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Cha, Byung-Hyun,Jung, Moon-Joo,Moon, Bo-Kyung,Kim, Jin-Su,Ma, Yoonji,Arai, Yoshie,Noh, Myungkyung,Shin, Jung-Youn,Kim, Byung-Soo,Lee, Soo-Hong Elsevier 2016 Bone Vol.83 No.-
<P><B>Abstract</B></P> <P>It is known that osteogenic differentiation of mesenchymal stem cells (MSCs) can be promoted by suppression of adipogenesis of MSCs. We have recently found that the chemical chaperone tauroursodeoxycholic acid (TUDCA) significantly reduces adipogenesis of MSCs. In the present study, we examined whether TUDCA can promote osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) by regulating Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway and thereby enhance bone tissue regeneration by reducing apoptosis and the inflammatory response. TUDCA treatment promoted <I>in vitro</I> osteogenic differentiation of BMMSCs and <I>in vivo</I> bone tissue regeneration in a calvarial defect model, as confirmed by micro-computed tomography, histological staining, and immunohistochemistry for osteocalcin. In addition, TUDCA treatment significantly decreased apoptosis and the inflammatory response <I>in vivo</I> and <I>in vitro</I>, which is important to enhance bone tissue regeneration. These results indicate that TUDCA plays a critical role in enhancing osteogenesis of BMMSCs, and is therefore a potential alternative drug for bone tissue regeneration.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Tauroursodeoxycholic acid (TUDCA) promotes osteogenic differentiation of mouse bone marrow mesenchymal stem cells (mBMMSCs). </LI> <LI> TUDCA stimulates Integrin 5 (ITGA5) associated with activation of ERK1/2 signal pathway. </LI> <LI> TUDCA enhances bone tissue regeneration by the suppression of apoptosis and inflammatory response. </LI> <LI> TUDCA promotes bone tissue regeneration in mouse calvarial defects. </LI> <LI> Ursodeoxycholic acid (UDCA), which has a similar chemical structure to TUDCA, also increases bone regeneration. </LI> <LI> TUDCA is a useful pharmacological substitute for BMP-2, which is clinically available for bone tissue regeneration. </LI> </UL> </P>
Drug repositioning of tauroursodeoxycholic acid for bone tissue regeneration
이수홍,차병현,김병주,( Arai Yoshie ),김병수,한인보 한국공업화학회 2016 한국공업화학회 연구논문 초록집 Vol.2016 No.0
Bone tissue engineering from bone morphogenetic protein (BMP) and stem cells has been developed with various strategies for enhancement of therapeutic effect. Our recent study found that chemical chaperone tauroursodeoxycholic acid (TUDCA) significantly reduces adipogenesis of mesenchymal stem cells (MSCs). In present study, we examine whether TUDCA as an alternative drug of BMP is able to activate bone tissue regeneration by reducing adipose tissue. It was observed that TUDCA treatment was able to promote in vivo bone tissue regeneration at calvarial defect model and spinal fusion model. In addition, TUDCA treatment significantly decreases apoptosis and inflammatory response in vivo as well as in vitro. The results indicate that TUDCA plays a critical role in not only enhancing in vivo bone regeneration also reducing adipose tissue at implantation site, therefore, would be a potential alternative drug for bone tissue regeneration in pharmacologic and therapeutic applications.
( Dong Hyeon Lee ),( Yu Ri Cho ),( Yun Bin Lee ),( Jung Hee Kwon ),( Eun Ju Cho ),( Jeong Hoon Lee ),( Su Jong Yu ),( Hyo Suk Lee ),( Jung Hwan Yoon ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1
Background & Aims: Endoplasmic reticulum (ER) stress is critically involved in the initiation and progression of nonalcoholic steatohepatitis (NASH). Modulation of ER stress by chemical chaperones may be beneficial in various ER stress-related diseases. The aim of this study was to evaluate whether the administration of the chemical chaperone tauroursodeoxycholic acid (TUDCA) could limit development and progression of NASH. Methods: Huh-BAT cells were used in this study. Experimental steatohepatitis was induced in C57BL6 mice by a methioninecholine deficient (MCD) diet, and three different doses of TUDCA (500 or 1000 mg/kg once daily, 500 mg/kg twice daily) were administered by gavage. Results: TUDCA reduced palmitate (PA)-induced ER stress as manifested by decreased eIF2a phosphorylation and CHOP induction. TUDCA also decreased PA-induced JNK phosphorylation, PUMA upregulation and BAX activation, which in turn suppressed caspase-dependent lipoapoptosis. Mice given TDUCA showed a significant attenuation of hepatic damage compared to the control mice. Moreover, TUDCA treatment decreased lipid peroxidation and nitrotyrosylation in the liver of MCD diet-fed mice, indicating attenuation of oxidative stress. TUDCA also reduced the expression levels of ER stress markers and pro-apoptotic proteins, which led to decreased apoptosis evidenced by TUNEL assay. Finally, TUDCA reversed histological fibrosis along with the down-regulation of profibrotic gene expression. Conclusions: This study showed that TUDCA prevents progression of experimental steatohepatitis through modulation of ER stress. With its outstanding safety profile, TUDCA may be implicated in the treatment of NASH.
( Dong Hyeon Lee ),( Yuri Cho ),( Yun Bin Lee ),( Jung Hee Kwon ),( Eun Ju Cho ),( Jeong Hoon Lee ),( Su Jong Yu ),( Hyo Suk Lee ),( Jung Hwan Yoon ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-
Background & Aims: Endoplasmic reticulum (ER) stress is critically involved in the initiation and progression of nonalcoholic steatohepatitis (NASH). Modulation of ER stress by chemical chaperones may be beneficial in various ER stress-related diseases. The aim of this study was to evaluate whether the administration of the chemical chaperone tauroursodeoxycholic acid (TUDCA) could limit development and progression of NASH. Methods: Huh-BAT cells were used in this study. Experimental steatohepatitis was induced in C57BL6 mice by a methioninecholine deficient (MCD) diet, and three different doses of TUDCA (500 or 1000 mg/kg once daily, 500 mg/kg twice daily) were administered by gavage. Results: TUDCA reduced palmitate (PA)-induced ER stress as manifested by decreased eIF2a phosphorylation and CHOP induction. TUDCA also decreased PA-induced JNK phosphorylation, PUMA upregulation and BAX activation, which in turn suppressed caspase-dependent lipoapoptosis. Mice given TDUCA showed a significant attenuation of hepatic damage compared to the control mice. Moreover, TUDCA treatment decreased lipid peroxidation and nitrotyrosylation in the liver of MCD diet-fed mice, indicating attenuation of oxidative stress. TUDCA also reduced the expression levels of ER stress markers and pro-apoptotic proteins, which led to decreased apoptosis evidenced by TUNEL assay. Finally, TUDCA reversed histological fibrosis along with the down-regulation of profibrotic gene expression. Conclusions: This study showed that TUDCA prevents progression of experimental steatohepatitis through modulation of ER stress. With its outstanding safety profile, TUDCA may be implicated in the treatment of NASH.
쥐에서 Taurocholate 부하에 의한 간의 Glyoxalase I의 유도
정상호,김여희,곽춘식 계명대학교 의과학연구소 2001 계명의대학술지 Vol.20 No.1
The possible mechanisms of increased glyoxalase I (GLO-I) activity in cholestatic rat liver and serum were studied. These hepatic and serum enzyme activities were determined from the experimental rats with choledocho-caval shunt (CCS) or bile duct obstruction (BDO). The Michaelis-Menten constants in this hepatic enzyme were also measured. The activities of hepatic and serum GLO-I as well as the Vmax value of this hepatic enzyme were found to be increased significantly in both CCS plus taurocholic acid (TCA) injected group, and BDO plus TCA injected group than in each control group such as CCS alone and BDO alone. In addition, these serum and hepatic enzyme activities did not change in both the CCS plus tauroursodeoxycholic acid injected group and the BDO plus tauroursodeoxycholic acid injected group. On the other hand, the value of Km of the above hepatic enzyme did not change in any experimental group. Above results suggest that TCA induce the biosynthesis of GLO-I in the liver. The elevated activity of the serum GLO-I is believed to be caused by the increment of membrane permeabiliry of hepatocytes upon TCA mediated liver cell necrosis.
김병주,ARAIYOSHIE,최보규,박성현,안진성,한인보,이수홍 한국공업화학회 2018 Journal of Industrial and Engineering Chemistry Vol.61 No.-
Tauroursodeoxycholic acid (TUDCA) has a role in the regulation of the differentiation of mesenchymal stem cells. In this study, TUDCA was demonstrated to increase osteogenic differentiation at a low concentration (25 μM) and chondrogenic differentiation at a high concentration (2500 μM). We investigated the regeneration of osteochondral defects in a rat model using a bilayer plug loaded with two different concentration of TUDCA-PLGA microspheres (TUDCA-MS bilayer plug). The TUDCA-MS bilayer plug successfully regenerated cartilage and subchondral bone layer. Therefore, we suggest that the TUDCA-MS bilayer plug as a new treatment method for simultaneous regeneration of cartilage and subchondral bone layer.
타우로우루소데옥시콜린산이 흰쥐의 적출심장에서 허혈 및 재관류 손상에 미치는 영향
한석희,이우용,박진혁,이선미 성균관대학교 약학연구소 1999 成均藥硏論文集 Vol.11 No.-
Abstract - In this study, the effects of tauroursodeoxycholic acid (TUDCA) on ischemia/ reperfusion injury were investigated on isolated heart perfusion models. Hearts were perfused with oxygenated Krebs-Henseleit solution (pH 7.4, 37℃) on a Langendorff apparatus. After equilibration, isolated hearts were treated with TUDCA 100 and 200μM or vehicle (0.02% DMSO) for 10 min before the onset of ischemia in single treatment group. In 7 day pretreatment group, TUDCA 50, 100 and 200 mg/kg body weight were given orally for 7days before operation. After global ischemia (30 min), ischemic hearts were reperfused for 30 min. The physiological (i.e. heart rate, left ventricular developed pressure, coronary flow, double product, time to contracture formation) and biochemical (lactate dehydrogenase; LDH) parameters were evaluated. In vehicle-treated group, time to contracture formation was 810 sec during ischemia, LVDP was 34.0 mmHg at the endpoint of reperfusion and LDH activity in total reperfusion effluent was 34.3 U/L. Single treatment with TUDCA did not change the postischemic recovery of cardiac function, LDH and time to contracture compared with ischemic control group. TUDCA pretreatment showed the tendency to decrease LDH release and to increase time to contracture and coronary flow. Our findings suggest that TUDCA does not ameliorate ischemia/reperfusion-induced myocardial damage.
Yun, Seung Pil,Yoon, Yeo Min,Lee, Jun Hee,Kook, Minjee,Han, Yong-Seok,Jung, Seo Kyung,Lee, Sang Hun MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.2
<P>Mesenchymal stem cells (MSCs) could be a promising solution in the treatment of various diseases including chronic kidney disease (CKD). However, endoplasmic reticulum (ER) stress induced by ischemia in the area of application limits the integration and survival of MSCs in patients. In our study, we generated ER stress-induced conditions in MSCs using <I>P</I>-cresol. As <I>P</I>-cresol is a toxic compound accumulated in the body of CKD patients and induces apoptosis and inflammation through reactive oxygen species (ROS), we observed ER stress-induced MSC apoptosis activated by oxidative stress, which in turn resulted from ROS generation. To overcome stress-induced apoptosis, we investigated the protective effects of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs. In ER stress, TUDCA treatment of MSCs reduced ER stress-associated protein activation, including GRP78, PERK, eIF2α, ATF4, IRE1α, and CHOP. Next, to explore the protective mechanism adopted by TUDCA, TUDCA-mediated cellular prion protein (PrP<SUP>C</SUP>) activation was assessed. We confirmed that PrP<SUP>C</SUP> expression significantly increased ROS, which was eliminated by superoxide dismutase and catalase in MSCs. These findings suggest that TUDCA protects from inflammation and apoptosis in ER stress via PrP<SUP>C</SUP> expression. Our study demonstrates that TUDCA protects MSCs against inflammation and apoptosis in ER stress by PrP<SUP>C</SUP> expression in response to <I>P</I>-cresol exposure.</P>