High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells

Hong, Oak-Kee,Yoo, Soon-Jib,Son, Jang-Won,Kim, Mee-Kyoung,Baek, Ki-Hyun,Song, Ki-Ho,Cha, Bong-Yun,Jo, Hanjoong,Kwon, Hyuk-Sang The Korean Society of Pharmacology 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2

Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) affect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a pro-inflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of inflammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL.

High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells

Oak-Kee Hong,Soon-Jib Yoo,Jang-Won Son,Mee-Kyoung Kim,Ki Hyun Baek,Ki-Ho Song,Bong-Yun Cha,Hanjoong Jo,Hyuk-Sang Kwon 대한생리학회-대한약리학회 2016 The Korean Journal of Physiology & Pharmacology Vol.20 No.2

Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/ or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this effect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinfl ammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL.

Proteomic analysis of differential protein expression in response to epidermal growth factor in neonatal porcine pancreatic cell monolayers

Hong, Oak-Kee,Suh, Sun-Hee,Kwon, Hyuk-Sang,Ko, Seung-Hyun,Choi, Yoon-Hee,Moon, Sung-Dae,Yoo, Soon-Jib,Son, Ho-Young,Park, Kyung-Soo,Lee, In-Kyu,Yoon, Kun-Ho Wiley Subscription Services, Inc., A Wiley Company 2005 Journal of cellular biochemistry Vol.95 No.4

<P>We have proposed that porcine neonatal pancreatic cell clusters (NPCCs) may be a useful alternative source of cells for islet transplantation, and that monolayer cultures might provide an opportunity to manipulate the cells before transplantation. In addition we previously identified 10 genes up-regulated by epidermal growth factor (EGF) in cultured porcine NPCC monolayers. We have now analyzed the intracellular signaling pathways activated by EGF and searched for proteins differentially expressed following EGF treatment of the monolayers, using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). EGF treatment resulted in phosphorylation of both Erk 1/2 and Akt, as well as increased cell proliferation. Five unknown and 13 previously identified proteins were differentially expressed in response to EGF. EGF treatment increased the expression of several structural proteins of epithelial cells, such as cytokeratin 19 and plakoglobin, whereas vimentin, the intermediate filament protein of mesenchymal cells, and non-muscle myosin alkali chain isoform 1, decreased. Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 factor, which promotes epithelial cell proliferation, and hemoglobin alpha I & II also increased, whereas cyclin A1, immunoglobulin heavy chain, apolipoprotein A1, 5,10-ethylenetetrahydrofolated reductase (5,10-MTHFR), angiotensin-converting enzyme 2 (ACE2), co-lipase II precursor, and NAD<SUP>+</SUP> isocitrate dehydrogenase (NAD<SUP>+</SUP> IDH) alpha chain proteins decreased. Our results show that EGF stimulates proliferation of pancreatic epithelial cells by simultaneously activating the MAPK and PI-3K pathways. HnRNP A2/B1, hemoglobin, cyclin A1, and ACE2 may play roles in the proliferation of epithelial cells in response to EGF. © 2005 Wiley-Liss, Inc.</P>

Transforming growth factor‐β induces epithelial to mesenchymal transition and suppresses the proliferation and transdifferentiation of cultured human pancreatic duct cells

Shin, Jeong‐,Ah,Hong, Oak‐,Kee,Lee, Hye‐,Jung,Jeon, Sung‐,Yoon,Kim, Ji‐,Won,Lee, Seung‐,Hwan,Cho, Jae‐,Hyoung,Lee, Jung‐,Min,Choi, Yoon‐,Hee,Chang Wiley Subscription Services, Inc., A Wiley Company 2011 Journal of cellular biochemistry Vol.112 No.1

<P><B>Abstract</B></P><P>Pancreatic duct cells are considered a potential source of β‐cell regeneration, and transforming growth factor‐β (TGF‐β) has been suggested to perform an important role in these processes, but the underlying mechanism of the signal pathways, especially in humans, remains poorly understood. To evaluate the role of TGF‐β1, pancreatic duct cells were isolated from three brain‐dead organ donors. Pancreatic cell clusters harvested after islet isolation were dispersed to single cells and cultured in monolayers, then treated with TGF‐β1. We analyzed the characteristics of the cultured cells, the TGF‐β1 intracellular signaling pathway, the proliferation, and transdifferentiation rates of the duct cells. We also evaluated the genes and protein expression patterns after TGF‐β1 treatment. After TGF‐β1 treatment, typical morphologic changes representative of EMT were observed and Erk1/2, JNK, and AKT phosphorylation, Ras downstream effectors, were increased. β cell‐specific transcription factors including PDX‐1, Beta2/NeuroD, Ist‐1, and NGN3 were markedly suppressed and the rate of transdifferentiation into β cells was also suppressed. Genomic and proteomic analyses suggested that TGF‐β1 induces marked changes in a variety of structural genes and proteins associated with EMT. In conclusion, TGF‐β1 induces EMT in cultured human pancreatic duct cells, but suppresses its proliferation and transdifferentiation into β cells. Our results are the first report of TGF‐β1 effects for EMT and ductal cell transdifferentiation and proliferation at the protein level in human pancreatic duct cells. J. Cell. Biochem. 112: 179–188, 2011. © 2010 Wiley‐Liss, Inc.</P>

Serum Bone Morphogenic Protein-4 Contributes to Discriminating Coronary Artery Disease Severity

Park, Chul Soo,Hong, Oak-Kee,Kim, Mee Kyoung,Chung, Woo Baek,Choi, Yun Seok,Baek, Ki-Hyun,Song, Ki-Ho,Lee, Man Young,Kwon, Hyuk-Sang Williams & Wilkins Co 2015 Medicine Vol.94 No.39

<P><B>Abstract</B></P><P>Bone morphogenic protein 4 (BMP-4) is a known pro-inflammatory and pro-atherogenic cytokine. Here, we investigated whether the serum BMP-4 level predicts coronary artery disease (CAD) severity in humans.</P><P>We measured serum BMP-4 concentrations in 1044 consecutive patients who underwent elective coronary angiography and percutaneous coronary intervention. CAD severity was estimated by the number of diseased vessels showing ≥50% diameter stenosis.</P><P>Among males, the serum BMP-4 level was significantly lower in patients with multivessel disease (MVD) compared with those with single-vessel disease (SVD) (16.3 ± 22.6 vs. 22.0 ± 28.4 pg/mL, <I>P</I> < 0.01). After adjustment for other cardiovascular risk factors, a high serum BMP-4 level was an independent predictor for a decreased risk of MVD (odds ratio, 0.992; 95% confidence interval [CI], 0.985–0.998; <I>P</I> = 0.01) and patients in the lower tertile were 1.55-fold more likely to have MVD compared with upper tertile patients. Receiver-operating characteristic curve analysis demonstrated that the serum BMP-4 level had a 54% sensitivity and 54% specificity for predicting MVD (area under the curve [AUC], 56.5%; 95% CI, 51.9–61.0%; <I>P</I> < 0.01). Serum BMP-4 improved the predictive capability of risk factors for MVD (AUC with and without BMP-4: 64.9 and 63.6%, respectively). Considering the likelihood ratio and number of parameters, adding the serum BMP-4 level provided a better-fit model for predicting MVD compared with the model consisting of conventional risk factors (likelihood ratio <I>χ</I><SUP>2</SUP> = 6.20, <I>P</I> = 0.01). However, an association between serum BMP-4 and CAD was not observed in females.</P><P>Serum BMP-4 levels are independently associated with CAD severity and contribute to discriminating CAD severity in males.</P>

Chronic Alcohol Consumption Results in Greater Damage to the Pancreas Than to the Liver in the Rats

Lee, Seong-Su,Hong, Oak-Kee,Ju, Anes,Kim, Myung-Jun,Kim, Bong-Jo,Kim, Sung-Rae,Kim, Won-Ho,Cho, Nam-Han,Kang, Moo-Il,Kang, Sung-Koo,Kim, Dai-Jin,Yoo, Soon-Jib The Korean Society of Pharmacology 2015 The Korean Journal of Physiology & Pharmacology Vol.19 No.4

Alcohol consumption increases the risk of type 2 diabetes. However, its effects on prediabetes or early diabetes have not been studied. We investigated endoplasmic reticulum (ER) stress in the pancreas and liver resulting from chronic alcohol consumption in the prediabetes and early stages of diabetes. We separated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type-2 diabetic animal model, into two groups based on diabetic stage: prediabetes and early diabetes were defined as occurrence between the ages of 11 to 16 weeks and 17 to 22 weeks, respectively. The experimental group received an ethanol-containing liquid diet for 6 weeks. An intraperitoneal glucose tolerance test was conducted after 16 and 22 weeks for the prediabetic and early diabetes groups, respectively. There were no significant differences in body weight between the control and ethanol groups. Fasting and 120-min glucose levels were lower and higher, respectively, in the ethanol group than in the control group. In prediabetes rats, alcohol induced significant expression of ER stress markers in the pancreas; however, alcohol did not affect the liver. In early diabetes rats, alcohol significantly increased most ER stress-marker levels in both the pancreas and liver. These results indicate that chronic alcohol consumption increased the risk of diabetes in prediabetic and early diabetic OLETF rats; the pancreas was more susceptible to damage than was the liver in the early diabetic stages, and the adaptive and proapoptotic pathway of ER stress may play key roles in the development and progression of diabetes affected by chronic alcohol ingestion.

유육종증 1예

김광,전성진,서기석,김상태,정만홍,옥순애,장희경,허만하 高神大學 醫學部 1991 高神大學醫學部 論文集 Vol.7 No.1

Streptozotocin으로 유발된 당뇨쥐의 간세포 내 Gi 단백의 양과 기능 변화

옥선명,손현식,홍옥기,이정민,김성래,장상아,윤건호,강무일,차봉연,이광우,손호영,강성구 대한당뇨병학회 2002 Diabetes and Metabolism Journal Vol.24 No.6

연구배경:당뇨병과 인슐린 작용에 있어 Gi 단백의 역할은 정설이 없는 상태이며, 당뇨병의 유병 기간에 따른 Gi 단백의 변화는 잘 알려져 있지 않다. 본 연구에서는 streptozotocind으로 유발된 인슐린의존성 당뇨쥐의 간세포를 대상으로 당뇨병의 유병 기간에 따른 Gi 단백의 기능적 변화와 Gi 단백의 양적인 변화를 α소단위의 종류에 따라 비교함으로서 인슐린 작용 및 당뇨병의 병인에서 Gi 단백의 역할을 평가하고자 하였다. 방법:Sprague­Dawley계 흰쥐 수컷에 streptozotocin을 정맥 주사하여 당뇨병을 유발시킨 후 1, 2, 3 및 5주에 간조직을 differential ultracentrifugation와 gradient centrifrgation방법으로 전세포분쇄물과 중간분쇄물 및 간세포막으로 분획한 다음 Giα의 양적 변화를 평가하기 위해서 Giα1&2, Giα₃에 대한 항체로 western blot을 실시하였고, 기능적 변화를 평가하기 위해서 pertussis toxin­catalyzed ADP­ribosylation과[35S]­GTPγS binding assay를 실시하였다. 결과:당뇨군과 대조군의 간세포에는 Giα², Giα³이 존재하는데 주로 간세포막에 존재하며, 대조군에 비해 당뇨군의 간세포막의 Giα²와 Giα³의 양이 유의하게 높게 측정되었으나 (p<0.01)당뇨병의 유병 기간 증가에 따른 변화는 없었다. Pertussis toxin­catalyzed ADP­ribosylation와[35S]­GPTγS 결합률을 실시한 결과 대조군에 비해서 당뇨군의 간세포막에서 저하되었으나(p<0.01), 당뇨병의 유병 기간 증가에 따른 변화는 없었다. 결론:인슐린의존성 당뇨쥐의 간세포에서 Gi 단백의 양적 및 기능적 변화가 있으나, 당뇨병의 유병 기간과 관계가 없는 것으로 보아, 인슐린 결핍에 의한 인슐린저항성에 대한 보상 반응으로 생각되며, 이는 인슐린 작용 및 당뇨병에서 Gi 단백이 관여함을 알 수 있었다. Background : The functional and expressional changes of Gi proteins in diabetes have been investigated extensively, no agreement has been reached in the results. Moreover, studies using rats with different diabetic duration, and using α subunits (G_ia) of Gi proteins are lacking in literatures. Thus, we assessed the changes according to the duration of diabetes and examined the expressional changes of G_ia and functional changes of G_i proteins in hepatocytes from streptozotocin-induced diabetic rats. Methods : Male Sprague-Dawley rats were injected with streptozotocin to induce diabetes ; 1, 2, 3 and 5 weeks after teh onset of diabetes, livers from the control and diabetic rats were fractionated into homogenate, interface, and plasma membrane. The levels of G_ia 1&2, G_ia 3 were quantified with western blots in each fraction. The functional changes of Gi proteins were evaluated by performing pertussis to xin-catalyzed ADP-ribosylation and measuring GTPγS binding activity. Results : 1) G_ia 2 and G_ia 3 were present mainly in the plasma membrane of hepatocytes in the diabetic and control rats, but the levels of these subunits were significantly higher in the diabetic rats, but the levels of these subunits were significantly higher in the diabetic rates than in the control rats (p<0.01). The levels of these subunits were not affected by the duration of diabetes. 2) In streptozotocin-induced diabetic rats, the levels of ADP-ribosylation of Gi proteins in liver plasma membranes decreased when pertussis toxin-catalyzed ADP-ribosylation was performed with liver tissues. However, the levels of these proteins were not affected by the duration of diabetes. 3) For the GTPγS binding activity of G_i proteins in liver plasma membranes, the diabetic rats showed significantly less activity than the control rats (p<0.01). However, the activity was not affected by the duration of diabetes. The activity was somewhat restored by the insulin treatment of liver plasma membranes in diabetic rats. Conclusion : These results suggest that the insulin-deficient diabetic state induces the quantitative and functional changes in G_i proteins may be the important compensatory reactions for the insulin resistance occurring in the insulin deficient state (J Kor Diabetes Asso 24:666~677, 2000).

Development of experimental model of adhesive capsulitis in rat

Suk-Hwan Jang(장석환),Yang-Soo Kim,Oak-Kee Hong,Jang-Un Kim,Kyu-Rim Kim 대한견주관절의학회 2015 대한견주관절학회 학술대회논문집 Vol.2015 No.4

유육종증 1예

김광,전성진,서기석,김상태,정만홍,옥순애,장희경,허만하 고신대학교 의학부 1991 高神大學校 醫學部 論文集 Vol.7 No.1

We report a case of sarcoidosis in 48-year-old female. She showed skin manifestation of subcutaneous nodules in previously scarred area and non-scarred skin. Chest X-ray and gallium 67-scan revealed bilateral lymphadenopathy, and pulmonary function test showed moderate degree of restrictive ventilatory pattern. Histopathologically, subcutaneous nodules at the scarred area of forehead as well as non-scarred skin of knee and forearm, were subcutaneous noncaseating granulomas composed of epithelioid cells admixed with a few Langhans giant cells. Reticulum fibers surrounded and permeated the granulomas. She was treated with systemic corticosteroids for 10 months and improvements of skin lesions and pulmonary symptoms could be noted.