ISALPDC-04 : Chronic Alcohol Consumption Alters the Phenotype of F4/80+CD11b+ Bone Marrow Cells by Neuro-Metabolic Signaling Pathway

( Young-ri Shim ),( Jun-hee Lee ),( Won-mook Choi ),( Myung-ho Kim ),( Hee-hoon Kim ),( Hyuk Soo Eun ),( Won-il Jeong ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Alcohol-medicated metabolic and immunologic stress is generated not only in the liver, but also adipose tissue, gut and bone marrow (BM). However, the metabolic and immunologic effects of alcohol on BM have not been investigated. Here, we investigated that novel neuro-metabolic signaling pathway changed the phenotype of BM-derived macrophages and its detrimental contribution to alcoholic liver disease. Methods: C57BL/6J wild type (WT), and natural killer (NK) cell-specific metabotropic glutamate receptor 5 (mGluR5) knock-out (mGluR5△NK) mice were fed with liquid ethanol or isocaloric diet for 8 weeks. The phenotypic changes of immune cells in BM, blood and liver were assessed by flow cytometry. In vitro, BM stromal cells (BMSCs), NK cells and macrophages were treated with ethanol, glutamate or interferon (IFN)-γ. In addition, western blotting, immunostaining, and qRT-PCR analysis were performed. Results: In immunostaining, alcohol dehydrogenase (ADH) 1 was detected around sinusoids of BM in EtOH-fed mice. Additionally, we found that the mRNA expression of Adh1 and Aldh2 was highest in leptin receptor-positive (LepR+) BMSC by analyzing the public data. In vitro, PCR analysis exhibited increased expression of cystine/glutamate transporter xCT in EtOH-treated BMSC, thereby leading to glutamate secretion into BM. Interestingly, IFN-γ production was increased in BM NK cells of EtOH-fed WT mice. Moreover, chronic alcohol consumption decreased the expression of CX3CR1 but increased the expression of inflammatory mediators in F4/80+CD11b+ BM cells in an IFN-γ-dependent way, leading to egression of pro-inflammatory F4/80+CD11b+ cells from BM and migration to the liver to exacerbate alcoholic liver injury. However, all these findings were not observed in mGluR5△NK mice. Conclusions: In BM, glutamate excretion by alcohol metabolism in BMSC stimulated mGluR5-expressing NK cells to produce IFN-γ, polarizing F4/80+CD11b+ BM cells into pro-inflammatory cells and aggravating alcoholic liver injury. Thus, mGluR5 in NK cells might be a potential target for alcoholic liver disease.

Recent advances of sterile inflammation and inter-organ cross-talk in alcoholic liver disease

Shim Young-Ri,정원일 생화학분자생물학회 2020 Experimental and molecular medicine Vol.52 No.-

Alcoholic liver disease (ALD) is one of the fastest-growing concerns worldwide. In addition to bacterial endotoxins in the portal circulation, recent lines of evidence have suggested that sterile inflammation caused by a wide range of stimuli induces alcoholic liver injury, in which damage-associated molecular patterns (DAMPs) play critical roles in inducing de novo lipogenesis and inflammation through the activation of cellular pattern recognition receptors such as Toll-like receptors in non-parenchymal cells. Interestingly, alcohol-mediated metabolic, neurological, and immune stresses stimulate the generation of DAMPs that are released not only in the liver, but also in other organs, such as adipose tissue, intestine, and bone marrow. Thus, diverse DAMPs, including retinoic acids, proteins, lipids, microRNAs, mitochondrial DNA, and mitochondrial double-stranded RNA, contribute to a broad spectrum of ALD through the production of multiple pro-inflammatory cytokines, chemokines, and ligands in non-parenchymal cells, such as Kupffer cells, hepatic stellate cells, and various immune cells. Therefore, this review summarizes recent studies on the identification and understanding of DAMPs, their receptors, and cross-talk between the liver and other organs, and highlights successful therapeutic targets and potential strategies in drug development that can be used to combat ALD.

Chronic alcohol consumption induces migration of IL-1R2+ monocytes from the bone marrow into the liver by neuro-immunologic pathway

Young-Ri Shim,Hee-Hoon Kim,Keungmo Yang,Tom Ryu,Kyurae Kim,Sung Eun Choi,Minjeong Kim,Chae-Rin Woo,Young-Sun Lee,Won-Il Jeong 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Liver is challenged by diverse detrimental substances through multiple metabolic processes, but it is less prone to inflammation. In chronic alcohol consumption, although the migration of monocytes from bone marrow (BM) into liver is increased, alcoholic hepatitis rarely occurs. Thus, we investigated the sub-population of liver macrophages showing anti-inflammatory roles through single-cell RNA sequencing (scRNA-Seq) after chronic EtOH-feeding. Interestingly, in scRNA-seq and flow cytometry analyses of hepatic macrophages, the phenotype of Ly6Clow (anti-inflammatory) cells was dramatically altered by ethanol intake. In particular, they were highly expressed interleukin-1 type II receptor (IL-1R2), a decoy receptor of IL-1β. Intriguingly, IL-1R2+ Ly6Clow macrophages showed decreased CX3CR1 expression, which was confirmed not only in the liver, but also BM and blood, suggesting monocytes from BM affected by ethanol might migrate into the liver. We found that the Leptin Receptor+ mesenchymal stromal cells (LepR+ MSCs), which were located around blood vessels expressing CX3CL1 to hold CX3CR1+ macrophages, could express alcohol dehydrogenase to metabolize ethanol in BM. Ethanol metabolism in LepR+ MSCs was induced both production of chemokines (CXCL9 and 10) and the excretion of glutamate via cystine-glutamate anti-porter xCT to recruit and activate the CXCR3+ BM NK cells to produce interferon-γ in a metabotropic glutamate receptor 5 (mGluR5)-dependent manner. Indeed, IFN-γ production was significantly decreased in EtOH-fed mice when we depleted mGluR5 in NK cells. In turn, NK cell-derived IFN-γ down-regulated CX3CR1 expression in BM Ly6Clow monocytes, consequently induced egress of Ly6Clow monocytes into the blood and migration into the liver to suppress alcoholic inflammation. In conclusion, glutamate of LepR+ MSCs imposed egress license on anti-inflammatory IL-1R2+ Ly6Clow monocytes through NK cell-derived IFN-γ-mediated suppression of CX3CR1, suggesting a potential therapeutic inter-organ crosstalk between BM and liver in alcoholic liver disease.

혈액투석 환자에서 발생한 원인 불명의 가역성 반무도증

윤나리 ( Na Ri Yoon ),최정란 ( Joung Ran Choi ),심병주 ( Byung Joo Shim ),강현희 ( Hyun Hee Kang ),김영수 ( Young Soo Kim ),윤선애 ( Sun Ae Yoon ),김영주 ( Young Joo Kim ),박정욱 ( Jung Wook Park ),김영옥 ( Young Ok Kim ) 대한신장학회 2006 Kidney Research and Clinical Practice Vol.25 No.5

Uremic patients undergoing hemodialysis (HD) therapy are prone to develop encephalopathy, but the cause is often unclear. Clinical signs of encephalopathy in the uremic patient often overlap with several other affections causing neurological disorders. Chorea or hemichorea occurs very rare, when basal ganglia are injured in HD patients. We hereby report a case of hemichorea of unknown cause in a hemodialysis patients. A 57-year-old diabetic HD patient was presented with sudden onset of right hemi-chorea. We could not find causes of hemichorea such as hyperglycemia, hepatic failure, drug, hyponatremia, and thiamine deficiency. T1-weighted MRI demonstrated hyperintense lesion limited to the left basal ganglion. Hemichorea disappeared completely 6 months after the onset with support care. (Korean J Nephrol 2006;25(5):847-850)

상피세포 성장인자의 경피흡수 : 정상피부 , 각질제거피부 및 화상피부에 있어서

심창구,조애리,이정욱,안병락,정주영,고여욱 한국약제학회 1996 Journal of Pharmaceutical Investigation Vol.26 No.1

In vivo and in vitro skin permeation of recombinant ^(125)I-EGF through normal. stripped and the first degree burn skin were studied. The in vitro skin permeation rate through the first degree burn skin (296 cpm/㎠/hr) and the stripped skin (1131 cpm/㎠/hr) were 3.5 times and 13 times higher, respectively, as compared with the one through normal skin. In vivo absorption study with the first degree burn skin, the peak concentration of EGF in the skin was achieved at 1-3 hr and decreased afterward up to 8 hr with an elimination constant of 1.31 × 10³g/㎖/hr. To investigate the higher elimination rate of EGF in burn skin, binding and metabolism studies were conducted. No significant metabolism of EGF in burn skin (100℃, 5second burning) was observed. With the presence of unlabelled-EGF, ^(125)I-EGF permeation through the burn skin showed higher permeation rate than the one without unlabelled-EGF. The result may indicate that EGF-receptor binding play a role in determining the skin permeation rate.

황기 싹 및 잎 추출물의 랫드를 이용한 90일 반복경구투여 독성시험

최리나(Ri Na Choi),박해일(Hae il park),심훈섭(Hun Seob Shim),임정대(Jung Dae Lim),유창연(Chang Yeon Yu),최대성(Dae-Sung Cheoi),최유순(Yu-Soon Cheoi),정일민(Ill-Min Chung),박영철(Young Cheol Park) 한국약용작물학회 2013 한국약용작물학회 학술대회논문집 Vol.2013 No.1

Molecular Geometries and Electronic Structures of Methyl Pyropheophorbide-a and (Cationic) Tropolonyl Methyl Pyropheophorbides: DFT Calculation

Na-Ri Kim,Sujin Kim,Jin Dong Kim,Do Sung Huh,Young Key Shim,Sang Joon Choe 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.1

This study reports on the geometry optimizations and electronic structure calculations for methyl pyropheophorbide (MPPa), tropolonyl methyl pyropheophorbides (TMPPa, ITMPPa), and cationic tropolonyl methyl pyropheophorbides (TMPPa+․BF4 -, ITMPPa+․BF4 -, TMPPa+, and ITMPPa+) using Local Spin Density Approximation (LSDA/ 6-31G*) and the Restricted Hatree-Fock (RHF/6-31G*) level theory. From the calculated results, we found that substituted cationic tropolonyl groups have larger structural effects than those of substituted neutral tropolonyl groups. The order of structural change effects is ITMPPa+ > ITMPPa+․BF4 - > ITMPPa, as a result of the isopropyl group. Because it is an electron-releasing group, the substituted isopropyl group electronic effect on a 3-position tropolone increases the Highest Occupied Molecular Orbital and Lowest Unoccupied Molecular Orbital (HOMO-LUMO) energy gap. It was constituted that the larger the cationic characters of these photosensitizers, the smaller the HOMOLUMO band gaps are. The orbital energies of the cationic systems and the ions are stronger than those of a neutral system because of a strong electrostatic interaction. However, this stabilization of orbital energies are counteracted by the distortion of chlorin macrocycle, which results in a large destabilization of chlorin-based compound HOMOs and smaller destabilization of LUMOs as shown in TMPPa (ITMPPa), TMPPa+․BF4 - (ITMPPa+․BF4 -), and TMPPa+ (ITMPPa+) of Figure 6 and Table 6-7. These results are in reasonable agreement with normal-coordinate structural decomposition (NSD) results. The HOMO-LUMO gap is an important factor to consider in the development of photodynamic therapy (PDT).

Four Cases of Carbapenem-Resistant Enterobacteriaceae Infection from January to March in 2014

So Ri Kim,Chang Bun Rim,Younghun Kim,Jong Woo Kim,Young Woong Song,Sang Ho Shin,Hee Jung Yoon,Sehoon Shim 대한가정의학회 2015 Korean Journal of Family Medicine Vol.36 No.4

Molecular Geometries and Electronic Structures of Methyl Pyropheophorbide-a and (Cationic) Tropolonyl Methyl Pyropheophorbides: DFT Calculation

Kim, Na-Ri,Kim, Su-Jin,Kim, Jin-Dong,Huh, Do-Sung,Shim, Young-Key,Choe, Sang-Joon Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.1

This study reports on the geometry optimizations and electronic structure calculations for methyl pyropheophorbide (MPPa), tropolonyl methyl pyropheophorbides (TMPPa, ITMPPa), and cationic tropolonyl methyl pyropheophorbides ($TMPPa^+{{\cdot}BF_4}^-,\;ITMPPa^+{{\cdot}BF_4}^-,\;TMPPa^+,\;and\;ITMPPa^+$) using Local Spin Density Approximation (LSDA/ 6-31G*) and the Restricted Hatree-Fock (RHF/6-31G*) level theory. From the calculated results, we found that substituted cationic tropolonyl groups have larger structural effects than those of substituted neutral tropolonyl groups. The order of structural change effects is $ITMPPa^+ > ITMPPa^+{{\cdot}BF_4}^-$ > ITMPPa, as a result of the isopropyl group. Because it is an electron-releasing group, the substituted isopropyl group electronic effect on a 3-position tropolone increases the Highest Occupied Molecular Orbital and Lowest Unoccupied Molecular Orbital (HOMO-LUMO) energy gap. It was constituted that the larger the cationic characters of these photosensitizers, the smaller the HOMOLUMO band gaps are. The orbital energies of the cationic systems and the ions are stronger than those of a neutral system because of a strong electrostatic interaction. However, this stabilization of orbital energies are counteracted by the distortion of chlorin macrocycle, which results in a large destabilization of chlorin-based compound HOMOs and smaller destabilization of LUMOs as shown in TMPPa (ITMPPa), $TMPPa^+{{\cdot}BF_4}^- (ITMPPa^+{{\cdot}BF_4}^-),\;and\;TMPPa^+\;(ITMPPa^+)$ of Figure 6 and Table 6-7. These results are in reasonable agreement with normal-coordinate structural decomposition (NSD) results. The HOMO-LUMO gap is an important factor to consider in the development of photodynamic therapy (PDT).

전해수를 이용한 들깻잎 중 Salmonella Typhimurium과 Staphylococcus aureus의 저감화 효과 분석

김세리(Se-Ri Kim),류경열(Kyoung Yul Ryu),이명희(Myoung-Hee Lee),정찬식(Chan-Sik Jung),윤요한(Yohan Yoon),심현보(Won-Bo Shim),김주희(Ju-Hee Kim),김병석(Byung-Seok Kim),유순영(Soon-Young Yoo),김두호(Doo-Ho Kim),윤종철(Jong-Chul Yun),정덕 한국식품과학회 2012 한국식품과학회지 Vol.44 No.4

본 연구는 들깻잎에 존재하는 Salmonella Typhimurium, Staphylococcus aureus에 대한 전해수의 저감효과를 분석하고 전해수로의 유기물의 유입과 들깻잎과 전해수의 비율이 전해수의 효과에 미치는 영향을 분석하고자 수행하였다. 들깻잎에 S. Typhimurium과 S. aureus을 7.0 log10CFU/g 정도로 접종 한 후 25, 50, 75, 100 ppm에서 1, 3, 5분 동안 각각 처리하여 시간과 농도에 따른 전해수 효과를 분석하였다. 또한 유기물이 전해수의 효과에 미치는 영향을 분석하기 위해 전해수에 첨가한 유기물 농도는 150, 300, 450, 600 μg/L 수준이었고, 들깻잎과 전해수의 처리비율은 1:10, 1:25, 1:50이었다. 그 결과, S. Typhimurium과 S. aureus 모두 유효 염소 농도가 증가할수록 미생물 저감효과도 높아지는 경향을 보였으며(p<0.05) 두 균주 모두 100 ppm 처리에서 25 ppm 처리에서 보다 전해수의 저감효과가 약 0.7 log10CFU/g 정도 높게 나타났다(p<0.05). 하지만 처리 시간에 따른 효과는 없었다 (p>0.05). 또한 전해수 중 유기물 함량이 증가할수록 S. Typhimurium과 S. aureus의 제어효과는 감소하였다(p<0.05). 유기물 600 μg/L 첨가시 유기물 첨가를 하지 않았을 때에 비하여 S. Typhimurium은 1.10 log<SUB>10</SUB>CFU/g, S. aureus는 0.8 log10CFU/g의 전해수 효과가 감소하였다. 들깻잎과 전해수의 처리비율은 1:10으로 처리하였을 때 미생물 저감효과는 S. Typhimurium 0.57 log10CFU/g, S. aureus 0.79 log10CFU/g로 전해수에 의한 미생물저감 효과를 기대하기 어려웠다. 따라서 들깻잎에서 S. Typhimurium과 S.aureus의 효과적인 제어를 위해서는 전해수 처리전에 물 세척을 통하여 흙과 먼지를 제거하고 전해수 농도 100 ppm에서 1분 이상 처리해야한다. 또한 들깻잎과 전해수 비율은 1:25 이상 유지 하는 것이 바람직할 것으로 사료된다. This study was conducted to evaluate the bactericidal activity of weakly alkalic electrolyzed water (WEW)against Salmonella Typhimurium and Staphylococcus aureus on perilla leaves. The influences of organic matter, inform of bovine serum, and the ratio of WEW to perilla leaves on bactericidal activity of WEW were also examined. Treatment of these organisms with 25, 50, 75, and 100 ppm WEW was performed for 1 min, 3 min and 5 min, respectively. Higher bactericidal activity was observed after a treatment with 100 ppm WEW compared to a treatment with 25 ppm WEW by 0.7 log<SUB>10</SUB>CFU/g. The bactericidal activity of WEW also decreased with increasing bovine serum concentration. At the ratio of 10:1 (WEW: perilla leave), levels of Salmonella Typhimurium and Staphylococcus aureus were only reduced by 0.57 and 0.79 log10CFU/g, respectively. It is suggested that the removal of organic debris prior to application of sanitizers and treatment above the ratio of 25:1 (WEW: perilla leave) is needed in order to improve WEW activity.