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( Tilak Khanal ),( Hyung Gyun Kim ),( Minh Truong Do ),( Jae Ho Choi ),( Seong Su Won ),( Wonku Kang ),( Young Chul Chung ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells.ⓒ2014 Elsevier inc. All rights resenved.
( Tilak Khanal ),( Hyung Gyun Kim ),( Jae Ho Choi ),( Bong Hwan Park ),( Minh Truong Do ),( Mi Jeong Kang ),( Hee Kyung Yeo ),( Dong Hyun Kim ),( Won Ku Kang ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2012 영남대학교 약품개발연구소 연구업적집 Vol.22 No.0
Baicalin, a glycoside present in Scutellaria baicalensis Georgi, is metabolized to its aglycone, baicalein, in intestine. In the present study, possible role of metabolism of baicalin by intestinalbacteria to baicalein in baicalin-induced toxicity was investigated in HepG2 cell cultures. As anintestinal bacterial metabolic system for baicalin, human fecal preparation containing intestinalmicroflora (fecalase) was employed. Initially, when cytotoxic effects of baicalin and baicalein were compared, baicalin was more cytotoxic than baicalein in HepG2 cells. When baicalin was incubated with fecalase, it was metabolized to baicalein. In addition, baicalin-incubated with fecalase reduced cytotoxicity of HepG2 cells in a concentration-dependent manner. Moreover, baicalin-incubated with fecalase significantly caused an increase in Bcl-2 expression together with a decrease in Bax expression and cleaved Caspase-3. Furthermore, anti-apoptotic effect by the incubation of baicalin with fecalase was also confirmed by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling assay. Taken all together, the findings suggested that metabolism of baicalin by human fecalase to baicalein might have protective effects against baicalin-induced toxicity in HepG2cells.
( Tilak Khanal ),( Hyung Gyun Kim ),( Sun Woo Jin ),( Eol Shim ),( Hwa Jeong Han ),( Keumhan Noh ),( Sunkyoung Park ),( Dae Hun Lee ),( Wonku Kang ),( Hee Kyung Yeo ),( Dong Hyun Kim ),( Tae Cheon Jeo 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Parabens are alkyl esters of p-hydroxybenzoic acid (BA), including methyl paraben (MP), ethyl paraben, propyl paraben (PP), and butyl paraben (BP). In the present study, possible role of metabolism by fecalase in BP-induced cytotoxicity was investigated in HepG2 cell cultures. As an intestinal bacterial metabolic system, a human fecalase prepared from human fecal specimen was employed. Among the parabens tested, cytotoxicity of BP was most severe. BA, the de-esterified metabolite, did not induce cytotoxicity when compared to other parabens. When BP was incubated with fecalase, it rapidly disappeared, in association with reduced cytotoxicity in HepG2 cells. In addition, BP incubated with fecalase significantly caused an increase in Bcl-2 expression together with a decrease in Bax expression and cleaved caspase-3. Moreover, anti-apoptotic effect by the incubation of BP with fecalase was also confirmed by the TUNEL assay. Furthermore, BP induced a sustained activation of the phosphorylation of JNK only when it was treated alone. Meanwhile, BP-induced cell death was reversed by the pre-incubation of BP with either fecalase or SP600125. Taken together, the findings suggested that metabolism of BP by human fecalase might have protective effects against BP-induced toxicity in HepG2 cells. ⓒ2012 Elsevier lreland Lrd. Al rights reserved.
( Tilak Khanal ),( Hyung Gyun Kim ),( Minh Truong Do ),( Jae Ho Choi ),( Yong Chul Chung ),( Hee Suk Kim ),( Youn Joon Park ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Genipin is a compound found in gardenia fruit extract with diverse pharmacological activities. However, the mechanism underlying genipin-induced cyclooxygenase-2 (COX-2) expression remains unknown. In this study, we investigated the effects of genipin on COX-2 expression and determined that exposure to genipin dose-dependently enhanced the production of prostaglandin E2 (PGE2), a major COX-2 metabolite, in RAW 264.7 cells. These effects were mediated by genipin-induced activation of the COX-2 promoter, as well as AP-1 and NF-κB luciferase constructs. Phosphatidylinositol-3-kinase/Akt and MAPKs were also significantly activated by genipin, and Akt and MAPKs inhibitors (PD98059, SB20358, SP600125, and LY294002) inhibited genipin-induced COX-2 expression. Moreover, genipin increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2 and NOX3. Inhibition of NADPH with diphenyleneiodonium attenuated ROS production, COX-2 expression and NF-κB and AP-1 activation. These results suggest that the molecular mechanism mediating ROS-dependent COX-2 up-regulation and PGE2 production by genipin involves activation of Akt, MAPKs and AP-1/NF-κB.ⓒ2013 Elsevier Ltd. All rights reserved.
Role of Metabolism by Human Intestinal Microflora in Geniposideinduced Toxicity in HepG2 Cells
Mi Jeong Kang,Tae Cheon Jeong,Tilak Khanal,Hyung Gyun Kim,Dae Hun Lee,Hee Kyung Yeo,이용섭,Young Tae Ahn,김동현,정혜광 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.4
Possible role of metabolism by the intestinal bacteria in geniposide-induced cytotoxicity was investigated in human hepatoma HepG2 cells. Initially, toxic effects of geniposide and its metabolite genipin were compared. Genipin, a deglycosylated form of geniposide, was cytotoxic at the concentrations that geniposide was not. As metabolic activation systems for geniposide, human intestinal bacterial cultures, fecal preparation (fecalase) and intestinal microbial enzyme mix were employed in the present study. When geniposide was incubated with human intestinal bacteria, either Bifidobacterium longum HY8001 or Bacteroides fragilis, for 24 h, the cultured media caused cytotoxicity in HepG2 cells. Fecalase and intestinal enzyme mix were also effective to metabolically activate geniposide to its cytotoxic metabolite. The present results indicated that genipin, a metabolite of geniposide, might be more toxic than geniposide, and that intestinal bacteria might have a role in biotransformation of geniposide to its toxic metabolite. In addition, among three activation systems tested, intestinal microbial enzyme mix would be convenient to use in detecting toxicants requiring metabolic activation by intestinal bacteria.
( Minh Truong Do ),( Hyung Gyun Kim ),( Jae Ho Choi ),( Tilak Khanal ),( Bong Hwan Park ),( Thu Phuong Tran ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Piperine is a bioactive component of black pepper, Piper nigrum Linn, commonly used for daily consumption and in traditional medicine. Here, the molecular mechanisms by which piperine exerts antitumor effects in HER2-overexpressing breast cancer cells was investigated. The results showed that piperine strongly inhibited proliferation and induced apoptosis through caspase-3 activation and PARP cleavage. Furthermore, piperine inhibited HER2 gene expression at the transcriptional level. Blockade of ERK1/2 signaling by piperine significantly reduced SREBP-1 and FAS expression. Piperine strongly suppressed EGF-induced MMP-9 expression through inhibition of AP-1 and NF-κB activation by interfering with ERK1/2, p38 MAPK, and Akt signaling pathways resulting in a reduction in migration. Finally, piperine pretreatment enhanced sensitization to paclitaxel killing in HER2-overexpressing breast cancer cells. Our findings suggest that piperine may be a potential agent for the prevention and treatment of human breast cancer with HER2 overexpression. ⓒ2013 Elsevier Ltd. All rights reserved.
( Jae Ho Choi ),( Sun Woo Jin ),( Bong Hwan Park ),( Hyung Gyun Kim ),( Tilak Khanal ),( Hwa Jeong Han ),( Yong Pil Hwang ),( Jun Min Choi ),( Young Chul Chung ),( Sang Kyu Hwang ),( Tae Cheon Jeong ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Ginseng contains many bioactive constituents, including various ginsenosides that are believed to have anti-allergic, anti-oxidant, and immunostimulatory activities; however, its effects on atopic dermatitis (AD) remain unclear. In the current study, we hypothesized that cultivated ginseng (CG) would inhibit 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions inNC/Nga mice by regulating the T helper (Th)1/Th2 balance. Also, CG inhibits TNF-α/IFN-γ-induced thymus- and activation-regulated chemokine (TARC) expression through nuclear factor-kappa B (NF-κB)-dependent signaling in HaCaT cells. CG ameliorated DNCB-induced dermatitis severity, serum levels of IgE and TARC, and mRNA expression of TARC, TNF-α, IFN-γ, IL-4, IL-5, and IL-13 in mice. Histopathological examination showed reduced thickness of the epidermis/dermis and dermal infiltration of inflammatory cells in the ears. Furthermore, CG suppressed the TNF-α/IFN-γ-induced mRNA expression of TARC in HaCaT cells. CG inhibited TNF-α/IFN-γ-induced NF-κB activation. These results suggest that CG inhibited the development of the AD-like skin symptoms by modulating Th1 and Th2 responses in the skin lesions in mice and TARC expression by suppressing TNF-α/IFN-γ-induced NF-κB activation in keratinocytes, and so may be a useful tool in the therapy of AD-like skinsymptoms.ⓒ2013 Elsevier Ltd. All rights reserved.
( Jae Ho Choi ),( Hyung Gyun Kim ),( Sun Woo Jin ),( Eun Hee Han ),( Tilak Khanal ),( Minh Truong Do ),( Yong Pil Hwang ),( Jun Min Choi ),( Sung Sik Chun ),( Young Chul Chung ),( Tae Cheon Jeong ),( 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Pleurotus eryngii is a nutritional and medicinal food rich in polysaccharides that enhance the host immune system as a response to various diseases. The present study investigated the effects of P.eryngii extracts (PEE) on the progress of atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by 2,4-dinitrochlorobenzene (DNCB). We evaluated skin dermatitis severity, ear thickness, histopathological examination, and cytokines level in DNCB-applied mice treated with PEE. Continuous treatment of PEE inhibited the development of the AD-like skin lesions. PEE suppressed DNCB-induced dermatitis severity, serum level of IgE and thymus and activation-regulated chemokine (TARC), and mRNA expression of TNF-α, INF-γ, IL-4, IL-5, and IL-13 in mice. In addition, PEE reduced thickness of the dermis and dermal infiltration of inflammatory cells and mast cells in histopathological examination. These results indicate that PEE inhibits allergic contact dermatitis through the modulating of T helper (Th)1 and Th2 responses and diminishing the inflammatory cells and mast cells infiltration in the skin lesions in NC/Nga mice.ⓒ2012 Elsevier Ltd. All rights reserved.
( Hyung Gyun Kim ),( Ji Hye Yang ),( Eun Hee Han ),( Jae Ho Choi ),( Tilak Khanal ),( Myung Ho Jeong ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua L., has recently been shown to possess antitumor activity in various cancer cells. However, the effect of anti-inflammatory potentials of DHA in murine macrophage RAW 264.7 cells has not been studied. The present study investigated the effect of COX-2 and molecular mechanisms by DHA in PMA stimulated RAW 264.7 cells. DHA dose-dependently decreased PMA-induced COX-2 expression and PGE2 production, as well as COX-2 promoter-driven luciferase activity. Additionally, DHA decreased luciferase activity of COX-2 regulation-related transcription factors including NF-κB, AP-1, C/EBP and CREB. DHA also remarkably reduced PMA-induced p65, C/EBPβ, c-jun and CREB nuclear translocation. Furthermore, DHA evidently inhibited PMA-induced phosphorylation of AKT and the MAP Kinases, such as ERK, JNK and p38. Taken together, our data indicated that DHA effectively attenuates COX-2 production via down-regulation of AKT and MAPK pathway, revealing partial molecular basis for the anti-inflammatory properties of DHA.ⓒ2013 Elsevier Ltd. All rights reserved.