• The Korean Journal of Physiology and Pharmacology
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• v.10 no.1
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• pp.39-44
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• 2006

Type I diabetes (T1D) is an organ-specific autoimmune disease caused by the T cell-mediated destruction of the insulin-producing ${\beta}$ cells in the pancreatic islets. The onset of T1D is the consequence of a progressive destruction of islet ${\beta}$ cells mediated by an imbalance between effector $CD4^+$ T helper (Th)1 and regulatory $CD4^+$ Th2 cell function. Since interferon-alpha (IFN-${\alpha}$) has been known to modulate immune function and autoimmunity, we investigated whether administration of adenoviralmediated IFN-${\alpha}$ gene would inhibit the diabetic process in NOD mice. The development of diabetes was significantly inhibited by a single injection of adenoviral-mediated IFN-${\alpha}$ gene before 8 weeks of age. Next, we examined the hypothesis that Th2-type cytokines are associated with host protection against autoimmune diabetes, whereas Th1-type cytokines are associated with pathogenesis of T1D. The expression of IFN-${\alpha}$ induced increase of serum IL-4 and IL-6 (Th2 cytokines) levels and decrease of serum IL-12 and IFN-${\gamma}$ (Th1 cytokines) levels. Therefore, overexpression of IFN-${\alpha}$ by adenoviralmediated delivery provides modulation of pathogenic progression and protection of NOD mice from T1D.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.3
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• pp.580-584
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• 2008

In the present study, Radix clematidis extract (RCE) was evaluated to determine if it could protect pancreatic ${\beta}$ cells against multiple low dose streptozotocin (MLDS)-induced diabetes. Injection of mice with MLDS resulted in hyperglycemia and hypoinsulinemia, which was confirmed by immunohistochemical staining. However, the induction of diabetes by MLDS was completely prevented when mice were pre-administrated with RCE. Generation of oxidative stress is implicated in MLDS, a ${\beta}$ cell specific toxin-induced islet cell death. In this context, to elucidate the mechanisms of protective effects in RCE pre-administrated diabetic mice, we investigated the expression of heme oxygenase-1 (HO-1), which is one of the anti-oxidant enzymes. MLDS-induced HO-1 expressions were significantly reduced in MLDS-treated mice. However, the decrease of HO-1 by MLDS were protected by pretreatment of RCE. The molecular mechanism by which RCE inhibits diabetic conditions by MLDS appears to involve inhibition of HO-1 expression. Taken together, these results reveal the possible therapeutic value of RCE for the prevention of type 1 diabetes progression.

• Molecules and Cells
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• v.43 no.1
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• pp.66-75
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• 2020

Saturated fatty acids contribute to β-cell dysfunction in the onset of type 2 diabetes mellitus. Cellular responses to lipotoxicity include oxidative stress, endoplasmic reticulum (ER) stress, and blockage of autophagy. Palmitate induces ER Ca²⁺ depletion followed by notable store-operated Ca²⁺ entry. Subsequent elevation of cytosolic Ca²⁺ can activate undesirable signaling pathways culminating in cell death. Mitochondrial Ca²⁺ uniporter (MCU) is the major route for Ca²⁺ uptake into the matrix and couples metabolism with insulin secretion. However, it has been unclear whether mitochondrial Ca²⁺ uptake plays a protective role or contributes to lipotoxicity. Here, we observed palmitate upregulated MCU protein expression in a mouse clonal β-cell, MIN6, under normal glucose, but not high glucose medium. Palmitate elevated baseline cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and reduced depolarization-triggered Ca²⁺ influx likely due to the inactivation of voltage-gated Ca²⁺ channels (VGCCs). Targeted reduction of MCU expression using RNA interference abolished mitochondrial superoxide production but exacerbated palmitate-induced [Ca²⁺]_i overload. Consequently, MCU knockdown aggravated blockage of autophagic degradation. In contrast, co-treatment with verapamil, a VGCC inhibitor, prevented palmitate-induced basal [Ca²⁺]_i elevation and defective [Ca²⁺]_i transients. Extracellular Ca²⁺ chelation as well as VGCC inhibitors effectively rescued autophagy defects and cytotoxicity. These observations suggest enhanced mitochondrial Ca²⁺ uptake via MCU upregulation is a mechanism by which pancreatic β-cells are able to alleviate cytosolic Ca²⁺ overload and its detrimental consequences.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2010.10a
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• pp.7-7
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• 2010

전 세계적으로 폭발적으로 증가하고 있는 비만은 만병의 근원이다. 동시에 대사성질환의 발병을 증가시키는 결정적인 역할을 하고 있다. 이러한 상황을 극복할 수 있는 안전하고 효능이 우수한 약의 개발이 매우 시급하다. 시판되는 약들은 예견할 수 없는 지방변으로 실제생활을 매우 불편하게 하는 부작용과 우울증 및 자살충동 등의 심각한 부작용을 유발시키고 있다. 특히 생명을 위협하는 약은 시판이 금지되었다. 200여종의 한약재들을 In vitro screening (pancreatic lipase inhibition, PDE inhibition, c-AMP activity), ex vivo screening (lipolytic action on fat pad), short term animal screening(혈중 TG 함량 분석)을 토대로 long term animal model에서비만 예방 및 치료 효능을 검증하기 위하여 호장근 부탄올 분획을 선정하였다. 고지방 사료로 비만을 유도한 rat (Diet induced obesty (DIO) rat)에서 비만 치료 효능이, 고지방 사료로 비만을 유도한 ICR-mice에서 비만 예방 효능이 우수함을 입증하였다 (체중감소, 지방세포의 크기억제, 지방간 예방/치료(간무게, TG함량, 간 색상, 고지혈증 증상억제), 혈중 TNF-a, IL-6, leptin, adponectin 등, 간 조직에서의 pAMPK, SOCS, NF-${\kappa}B$ DNA biding activity, ACC level, FAS expression, CPT-1 activity의 정상화). 호장근 부탄올 분획의 이러한 효능은 AMPK 작용과 CPT-1 작용을 활성화하고 동시에 지방산 합성 억제와 지방산 산화를 촉진함으로 인함임을 규명하였다. 동시에 비만으로 인한 pancreatic beta cell의 파괴를 예방함으로 인슐린 내성을 예방(치료)함을 입증하였다. 이는 AMPK 활성화와 SOCS-3 단백질 억제와 NF-${\kappa}B$-DNA 결합 억제로 인함임을 증명하였다. 3T3-L1 지방 세포주에서 lipogenesis 예방(치료) 및 lipolytic effect에 관여하는 인자들의 변화를 확인하였다. 이는 Multi-compounds-multi-targets에 의한 시너지 효과임을 알 수 있었다.

• Clinical and Experimental Reproductive Medicine
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• v.35 no.3
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• pp.223-229
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• 2008

Objective: This pilot study was performed to investigate the effect of metformin on insulin resistance, hormone levels, and lipid profiles in non-obese patients with polycystic ovary syndrome. Methods: This study included 16 non-obese patients with polycystic ovary syndrome diagnosed at our hospital from June 2006 to September 2007. Blood samples were collected before and 6 months after metformin treatment for analysis of fasting serum glucose levels, fasting serum insulin levels, a glycemic response to 75 g oral glucose tolerance test (OGTT), and hormonal blood profile including FSH, LH, estradiol, testosterone, free testosterone, serum lipid profiles. Insulin resistance was estimated by calculating fasting glucose/insulin ratio (FGIR), 2 hr glucose/insulin ratio after 75 g glucose load. And we investigated insulin resistance and pancreatic beta cell function by calculating HOMA beta cell function and HOMA IR. Results: After the treatment of metformin, there was significant increase in 2 hr glucose/insulin ratio after 75 g glucose load (p=0.04) and decrease in HOMA IR (p=0.000). But serum lipid profiles did not change significantly. Also the metformin treatment induced a significant reduction in serum free testosterone and LH levels, and LH/FSH ratio (p=0.001, p=0.000, p=0.034). Conclusion: This pilot study showed that metformin might be effective in improving insulin sensitivity, ameliorating hyperandrogenemia in non-obese patients with polycystic ovary syndrome. Further investigations with larger number of patients and long-term observations are necessary to determine the role of metformin.

• Journal of Life Science
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• v.29 no.4
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• pp.499-508
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• 2019

Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.

• Korean Journal of Plant Resources
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• v.31 no.3
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• pp.218-227
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• 2018

In this study, we investigated the effect of the extracts from Vaccinium oldhamii on cell proliferation and the regulatory mechanisms of cyclin D1 protein level in human cancer cells. The branch extracts from Vaccinium oldhamii (VOB) showed higher inhibitor effect against the cell growth than leave extracts (VOL) and fruit extracts (VOF) in human colorectal cancer, breast cancer, prostate cancer, non-small lung cancer, pancreatic cancer and liver cancer cells. In addition, VOB decreased cyclin D1 level at both protein and mRNA level. MG132 treatment attenuated VOB-mediated cyclin D1 downregulation. A point mutation of threonine-286 to alanine attenuated cyclin D1 degradation by VOB. In addition, the inhibition of nuclear export by leptomycin B (LMB) attenuated cyclin D1 degradation by VOB. But, the treatment of PD98059 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), LiCl ($GSK3{\beta}$ inhibitor), LY294002 (PI3K inhibitor) or BAY 11-7082 ($I{\kappa}K$ inhibitor) did not affect VOB-induced cyclin D1 degradation. In conclusion, VOB induced cyclin D1 degradation through redistribution of cyclin D1 from the nucleus to cytoplasm via T286 phosphorylation of cyclin D1, which resulted in the inhibition of cancer cell proliferation.

• Journal of Ginseng Research
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• v.44 no.4
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• pp.619-626
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• 2020

Background: The effects of diol-ginsenoside fraction (Diol-GF) and triol-ginsenoside fraction (Triol-GF) from Korean Red Ginseng on the development of type 1 diabetes (T1D) were examined in diabetes-prone biobreeding (DP-BB) rats that spontaneously develop T1D through an autoimmune process. Methods: DP-BB female rats were treated with Diol-GF or Triol-GF daily from the age of 3-4 weeks up to 11-12 weeks (1 mg/g body weight). Results: Diol-GF delayed the onset, and reduced the incidence, of T1D. Islets of Diol-GF-treated DP-BB rats showed significantly lower insulitis and preserved higher plasma and pancreatic insulin levels. Diol-GF failed to change the proportion of lymphocyte subsets such as T cells, natural killer cells, and macrophages in the spleen and blood. Diol-GF had no effect on the ability of DP-BB rat splenocytes to induce diabetes in recipients. Diol-GF and diol-ginsenoside Rb1 significantly decreased tumor necrosis factor α production, whereas diol-ginsenosides Rb1 and Rd decreased interleukin 1β production in RAW264.7 cells. Furthermore, mixed cytokine- and chemical-induced β-cell cytotoxicity was greatly inhibited by Diol-GF and diol-ginsenosides Rc and Rd in RIN5mF cells. However, nitric oxide production in RAW264.7 cells was unaffected by diol-ginsenosides. Conclusion: Diol-GF, but not Triol-GF, significantly delayed the development of insulitis and T1D in DP-BB rats. The antidiabetogenic action of Diol-GF may result from the decrease in cytokine production and increase in β-cell resistance to cytokine/free radical-induced cytotoxicity.

• BMB Reports
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• v.43 no.2
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• pp.146-149
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• 2010

Exendin-4 (Ex-4), a peptide secreted from the salivary glands of the Gila monster lizard, can increase pancreatic $\beta$-cell growth and insulin secretion by activating glucagon-like peptide-1 receptor. In this study, we expressed a fusion protein consisting of exendin-4 and the human immunoglobulin heavy chain (Ex-4/IgG-Fc) in E. coli and explored its potential therapeutic use for the treatment of insulin-resistant type 2 diabetes. Here, we show that the Ex-4/IgG-Fc fusion protein induces expression of insulin receptor substrate-2 in rat insulinoma INS-1 cells. Our findings therefore suggest that Ex-4/IgG-Fc overexpressed in E. coli could be used as a potential, long-acting glucagon-like peptide-1 mimetic.

• Clinical and Experimental Pediatrics
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• v.54 no.2
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• pp.45-50
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• 2011

Compared to that in the Caucasian population, type 1 diabetes mellitus (T1DM) incidence rates are very low in Koreans. Therefore, compared to the recent development of pharmacological therapy applicable to Korean children with T1DM, interest in nonpharmacological therapy and psychosocial support systems remains low, as is the development of Korean-style T1DM education programs for therapeutic application. Children who have been newly diagnosed with diabetes are placed in completely new environments for treatment. For appropriate control of diabetes, patients have to self-monitor blood glucose levels and inject insulin several times a day and must use extreme self-control when they eat foods to avoid increases in blood glucose levels. Blood glucose excursions resulting from impaired pancreatic ${\beta}$ cell functions cause mental stress due to vague fears of chronic complications of diabetes. In addition, children with diabetes cannot be excluded from the substantial amount of studies required of Korean adolescents, and the absolute shortage of time for ideal control of diabetes adds to their mental stress. Many of these patients are psychologically isolated in school where they spend most of their time, and they are not appropriately considered or supported with respect to blood glucose control in many cases. In this respect, this author will introduce some of the newest views on nonpharmacological therapy and psychosocial support systems that account for important parts of T1DM management and seek measures to apply them in conformity with the social characteristics of Korea.