• Toxicological Research
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• v.32 no.1
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• pp.21-33
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• 2016

Dichlorodiphenyltrichloroethane (DDT) is still used in certain areas of tropics and subtropics to control malaria and other insect-transmitted diseases. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in animals and humans and shown to have an endocrine disrupting potential affecting reproductive system although the effects may vary among animal species in correlation with exposure levels. Epidemiologic studies revealed either positive or negative associations between exposure to DDT and tumor development, but there has been no clear evidence that DDT causes cancer in humans. In experimental animals, tumor induction by DDT has been shown in the liver, lung, and adrenals. The mechanisms of hepatic tumor development by DDT have been studied in rats and mice. DDT is known as a non-genotoxic hepatocarcinogen and has been shown to induce microsomal enzymes through activation of constitutive androstane receptor (CAR) and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. The results from our previously conducted 4-week and 2-year feeding studies of p,p'-DDT in F344 rats indicate that DDT may induce hepatocellular eosinophilic foci as a result of oxidative DNA damage and leads them to hepatic neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.

• Food Science and Biotechnology
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• v.17 no.6
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• pp.1185-1190
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• 2008

When 10 kinds of herbal medicines were fractionated into hexane, MeOH, cold-water, and hot-water extracts, hot-water extracts from Acanthopanax senticosus (AS), Glycyrrhiza uralensis (GU), Cichorium intybus (CI), and Polygonatum odoratum (PO) showed the potent intestinal immune system modulating activity (1.72-, 1.62-, 1.60-, and 1.53-fold of control at $100{\mu}g/mL$, respectively). Especially, hot-water extracts from AS (215% compared with the control) and GU (187%) also had macrophages stimulating activity and mitogenic activity of splenocytes (7.1- and 6.5-fold) at $100{\mu}g/mL$. In addition, the effects of hot-water extracts from herbal medicines on anticancer activities were studied in mice. Hot-water extracts from AS and GU enhanced cytotoxicity of natural killer cell against cancer cell, Yac-1 (37 and 34% cytotoxicity) at E/T ratio 100:1, and colon 26-M3.1 cancer cell lines had significantly inhibited (82.1 and 75.2%) in experimental lung metastasis. These results suggest that hot-water extracts from A. senticosus and G. uralensis can be used as biological response modifiers to stimulate immune system and inhibit tumor.

• The Journal of Internal Korean Medicine
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• v.30 no.3
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• pp.451-464
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• 2009

Background and Objective : Cyperus rotundus L. (CR) is a commonly used herbal medicine in Asian countries such as Korea, China and Japan. The present study was designated to evaluate the direct effects of CR on helper T cell activities and on Th1/Th2 lineage development in vitro. Materials and Methods : Spleen cells from 8 week BALB/c mice were cultured in CR extracts containing medium without activation for 24 hours and with activation for 48 hours. CD4+ T cells were isolated and analyzed for mRNA expression levels of INF-$\gamma$, IL-4, T-bet and GATA-3 by RT-PCR and secretion cytokines levels of INF-$\gamma$, IL-4, IL-5 and IL-10 by ELISA. Results : The results demonstrated that CR had no mitogenic effects on unstimulated CD4+ T cells, but augmented CD4+ T-cell proliferation upon activation with anti-CD3/anti-CD28 antibodies in a dose-dependent manner. CR treatment significantly increased CD4+ T cell population and the IFN-$\gamma$ expression was significantly enhanced, while IL-4 expression was significantly decreased. In addition, in vitro Th1/Th2 polarization experiments revealed that CR enhanced IFN-$\gamma$ secretion in Th1 cells, but reduced the IL-4 in Th2 cells in a dose-dependent manner. Conclusion : These results suggest that CR treatment could be a desirable alternative therapy for the prevention or correction of Th2 dominant pathological disorders, such as allergy and asthma.

• The Journal of Internal Korean Medicine
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• v.28 no.4
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• pp.681-693
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• 2007

Background and Objective : Atractylodes japonica (AJ) is a commonly-used herbal medicine in Asian countries such as Korea, China and Japan. The present study was designated to evaluate the direct effects of AJ on helper T cell activities and on Th1/Th2 lineage development in vitro. Materials and Methods : Spleen cells from 8-week BALB/c mice were cultured in CR extracts containing medium without activation for 24 hours and with activation for 48 hours. CD4+ T cells were isolated and analyzed for mRNA expression levels of INF-$\gamma$, IL-4, T-bet and GATA-3 by RT-PCR and secretion cytokines levels of INF-$\gamma$, IL-2, IL-4, IL-5 and IL-10 by ELISA. Results : The results demonstrated that AJ had no mitogenic effects on unstimulated CD4+ T cells, but augmented CD4+T-cell proliferation upon activation with anti-CD3/anti-CD28 antibodies in a dose-dependent manner. AJ treatment significantly increased CD4+ T cell population and IFN-$\gamma$ expression was significantly enhanced, while IL-4 expression significantly decreased. In addition, in vitro Th1/Th2 polarization experiments revealed that AJ enhanced IFN-$\gamma$ secretion in Th1 cells, but reduced the IL-4 in Th2 cells in dose-dependent manner. Conclusion : These results suggest that AJ treatment could be a desirable alternative therapy for the prevention or correction of Th2 dominant pathological disorders, such as allergy and asthma.

• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.2
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• pp.414-424
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• 2007

Adenophorae Radix (AR), Liriopis Tuber (LT), Dendrobii Monile (DM), Polygonati Officinalis (PO), Polygonati Rhizoma (PR) have been used to treated a variety condition/diseases in traditional oriental medicine. The present study was conducted to investigate the immunmodulatory effects of the water-extracted AR, LT, DH, PO and PR. In spleen cell proliferation assay, DH was significantly enhanced mitogenic activity compared with control group. In RT-PCR, DH ad PO induced IL-2 and IFNr cytokine gene expression in mouse spleen cells. Methotrexate(MTX), immune supression agent, was significantly inhibited mouse spleen cell proliferation(1600 mg/ml). In spite of MTX treatement, DH and PO sustained the spleen cell proliferation, In the flow cytometry analysis, DH stimulated mouse spleen cells showed an increase in B-cell phenotype (CD45R/B220). The water-extracted DH and PO inhibited NO production and iNOS expression in LPS-stimulated RAW 264.7 macrophage cell. DH induced IL-2 and IFNg gene expression in human peripheral mononuclear cells. The GC-MS analysis show that the main component of water-extracted DH was b-Nitroethyl alcohol. The main components of water-extracted PO were Dipirartril-tropico, Methyl sulfoxide and Demsodrox. These data suggest that among these extracts, DH has a protective effcet of immune suppression caused by MTX. DH may be enhance cellular and humoral immune response by the regulation of cytokine gene expression, NO production and B cell production.

• Proceedings of the Korean Nutrition Society Conference
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• 1995.11b
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• pp.11-34
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• 1995

Growth hormone (GH) plays a key role in regulating postnatal growth and can stimulate growth of animals by acting directly on specific receptors on the plasma membrane of tissues or indirectly through stimulating insulin-like growth factor (IGF)-I synthesis and secretion by the liver and other tissues. IGF-I and IGF-Ⅱ are polypeptides with structural similarity with proinsulin that stimulate cell proliferation by endocrine, paracrine and autocrine mechanisms. The initial event in the metabolic action of IGFs on target cells appears to be their binding to specific receptors on the plasma membrane. Current evidence indicates that the mitogenic actions of both IGFs are mediated primarily by binding to the type I IGF receptors, and that IGF action is also mediated by interactions with IGF-binding proteins (IGFBPs). Six distinct IGFBPs have been identified that are characterized by cell-specific interaction, transcriptional and post-translational regulation by many different effectors, and the ability to either potentiate or inhibit IGF actions. Nutritional deficiencies can have their devastating consequence during growth. Although IGF-I is the major mediator of GH's action on somatic growth, nutritional status of an organism is a critical regulator of IGF-I and IGFBPs. Various nutrient deficiencies result in decreased serum IGF-I levels and altered IGFBP levels, but the blood levels of GH are generally unchanged or elevated in malnutrition. Effects of protein, energy, vitamin C and D, and zinc on serum IGF and IGFBP levels and tissue mRNA levels were reviewed in the text. Multiple factors are involved in the regulation of intestinal epithelial cell growth and differentiation. Among these factors the nutritional status of individuals is the most important. The intestinal epithelium is an important site for mitogenic action of the IGFs in vivo, with exogenous IGF-I stimulating mucosal hyperplasia. Therefore, the IGF system appears to provide and important mechanism linking nutrition and the proliferation of intestinal epithelial cells. In order to study the detailed mechanisms by which intestinal mucosa is regulated, we have utilized IEC-6 cells, an intestinal epithelial cell line and Caco-2 cells, a human colon adenocarcinoma cell line. Like intestinal crypt cells analyzed in vivo or freshly isolated intestinal epithelial cells, IEC-6 cells and Caco-2 cells possess abundant quatities of both type Ⅰ and type Ⅱ IGF receptors. Exogenous IGFs stimulate, whereas addition of IGFBP-2 inhibits IEC-6 cell proliferation. To investigate whether endogenously secreted IGFBP-2 inhibit proliferation, IEC-6 cells were transfected with a full-length rat IGFBP-2 cDNA anti-sense expression construct. IEC-6 cells transfected with anti-sense IGFBP-2 protein in medium. These cells grew at a rate faster than the control cells indicating that endogenous IGFBP-2 inhibits proliferation of IEC-6 cells, probably by sequestering IGFs. IEC-6 cells express many characteristics of enterocyte, but do not undergo differentiation. On the other hand, Caco-2 cells undergo a spontaneous enterocyte differentiation. On the other hand, Caco-2 cells undergo a spontaneous enterocyte differentiation after reaching confluency. We have demonstrated that Caco-2 cells produce IGF-Ⅱ, IGFBP-2, IGFBP-3, and an as yet unidentified 31,000 Mr IGFBP, and that both mRNA and peptide secretion of IGFBP-2 and IGFBP-3 increased, but IGFBP-4 mRNA and protein secretion decreased after the cells reached confluency. These changes occurred in parallel to and were coincident with differentiation of the cells, as measured by expression of sucrase-isomaltase. In addition, Caco-2 cell clones forced to overexpress IGFBP-4 by transfection with a rat IGFBP-4 cDNA construct exhibited a significantly slower growth rate under serum-free conditions and had increased expression of sucrase-isomaltase compared with vector control cells. These results indicate that IGFBP-4 inhibits proliferation and stimulates differentiation of Caco-2 cells, probably by inhibiting the mitogenic actions of IGFs.

• The Journal of Internal Korean Medicine
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• v.27 no.1
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• pp.40-54
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• 2006

Objective: This study aimed to identify the different effects of GMCSBHT water-extract and ethanol-extract on Th1/Th2 differentiation by monitoring Th1/Th2 specific cytokine secretion patterns and the transcriptional activities of T-bet, GATA-3, c-maf, $INF{\gamma}$ and IL-4. Materials and Methods: Spleen cells from eight week-old BALB/c mice were cultured in GMCSBHT extracts containing medium without activation for 24 hours and with activation for 48 hours. CD4+ T cells were isolated and mRNA expression levels of $INF{\gamma}$, IL-4, T-bet, GATA-3, c-maf by RT-PCR and secretion cytokines levels of $IFN{\gamma}$, IL-4 by ELISA were analyzed. Results: GMCSBHT extracts didn't have mitogenic effects on the unstimulated CD4+ T cells. In Th1 skewed condition, GMCSBAHT water extract had no significant effects on mRNA expression levels of $IFN{\gamma}$, T-bet and c-maf, but inhibited mRNA expression levels of IL-4, GATA-3. It showed significantly increased secretion cytokine levels of $IFN{\gamma}$, but had no significant effect on secretion cytokine levels of IL-4. In Th2 skewed condition, GMCSBHT ethanol extract inhibited mRNA expression levels of $INF{\gamma}$, IL-4, GATA-3 and c-maf significantly, but had no significant effects on mRNA expression levels of T-bet. It had no significant effects on secretion cytokine levels of $INF{\gamma}$, but showed remarkable inhibitory effects on secretion cytokine levels of IL-4. Conclusion: Results suggest that on Th1/Th2 deviation, GMCSBHT water extract has both amplifying effects on Th1 differentiation and inhibitory effects on Th2, but GMCSBHT ethanol extract has stronger inhibitory effects on Th2 differentiation than on Th1.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.6
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• pp.547-551
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• 2013

We recently reported a Philyra pisum lectin (PPL) that exerts mitogenic effects on human lymphocytes, and its molecular characterization. The present study provides a more detailed characterization of PPL based on the results from a monosaccharide analysis indicating that PPL is a glycoprotein, and circular dichroism spectra revealing its estimated ${\alpha}$-helix, ${\beta}$-sheet, ${\beta}$-turn, and random coil contents to be 14.0%, 39.6%, 15.8%, and 30.6%, respectively. These contents are quite similar to those of deglycosylated PPL, indicating that glycans do not affect its intact structure. The binding properties to different pathogen-associated molecular patterns were investigated with hemagglutination inhibition assays using lipoteichoic acid from Gram-positive bacteria, lipopolysaccharide from Gram-negative bacteria, and both mannan and ${\beta}$-1,3-glucan from fungi. PPL binds to lipoteichoic acids and mannan, but not to lipopolysaccharides or ${\beta}$-1,3-glucan. PPL exerted no significant antiproliferative effects against human breast or bladder cancer cells. These results indicate that PPL is a glycoprotein with a lipoteichoic acid or mannan-binding specificity and which contains low and high proportions of ${\alpha}$-helix and ${\beta}$-structures, respectively. These properties are inherent to the innate immune system of P. pisum and indicate that PPL could be involved in signal transmission into Gram-positive bacteria or fungi.

• Korean Journal of Poultry Science
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• v.39 no.1
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• pp.17-25
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• 2012

Coccidiosis control programs such as vaccines or in-feed anticoccidials are commonly practiced in the poultry industry to improve growth performance and health of commercial broiler chickens. In this study, we assessed the effects of various coccidiosis control programs (e.g., in ovo vaccination, synthetic chemicals, and antibiotic ionophores) on immune status of broiler chickens vaccinated against infectious bronchitis virus and Newcastle disease virus (ND) and raised on an Eimeria-contaminated used litter. In general, the levels of ${\alpha}$-1-acid glycoprotein, an acute phase protein, were altered by the treatments when measured at 34 days of age. Splenocyte subpopulations and serum antibody titers against ND were altered by various coccidiosis control programs. In-ovo-vaccinated chickens exhibited highest mitogenic response when their spleen cells were stimulated with concanavalin A (Con A) at 7 days of age. It is clear from this study that the type of coccidiosis control program influenced various aspects of innate and adaptive immune parameters of broiler chickens. Further studies will be necessary to delineate the underlying relationship between the type of coccidiosis control program and host immune system and to understand the role of other external environmental factors such as gut microbiota on host-pathogen interaction in various disease control programs.

• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.3
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• pp.771-776
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• 2003

The present study was conducted to evaluate the regulation mechanism of nitric oxide(NO) by water-extracted Cyperus rotundus (WCR) in RAW 264.7 macrophages. We investigated the effects of cell proliferation in mouse spleen cell and RAW 264.7 macrophages cells. WCR enhanced mitogenic activity in the dose-response manner in mouse spleen cells and RAW 264.7 macrophages cells. In nitric oxide (NO) synthesis by WCR, WCR alone had an effect on NO synthesis. It was found that the production of NO of RAW 264.7 cells stimulated with lipopolysaccharide (LPS) could be markedly inhibited by WCR. Inhibition of NO production was achieved by reducing inducible nitric oxide syntheses(iNOS) mRNA expression. The expression of IL-I gene by WCR was investigated using reverse transcription polymerase chain reaction (RT-PCR). In RT-PCR, IL-1 family(IL-1 α, IL-1β) expressions were induced by WCR. These finding suggested that regulation of NO production by WCR may be, at least in part, associated with the regulation of iNOS mRNA expression and IL-1 family gene expression.