest that that ovarian teratoma MSCLCs have a higher potency for proliferation and angiogenesis and GSTM2 appears to be involved in the regulation of other survival genes.

• Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition.

  Authors: Hyo-Jeong Lee, Nam-Jun Seo, Soo-Jin Jeong, Yongjin Park, Deok-Beom Jung, Wonil Koh, Hyo-Jung Lee, Eun-Ok Lee, Kwang Seok Ahn, Kyoo Seok Ahn, Junxuan Lü, Sung-Hoon Kim

  Carcinogenesis. 02/2011; 32(6):804-11.

  There is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compoundThere is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compound 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) can inhibit the growth and metastasis of TNBCa xenograft and target Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) 3-signaling axis. Daily oral gavage of 10 mg PGG/kg body wt decreased MDA-MB-231 xenograft weight by 49.3% (P < 0.01) at 40 days postinoculation, whereas weekly intraperitoneal injections of Taxol at the same dosage resulted in a 21.4% reduction (P > 0.1). PGG treatment also decreased the incidence of lung metastasis. Immunohistochemical staining detected decreased Ki-67 (proliferation) index and increased terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (apoptosis) index in PGG-treated and Taxol-treated xenografts. However, the CD34 (angiogenesis) index was decreased only in PGG-treated xenografts along with decreased phospho-STAT3. In cell culture of MDA-MB-231 cells, PGG decreased pSTAT3 and its downstream target proteins, decreased its upstream kinase pJAK1 and induced the expression of SHP1, a JAK1 upstream tyrosine phosphatase, within as early as 1 h of exposure. The phosphatase inhibitor pervanadate reversed the PGG-induced downregulation of pSTAT3 and caspase activation. Orally administered PGG can inhibit TNBCa growth and metastasis, probably through anti-angiogenesis, antiproliferation and apoptosis induction. Mechanistically, PGG-induced inhibition of JAK1-STAT3 axis may contribute to the observed in vivo efficacy and the effects on the cellular processes.

• Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1α inactivation in hypoxic PC-3 prostate cancer cells.

  Authors: Sung-Yun Cho, Hyo-Jeong Lee, Soo-Jin Jeong, Hyo-Jung Lee, Hyun-Seok Kim, Chang Yan Chen, Eun-Ok Lee, Sung-Hoon Kim

  Journal of pineal research. 02/2011; 51(1):87-93.

  Sphingosine kinase 1 (SPHK1) is a newly discovered modulator of hypoxia inducible factor 1α (HIF-1α) with various biological activities such as cell growth, survival, invasion, angiogenesis, andSphingosine kinase 1 (SPHK1) is a newly discovered modulator of hypoxia inducible factor 1α (HIF-1α) with various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, the biological mechanisms of melatonin were elucidated in association with SPHK1 pathway in PC-3 prostate cancer cells under hypoxia. Melatonin inhibited the stability of HIF-1α in a time- and concentration- dependent manners. Also, melatonin decreased SPHK1 activity in PC-3 cells during hypoxia. Furthermore, melatonin suppressed AKT/glycogen synthase kinase-3β (GSK-3β) signaling pathway, which stabilizes HIF-1α via inhibition of von Hippel-Lindau tumor suppressor protein. Consistently, siRNA-SPHK1 and sphingosine kinase inhibitor (SKI) effectively blocked the expression of HIF-1α, phospho-AKT and vascular endothelial growth factor (VEGF) production in PC-3 cells under hypoxia, suggesting the role of SPHK1 in melatonin-inhibited HIF-1α accumulation. Moreover, reactive oxygen species (ROS) scavenger N-acteylcysteine enhanced melatonin-inhibited HIF-1α expression and SPHK1 activity. Overall, our findings suggest that melatonin suppresses HIF-1α accumulation via inhibition of SPHK1 pathway and ROS generation in PC-3 cells under hypoxia.

• Anethole exerts antimetatstaic activity via inhibition of matrix metalloproteinase 2/9 and AKT/mitogen-activated kinase/nuclear factor kappa B signaling pathways.

  Authors: Eun Jeong Choo, Yun-Hee Rhee, Soo-Jin Jeong, Hyo-Jung Lee, Hyun Seok Kim, Hyun Suk Ko, Ji-Hyun Kim, Tae-Rin Kwon, Ji Hoon Jung, Jin Hyoung Kim, Hyo-Jeong Lee, Eun-Ok Lee, Dae Keun Kim, Chang-Yan Chen, Sung-Hoon Kim

  Biological & pharmaceutical bulletin. 01/2011; 34(1):41-6.

  Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptoticAnethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-κB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-κB signal transducers.

• Melatonin promotes puromycin-induced apoptosis with activation of caspase-3 and 5'-adenosine monophosphate-activated kinase-alpha in human leukemia HL-60 cells.

  Authors: Wonil Koh, Soo-Jin Jeong, Hyo-Jung Lee, Ho-Geon Ryu, Eun-Ok Lee, Kyoo Seok Ahn, Hyunsu Bae, Sung-Hoon Kim

  Journal of pineal research. 01/2011; 50(4):367-73.

  Melatonin, a naturally occurring molecule, is produced by the pineal gland in a circadian manner to regulate biologic rhythms in humans. Recent studies report that melatonin may be an attractiveMelatonin, a naturally occurring molecule, is produced by the pineal gland in a circadian manner to regulate biologic rhythms in humans. Recent studies report that melatonin may be an attractive candidate as an anticancer agent or for combined therapy because of its antioxidant, oncostatic and immunoregulatory activities. In this study, the potentiating effect of melatonin was evaluated on the apoptosis induced by puromycin as an anticancer drug in acute promyelocytic leukemia HL-60 cells. Melatonin did not show significant cytotoxicity against HL-60 cells compared to puromycin. However, melatonin significantly augmented the cytotoxicity of puromycin. Consistently, combined treatment of melatonin and puromycin reduced the expression of anti-apoptotic proteins, such as bcl-2 and bcl-x(L) , and also induced caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage compared to puromycin treatment alone. Furthermore, cell cycle analysis revealed that melatonin promoted puromycin-induced apoptosis by increasing the sub-G1 population, but suppressing G2/M arrest in HL-60 cells. Interestingly, melatonin activated the phosphorylation of 5'-adenosine monophosphate-activated kinase (AMPK) in combination with puromycin. Taken together, our results suggest that melatonin potentiates puromycin-induced apoptosis with caspase-3 and AMPK activation in HL-60 cells, and thus, melatonin treatment can be effectively applied to leukemia treatment as a potential sensitizer for chemotherapeutic agents.

• Antiangiogenic phytochemicals and medicinal herbs.

  Authors: Soo-Jin Jeong, Wonil Koh, Eun-Ok Lee, Hyo-Jung Lee, Hyo-Jeong Lee, Hyunsu Bae, Junxuan Lü, Sung-Hoon Kim

  Phytotherapy research : PTR. 01/2011; 25(1):1-10.

  Medicinal herbs and their phytochemicals are potential novel leads for developing antiangiogenic drugs. This review aims to assess the current status of research with medicinal herbs and theirMedicinal herbs and their phytochemicals are potential novel leads for developing antiangiogenic drugs. This review aims to assess the current status of research with medicinal herbs and their phytochemicals for the development of antiangiogenic agents for cancer and other angiogenesis-related diseases including inflammation, diabetic retinopathy, endometriosis and obesity. Most studies reviewed have focused on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR-2) signaling for endothelial response processes and have led to the identification of many potential antiangiogenic agents. Since human clinical trials with antiangiogenic modalities targeting VEGF/VEGFR-2 signaling have shown limited efficacy and occasional toxic side effects, screening strategies for herbal phytochemicals based on other signaling pathways important for cancer-endothelial and stromal crosstalks should be emphasized in the future.

• Rhapontigenin inhibited hypoxia inducible factor 1 alpha accumulation and angiogenesis in hypoxic PC-3 prostate cancer cells.

  Authors: Deok-Beom Jung, Hyo-Jeong Lee, Soo-Jin Jeong, Hyo-Jung Lee, Eun-Ok Lee, Young Chul Kim, Kyoo Seok Ahn, Chang-Yan Chen, Sung-Hoon Kim

  Biological & pharmaceutical bulletin. 01/2011; 34(6):850-5.

  Hypoxia inducible factor 1 alpha (HIF-1α) is frequently over-expressed in the numerous types of cancer and plays an important role in angiogenesis. In the present study, the inhibitory mechanism ofHypoxia inducible factor 1 alpha (HIF-1α) is frequently over-expressed in the numerous types of cancer and plays an important role in angiogenesis. In the present study, the inhibitory mechanism of rhapontigenin isolated from Vitis coignetiae was investigated on HIF-1α stability and angiogenesis in human prostate cancer PC-3 cells. Rhapontigenin significantly suppressed HIF-1α accumulation at protein level but not at mRNA level in PC-3 cells under hypoxia. Also, rhapontigenin suppressed hypoxia-induced HIF-1α activation in various cancer cells, such as colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF-7), fibrosarcoma (HT-1080) and prostate carcinoma (LNCaP). Interestingly, rhapontigenin had more potency in inhibition of hypoxia-induced HIF-1α expression than that of resveratrol, a known HIF-1α inhibitor. In addition, rhapontigenin promoted hypoxia-induced HIF-1α degradation and cycloheximide (CHX) blocked protein synthesis. A prolyl hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) is usually utilized to examine whether prolyl hydroxylation is involved in inhibition of HIF-1α accumulation. Here, DMOG recovered HIF-1α accumulation inhibited by rhapontigenin. Immunoprecipitation assay also revealed that rhapotigenin enhanced the binding of hydroxylated HIF-1α to von Hippel-Lindau (VHL) tumor suppressor protein. Furthermore, rhapontigenin reduced vascular endothelial growth factor (VEGF) secretion in hypoxic PC-3 cells as well as suppressed tube formation in human umbilical vein endothelial cells (HUVECs) treated by the conditioned media of hypoxic PC-3 cells. However, anti-angiogenic effect of rhapontigenin in hypoxic PC-3 cells was reversed by DMOG. Taken together, these findings suggest that rhapontigenin inhibits HIF-1α accumulation and angiogenesis in PC-3 prostate cancer cells.

• Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells.

  Authors: Jimin Shin, Hyo-Jeong Lee, Deok-Beom Jung, Ji Hoon Jung, Hyo-Jung Lee, Eun-Ok Lee, Seok Geun Lee, Beom Sang Shim, Seung Hoon Choi, Seong Gyu Ko, Kwang Seok Ahn, Soo-Jin Jeong, Sung-Hoon Kim

  PloS one. 01/2011; 6(6):e21492.

  Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the presentSignal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1α (HIF-1α) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1α and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia. Taken together, our results suggest that BA has anti-angiogenic activity by disturbing the binding of HIF-1α and STAT3 to the VEGF promoter in hypoxic PC-3 cells.

• Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic rheumatoid synoviocytes.

  Authors: Mi-Kyoung Ha, Young Hoon Song, Soo-Jin Jeong, Hyo-Jung Lee, Ji Hoon Jung, Bonglee Kim, Hyo Sook Song, Jeong-Eun Huh, Sung-Hoon Kim

  Biological & pharmaceutical bulletin. 01/2011; 34(9):1432-7.

  Chronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects ofChronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) isolated from the root of Rheum palmatum L. in interleukin 1 beta (IL-1β) and lipopolysaccharide (LPS)-stimulated RA synoviocytes under hypoxia. Emodin significantly inhibited IL-1β and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Also, enzyme linked immunosorbent assay (ELISA) revealed that emodin significantly reduced the production of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), IL-6 and IL-8], mediators [prostagladin E(2) (PGE(2)), matrix metalloproteinase (MMP)-1 and MMP-13] and vascular endothelial growth factor (VEGF) as an angiogenesis biomarker in IL-1β and LPS-treated synoviocytes under hypoxia. Consistently, emodin attenuated the expression of cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1α), MMP-1 and MMP-13 at mRNA level in IL-1β and LPS-treated synoviocytes under hypoxia. Furthermore, emodin reduced histone deacetylase (HDAC) activity as well as suppressed the expression of HDAC1, but not HDAC2 in IL-1β and LPS-treated synoviocytes under hypoxia. Overall, these findings suggest that emodin inhibits proinflammatory cytokines and VEGF productions, and HDAC1 activity in hypoxic RA synoviocytes.