Metformin Down-regulates $TNF-{\alpha}$ Secretion via Suppression of Scavenger Receptors in Macrophages

Hyun, Bobae,Shin, Seulmee,Lee, Aeri,Lee, Sungwon,Song, Youngcheon,Ha, Nam-Joo,Cho, Kyung-Hea,Kim, Kyungjae The Korean Association of Immunobiologists 2013 Immune Network Vol.13 No.4

Obesity is consistently increasing in prevalence and can trigger insulin resistance and type 2 diabetes. Many lines of evidence have shown that macrophages play a major role in inflammation associated with obesity. This study was conducted to determine metformin, a widely prescribed drug for type 2 diabetes, would regulate inflammation through down-regulation of scavenger receptors in macrophages from obesity-induced type 2 diabetes. RAW 264.7 cells and peritoneal macrophages were stimulated with LPS to induce inflammation, and C57BL/6N mice were fed a high-fat diet to generate obesity-induced type 2 diabetes mice. Metformin reduced the production of NO, $PGE_2$ and pro-inflammatory cytokines ($IL-1{\beta}$, IL-6 and $TNF-{\alpha}$) through down-regulation of $NF-{\kappa}B$ translocation in macrophages in a dose-dependent manner. On the other hand, the protein expressions of anti-inflammatory cytokines, IL-4 and IL-10, were enhanced or maintained by metformin. Also, metformin suppressed secretion of $TNF-{\alpha}$ and reduced the protein and mRNA expression of $TNF-{\alpha}$ in obese mice as well as in macrophages. The expression of scavenger receptors, CD36 and SR-A, were attenuated by metformin in macrophages and obese mice. These results suggest that metformin may attenuate inflammatory responses by suppressing the production of $TNF-{\alpha}$ and the expressions of scavenger receptors.

Metformin Down-regulates TNF-α Secretion via Suppression of Scavenger Receptors in Macrophages

Bobae Hyun,Seulmee Shin,Aeri Lee,이성원,송영천,하남주,Kyung-HeaCho,김경제 대한면역학회 2013 Immune Network Vol.13 No.4

Obesity is consistently increasing in prevalence and can trigger insulin resistance and type 2 diabetes. Many lines of evidence have shown that macrophages play a major role in inflammation associated with obesity. This study was conducted to determine metformin, a widely prescribed drug for type 2 diabetes, would regulate inflammation through downregulation of scavenger receptors in macrophages from obesity- induced type 2 diabetes. RAW 264.7 cells and peritoneal macrophages were stimulated with LPS to induce inflammation, and C57BL/6N mice were fed a high-fat diet to generate obesity-induced type 2 diabetes mice. Metformin reduced the production of NO, PGE2 and pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) through down-regulation of NF-κB translocation in macrophages in a dose-dependent manner. On the other hand, the protein expressions of anti- inflammatory cytokines, IL-4 and IL-10, were enhanced or maintained by metformin. Also, metformin suppressed secretion of TNF-αand reduced the protein and mRNA expression of TNF-α in obese mice as well as in macrophages. The expression of scavenger receptors, CD36 and SR-A, were attenuated by metformin in macrophages and obese mice. These results suggest that metformin may attenuate inflammatory responses by suppressing the production of TNF-α and the expressions of scavenger receptors.

Metformin의 TNF-α 생성 억제에 의한 항염증 및 대식세포 표현형 변화

현보배, 김경제, 조경혜 서울여자대학교 자연과학연구소 2014 자연과학연구논문집 Vol.26 No.-

보조생식술 관련 법제도 개선방안 연구

이현아(Hyun A Lee),문한나(Hannah Moon),김보배(Bobae Kim),김명희(Myung-Hee Kim) 국가생명윤리정책원 2017 생명, 윤리와 정책 Vol.1 No.1

「모자보건법」은 지난 2015년과 2016년의 법 개정을 통하여 난임치료 지원을 위한 제도를 정비하였는데, 이는 보조생식술과 관련된 또 다른 법인「생명윤리법」과 함께 고려할 때 크게 두 가지 사항에 대한 논의를 이끈다. 첫째, 「모자보건법」의 추가조항 중 ‘난임시술 의료기관’의 지정 및 관리요건 등이 이미 2005년부터 시행되고 있는 「생명윤리법」의 ‘배아생성의료기관’의 관련 요건들과 일으키는 비정합성의 문제들이다. 이 글은 먼저 실무적 차원에서 법의 일관성과 실효성 담보를 위해 의료기관 지정 및 관리에 있어서 조율이 필요한 지점을 제시했다. 둘째, 보조생식술은 이 시술이 갖는 의료적, 사회적, 윤리적 특성으로 인해 엄격하면서도 포괄적인 법적 관리가 필요하다. 위에서 언급한 「모자보건법」개정은 이와 같은 보조생식술의 총체적인 관리 가능성에 대한 기대감을 안겨주었고, 이 법의 개정안들이 보조생식술 관리에서 수행하는 역할과 한계점을 「생명윤리법」과의 비교 속에서 살펴볼 필요성을 가져왔다. 이 글은 「생명윤리법」은 보조생식술과 관련된 연구부분을 관리하기 위한 법으로서의 그 특수 목적으로 인해, 그리고 「모자보건법」 역시 난임부부시술비지원사업의 체계화를 지원하는 법의 구조적 제한으로 인해 보조생식술의 총체적 관리에 한계를 가지고 있으며, 그 결과 특히 의료기관의 관리, 시술대상자의 보호, 통계관리 등에서 한계를 노출함을 살펴보았으며, 결론적으로 이러한 문제들은 보조생식술의 총체적 관리를 전담하는 새로운 법제도의 필요성에 대한 논의를 이끈다는 점을 제시했다. By comparing and analyzing two Laws which regulate the Assisted Reproductive Technology(ART) in Korea, namely, the "Mother and Child Health Act" and the "Bioethics and Safety Act", this paper has two aims. First, in order to secure the consistency of the two laws in the management of assisted reproductive medical institutions, this Study indicated concrete contradictions of the Articles of two Laws regarding their regulations about medical institutions for ART. The second aim of this paper is to suggest the necessity of a new legal system that can manage the overall assistive reproductive technology of Korea. For it, this study has analyzed structural limits of the two laws, which especially leads to the absence and lack of the management of assisted reproductive medical institutions, of protection for patients and of statistic collection system in ART Praxis.

Inhibitory Effect of Biotransformed-Fucoidan on the Differentiation of Osteoclasts Induced by Receptor for Activation of Nuclear Factor-κB Ligand

Park, Bobae,Yu, Sun Nyoung,Kim, Sang-Hun,Lee, Junwon,Choi, Sung Jong,Chang, Jeong Hyun,Yang, Eun Ju,Kim, Kwang-Youn,Ahn, Soon-Cheol The Korean Society for Microbiology and Biotechnol 2022 Journal of microbiology and biotechnology Vol.32 No.8

Bone homeostasis is regulated by constant remodeling through osteogenesis by osteoblasts and osteolysis by osteoclasts and osteoporosis can be provoked when this balance is broken. Present pharmaceutical treatments for osteoporosis have harmful side effects and thus, our goal was to develop therapeutics from intrisincally safe natural products. Fucoidan is a polysaccharide extracted from many species of brown seaweed, with valuable pharmaceutical activities. To intensify the effect of fucoidan on bone homeostasis, we hydrolyzed fucoidan using AMG, Pectinex and Viscozyme. Of these, fucoidan biotransformed by Pectinex (Fu/Pec) powerfully inhibited the induction of tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts differentiated from bone marrow macrophages (BMMs) by the receptor for activation of nuclear factor-κB ligand (RANKL). To investigate potential of lower molecular weight fucoidan it was separated into >300 kDa, 50-300 kDa, and <50 kDa Fu/Pec fractions by ultrafiltration system. The effects of these fractions on TRAP and alkaline phosphatase (ALP) activities were then examined in differentiated osteoclasts and MC3T3-E1 osteoblasts, respectively. Interestingly, 50-300 kDa Fu/Pec suppressed RANKL-induced osteoclasts differentiation from BMMs but did not synergistically enhance osteoblasts differentiation induced by osteogenic agents. In addition, this fraction inhibited the expressions of NFATc1, TRAP, OSCAR, and RANK, which are all key transcriptional factors involved in osteoclast differentiation, and those of Src, c-Fos and Mitf, as determined by RT-PCR. In conclusion, enzymatically low-molecularized 50-300 kDa Fu/Pec suppressed TRAP by downregulating RANKL-related signaling, contributing to the inhibition of osteoclasts differentiation, and represented a potential means of inducing bone remodeling in the background of osteoporosis.

Syringin attenuates insulin resistance via adiponectin-mediated suppression of low-grade chronic inflammation and ER stress in high-fat diet-fed mice

Kim, Bobae,Kim, Min-Seok,Hyun, Chang-Kee Academic Press 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>In the treatment of type 2 diabetes, improvements in glucose control are often linked to side effects such as weight gain and altered lipid metabolism, increasing the risk of cardiovascular disease. It is therefore important to develop antidiabetic drugs that exert beneficial effects on insulin sensitivity and lipid metabolism at the same time. Here we demonstrate that syringin, a naturally occurring glucoside, improves glucose tolerance without increased weight gain in high-fat diet-induced obese mice. Syringin augmented insulin-stimulated Akt phosphorylation in skeletal muscle, epididymal adipose tissue (EAT), and the liver, showing an insulin-sensitizing activity. Syringin-treated mice also showed markedly elevated adiponectin production in EAT and suppressed expression of pro-inflammatory cytokines in peripheral tissues, indicating a significant reduction in low-grade chronic inflammation. Additionally, syringin enhanced AMP-activated protein kinase activity and decreased the expression of lipogenic genes in skeletal muscle, which was associated with reduced endoplasmic reticulum (ER) stress. Taken together, our data suggest that syringin attenuates HFD-induced insulin resistance through the suppressive effect of adiponectin on low-grade inflammation, lipotoxicity, and ER stress, and show syringin as a potential therapeutic agent for prevention and treatment of type 2 diabetes with low risk of adverse effects such as weight gain and dysregulated lipid metabolism.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Syringin enhances insulin sensitivity under HF feeding condition. </LI> <LI> Akt phosphorylation was increased in skeletal muscle, EAT, and the liver. </LI> <LI> Adiponectin-mediated AMPK activation in skeletal muscle was augmented. </LI> <LI> Pro-inflammatory cytokine expression was reduced in muscle, EAT, and the liver. </LI> <LI> Expression of genes related to ER stress was reduced in skeletal muscle. </LI> </UL> </P>

Colorectal cancer mortality trends in the era of cancer survivorship in Korea: 2000–2020

Kim Min Hyun,Park Sanghee,Yi Nari,Kang Bobae,Park In Ja 대한대장항문학회 2022 Annals of Coloproctolgy Vol.38 No.5

Purpose: Korea has implemented an early screening for colorectal cancer since 2004. However, it is not known whether this has translated into improved survival over the years. Methods: We acquired colorectal cancer mortality data from the Cause of Death Statistics in Korea from 2000 to 2020. We characterized the data into year of death, cancer-specific loci, and age group. We analyzed age-standardized mortality rates (ASMR) according to year of death, age group, and primary location to find trends in colorectal cancer mortality over a 20-year period. Results: The crude mortality rate of colorectal cancer increased from 8.78 per 100,000 in 2000 to 17.27 per 100,000 in 2020. The second decade was slower in increments compared to the first decade. ASMR showed a decrease over the second decade after an initial increase in the first decade. The decrease was primarily from the lowering of ASMR for rectosigmoid cancers. Age group analysis showed a lowering of ASMR mainly in the 45–59-year, 60–74-year, and ≥75-year age groups; however, 0–29-year and 30–44-year age groups showed generally unchanged ASMR over the total period. Conclusion: After a brief incline of age-specific mortality of colorectal cancers during the early 2000s, colorectal cancer mortality has gradually been decreasing in the past decade. This was mainly due to decreased mortalities in rectosigmoid colon cancers especially in the age groups that were the target of early screening.

<i>Lactobacillus rhamnosus</i> GG improves glucose tolerance through alleviating ER stress and suppressing macrophage activation in db/db mice

Park, Kun-Young,Kim, Bobae,Hyun, Chang-Kee the Society for Free Radical Research Japan 2015 Journal of clinical biochemistry and nutrition Vol.56 No.3

<P>Although recent studies have reported that <I>Lactobacillus rhamnosus</I> GG (LGG), the most extensively studied probiotic strain, exerts an anti-hyperglycemic effect on several rodent models, the underlying mechanism remains unclear. In this study, twenty male C57BL/KsJ-db/db (db/db) mice were divided into 2 groups, LGG-treated and control group, which received a daily dose of LGG (1 × 10<SUP>8</SUP> CFU per mouse) and PBS orally for 4 weeks, respectively. We observed that glucose tolerance was significantly improved in LGG-treated db/db mice. Insulin-stimulated Akt phosphorylation and GLUT4 translocation were higher in skeletal muscle of LGG-treated mice relative to their controls. It was also observed that LGG treatment caused significant reductions in endoplasmic reticulum (ER) stress in skeletal muscle and M1-like macrophage activation in white adipose tissues. Our results indicate that the anti-diabetic effect of LGG in db/db mice is associated with alleviated ER stress and suppressed macrophage activation, resulting in enhanced insulin sensitivity. These findings suggest a therapeutic potential of probiotics for prevention and treatment of type 2 diabetes.</P>

최소 비용할당 기반 온라인 지게차 운영 알고리즘

권보배,손정열,하병현,kwon, BoBae,Son, Jung-Ryoul,Ha, Byung-Hyun 한국시뮬레이션학회 2018 한국시뮬레이션학회 논문지 Vol.27 No.2

조선소의 지게차는 작업 특성상 무거운 물건을 상/하차하거나 이송하는 작업이 빈번하다. 작업은 동적이며 시간대별로 생성 비율이 다르다. 특히 오전과 오후 업무시간 직후에 작업 발생 비율이 높은 경향을 보인다. 이러한 상/하차 작업과 이송작업의 무게는 매번 다르며, 활용되는 지게차 역시 작업 가능한 허용무게의 제약이 있다. 본 연구에서는 지게차의 원활한 운영을 위해 최소 비용할당을 사용한 최근린 배차 규칙 알고리즘을 제안한다. 제시된 알고리즘은 다양한 종류의 지게차와 다수의 작업을 동시에 고려하여 배차를 결정하며, 지게차 종류에 따른 작업 불가능을 고려하기 위해 가상 지게차와 가상 작업을 생성하는 방법을 제안한다. 그리고 차량의 상태를 고려하여 체계적으로 지게차를 선택하는 방법도 함께 제시한다. 성능지표는 평균 공차이동거리와 평균 작업대기시간으로 한다. 성능비교를 위해 조선소의 지게차 운영방식을 모델링한 우선순위 규칙을 비교 대상으로 한다. 시뮬레이션을 통해 제시한 알고리즘의 우수성을 확인한다. Forklifts in a shipyard lift and transport heavy objects. Tasks occur dynamically and the rate of the task occurrence changes over time. Especially, the rate of the task occurrence is high immediately after morning and afternoon business hours. The weight of objects varies according to task characteristic, and a forklift also has the workable or allowable weight limit. In this study, we propose an online forklift dispatching algorithm based on nearest-neighbor dispatching rule using minimal cost assignment approach in order to attain the efficient operations. The proposed algorithm considers various types of forklift and multiple jobs at the same time to determine the dispatch plan. We generate dummy forklifts and dummy tasks to handle unbalance in the numbers of forklifts and tasks by taking their capacity limits and weights. In addition, a method of systematic forklift selection is also devised considering the condition of the forklift. The performance indicator is the total travel distance and the average task waiting time. We validate our approach against the priority rule-based method of the previous study by discrete-event simulation.

Cordycepin Suppresses MHC-restricted Antigen Presentation and Leads to Down-regulation of Inflammatory Responses in Antigen Presenting Cells

신슬미,김경제,Seulah Kim,Bobae Hyun,Aeri Lee,Sungwon Lee,박찬수,Hyunseok KONG,송영천,이종길 한국생약학회 2013 Natural Product Sciences Vol.19 No.4

Cordyceps militaris, a traditional medicinal mushroom, produces a component compound, cordycepin (3'-deoxyadenosine). Cordycepin has many pharmacological activities including immunological stimulating, anti-cancer, and anti-infection activities. However, the therapeutic mechanism has not yet been elucidated. In this study, we examined the effects of cordycepin on the antigen-presenting function of antigen-presenting cells (APCs). Dendritic cells (DCs) were cultured in the presence of cordycepin and then allowed to phagocytose microspheres containing ovalbumin (OVA). After washing and fixing, the efficacy of OVA peptide presentation by DCs was evaluated using CD8 and CD4 T cells. Also, we confirmed the protein levels of proinflammatory cytokines through RT-PCR and Western blot analysis. Cordycepin decreased both MHC class I and class II-restricted presentation of OVA and suppressed the expression of both MHC molecules and the phagocytic activity toward exogenous OVA. The class II-restricted OVA presentation-regulating activity of cordycepin was also confirmed using mice that had been injected with cordycepin followed by soluble OVA. Furthermore, cordycepin suppressed the mRNA and protein levels of iNOS, COX-2, pro-inflammatory cytokines in a concentration-dependent manner. These results provide an understanding of the mechanism of the T cell response-regulating activity of cordycepin through the inhibition of MHC-restricted antigen presentation in relation to its actions on APCs.