• The Korea Genome Conference
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• 2002.08a
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• pp.41.2-41.2
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• 2002

• IMMUNE NETWORK
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• v.8 no.3
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• pp.90-97
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• 2008

Background: Hypersensitivity pneumonitis (HP) comprises a group of lung diseases resulting from repeated inhalation of various antigens such as Saccharopolyspora rectivirgula (SR). HP is categorized as a Th1 disease. Therefore, it has been suggested that IL-4, Th2 type cytokine, plays a protective role in the development of HP. However, the functional role of IL-4 in HP has not been extensively investigated in vivo. Therefore, we investigated the functional role of IL-4 in HP using IL-4 knockout (KO) mice. Methods: HP was induced by repeated exposure to SR in C57BL/6 (B6) and IL-4 KO (C57BL/6 background) mice. Results: IL-4 KO mice aggravated HP in terms of histological alteration, SR-specific immune responses, and inflammatory cell infiltration in the lungs compared with B6 mice. IL-4 KO mice produced high levels of IFN-${\gamma}$, TGF-${\beta}$ and TNF-${\alpha}$ in the lungs, whereas B6 mice showed the enhanced production of IL-4. Moreover, chemokines such as MIP-1${\alpha}$, MCP-1, and RANTES were highly expressed in IL-4 KO mice. IFN-${\gamma}$-secreting CD4, CD8 T cells, and neutrophils were enhanced in the bronchoalveolar lavage fluid (BALF) of IL-4 KO mice than those of B6 mice. The administration of recombinant(r) IL-4 restored these immunologic parameters in IL-4 KO mice. Conclusion: These results indicate that IL-4 plays a suppressive role in SR-induced HP by attenuating Th1-dominant immune responses.

• Journal of Ginseng Research
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• v.47 no.4
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• pp.561-571
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• 2023

Background: Escalating evidence shows that ginseng possesses an antiaging potential with cognitive enhancing activity. As mountain cultivated ginseng (MCG) is cultivated without agricultural chemicals, MCG has emerged as a popular herb medicine. However, little is known about the MCG-mediated pharmacological mechanism on brain aging. Methods: As we demonstrated that glutathione peroxidase (GPx) is important for enhancing memory function in the animal model of aging, we investigated the role of MCG as a GPx inducer using GPx-1 (a major type of GPx) knockout (KO) mice. We assessed whether MCG modulates redox and cholinergic parameters, and memory function in aged GPx-1 knockout KOmice. Results: Redox burden of aged GPx-1 KO mice was more evident than that of aged wild-type (WT) mice. Alteration of Nrf2 DNA binding activity appeared to be more evident than that of NFκB DNA binding activity in aged GPx-1 KO mice. Alteration in choline acetyltransferase (ChAT) activity was more evident than that in acetylcholine esterase activity. MCG significantly attenuated reductions in Nrf2 system and ChAT level. MCG significantly enhanced the co-localization of Nrf2-immunoreactivity and ChAT-immunoreactivity in the same cell population. Nrf2 inhibitor brusatol significantly counteracted MCG-mediated up-regulation in ChAT level and ChAT inhibition (by k252a) significantly reduced ERK phosphorylation by MCG, suggesting that MCG might require signal cascade of Nrf2/ChAT/ERK to enhance cognition. Conclusion: GPx-1 depletion might be a prerequisite for cognitive impairment in aged animals. MCG-mediated cognition enhancement might be associated with the activations of Nrf2, ChAT, and ERK signaling cascade.

• Journal of Pharmaceutical Investigation
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• v.37 no.5
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• pp.297-303
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• 2007

The purposes of this study were to clarify the involvement of P-glycoprotein (P-gp) in the efflux of levosulpiride in knockout mice that lack the mdr1a1b gene and to evaluate the relationship between the genetic polymorphisms in MDR1 gene (exon 21) and levosulpiride disposition in healthy Korean subjects. After oral administration ($10\;{\mu}g/g$) of levosulpiride to mdr1a/1b(-/-) and wild-type mice, plasma and brain samples were obtained at 45 min. We also investigated the genotype for MDR1 (exon 21) gene in humans using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A single oral dose of 25 mg levosulpiride was administered to 58 healthy subjects, who were based on the MDR1 genotype for the G2677T SNP. Blood samples were taken up to 36 hr after dosing. The concentrations of levosulpiride in mouse plasma and brain were statistically significant difference between the two animal groups (P<0.05). In addition, the average brain-to-plasma concentration ratio (Kp) of levosulpiride was 3.4-fold (P<0.01) higher in the mdr1a/1b(-/-) mice compared with the wild-type mice. We also found that the values of $AUC_{0-{\infty}$, partial AUC ($AUC_{0-4h}$) and $C_{max}$ were significantly different between homozygous 2677TT subjects and the subjects with at least one wild-type allele (GG and GT subjects, P=0.012 for $AUC_{0-{\infty}$; P=0.008 for $AUC_{0-4h}$; P=0.038 for $C_{max}$). The results confirm that levosulpiride is a P-gp substrate in vivo, and clearly demonstrate the effect of SNP 2677G>T in exon 21 of the MDR1 gene on levosulpiride disposition.

• Clinical and Experimental Reproductive Medicine
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• v.50 no.3
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• pp.170-176
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• 2023

Objective: Autophagy is highly active in ovariectomized mice experiencing hormone deprivation, especially in the uterine mesenchyme. Autophagy is responsible for the turnover of vasoactive factors in the uterus, which was demonstrated in anti-Müllerian hormone receptor type 2 receptor (Amhr2)-Cre-driven autophagy-related gene 7 (Atg7) knockout (Amhr-Cre/Atg7^f/f mice). In that study, we uncovered a striking difference in the amount of sequestosome 1 (SQSTM1) accumulation between virgin mice and breeder mice with the same genotype. Herein, we aimed to determine whether repeated breeding changed the composition of mesenchymal cell populations in the uterine stroma. Methods: All female mice used in this study were of the same genotype. Atg7 was deleted by Amhr2 promoter-driven Cre recombinase in the uterine stroma and myometrium, except for a triangular stromal region on the mesometrial side. Amhr-Cre/Atg7^f/f female mice were divided into two groups: virgin mice with no mating history and aged between 11 and 12 months, and breeder mice with at least 6-month breeding cycles with multiple pregnancies and aged around 12 months. The uteri were used for Western blotting and immunofluorescence staining. Results: SQSTM1 accumulation, representing Atg7 deletion and halted autophagy, was much higher in virgin mice than in breeders. Breeders showed reduced accumulation of several vasoconstrictive factors, which are potential autophagy targets, in the uterus, suggesting that the uterine stroma was repopulated with autophagy-intact cells during repeated pregnancies. Conclusion: Multiple pregnancies seem to have improved the uterine environment by replacing autophagy-deficient cells with autophagy-intact cells, providing evidence of cell mixing.

• Molecules and Cells
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• v.38 no.3
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• pp.251-258
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• 2015

Germline mutations in the breast cancer type 2 susceptibility gene (BRCA2) are linked to familial breast cancer and the progressive bone marrow failure syndrome Fanconi anaemia. Established Brca2 mouse knockout models show embryonic lethality, but those with a truncating mutation at the C-terminus survive to birth and develop thymic lymphoma at an early age. To overcome early lethality and investigate the function of BRCA2, we used T cell-specific conditional Brca2 knockout mice, which were previously shown to develop thymic lymphoma at a low penetrance. In the current study we showed that the number of peripheral T cells, particularly na$\ddot{i}$ve pools, drastically declined with age. This decline was primarily ascribed to improper peripheral maintenance. Furthermore, heterozygous mice with one wild-type Brca2 allele manifested reduced T cell numbers, suggesting that Brca2 haploinsufficiency might also result in T cell loss. Our study reveals molecular events occurring in Brca2-deficient T cells and suggests that both heterozygous and homozygous Brca2 mutation may lead to dysfunction in T cell populations.

• BMB Reports
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• v.51 no.1
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• pp.39-44
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• 2018

Exchange protein directly activated by cAMP (Epac) 2a-knockout (KO) mice exhibit accelerated diet-induced obesity and are resistant to leptin-mediated adipostatic signaling from the hypothalamus to adipose tissue, with sustained food intake. However, the impact of Epac2a deficiency on hypothalamic regulation of sympathetic nervous activity (SNA) has not been elucidated. This study was performed to elucidate the response of Epac2a-KO mice to dexamethasone-induced muscle atrophy and acute cold stress. Compared to age-matched wild-type mice, Epac2a-KO mice showed higher energy expenditures and expression of myogenin and uncoupling protein-1 in skeletal muscle (SM) and brown adipose tissue (BAT), respectively. Epac2a-KO mice exhibited greater endurance to dexamethasone and cold stress. In wild-type mice, exogenous leptin mimicked the responses observed in Epac2a-KO mice. This suggests that leptin-mediated hypothalamic signaling toward SNA appears to be intact in these mice. Hence, the potentiated responses of SM and BAT may be due to their high plasma leptin levels.

• Molecules and Cells
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• v.47 no.3
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• pp.100007.1-100007.11
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• 2024

Recent evidence establishes a pivotal role for obesity-induced inflammation in precipitating insulin resistance and type-2 diabetes. Central to this process is the proinflammatory M1 adipose-tissue macrophages (ATMs) in epididymal white adipose tissue (eWAT). Notably, natural killer (NK) cells are a crucial regulator of ATMs since their cytokines induce ATM recruitment and M1 polarization. The importance of NK cells is shown by the strong increase in NK-cell numbers in eWAT, and by studies showing that removing and expanding NK cells respectively improve and worsen obesity-induced insulin resistance. It has been suggested that NK cells are activated by unknown ligands on obesity-stressed adipocytes that bind to NKp46 (encoded by Ncr1), which is an activating NK-cell receptor. This was supported by a study showing that NKp46-knockout mice have improved obesity-induced inflammation/insulin resistance. We therefore planned to use the NKp46-knockout mice to further elucidate the molecular mechanism by which NKp46 mediates eWAT NK-cell activation in obesity. We confirmed that obesity increased eWAT NKp46⁺ NK-cell numbers and NKp46 expression in wild-type mice and that NKp46-knockout ablated these responses. Unexpectedly, however, NKp46-knockout mice demonstrated insulin resistance similar to wild-type mice, as shown by fasting blood glucose/insulin levels and glucose/insulin tolerance tests. Obesityinduced increases in eWAT ATM numbers and proinflammatory gene expression were also similar. Thus, contrary to previously published results, NKp46 does not regulate obesity-induced insulin resistance. It is therefore unclear whether NKp46 participates in the development of obesity-induced inflammation and insulin resistance. This should be considered when elucidating the obesity-mediated molecular mechanisms that activate NK cells.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2002.05a
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• pp.46-46
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• 2002

• The Korea Journal of Herbology
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• v.31 no.2
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• pp.13-19
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• 2016

Objectives : The present study was designed to evaluate the protective effect of Allium tuberosum (AT) extract on atherosclerosis in LDL receptor knockout (LDLr KO) mouse fed western diet.Methods : The AT was extracted 70% ethanol. The experimental groups were divided with four groups of LDLr KO mice, one group fed a normal diet and the others fed a Western diets for 8weeks. Two Western diet groups were orally administered AT extract at dosage of 100 and 300 mg/kg body weight. The body weight and food intake were measured every day. We measured levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and Glucose in serum. Also, effect of AT extract performed using H&E staining.Results : The AT treatment groups showed decrease in body weight and food efficiency in comparison with control group. Blood biochemistry parameters such as TG, TC, LDL, and glucose levels were increased in control group, while AT treatment groups were reduced. Also, the increased levels of ALT and AST were improved by AT extract. We confirmed that the weights of liver, kidney, subcutaneous fat, epididymal fat, kidney leaf fat, and intraabdominal fat were change in LDLr KO mice treated AT extract. In addition, histopathological changes in liver and aorta were similar to normal group.Conclusions : Based on these results, the AT extract is considered to make prevention of atherosclerosis through reduction and functional improvement of the liver and vascular endothelial cells in the body fat accumulation and lipid content in LDLr ko mouse model.