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  1. Prevention of Diabetic Complication (당뇨병성 합병증 치료 연구)    


   1-1 Diabetic vascular disease (당뇨병성 혈관질환)

     ○ Bhatt MP et al.(2013) C-Peptide prevents hyperglycemia- induced endothelial apoptosis through inhibition of reactive oxygen species-mediated 
     transglutaminase 2 activation. Diabetes 62(1), 243-253 [link],[F1000-link],[BRIC] (Faculty of 1000 추천 논문, BRIC 한국을 빛내는 사람들 추천 논문)

     ○ Bhatt MP et al.(2013)C-peptide activates AMPKα and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes mellitus.
     Diabetes  62(1),3851-3862 [link] 

Fig.1 C-peptide inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis in mouse tissues. Transamidating activity (green) in mouse tissues was double-stained with endothelial cell marker platelet endothelial cell adhesion molecule-I (red). (A): C-peptide replacement therapy inhibits hyperglycemia-induced stimulation of transamidating activity and apoptosis ex vivo and in vivo (n = 8 for control and diabetes, n = 7 for diabetes + C-peptide). Apoptotic cells in aortic segments, heart, and renal cortex were stained by TUNEL (green, indicated by arrows) with nuclear counterstaining using Hoechst dye 33258(blue). (B): Proposed mechanism for C-peptide prevention of hyperglycemia-induced endothelial apoptosis via inhibition of ROS-mediated TG2 activation.GPCR, guanosine triphosphate-binding protein-coupled receptor. 1-2 Diabetic retinopathy (당뇨병성 망막증) ○ Lim YC et al.(2014) Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice. Cardiovascular Research 101, 155-164 [link]

Fig. 2 C-peptide prevents against vascular leakage in the retinas of diabetic mice. Streptozotocin diabetic mice were intravitreally injected with 2 μL C-peptide (Diabetic+C-pep, n = 6), anti-VEGF (Diabetic+anti-VEGF, n = 6), NAC (Diabetic+NAC, n = 6), Trolox (Diabetic+Trolox, n = 6), and BAPTA-AM (Diabetic + BAPTA) into one eye, and an equal volume of PBS into the contralateral eye (Diabetic; n = 6 per group). Non-diabetic mice were also intravitreally injected with 2 μL PBS into eyes (Normal; n = 6 per group).(A) Representative fluorescent images of the retinas from Normal, Diabetic, and Diabetic+C-peptide eyes. The square areas are displayed as magnified images at the bottom of each image. Scale bar, 100 μm. (B) Retina permeability was quantified by measuring the fluorescence intensities of whole retina tissues (n = 6). **P < 0.01. (C) Increased number of infiltrated leucocytes was quantified by counting CD11b+ cells of retina tissues (n = 8). **P < 0.01. 1-3 Impaired Wound healing (상처치료연구) ○ Lim YC et al.(2014) Proinsulin C-peptide prevents impaired wound healing by activating angiogenesis in diabetes. Journal of Investigative Dermatology, in press
Fig. 3 C-peptide prevention against impaired wound healing in diabetic mice. (A,B) Wounds of 4-mm diameter were created on the dorsal skin of the hindlimbs of normal (n=10), diabetic (n=10), and C-peptide-supplemented diabetic mice (Diabetic+C-peptide; n=10) and wound closure was photographically monitored for 14 d. (A) Representative macroscopic images in each group. (B) Wound area was determined by measuring the diameter of open wounds. (C) H&E stained transverse sections of the wounds (n=6) were observed at the indicated time using an inverted microscope. Endpoints are 10, 20, and 12 d for normal, diabetic, and C-peptide-supplemented diabetic mice, respectively. Wound diameter was calculated using the distance of open wounds. **p<0.01. 2. Application of Protein chip (단백질 칩) 2-1 Serodiagnosis (혈액진단) - Protein array, Antibody array, Sandwich array, Tagged-internal standard(TIS) array ○ Kong DH et al. (2012) Normalization using a tagged-internal standard assay for analysis of antibody arrays and the evaluation of serological biomarkers for liver disease. Analytica Chimica Acta 718, 92-98 [link]
○ Kong DH et al. (2010) On-chip assay of matrix metalloproteinase-3 activity using fluorescence-conjugated gelatin arrays. BioChip J. 4, 210-216 ○ Jung JW et al. (2009) Label-free and quantitative analysis of C-reactive protein in human sera by tagged-internal standard assay on antibody arrays. Biosens. Bioelectron. 24, 1469-1473 [link] ○ Park JY et al. (2009) A novel array-based assay of in situ tissue transglutaminase activity in human umbilical vein endothelial cells. Anal Biochem 394, 217-222 (in situ) [link] Fig. 4 Profiling the expression of eight proteins in human sera from patients with liver disease. Fluorescence intensities (FI) of six proteins were normalized using the median-centered/TIS assay, and distributed based on serum levels from normal controls (n = 25) and patients with liver cirrhosis (n = 25) or HCC (n = 29). Boxes represent the upper and lower quartiles of the fluorescence intensities. Horizontal lines in each box indicate median values. Lines represent the ranges of the measurements, excluding outliers that are represented by *p < 0.05; **p < 0.001. 2-2 Enzyme activity assay (효소 활성도 분석) - MMP-3 activity assay, TG2 activity assay, FXIII activity assay, PKA activity assay ○ Kong DH et al. (2012) Normalization using a tagged-internal standard assay for analysis of antibody arrays and the evaluation of serological biomarkers for liver disease. Analytica Chimica Acta. 718, 92-98 [link]
○ Kwon MH et al. (2011) Simultaneous activity assay of two transglutaminase isozymes, blood coagulation factor XIII and transglutaminase 2, by use of fibrinogen arrays. Anal Chem 83, 8718-8724 [link]
○ Kwon MH et al. (2011) Rapid determination of blood coagulation factor XIII activity using protein arrays for serodiagnosis of human plasma. Anal Chem 83, 2317-2323 [link]
○ Kong DH et al. (2010) On-chip assay of matrix metalloproteinase-3 activity using fluorescence-conjugated gelatin arrays. BioChip J. 4, 210-216
○ Jung SH et al. (2010) Rapid analysis of matrix metalloproteinase-3 activity by protein arrays using a spectral surface plasmon resonance biosensor. Analyst 135 (5), 1050-1057 [link]

Fig. 5 Determination of FXIII activity in the patients of liver disease. Human plasma samples (n = 127) were collected in EDTA tubes from normal individuals (n = 41) and from patients with hepatitis (n = 21), liver cirrhosis (LC, n = 41), or hepatocellular carcinoma (HCC, n = 24). Next, reaction mixtures containing plasma (400-fold dilution) and the indicated concentrations of human plasma FXIII were applied to the fibrinogen arrays, and the arrays were analyzed with a fluorescence scanner. The FXIII activities of 127 plasma samples were determined using a standard curve (r2 = 0.99), as described in the Experimental Section, and the distribution is expressed in box plots (*, p < 0.001). 2-3 Protein interaction assay (단백질 상호작용 분석) - Kinetics analysis of caspase-9, caspase-3, MMP-3 and calpain-1 - Real-time monitoring of MMP-3 activity - Integrative proteomic profiling of TG2 activity and interactions ○ Lee KS et al. (2013) Comparative characterization of direct and indirect substrate probes for on-chip transamidating activity assay of transglutaminases. Journal of Biotechnology 168. 324-330 [link]
○ Jung SH et al. (2012) Quantitative kinetics of proteolytic enzymes determined by a surface concentration-based assay using peptide arrays. Analyst 137, 3814-3820 [link]
○ Kong DH et al. (2012) Monitoring of proteolytic enzyme activity using phase transition-based peptide arrays. Biosens. Bioelectron. 36, 147-153 [link]
○ Jung SH et al. (2012) Integrative proteomic profiling of protein activity and interactions using protein arrays. Molecular & Cellular Proteomics. 11(11), 1167-1176 [link]

Fig. 6 Quantitative activity-interaction map of TG2 with its related proteins. Normalized transamidating activities and dissociation constants (Kd) of TG2 with 16 proteins were used to construct an integrative proteomic map. In this map, the node volume represents the transamidating activity and the distance between the node and TG2 indicates the Kd value. ALDOA, aldolase A; ANXA, annexin A1; Bcl2, B-cell lymphoma 2; E-cad, E-cadherin; FI, fibrinogen; FN, fibronectin; GCA, grancalcin; GST, gluatathione S-transferase; HSA, human serum albumin; OPN, osteopontin; RB1, retinoblastoma; S100A7, S100 calcium binding protein A7; SMAD2, Sma- and Mad-related protein 2; SNCA, -synuclein. 3. Photodynamic therapy (광역동 치료연구) 3-1 In vitro ○ Yoo JO et al (2012) Transglutaminase 2 promotes both caspase-dependent and caspase-independent apoptotic cell death via the calpain/Bax protein signaling pathway. J. Biological Chemistry 287(18), 14377-14388 [link]
○ Je-Ok Yoo et al (2012) New insights into the mechanisms for photodynamic therapy-induced cancer cell death. International Review of Cell & Molecular Biology 295, 139-174 [link]
○ Lim YC et al (2011) Cellular responses to chlorin-based photosensitizer DH-II-24 under darkness in human gastric adenocarcinoma AGS cells Cancer Science 102(3), 549-556 [link]
○ Yoo JO et al (2011) Differential Cytotoxic Response to Low- and High-Dose Photodynamic Therapy in Human Gastric and Bladder Cancer Cells. Journal of Cellular Biochemistry. 112(10), 3061-3071 [link]
3-2 In vivo ○ Lim YC et al (2009) Antitumor effect of photodynamic therapy with a chlorin-based photosensitizer DH-II-24 in colorectal carcinoma. Cancer Science 100(12), 2431-2436 [link]
Fig. 7 Phamacokinetics of DH-II-24. Mice were given i.v. injection of 1 mg/kg DH-II-24, and spatial distribution of DH-II-24 was monitored at the indicated post-injection time using the In Vivo Imaging System (IVIS200). Note the rapid distribution (at 6 h) and clearance (at 48 h) across the entire body.

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