Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

( Sun-uk Bak ),( Suji Kim ),( Hae-jun Hwang ),( Jung-a Yun ),( Wan-sung Kim ),( Moo-ho Won ),( Ji-yoon Kim ),( Kwon-soo Ha ),( Young-guen Kwon ),( Young-myeong Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKLinduced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO-1^+/-cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-κB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-κB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]

NAFLD Is Associated with High Prevalence and High Recurrence Rate in Patients with Breast Cancer

( Young-sun Lee ),( Sung Won Chang ),( Ha Seok Lee ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Breast cancer is most common cancer in women worldwide. The incidence of breast cancer is correlated with metabolic component including diabetes, hypertension, and obesity. Likewise breast cancer, metabolic components are important risk factors for development of NAFLD. In this study, we analyzed the prevalence of NAFLD in patients with breast cancer and the effect of NAFLD on the prognosis of breast cancer. Methods: Patients with breast cancer were enrolled from January 2007 to June 2017. Patients who had other chronic liver were excluded. Hepatic steatosis was evaluated by non-enhanced CT scan. We diagnosed NAFLD when the mean attenuation of the liver is lower than 40 HU or 10 HU lower than that of the spleen. 123 healthy controls who took non-enhanced CT scan were also analyzed. Results: Total 1587 patients were enrolled from January 2007 to June 2017. The prevalence of NAFLD in patients with breast cancer was 15.8% (251/1587) and it was significantly higher comparing with healthy control (8.9%, 11/123)(P=0.036). After propensity score matching, the difference of NAFLD prevalence was still significant between control group (8.9%, 11/123) and breast cancer patients (17.9%, 22/123) (P=0.040). In breast cancer patients, overall survival did not showed significant difference between NAFLD group and non-NAFLD group (P=0.304) (Figure A). However, recurrence-free survival was significantly higher in patients without NAFLD comparing with those with NAFLD (P=0.009) (Figure B). Among breast cancer patients received endocrine treatment, NAFLD group showed higher cumulative incidence of significant liver injury comparing with non-NAFLD group (P<0.001). Conclusions: The prevalence of NAFLD in patients with breast cancer is significantly high compared to healthy control group. Moreover, breast cancer patients with NAFLD showed poor prognosis in terms of recurrence. Therefore, diagnostic evaluation to determine whether or not NAFLD is present would be important in managing patients with breast cancer.

Role of tenofovir disoproxil fumarate in prevention of perinatal transmission of hepatitis B virus from mother to child: a systematic review and meta-analysis

( Young-sun Lee ),( Ha Seok Lee ),( Ji Hoon Kim ),( Sung Won Chang ),( Myung Han Hyun ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Yeon Seok Seo ),( Hyung Joon Yi 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.1

Background/Aims: To prevent the perinatal transmission of hepatitis B virus (HBV) from mother to child, administration of an antiviral agent during pregnancy has been attempted in women who are either hepatitis B e antigen positive or have a high viral load. In this systematic review and meta-analysis with randomized controlled trials, we analyzed the efficacy and safety of tenofovir disoproxil fumarate (TDF) in preventing the perinatal transmission of HBV in pregnant women who have high HBV DNA titers. Methods: Multiple comprehensive databases (PubMed, EMBASE, and Cochrane databases) were searched for studies evaluating the efficacy of TDF for the prevention of perinatal transmission of HBV. Results: Two studies (one open label study and one double blind study) were included and analyzed. Intention-to-treat analysis (527 pregnancies) showed that the preventive effect of TDF was not significant (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.13 to 2.17; p = 0.38, I² = 81%). However, the per-protocol analysis showed that TDF significantly reduced perinatal transmission (OR, 0.10; 95% CI, 0.01 to 0.77; p = 0.03, I² = 0%). There was no significant difference between the TDF group and the control group with respect to maternal and fetal safety outcomes. Conclusions: In pregnant women who have high HBV DNA titers, TDF can reduce the perinatal transmission from mother to child without significant adverse events.

The Direct Comparison between 7th AJCC Staging System and 8th AJCC Staging System for Prediction of Survival with Korean Multicenter HCC Patients

( Young-sun Lee ),( Sung Won Chang ),( Ha Seok Lee ),( Haein Bak ),( Sehwa Kim ),( Min-jin Lee ),( Chan Uk Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Jong Eun Yeon 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: AJCC staging is the most commonly used staging system in most solid tumors, and recent AASLD hepatocellular carcinoma (HCC) guideline also endorsed this AJCC staging system based on status of tumor, node, and metastasis. Recently, 8th edition of AJCC staging system was released in December 2016. This study aimed to compare prediction of survival in HCC patients between 7th AJCC staging system and 8th AJCC staging system. Methods: From 2004 to 2013, 2211 newly diagnosed HCC patients were consecutively enrolled in three Korea University medical centers and the medical records of patients were retrospectively reviewed. Each patients were classified following both of 7th AJCC staging system and 8th AJCC staging system. Results: Chronic hepatitis B (1523, 68.9%) was main attributable factor in development of HCC, followed by chronic hepatitis C (256, 11.6 %) and alcohol consumption (241, 10.9%). 1514 patients (68.5%) died during study period and median overall survival (OS) was 24.7 months. According to 7th AJCC staging system, 894 (40.4%) patients were included into stage I; 459 patients (20.8%) into stage II; 180 patients (8.1%) into stage IIIa; 354 patients (16.0%) into stage IIIb; 3 patients (0.1%) into stage IIIc; 119 patients (5.4%) into stage IVa; and 202 patients (9.1%) into stage IVb. According to 8th AJCC staging system, 400 (18.1%) patients were categorized into stage IA; 498 patients (22.5%) into stage IB; 442 patients (20.2%) into stage II; 193 patients (8.7%) into stage IIIa; 357 patients (16.1%) into stage IIIb; 119 patients (5.4%) into stage IVa; and 202 patients (9.1%) into stage IVb. Both 7th staging system and 8th staging system show distinct survival outcomes according to each stage. Although 7th AJCC staging system significantly well predicted 1 year of survival than 8th AJCC staging system (AUROC; 0.796 vs 0.784, P=0.013), AUROCs of 3 year and 5 year were similar in 7th and 8th AJCC staging system (0.754 vs 0.752 in 3 year, P=0.601; 0.744 vs 0.742 in 5 year, P=0.643). Conclusions: Both 7th and 8th AJCC staging system show distinct survival outcome according to each stage. Moreover, both 7th and 8th AJCC staging system are similar in prediction of survival outcomes.

소리가 집중력 향상에 미치는 영향 분석

이선경(Sun-Kyoung Lee),전상준(Sang-Jun Jeon),채민성(Min-Sung Chae),진현수,박영순(Yeong-Sun Bak),이회문(Hoe-Moon Lee),조동욱(Dong-Uk Cho) 한국통신학회 2018 한국통신학회 학술대회논문집 Vol.2018 No.11

피부투과 기능성 펩타이드를 이용한 경피투과성 상피세포성장인자의 개발

강진선 ( Jin Sun Kang ),나하나 ( Ha Na La ),박선욱 ( Sun Uk Bak ),엄효정 ( Hyo Jung Eom ),이병규 ( Byung Kyu Lee ),신희제 ( Hee Je Shin ) 대한화장품학회 2019 대한화장품학회지 Vol.45 No.2

상피세포성장인자(epidermal growth factor, EGF)는 인간의 표피 및 진피에서 세포막 수용체와 상호작용을 통하여 세포의 생장 및 증식을 유도하는 기능을 갖고 있다. 이 같은 EGF의 기능은 의료 및 화장품분야에서 상처치유 의약품 및 노화방지 화장품의 주요원료로 사용되고 있다. 화장품 원료로서 EGF는 피부장벽으로 알려져 있는 피부 각질층의 투과가 잘 안되기 때문에 가지고 있는 본연의 효능을 구현하는 데 문제가있다. 본 연구에서는 EGF의 경피투과 효율을 개선하기 위하여 피부 투과능이 확인된 거대분자 전송 도메인(macromolecule transduction domain, MTD) 151이 융합된 형태로 재조합 인간 상피세포성장인자(MTD₁₅₁-EGF)를 개발하였다. MTD₁₅₁-EGF의 유전자가 coding된 vector로 형질전환된 대장균에서MTD₁₅₁-EGF 발현시킨 후 정제를 진행하였다. 정제된 MTD-EGF를 대상으로 세포증식시험, 세포독성시험, 생체외 피부흡수시험 그리고 인공피부를 이용한 경피투과능을 평가하였다. 99% 이상 고순도로 정제된MTD₁₅₁-EGF의 세포증식 활성은 EGF 대비 동등 이상의 수준이었으며, 세포독성은 관찰되지 않았다. 또한, 인공피부 투과모델에서 FITC로 표지된 EGF와 MTD₁₅₁-EGF의 진피층까지의 투과를 공초점 현미경으로 관찰한 결과, MTD₁₅₁-EGF는 EGF 대비 우수한 투과능을 보였으며, 경피흡수 시스템을 이용한 투과물질의 정량분석 결과, EGF 대비 약 16 배 이상 투과량이 많은 것으로 확인되었다. 이러한 결과들은 다양한 활성물질들의화장품용 원료로서의 경피투과에 MTD가 기존의 물리적인 경피투과 방법을 효율적으로 개선한 대안이 될것으로 판단된다. The epidermal growth factor (EGF) has a intrinsic function of inducing growth and proliferation of cells through interacting with cell membrane receptors in human epidermis and dermis layer. These functions of EGF are used as a main ingredient for wound healing medicines and anti-aging cosmetics. As a cosmetic ingredient, the EGF has a problem in exhibiting its natural efficacy due to the lack of the ability to penetrate through the stratum corneum, which is known as the skin barrier. In this study, a recombinant human epidermal growth factor (MTD₁₅₁-EGF) fused with the macromolecule transduction domain (MTD)₁₅₁ with the skin penetration ability was developed to improve the skin penetration efficiency of the EGF. Expression of MTD₁₅₁-EGF was performed in E. coli transformed with a vector encoding the MTD₁₅₁-EGF gene and then purified. The purified MTD₁₅₁-EGF was evaluated using cell proliferation assay, cytotoxicity test and skin penetration test by franz diffusion cell assay and artificial skin. Cell proliferation activity of MTD₁₅₁-EGF purified to high purity of 99% or above was equivalent to the EGF or better, and cytotoxicity was not observed. In addition, the MTD₁₅₁-EGF showed an excellent penetration efficiency compared to the EGF in the skin penetration test with EGF and MTD₁₅₁-EGF labeled by FITC in an artificial skin penetration model. Based on the quantitative analysis of the penetrating substance using franz diffusion cell assay, the amount of penetration was about 16 times more than that of EGF. These results can be regarded as an effective alternative to improve the existing physical transdermal penetration method related to the use of various active ingredients for cosmetics.

Association between Non-Alcoholic Fatty Liver Disease Incidence and Colorectal Cancer

( Se Hwa Kim ),( Haein Bak ),( Sungwon Jang ),( Ha Seok Lee ),( Chan Uk Lee ),( Young Sun Lee ),( Young Kul Jung ),( Ji Hoon Kim ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Kwan Soo Byun ),( Minjin Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases(CLD) globally(prevalence of 25.2%). Recently, It is stipulated that NAFLD may be an independent risk factor for developing colorectal cancer(CRC). We analyzed the prevalence of NAFLD in patients with CRC and the effect of NAFLD on the prognosis of CRC. Methods: Total 293 patients with CRC were enrolled from March 2003 to April 2018. Patients who had other CLD including chronic viral hepatitis B/C, autoimmune hepatitis, and primary biliary cholangitis and significant alcohol abuse (more than 140 g/week in women and 210 g/week in men) were excluded. Hepatic steatosis was evaluated by non-enhanced computed tomography (CT) scan. We measured values of regions of interest (ROI) for 3 times in liver and spleen, respectively. We diagnosed NAFLD when the average ROI of liver 10 less than it of spleen. 123 healthy controls who took non-enhanced CT scan were also analyzed. Results: The median age was 65.0(interquartile range[IQR] 54.0-73.0 years), and median Body mass index(BMI) was 24.02 (IQR 21.4-26.1). The median BMI of CRC patients without NAFLD was 23.75(IQR 21.3-25.7), and CRC patients with NAFLD was 25.16(IQR 21.8-27.0). The prevalence of Hypertension was 49.8%(146/293) in CRC group, and 35.77%(4/123) in control group (P=0.009). The prevalence of Diabetes Mellitus was 32.08% (94/293) in CRC group, and 16.26%(20/123) in control group(P=0.001). The prevalence of NAFLD was significantly higher in CRC group(24.57%, 72/293) than in the healthy group. (13%, 16/123) (P=0.008). Overall survival did not showed significant difference between NAFLD group and non-NAFLD group (P=0.706 by log-rank test). Conclusions: The prevalence of NAFLD in patients with CRC is significantly higher than control group. But the overall survival didn’t show singnificant difference. Further studies are needed to specify the effect of NAFLD on CRC prognosis in terms of recurrence and progression.

Wnt/β-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus

( Yeong Chan Ryu ),( You-rin Kim ),( Jiyeon Park ),( Sehee Choi ),( Geon-uk Kim ),( Eunhwan Kim ),( Yumi Hwang ),( Heejene Kim ),( Soon Sun Bak ),( Jin Eun Lee ),( Young Kwan Sung ),( Gyoonhee Han ),( 생화학분자생물학회 2022 BMB Reports Vol.55 No.11

Diabetes mellitus is one of the most prevalent diseases in modern society. Many complicationssuch as hepatic cirrhosis, neuropathy, cardiac infarction, and so on are associated with diabetes. Although a relationship between diabetes and hair loss has been recently reported, the treatment of diabetic hair loss by Wnt/β-catenin activators has not been achieved yet. In this study, we found that the depilation-induced anagen phase was delayed in both db/db mice and high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice. In diabetic mice, both hair regrowth and wound-induced hair follicle neogenesis (WIHN) were reduced because of suppression of Wnt/β- catenin signaling and decreased proliferation of hair follicle cells. We identified that KY19382, a small molecule that activates Wnt/β-catenin signaling, restored the capabilities of regrowth and WIHN in diabetic mice. The Wnt/β-catenin signaling activator also increased the length of the human hair follicle which was decreased under high glucose culture conditions. Overall, the diabetic condition reduced both hair regrowth and regeneration with suppression of the Wnt/β-catenin signaling pathway. Consequently, the usage of Wnt/β-catenin signaling activators could be a potential strategy to treat diabetes-induced alopecia patients. [BMB Reports 2022; 55(11): 559-564]