Biomedical subjects

Yong-Soon Lee

Publications and source records attributed to Yong-Soon Lee.

At least 37 records · Page 2Linked to original sources

PubMed2004

Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate.

Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.

Animals↗

PubMed2004

CpG methylation of the mouse CYP1A2 promoter.

Cytochrome P450 1A2 (CYP1A2) is a xenobiotic metabolizing enzyme that is tissue-specifically regulated in the mammalian liver by arylhydrocarbon receptor (AhR)-dependent and -independent pathways. In this study, CpG methylation of the CYP1A2 promoter was analyzed in mouse tissues and liver-derived cells. Compared to lung and kidney, the CYP1A2 promoter is undermethylated in the liver in a promoter domain-specific manner. The CYP1A2 promoter showed a similar methylation pattern in wild-type and AhR-null liver. At birth, the promoter was hypermethylated and CYP1A2 was negligibly expressed in the liver. However, CYP1A2 expression increased following birth, coincident with the demethylation of the promoter. In hepatoma Hepa1c1c7 cells not expressing CYP1A2, the promoter was hypermethylated at specific CpG sites. In isolated hepatocytes, CYP1A2 expression declined over time and the degree of CYP1A2 methylation increased, albeit only after a delay. Exposure to 5-aza-2'-deoxycytidine did not induce CYP1A2 in Hepa1c1c7 cells and hepatocytes. Taken together, our findings suggest that CpG methylation is involved in the tissue-specific and developmental regulation of CYP1A2, but the de novo methylation of the CYP1A2 promoter is induced by the silent state of the gene rather than causing it.

Animals↗

PubMed2004

Roles of p38 and c-jun in the differentiation, proliferation and immortalization of normal human endometrial cells.

BACKGROUND: It has been reported that p38 and c-jun operate as mediators of cell proliferation and differentiation. Therefore, by studying the roles of c-jun and p38 in the proliferation and differentiation of normal human endometrial cells, we can better understand the mechanism of these processes in endometrial cells. METHODS: Separation of glandular and stromal components was based on a modification of the work of Satyaswaroop et al. To confirm the purification of the endometrial cells and the expression of the transfected SV40 large T antigen, immunocytochemical analysis and western blot analysis were performed. RESULTS: There were polygonal shapes in the stromal cells in the early passage 1-2, while the aged endometrial stromal cells were spindle shaped. To investigate passage-dependent molecular events in endometrial cells, the c-jun and pp38 levels were examined. Both c-jun and pp38 were significantly reduced with cellular aging and passages. To understand the role of c-jun, endometrial stromal cells were treated with SP600125 which is a specific inhibitor of c-jun. SP600125 induced morphological changes of young endometrial stromal cells with polygonal shape; the young cells appeared as aged endometrial cells with spindle shape. In addition, an immortalized endometrial cell line was established and shown to express activated c-jun, similiar to normal endometrial cells. CONCLUSIONS: These results suggest that the modulation of p38 and c-jun may play an important role in the differentiation and proliferation of human endometrial cells.

Antigens, Polyomavirus Transforming↗

PubMed2004

Genetic polymorphisms of CYP1A1 in a Korean population.

Genetic polymorphisms in the coding exons of the CYP1A1 gene were analyzed in 100 Koreans. Three types of CYP1A1 polymorphisms, specifically G134A, G184C and A2455G, were identified with allelic frequencies of 18, 3, and 16%, respectively, and no linkage was observed among them. The novel G184C polymorphism identified in this study was associated with the mutation of an alanine residue at position 62 to proline. Other earlier-reported polymorphisms in the coding region of CYP1A1 were not detected.

Alleles↗

PubMed2004

Effect of retinoids on LPS-induced COX-2 expression and COX-2 associated PGE(2) release from mouse peritoneal macrophages and TNF-alpha release from rat peripheral blood mononuclear cells.

Anti-inflammatory activity of retinoids has been demonstrated earlier, but their mechanism is poorly understood. In this study, we examined the effects of retinoids on lipopolysaccharide (LPS)-induced prostaglandin (PG) E(2) production, an indicator of cyclooxygenase (COX) activity, and COX-2 protein expression in mouse peritoneal macrophages, and tumor necrosis factor (TNF)-alpha release in rat peripheral blood mononuclear cell (PBMC) to elucidate their possible mechanism for anti-inflammation. All-trans retinoic acid (t-RA) and all-trans retinol significantly inhibited a LPS-induced PGE(2) production as assessed by enzyme-linked immunosorbant assay (ELISA) and COX-2 protein expression as assessed by Western blot assay in mouse peritoneal macrophages, after knocking out the COX-1 activity by aspirin. All-trans retinoic acid, but not all-trans retinol, inhibited LPS-induced TNF-alpha release as assessed by ELISA in rat PBMC. These findings suggest that the modulation of COX-2 and TNF-alpha release could be one of the possible pathways by which retinoids function as anti-inflammatory agents.

Animals↗

PubMed2004

Modulations of the Bcl-2/Bax family were involved in the chemopreventive effects of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell.

Recently, cancer chemoprevention with strategies using foods and medicinal herbs has been regarded as one of the most visible fields for cancer control. Genistein in soy, American ginseng, and resveratrol are well-known to have antiproliferative properties in human breast cancer. Licorice root is a botanical, a shrub native to southern Europe and Asia, which primarily has desirable qualities in sweetening and herbal medicine. In this study, licorice (Glycyrrhiza uralensis Fisch) root also inhibits cell proliferation in human breast cancer cell. The cell proliferation study demonstrated that licorice root reduced the proliferation of MCF-7 cells in a dose- and time-dependent manner. The extracts were fractionated in CHCl(3), EtOAc, C(6)H(14), and CH(3)OH-H(2)O (70:30), and these extracts of licorice root (50 microg/mL) induced DNA fragmentation demonstrated by Hoechst 33258 staining. Apoptosis also determined the sub-G1 accumulation by flow cytometry analysis. These results were consistent with specific cleavage of PARP and antiapoptotic protein Bcl-2 and up-regulation of proapoptotic protein Bax demonstrated by Western blotting. Our findings suggest that licorice root may have chemopreventive effects against human breast cancer through the modulation of the expression of the Bcl-2/Bax family of apoptotic regulatory factors.

Anticarcinogenic Agents↗

PubMed2004

Gene expression analysis of peroxisome proliferators- and phenytoin-induced hepatotoxicity using cDNA microarray.

The recent DNA microarray technology enables us to understand a large number of gene expression profiling. The technology has potential possibility to comprehend mechanism of multiple genes were related to compounds which have toxicity in biological system. So, the toxicogenomics through this technology may be very powerful for understanding the effect of unknown toxic mechanisms in biological system. We have studied that the effect of compounds related to hepatotoxin in vivo system using DNA microarray and classified chemicals which have been well characterized. We have studied three compounds; 2 peroxisome proliferators: Clofibrate (ethyl-p-chlorophenoxyisobutyrate), gemfibrozil (5-2[2,5-dimethyl-phenoxy]2-2-dimethyl-pentanonic), and an antiepileptic drug: phenytoin (5,5-diphenylhydantoin). Male Sprague-Dawely VAF(+) albino rats of 5-6 weeks old were treated with each compound for 24 hr and 2 weeks. 4.8 K cDNA microarray in house has been used for gene expression profiling. We found that the clustering of gene expression had similarity like as the toxic phenotype of compounds.

Animals↗

PubMed2004

The intelligent data management system for toxicogenomics.

Toxicogenomics is now emerging as one of the most important genomic application because the toxicity test based on gene expression profiles is expected to be more precise and efficient than current histopathological approaches in a pre-clinical phase. One of the challenging issues in toxicogenomics is the construction of intelligent database management system which can deal with heterogeneous and complex data from many different experimental and information sources. TEST(Toxicogenomics for Efficient Safety Test) database is especially focused on the connectivity of heterogeneous data and the intelligent query system which enable users to obtain relevant useful information from the complex data sets. The database deals with four kinds of information; compound, histopathology, gene expression, and annotation information. Currently, TEST database maintains toxicogenomics information for 16 compounds, 45 microarrays, 190 animal experiments, and customized 4.8 K rat clone set. Our presented system is expected to be a good information source for studying of toxicology mechanism in the genome-wide level and can also be applied to the designing toxicity test chip.

Animals↗

PubMed2004

cDNA microarray gene expression analysis and toxicological phenotype for anticancer drug.

Toxicogenomics, the subdiscipline that merges genomics with toxicology, hold the promise to contributing toward the goal of elucidating mechanism by studying genomic profiling related with various drugs. The application of gene expression profiling technology to examine multiple genes and signaling pathways promises a significant advance in understanding the toxic mechanisms of various drugs and prediction of new drug candidate. Toxicogenomics is emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of drug and various compounds. The principal hypothesis underlying on this field is that chemical-specific pattern of altered gene expression is related with each chemicals properties, especially toxicological property, and it will be revealed using high-density microarray analysis of sample from exposed organisms. So, in this study we compare the gene expression pattern of two anticancer drugs paclitaxel and orally absorbable paclitaxel, using the cDNA microarray. And from the result of this study, it is possible to provide the new possibility for genome-wide insight into mechanism of their anticancer activity and toxicological phenotype.

Administration, Oral↗

PubMed2004

Malignant pleural mesothelioma in a woodchuck (Marmota monax).

A spontaneous pleural mesothelioma was observed in a 4-year-old female woodchuck (Marmota monax). At necropsy, multifocal, tan to white, firm discrete nodules, 2 to 40 mm in diameter, were scattered over the ventral parts of the lungs and their corresponding parts of the diaphragm and the thoracic wall. Histopathologically, the tumor cells were large, cuboidal-shaped and variable size, and were weakly positive with PAS and Alcian blue. Immunohistochemically, neoplastic cells were positive for both vimentin and cytokeratin, indicating mesothelial origin. This report represents, as far as we know, the first reported case of a spontaneous mesothelioma in woodchucks.

Animals↗

PubMed2004

Gene expression analysis in SV40-immortalized human breast luminal epithelial cells with stem cell characteristics using a cDNA microarray.

The epithelial compartment of the human breast comprises two distinct cell types. Type I human breast epithelial cells (HBECs) are expressing luminal epithelial cell markers and stem cell characteristics, whereas Type II HBECs show basal epithelial cell phenotypes. When defined in terms of markers for normal cell lineages, most invasive breast cancer cells correspond to the phenotype of the common luminal epithelial cell. We had developed simian virus 40-immortalized cell lines from normal HBECs with luminal and stem cell characteristics. To identify molecular changes involved in immortalization, we analyzed the differential gene expression profiles of normal and non-tumorigenic immortalized Type I HBECs using cDNA microarray with 7,448 sequence-verified clones. Out of the 7,448 genes screened, consistent gene expression changes among biological replicates included 67 in Type I HBECs and 86 in Type II HBECs for 4-fold change criteria. Surprisingly, we identified 148 genes (>2.0-fold) as being either up- or down-regulated related to immortalization: 67 genes (MYBL2, UCHL1 et al) were up-regulated, and 81 genes (IGFBP3, CDKN1A et al) were down-regulated significantly. The altered expression levels of the selected genes were subsequently confirmed by semiquantitative RT-PCR. Our studies suggest that the immortalization of Type I HBECs might be an early step in the initiation of a subset of breast cancer. Furthermore, these results will open up an avenue for more detailed understanding of breast stem cell and tumor biology.

Biomarkers↗

PubMed2004

Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription.

Prostate-specific antigen (PSA) is widely used clinically for prostate cancer diagnostics and as an indicator of therapeutic efficacy and recurrence. Several human chemoprevention trials are being conducted to validate the prostate cancer prevention efficacy of selenium and PSA is used in these trials as a biomarker of response. A better understanding of the effects of selenium metabolites on the kinetics of PSA turnover and secretion in prostate cancer cells treated with selenium at concentrations which are achievable physiologically will be important for interpreting the results of these trials. This study addresses whether the putative active anticancer selenium metabolite methylselenol or its precursor methylseleninic acid (MSeA) specifically inhibits PSA expression in the androgen-responsive LNCaP prostate cancer cell model. The results show that exposure to sub-apoptotic concentrations of MSeA and methylselenol inhibited PSA protein expression and secretion, whereas sodium selenite and selenomethionine lacked inhibitory effect. The inhibition was detectable at 3 h of exposure and required a threshold level of MSeA to sustain. Turnover experiments showed that MSeA caused rapid PSA degradation, which was partially blocked by lysosomal inhibitors, but not by a proteasomal inhibitor. Furthermore, MSeA treatment reduced PSA mRNA level, down-regulated androgen receptor protein expression, and inhibited androgen-stimulated PSA promoter transcription. In summary, methylselenol or MSeA specifically and rapidly inhibited PSA expression through two mechanisms of action: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. These findings may have important mechanistic implications for the prostate specific cancer chemopreventive action of selenium.

Androgens↗

PubMed2003

The mechanism of retinol-induced irritation and its application to anti-irritant development.

Despite many beneficial effects on dermatological applications, retinol and its derivatives cause severe local irritation manifested as mild erythema and stratum corneum peeling of the skin. It is hypothesized that cytokines may be important inflammatory mediators in retinoid-induced dermatitis. The present study was designed to determine cytokine mediators and thereby, to screen potential anti-irritants in retinoid-induced inflammation. The changes in mRNA expression of inflammation-related cytokines including mouse analogue of human monocyte chemoattractant protein-1 (MCP-1) (JE), mouse analogue of human interleukin-8 (IL-8) (KC), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-12p40, IL-6, IL-10, Eotaxin were determined in mouse epidermal cells treated by 2% retinol using a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The up-regulated mRNA level was confirmed with protein levels in culture supernatants from human epidermal keratinocytes, melanocytes, and fibroblasts treated with 10 microM retinol or retinoic acid. As results, retinoid-induced inflammation was mainly mediated through MCP-1 and IL-8 as evidenced by increased levels of mRNA expression and protein secretion. The potential anti-irritant substances including beta-sitosterol, Magnoliae flos, beta-glycyrrhetinic acid, SC-glucan, Ginko extract, Raspberry extract, Schisandra extract, Cola extract, Enna complex or Vegetol red grapevine extract were evaluated for their inhibitory effects on retinol-induced cytokine (MCP-1 and IL-8) secretion in vitro cultured human fibroblasts. Furthermore, in vivo efficacy tests for the retinol-induced irritancy were performed using Draize skin irritation test in the rabbit and human patch test. Most of the substances that reduced the secretion of MCP-1 and IL-8 in vitro cultured fibroblasts, showed a good inhibition against the retinol-induced irritation in the rabbit and human patch test. In conclusion, the present study demonstrated that among proinflammatory cytokines, MCP-1 and IL-8 mainly mediated retinol-induced skin irritation, and that inhibition of production of these cytokines can be applied as good markers to screen the anti-irritants against the retinol-induced irritation.

Animals↗

PubMed2003

Pre-validation study for OECD enhanced test guideline 407 protocol by gavage for 4 weeks using propylthiouracil and tamoxifen.

To develop and pre-validate an enhanced protocol for OECD Test Guideline 407, we performed a 28-day repeated-dose toxicity study using the administration of propylthiouracil (PTU) and tamoxifen (TAM) in Sprague-Dawley (SD) rats. Six male and female SD rats were treated orally with PTU in corn oil at the dose of 0, 0.1, 1, or 10 mg/kg per day and TAM at dose of 0, 5, 30 or 200 microg/kg per day for 4 weeks. In the study using PTU, the body weights were reduced from the third week of the study in 10 mg/kg per day group. In clinical biochemistry, the levels of 3,5,3'-triiodothyronine (T3) and thyroxine (T4, 3,5,3',5'-tetraiodothyrosine) were also significantly decreased in 10 mg/kg per day group. Also, thyroid glands in 10 mg/kg per day group were bigger than those in the control group. In the histopathological examination, diffuse hyperplasia and hypertrophy of thyroid follicular cells were observed in all treatment groups, leading to the reduction of lumen size and papillary enfolding of lining epithelium. In the study using TAM, the body weights were reduced from the first week of the study in 200 microg/kg per day group. Relative testes and epididymes weights were increased and relative right ovary and uterus weights were reduced in 200 microg/kg per day group. Also, in the histopathological finding severe endometrial squamous metaplasia and endometrial gland atrophy and severe follicular cystic change were observed in TAM 200 microg/kg per day-treated group. On the basis of the results, the thyroid hormone levels, gross findings, and histopathological findings may be useful parameters for the detection of the endocrine-related effect of PTU and also reproductive organ weight and histopathological findings may be good parameters to detect the effect of TAM. Therefore, it is concluded that enhanced OECD TG407 might be useful for screening and detecting endocrine disrupters.

Animals↗

PubMed2003

Strain-specific mammary proliferative lesion development following lifetime oral administration of ochratoxin A in DA and Lewis rats.

OTA, a potent nephrotoxin in several species, is a renal carcinogen in animals and is implicated in the etiology of BEN. The NTP classified OTA as having clear evidence of carcinogenic activity, based on uncommon tubular adenomas and tubular cell carcinomas of the kidney and multiple fibroadenomas of the mammary gland, seen in the rat. As shown previously (Castegnaro et al., Int J Cancer 1998;77:70-5), induction of renal tumors by OTA is sex- and strain-specific in DA and Lewis rats, with DA males being most responsive and DA females being resistant; however, that report was confined to the kidney and urinary tract. To obtain OTA-induced tumorigenic information in rats, we administered OTA (0.4 mg/kg) by oral gavage to both DA and Lewis rats for their lifetimes and extended the investigation to complete histopathology of all tissues and organs. We also observed the characteristic renal tumor that is highly strain- and sex-specific, and there were increased incidences of proliferative mammary lesions in Lewis rats but not in DA rats, indicating that these were also strain-specific. In view of the NTP report of OTA treatment-related mammary fibroadenoma in F344 rats, we observed increased mammary proliferative lesions in Lewis rats but not in DA rats. Our results suggest that OTA may play some role in mammary tumor development in some rat strains.

Administration, Oral↗

PubMed2003

Lack of effects of sodium 2-mercaptoethane sulfonate (mesna) on Ochratoxin A induced renal tumorigenicity following life-time oral administration of Ochratoxin A in DA and Lewis rats.

Sodium 2-mercaptoethane sulfonate (Mesna) reacts with urotoxic metabolites of oxazaphosphorine drugs (e.g. cyclophosphamide or ifosfamide) and has been used clinically to protect against damage induced by these aggressive anti-neoplastic drugs in the kidney and lower urinary and genital tracts. Ochratoxin A (OTA) is a potent nephrotoxin in several species. In order to elucidate whether mesna has curative or preventive effects on OTA-induced renal damage or renal tumor development, we administered OTA and/or mesna to both DA and Lewis rats for their life-time and examined kidney, urethra and urinary bladder histologically. OTA induced sex- and strain-specific renal tumors. However, there was no evidence of any effect of mesna on the incidence and distribution of any type of tumor or non-neoplastic finding in the kidney in either strain or treated group. In this study, we have confirmed that mesna treatment did not show any curative or preventive effects on either OTA-induced kidney damage or renal tumor development in two different strains that have distinct metabolic characteristics.

Animals↗

PubMed2002

Ganoderma lucidum extract induces cell cycle arrest and apoptosis in MCF-7 human breast cancer cell.

Although the pharmacology and clinical application of water extracts of Ganoderma lucidum have been extensively documented, little is known regarding its alcohol extract. In the present study, the anti-tumor effect of an alcohol extract of Ganoderma lucidum was investigated using MCF-7 cells. We found that the alcohol extract of Ganoderma lucidum inhibited cell proliferation in a dose- and time-dependent manner, which might be mediated through up-regulation of p21/Waf1 and down-regulation of cyclin D1. Furthermore, this compound can directly induce apoptosis in MCF-7 cells, which might be mediated through up-regulation of a pro-apoptotic Bax protein and not by the immune system. Our findings suggest that there are multiple mechanisms underlying the anti-tumor effects of Ganoderma lucidum.

Alcohols↗

PubMed2002

DI-(2-ethylhexyl) phthalate-induced cell proliferation is involved in the inhibition of gap junctional intercellular communication and blockage of apoptosis in mouse Sertoli cells.

Di-(2-ethylhexyl) phthalate (DEHP) has been studied on gap junctional intercellular communication (GJIC) and apoptosis in cultured normal mouse Sertoli cells. Since the inhibition of GJIC and programmed cell death or apoptosis play important roles in tumor promotion and developmental toxicity, it has been hypothesized that tumor promoters may inhibit apoptosis by blocking GJIC. The results showed that the most significant downregulation of GJIC was detected at 9 h after DEHP treatment. However, a significant concentration-dependent pattern was not observed at concentrations of 100 and 500 microM, but there was a time-dependent recovery of GJIC. DEHP inhibited the apoptotic changes in the cells such as chromatin condensation, nuclear fragmentation, and the cleavage of poly(ADP-ribose) polymerase. Morphological changes related to apoptosis appeared in the nontreated cells after 12 h of serum deprivation. These morphological changes were significantly reduced in the TM5 Sertoli cells treated with 500 microM DEHP for 24 h. These results suggest that DEHP inhibited apoptosis in this cell line, preceded by the downregulation of GJIC. It was also found that DEHP reduced the phosphorylation of Cx43, which might partly explain the mechanism of inhibition of GJIC.

Animals↗