Dissertations / Theses on the topic 'Advanced lipoxidation end product'
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Yong, P. H. "Advanced lipoxidation end-products and the pathogenesis of Mûller cell dysfunction in diabetic retinopathy." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546454.
Full textO'Neill, J. B. "The role of advanced lipoxidation end-products in age-related retinal pigmant epithelium (RPE) dysfunction." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501391.
Full textMOL, MARCO HENDRIKUS ADRIANUS. "Analytical Strategies for the Identification and Characterization of RAGE Binders of Proinflammatory mediators. AGEs and ALES." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/675044.
Full textGarzon, D. "HIGH RESOLUTION MASS SPECTROMETRIC STRATEGIES FOR DETECTION OF PROTEINS AND PEPTIDES COVALENTLY MODIFIED BY ELECTROPHILIC XENOBIOTICS AND ENDOGENOUS INTERMEDIATES." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/250677.
Full textLe, Brocq Michelle Louise. "Advanced glycation end product precursors in diabetes : a crucial link between oxidative stress and inflammation?" Thesis, University of the Highlands and Islands, 2010. https://pure.uhi.ac.uk/portal/en/studentthesis/advanced-glycation-end-product-precursors-in-diabetes(53be96a1-0fe3-4fc7-88c7-2bf2b4421d27).html.
Full textRahimkhani, Shermin. "Functional and immunochemical characterization of advanced glycation end-product (AGE)-modified low-density lipoproteins (AGE-LDL)." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/MQ57162.pdf.
Full textJyoti, Faidat. "Development of New Antibody Based Theranostic Agents Targeting the Receptor for Advanced Glycation End-Product (Rage)." Diss., North Dakota State University, 2013. https://hdl.handle.net/10365/26866.
Full textChen, Suzi Su-Hsin, and suzi chen@med monash edu au. "Cyclooxygenase Expression in Human Diabetes." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080206.121439.
Full textFriess, Ulrich. "Formation, distribution, and pathophysiological relevance of the "advanced glycation end-product" N(epsilon)-(carboxymethyl)-lysine in target tissues of diabetic organ damage and in degenerative and chronic inflammatory tissue lesions." [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11293395.
Full textRajaobelina, Kalina. "Autofluorescence cutanée des produits de glycation avancée (AGE), mémoire métabolique et complications du diabète." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0256/document.
Full textIn the context of the ageing of the population and the increase of age related diseases such as diabetes, new biomarquers of the long-term health status should be considered. Advanced glycation end products (AGE) are molecules indicators of the metabolic burden over time, called “metabolic memory”. AGE play an important role in long term diabetes injuries and in the global decline of the metabolism related to ageing. Skin accumulation of AGE can be measured by autofluorescence instantly and non-invasivly with a tool called AGE-READER. The objectives of my dissertation were to evaluate the value of the skin autofluorescence (sAF) of AGE as marker of metabolic memory in elderly people from the 3-City cohort and in parallel, in patients with type 1 diabetes, evaluate the prognostic value of sAF for diabetes complications. In the elderly population, we showed that sAF reflected glycemic and renal status of 10 years before. In patients with type 1 diabetes, sAF was associated to the presence of neuropathy 4 years later. Moreover, in this same population, we described the evolution of sAF in 4 years of follow-up and we showed that the principal determinants of the evolution of sAF were kidney function and insulin pump therapy. Finally, we also found that increase of sAF in 4 years was associated with the occurrence of kidney disease. This work rises new research opportunities about the interest of sAF at differents key ages as biomarker of pathologies which evolve in several decades
Lee, Chu-I., and 李築宜. "Leptin, angiotensin II and CTGF in advanced glycation end-product-induced effects in NRK-49F cells." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/37689994275706536080.
Full text高雄醫學大學
醫學研究所博士班
93
Diabetic nephropathy (DN) is characterized by glomerulopathy and tubulointerstitial expansion followed by renal fibrosis, including tubulointerstitial fibrosis. For example, we have shown that advanced glycation end-product (AGE)-induced mitogenesis and collagen production are dependent on the JAK2 pathway in normal rat kidney interstitial fibroblasts (NRK-49F cells). Leptin is a Janus kinase 2 (JAK2)-activating cytokine via the long form leptin receptor (Ob-Rb). Leptin and connective tissue growth factor (CTGF) are involved in renal fibrosis. However, the relationship between leptin and CTGF in terms of AGE-induced effects remains unknown. Moreover, angiotensin II (Ang II) and CTGF are important in the pathogenesis of DN. Thus, we studied the role of leptin, Ang II, JAK2 and CTGF in AGE-induced effects in NRK-49F cells. We found that leptin and AGE increased mitogenesis and type I collagen protein expression at 3 d and 7 d, respectively. AGE also increased leptin mRNA and protein expression at 2 d and 3 d. AGE increased CTGF mRNA and protein expression at 3 d and 5 d. AG-490 (JAK2 inhibitor) abrogated AGE-induced leptin mRNA and protein expression. AG-490 and Ob-Rb antisense oligodeoxynucleotides (ODN) abrogated AGE-induced CTGF mRNA and protein expression. AG-490 and CTGF antisense ODN abrogated AGE-induced mitogenesis and collagen protein expression. Additionally, leptin dose (0.2-1 �慊/ml) and time (1-2 d)-dependently increased CTGF protein expression. AG-490 abrogated leptin (1 �慊/ml)-induced CTGF protein expression at 2 d. AG-490 and CTGF antisense ODN abrogated leptin-induced mitogenesis and collagen protein expression at 3 d. Additionally, we found that Ang II (10-7 M) increased mitogenesis and type I collagen production at 3 d. We also found that AGE increased angiotensinogen protein at 2 d, which was attenuated by AG-490 (a JAK2 inhibitor). Ang II (10-7 M) increased CTGF mRNA and protein expression at 1 d and 2 d, which were attenuated by AG-490. Moreover, losartan (a type I angiotensin receptor blocker) and captopril (an angiotensin converting enzyme inhibitor) attenuated AGE-induced CTGF mRNA/protein expression while attenuating AGE-induced mitogenesis and type I collagen production. Moreover, AG-490 and CTGF antisense (but not sense) oligodeoxynucleotide attenuated Ang II (10-7 M)-induced mitogenesis and type I collagen production at 3 d. We conclude that AGE-induced mitogenesis and type I collagen production are dependent on the Ang II-JAK2-CTGF and leptin-JAK2-CTGF pathways while Ang II and leptin-induced mitogenesis and type I collagen production are dependent on the JAK2-CTGF pathway. Moreover, because previous studies by others showed that Ang II can induce leptin, we speculate that AGE-induced mitogenesis and type I collagen production may be dependent on the AGE-Ang II-leptin-JAK2-CTGF pathway in these cells.
CHORNG-JIA, CHEN, and 陳重嘉. "Effect of Tetrahydrobiopterin on Advanced Glycation End-Product-Induced Hypertrophic Growth in Renal Tubular Epithelial Cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/57680136054948671104.
Full text中華醫事學院
生物科技研究所
94
In Taiwan, diabetes mellitus and end-stage renal disease is the 4th and 8th leading cause of death, respectively. Moreover, diabetic nephropathy (DN) is the chief cause of new dialysis patients in our country. Based on others and our previous studies, we suggested that nitric oxide (NO), hyperglycemia and advanced glycation end product (AGE) are three of the most significant factors in the pathogenesis of DN. However, the interactions between the signal transduction pathway of NO/cGMP-dependent protein kinase (PKG) and AGE-mediated renal tubulointerstitial fibrosis remain poorly understood. In the present study, the mechanisms by which tetrahydrobiopterin (BH4) modulates the AGE-induced hypertrophic growth in renal tubular epithelial (LLC-PK1) cells were examined. We found that AGE time- and dose-dependently decreased nitric oxide (NO) production and GTP cyclohydrolase I (GTPCH I)/inducible NO synthase (iNOS) activation. These effects were not observed when cells were treated with non-glycated BSA. NO and iNOS stimulated by BH4 and the NO donor S-nitroso-N-acetylpenicillamine (SNAP) prevented AGE-induced JAK2/STAT1/STAT5, Raf-1/ERK, and JNK/p38 MAPK activation. Nevertheless, addition of 2,4-diamino-6-hydroxypyramidine (DAHP) that inhibits GTPCH I activity may enhance AGE-induced these effects. The ability of iNOS/NO to inhibit AGE-induced hypertrophic growth was verified by the observation that BH4 and SNAP inhibited both cyclin-dependent kinase inhibitors (CDKI) p21Waf1/Cip1 and p27Kip1 expression. Furthermore, BH4 significantly decreased extracellular matrix (ECM) proteins fibronectin and collagen IV synthesis in AGE-treated cells. These findings suggest that BH4 supplementation is renoprotective partly by attenuating AGE-induced renal tubular hypertrophy by increasing GTPCH I/iNOS activation and reducing CDKI/ECM expression.
Du, Chi-Ying, and 杜綺瑩. "Roles of NLRP3-related pathways in advanced glycation end product-induced effects in mesangial cells and monocytes." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/9cvedv.
Full text高雄醫學大學
醫學研究所碩士班
106
Diabetic nephropathy is a major cause of end stage renal disease, associated with inflammation, receptor for advanced glycation end product (RAGE) and TGF-receptor (TGF-R). NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome is pro-inflammatory. NLRP3 is activated by deubiquitinases or signal (e.g. ATP)-induced mitochondrial ROS to oligomerize with ASC and pro-caspase 1 to form an inflammasome, which activates IL-1β and IL-18. NLRP3 knockout and IL1R1 inhibitor-treated mice are protected from diabetic nephropathy (DN). However, the roles of NLRP3 inflammasome in DN were not proven because NLRP3 also has inflammasome-independent effects to active of the TGF-β-Smad3 pathway, but the roles of the cross-talk between monocyte and renal cells in terms of NLRP3 are not known. Thus, we studied the roles of NLRP3 in DN. We found that in Mes-13 (mouse mesangial) cells, high glucose (HG, 30 mM) increased NLRP3, ASC, and active caspase-1 and IL-1β levels. Concomitantly, HG increased TGF-β1 and UCHL5 levels. Advanced glycation end-products increased NLRP3, active caspase-1/IL-1β and TGF-β1, but not COX2 levels. In THP1 (human monocyte) cells, HG increased NLRP3, UCHL5 and TGF-β1, but not ASC levels. AGE increased NLRP3, ASC, UCHL5, active caspase 1 and COX2 levels in THP1 cells. Transwell studies showed that AGE-treated Mes-13 cells increased THP1 cell migration. Finally, we found that NLRP3 has a high level of tubular expression in the streptozotocin-diabetic mice at the 8th week. Thus, HG-and AGE-induced NLRP3-related pathways in Mes-13 and THP1 cells and NLRP3 (inflammasome-dependent or inflammasome-independent) may be a novel target for the treatment of DN.
Huang, Jau-Shyang, and 黃昭祥. "Studies on the Biological Responses and Signal Transduction Pathways of Advanced Glycation End-product in NRK-49F Cells." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/84917825090811422994.
Full text高雄醫學大學
醫學研究所
88
Advanced glycation end-product (AGE) is important in the pathogenesis of diabetic nephropathy, which is characterized by cellular hypertrophy/hyperplasia leading to renal fibrosis. However, the signal transduction pathways of AGE remain poorly understood. JAK (Janus kinase)/STAT (signal transducers and activators of transcription) pathway has been associated with cellular proliferation in some extra-renal cells. Because interstitial fibroblast proliferation may be important in renal fibrosis, we studied the role of the JAK/STAT pathway in NRK-49F (normal rat kidney fibroblast) cells cultured in AGE. We found that AGE dose-dependently increased cellular mitogenesis in NRK-49F cells at 5 and 7 d. AGE (100 g/ml) induced tyrosine phosphorylation of JAK2 (but not JAK1, JAK3, and TYK2) at 15-60 min. In addition, AGE also induced tyrosine phosphorylation of STAT1 and STAT3 at 1-2 h and 0.5-4 h, respectively. Being a transcription factor, AGE also increased the DNA-binding activities of STAT1 and STAT3. AG-490 (a specific JAK2 inhibitor) inhibited tyrosine phosphorylation of JAK2 and the DNA-binding activities of STAT1 and STAT3. The same results were obtained using the specific “decoy” oligodeoxynucleotides (ODNs) that prevented STAT1 and STAT3 from binding to DNA. Meanwhile, the STAT1 or STAT3 decoy ODN and AG-490 were effective in reversing AGE-induced cellular mitogenesis. To reveal the relationship between the JAK/STAT activity and cell cycle progression, we examined the effects of AGE on STAT5 activity and cell cycle progression in NRK-49F cells. We found that AGE rapidly induce tyrosine phosphorylation and protein-DNA binding activity of STAT5 at 5 min and 15 min, respectively. Among several G1 cyclins and cyclin-dependent kinases (cdks), cyclin D1 expression and cdk4 activity were both increased by AGE. Nevertheless, the levels of cdk inhibitors were not affected by AGE. Furthermore, our results showed that cyclin D1 expression and cdk4 activity were all inhibited by AG-490 and STAT5 decoy ODN. Interestingly, STAT5 decoy ODN and AG-490 both significantly blocked AGE-induced cell cycle progression and cellular mitogenesis. In this study, we also examined whether JAK/STAT are involved in AGE-regulated extracellular matrix (ECM) production in NRK-49F cells. We found that AGE time- and dose-dependently increased type I collagen and fibronectin productions in these cells. However, AGE did not increase TGF- bioactivity and TGF-1 mRNA expression. Additionally, AGE increased RAGE (receptor for AGE) protein expression and MAPK (ERK1/ERK2) activity. AGE-induced RAGE expression was dose-dependently inhibited by antisense RAGE ODN and captopril. AGE-induced type I collagen production and JAK2-STAT1/STAT3 activation were decreased by AG-490, antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. In contrast, they did not inhibit AGE-induced fibronectin synthesis. We concluded that the JAK2-STAT1/STAT3 signal transduction pathway is necessary for AGE-induced cellular mitogenesis in NRK-49F cells. In addition, STAT5 appears to modulate cyclin D1 synthesis and cdk4 activity, thereby contributing to AGE-induced cellular mitogenesis. On the other hand, we showed that RAGE-JAK2-STAT1/STAT3 pathway and MAPK kinase were involved in AGE-induced ECM production. Furthermore, renin-angiotensin system (RAS) may play an important role in AGE-induced biological effects.
Wu, Chia-Yi, and 吳佳宜. "Quantification of Free Advanced Glycation End Product (AGE) in Human Plasma Using Benzoyl Chloride Derivatization and HPLC-MS/MS." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/fwc94p.
Full text慈濟大學
藥理暨毒理學碩士班/博士班
102
Aging, long-term hyperglycemia or advanced glycation end product (AGE)-enrich diet will cause AGEs accumulation in the body. The accumulation of AGEs induces diabetic complication, renal impairment or atherosclerosis. Therefore, level of AGEs is considered a biomarker for assessing the occurrence of diabetic complications or cardiovascular disease. Previous studies indicated that the concentration range of free AGEs was less than 1000 nM in human plasma. Developing a general and sensitive assay for quantification of free AGEs is necessary. In this study, we developed a highly-sensitive assay using benzoyl chloride derivatization and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for Nε-carboxymethyl-lysine (CML). For free CML analysis, plasma was filtrated by Amicon Ultra-0.5 centrifugal filter and the filtrate was derivatized with benzoyl chloride. The derivatized sample with internal standard analyzed by HPLC-MS/MS. The method was validated for precision, accuracy, recovery and linearity. The chromatographic time is 6.5 min and the retention time of di-benzoyl-CML is 2.8 min. Limit of detection (LOD) and limit of quantification (LOQ) was 14.2 nM and 25 nM, respectively. The linear correlation was greater than 0.99 in the range from 0 nM to 5 μM. Intra- and inter-day accuracy were -7.0 %–2.6 %, and intra- and inter-day precision were less than 9.0%. Carryover was not detected and matrix effect was compensated by internal standard. Every parameter was validated according to the FDA Guidance for Industry and ICH Q2(R1) guideline. Addition of D5-benzoyl-derivatized standard showed better results than external standard calibration on quantitation. The benzoyl-derivatization elevates sensitivity and shortens analysis time. Adding D5-benzoyl-derivatized standard provides the same results as using isotope-labeled AGE and reduce the analysis cost. To our knowledge, this is the first report of free AGEs determination in human plasma using benzoyl chloride derivatization and HPLC-MS/MS.
LIN, SHENG HSUAN, and 林聖軒. "Effects of rosiglitazone on advanced glycation end-product and high glucose-induced effects in NRK-49F and MES-13 cells." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/j825q9.
Full text高雄醫學大學
生物化學研究所
91
In Taiwan and many other countries, diabetes mellitus is the major factor of end-stage renal disease (ESRD). The pathology of diabetic nephropathy is characterized by cellular hyperplasia, hypertrophy and expansion of extracellular matrix which result in renal fibrosis and ESRD. Although the pathogenesis of diabetic nephropathy is not clear yet. But in the previous studies, high glucose and advanced glycation end-product (AGE) have been shown to play the important roles of diabetic nephropathy. Rosiglitazone is a new drug for diabetes. It is the agonist of peroxisome proliferator activated receptor gamma (PPAR-gamma). PPAR-gamma heterodimerizes with 9-cis-retinoic acid receptor (RXRα) and, after ligand binding, functions as transcription factors in the regulation of glucose metabolism. However, we want to know if Rosiglitazone would get the effects through the other signal transduction pathways and its effect on diabetes nephropathy. We use two cell lines : kidney fibroblast of normal rat (NRK-49F) and the mesangial cell of normal mouse (MES-13). We found that Rosiglitazone could effectively reverse the increase of extracellular matrix induced by high glucose and AGE in NRK-49F and MES-13 cells. It also can reverse the increase of DNA synthesis by high glucose and AGE in NRK-49F cells. In NRK-49F and MES-13 cells, we also found that Rosiglitazone could reverse the increased expression of collagen type IV. We also observed that Rosiglitazone could reverse the hypertrophy of MES-13 cells induced by high glucose and AGE. In the molecular level, we found that in NRK-49F cells, Rosiglitazone could reverse the increase of cyclin D1, JAK2 and SOCS-3 induced by AGE in 2 hours. Then we used immunoprecipitations for the JAK2 protein and get the same result. Thus, we have demonstrated the effects of Rosiglitazone on cell cycle and the JAK signaling pathway in NRK-49F cells. In MES-13 cells, we found that rosiglitazone could inhibit the increased expression of TGF-β receptor type II and cyclin D1 induced by high glucose and AGE. Regard the effects of p21Waf1 and p27Kip1, our experiments showed that high glucose increased the expression of p21Waf1 and p27Kip1 while Rosiglitazone could reverse p27Kip1 expression. We also found that AGE could decrease the expression of p27Kip1 while Rosiglitazone could reverse this effect. Thus, rosiglitazone can improve the increase of ECM and cellular hypertrophy by decreasing cyclin D1, TGF-β signaling and p27Kip1. We concluded that Rosiglitazone can improve the effects induced by high glucose and AGE in NRK-49F and MES-13 by modulating cyclin D1, JAK2, TGF-β receptor type II and p27Kip1.
Lin, Kuan-Hua, and 林冠華. "Advanced glycation end-product-induced effects are dependent on glycogen synthase kinase-3b/b-catenin pathway in LLC-PK1 cells." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/77046539078788659704.
Full text高雄醫學大學
醫學研究所
96
Diabetic nephropathy is the complication of diabetes mellitus. In Taiwan, diabetes mellitus and end-stage renal disease is the 5th and 8th leading cause of death, respectively. Diabetic nephropathy is a major cause of morbidity and mortality, which comprise of 20-40% of the diabetic patients. The pathogenesis of diabetic nephropathy is characterized by the proliferation of mesangial cells in the early stage but hypertrophy of renal cell at the late stage of diabetes mellitus. Moreover, the thickening of glomerular basement membrane and the accumulation of extracellular matrix leading to renal fibrosis is related of high glucose and the advanced glycation end-products (AGE) . However, the signal pathway associated with AGE in diabetic nephropathy is poorly understood. Recently, the evidence shows that Wnt pathway is associated with the formation of renal fibrosis. According to the previous studies, the glycogen synthase kinase-3β (GSK-3β) , one of the key mediator of Wnt pathway, plays a role in the regulation of glucose metabolism. Thus, we studied the role of β-catenin, and GSK-3β in AGE-induced effects in the proximal tubule-like LLC-Pk1 cells, and their relationship to the diabetic nephropathy. We found that AGE (50, 75, 100 μg/ml) dose-dependently decreased β-catenin protein expression at 48 h incubation, but AGE did not decrease β-catenin protein expression until 48 h. Furthermore, we found that AGE (100 μg/ml) time-dependently (8-48 h) increased GSK-3β-Tyr216 (active GSK-3β) and time-dependently (4-24 h) decreased GSK-3β-Ser9 (inactive GSK-3β) protein expression. Meanwhile, AGE (100 μg/ml) activated GSK-3β kinase activity at 8-48 h. SB216763 (a GSK-3β inhibitor) attenuated AGE (100 μg/ml)-inhibited β-catenin protein expression at 48 h. SB216763 also attenuated AGE (100 μg/ml)-inhibited cell proliferation and attenuated AGE (100 μg/ml)-induced collagen production and type IV collagen protein expression at 48 h. We also found that JAk2, PI3K, MAPK, and PKC pathway inhibitor attenuated the AGE-inhibited β-catenin protein expression, but only JAk/STAT and MAPK pathway attenuated the AGE-inhibited cyclin-D1 protein expression. In immunohistochemistry experiments, we found that b-catenin level decreased in proximal tubules in 3-month STZ-induced diabetic rats and in patient with diabetic nephropathy. We concluded that AGE-inhibited cell proliferation and collagen production are dependent on GSK-3β in LLC-PK1 cells. Moreover, AGE-inhibted β-catenin and cyclin D1 protein expression are also dependent on GSK-3β. It was also the first report that b-catenin levels decreased in renal tissue of patients with diabetic nephropathy.
Chang, Ya-Ching, and 張雅菁. "Interactions Between LLC-PK1 Cells and NRK-49F Cells in Cellular Growth and Collagen synthesis in Glucose/Advanced Glycation End-product Culture." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/15433482560105721060.
Full text高雄醫學大學
生物化學研究所
88
Proximal tubule cells and fibroblasts are important in renal fibrosis in diabetic nephropathy (DN). Transforming growth factor-beta (TGF-beta)、 Insulin-like growth factor-I (IGF-I), high glucose (HG) and advanced glycation end-product (AGE) are also important in DN. Thus, we studied the interactions between LLC-PK1 (proximal tubule) and NRK-49F (fibroblasts) cells in terms of cellular growth (3H-thymidine incorporation, cell numbers and 3H-leucine incorporation, cellular hypertrophy), extracellular matrix (collagen synthesis by 3H-proline incorporation), TGF-beta/IGF-I expressions and the effects of antioxidants on the above events. We found that in NRK-49F cells, AGE-BSA (50、100g/ml)/HG (500mg/dl) increased 1.2 fold while LLC-PK1- conditioned media (CM) decreased cellular mitogenesis 30~40%. AGE/HG had no effects while LLC-PK1-CM increased cellular hypertrophy 1.2 fold. AGE/HG and LLC-PK1-CM also increased collagen synthesis 1.2~1.3 and 1.3~1.4 fold. Neutralizing TGF-beta antibody reversed LLC-PK1-CM-induced (but not AGE/HG-induced) growth inhibition, cellular hypertropy and collagen synthesis in these cells. Captopril and antioxidants (N-acetylcysteine, taurine) were also effective. In LLC-PK1 cells, AGE/HG decreased 30~40% while NRK-49F-conditioned media (CM) increased cellular mitogenesis 1.4~1.5 fold. AGE/HG increased 1.2 fold while NRK-CM had no effects on cellular hypertrophy. Both AGE/HG and NRK-CM increased collagen synthesis 1.2 fold. Additionally, neutralizing IGF-I antibody reversed NRK-CM-induced (but not AGE/HG-induced) proliferation and collagen synthesis. Captopril and antioxidants (N-acetylcysteine, taurine) were also effective. We conclude that AGE/high glucose induces TGF-beta/oxidants in LLC-PK1 cells to affect NRK-49F cells in terms of growth inhibition, cellular hypertrophy and collagen production. Additionally, AGE/high glucose induces IGF-I/oxidants in NRK-49F cells to affect LLC-PK1 cells in terms of mitogenesis and collagen production.
Huang, Yen Kai, and 黃彥凱. "Tranilast blocks the interaction between the protein S100A11 and Receptor for Advanced Glycation End Product (RAGE) V Domain and inhibits cell proliferation." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/44814745745961523472.
Full text國立清華大學
化學系
104
The human S100 calcium-binding protein A11 (S100A11) is a member of S100 protein family. Once S100A11 proteins bind to calcium ions at EF-hand motifs, S100A11 will change its conformation promoting interaction with target proteins. The receptor for advanced glycation end products (RAGE) consists of three extracellular domains, including V domain, C1 domain and C2 domain. In this case, V domain is the target for mS100A11 binding. RAGE binds to the ligands result in cell proliferation, cell growth and several signal transduction cascades. We used NMR and fluorescence spectroscopy to demonstrate the interactions between S100A11 and V domain. The Tranilast molecule is a drug used for treating allergic disorders. We found out that V domain and Tranilast would interact with S100A11 by using 1H-15N HSQC NMR titrations. According to the results, we obtained two binary complex models from the HADDOCK program, S100A11-RAGE V domain and S100A11-Tranilast, respectively. We superimposed these two models with the same orientation of S100A11 homodimer and demonstrated that Tranilast molecule would block the binding site between S100A11 and V domain. We further utilized the WST-1 assay to indicate that Tranilast indeed can inhibit the cell proliferation which is induced by the S100A11-V domain interaction. These results will be potentially useful in the development of derivative or new anti-cancer drugs for RAGE-dependent diseases.
劉靜怡. "The role of TGF-beta and Smads in advanced glycation end product (AGE), high glucose and ketone body-induced effects in HK-2 cells." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/70798067173716059245.
Full text高雄醫學大學
生物化學研究所
88
In Taiwan, diabetes mellitus and end-stage renal disease is the 5th and 7th leading cause of death, respectively. Furthermore, diabetic nephropathy (DN) is a major cause of morbidity and mortality, which occurs in 20-40﹪of the diabetic patients. Therefore, the study of the pathogenesis of DN is an important endeavor in biomedicine. In this regard, high glucose, advanced glycation end-product(AGE), ketone body transforming growth factor(TGF-β)and angiotensin Π have been proposed to be the essential factors. The hallmark of DN is cellular hyperplasia, hypertrophy and an expansion of extracellular matrix in the glomeruli and renal tubules. It often progresses to renal fibrosis(glomerulosclerosis and tubulointerstitial fibrosis). Although most studies focused only on glomerular cells, tubulointerstitial change may be more closely correlated with the decline in renal function than glomerulopathy in DN. Thus, we studied the role of TGF-β in the effects of AGE, high glucose and ketone body on cellular growth, cellular hypertrophy and collagen synthesis in human proximal tubular cell line (HK-2). We found that AGE (100 μg/ml, but not BSA), high glucose (500 mg/dl) and ketone body (10 mM) decreased cellular mitogenesis while increasing cellular hypertrophy and collagen synthesis in HK-2 cells at 48hr. Similarly, exogenous TGF-β (1 ng/ml) also decreased cellular mitogenesis while increasing cellular hypertrophy and collagen synthesis at 48hr. AGE, glucose and ketone body also increased TGF-β protein expression (by ELISA) and TGF-β bioactivity (by mink lung epithelial cell inhibition assay). We also found that anti-TGF-β antibody can reverse the effects of AGE, high glucose and ketone body. In addition, AGE/HG and ketone body increased TGF-β responsiveness by increasing type II TGF-β receptor protein expression. We found that AGE, high glucose and ketone body activated Smads-DNA binding activity at 2-4 hr (by electrophoretic mobility shift assay). In contrast, all three treatments did not have effects on receptor-regulated Smads (Smad2 and Smad3) protein expression, but decreased inhibitory Smad (Smad7) protein expression. We also found that Smad2 and 3 antisense oligonucleotides and transcription factor decoy can reverse the effects of AGE, high glucose and ketone body. These results indicate that TGF-β pathway and transcription factor (Smads) play important roles in the pathogenesis of diabetic nephropathy. Angiotensin converting enzyme inhibitors (e.g., captopril) is effective in treating DN because they antagonize the hemodynamic and growth effects of angiotensin II on the kidney. In this regard, we found that captopril reversed AGE/HG and ketone body induced effects in HK-2 cells partly by decreasing endogenous TGF-β protein expression. Thus, angiotensin II is a renal growth factor which can induce cellular hypertrophy and extracellular matrix production in HK-2 cells by upregulating TGF-β. In conclusion, AGE, high glucose and ketone body may affect cellular growth and induce collagen synthesis in HK-2 cells by inducing the expression of TGF-β. The effects of TGF-β are in turn mediated by activation of Smad2 and 3 due to a decrease in Smad7 protein.
Yang, Yu Lin, and 楊堉麟. "Growth Regulation of High Glucose and Advanced Glycosylation End-product on MDCK, a Distal Tubular Cell Line - an Exploration on Transforming Growth Factor-b and its Receptors." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/45255080018713693753.
Full text高雄醫學院
醫學研究所
86
Diabetes mellitus and renal disease is the 5th and 7th leading cause of death in Taiwan. Hence, they consume a major portion of medical resources in our country. Furthermore, diabetic nephropathy is a major cause of diabetic morbidity and mortality. Unfortunately, diabetic patients will almost always enter end-stage renal disease (ESRD) once they develop proteinuria. Therefore, the study for the pathogenesis of diabetic nephropathy has become a major topic in biomedical research.Hyperglycemia and advanced glycation end-product (AGE) are two of the essential factors in diabetic nephropathy. The pathology of diabetic nephropathy is characterized by cellular hyperplasia, hypertrophy and the expansion of extracellular matrix which result in renal fibrosis and ESRD. These processes are intimately associated with cytokines/growth factors, esp. transforming growth factor-b (TGF-b). The distal nephron is also important in diabetic nephropathy, although most studies regarding diabetic nephropathy were focused on glomerulopathy and occasionally proximal tubule. Therefore, we performed a series of studies in high glucose and AGE-cultured distal tubule-like MDCK cells. We found that, unlike other renal cells, high glucose did not increase TGF-b production, but it did increase the responsiveness of MDCK cells to TGF-b, which includes: inhibition of cellular mitogenesis, induction of cellular hypertrophy, increase of cell cycle-regulatory retinoblastoma protein (pRb) dephosphorylation and inhibition of cdc2 kinase activity. Affinity-labeling experiments showed that high glucose may increase TGF-b responsiveness by increasing type I and II TGF-b receptor protein expressions. This is the first demonstration that distal tubule is unique in that it responds to high glucose by increasing TGF-b (which may be derived from paracrine sources) responsiveness but not the production of endogenous TGF-b.Regarding the roles of intracellular signal transduction pathways in diabetic nephropathy, protein kinase C (PKC) had been shown to be important. However, the roles of various PKC isoenzymes in diabetic tubulopathy is still not known. Thus, we showed that high glucose induced PKC activation, PKCi and PKCe activation, cytosolic translocation of PKCi(l) and membrane translocation of PKCe. As for the roles of various transcription factors, only AP-1 had been suggested to be involved in diabetic glomerulopathy. Thus, we first showed that high glucose induced activation of transcription factors AP-1 and NF-kB in MDCK cells concomitantly with the induction of type II TGF-b receptor mRNA. We speculate that the above changes in the signal transduction pathways may be involved in the induction of type II TGF-b receptor mRNA, although this speculation awaits further confirmation.Regarding the effects of AGE, we found that, unlike high glucose, AGE inhibited cellular mitogenesis while inducing cellular hypertrophy in the MDCK cells. Moreover, AGE induced the production of bioactive TGF-b in these cells. Importantly, neutralizing anti-TGF-b1 antibody reversed the above AGE-induced effects. Therefore, endogenous TGF-b1 may mediate the above AGE- induced effects in the MDCK cells.Our experiments showed that distal tubular cells behave differently from glomerular and proximal tubular cells in high glucose and AGE cultures. Whereas AGE induced bioactive TGF-b, high glucose only induced the expression of type I and II TGF-b receptors. We conclude that the complex interaction between high glucose, AGE, TGF-b, TGF-b receptors and cell cycle-regulatory proteins (pRb and cdc2) may play important roles in diabetic nephropathy. In addition, PKCi( l), PKCe, AP-1 and NF-kB may mediate some of the above high glucose and AGE-induced effects.
Chen, Min-Chun, and 陳旻君. "Effect of high-advanced glycation end product (AGE) diet on oxidative damage of testes, kidney and pancreas in normal and diabetic rodents,and the intervention effect of silymarin." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/63558268502055988007.
Full text國立中興大學
食品暨應用生物科技學系所
102
Advanced glycation end products (AGEs) are produced from the Maillard reaction and present in food and biological systems. The present studies show that high levels of circulating AGEs are associated with diabetic complications, such as nephropathy, retinopathy and atherosclerosis.It is worth noting that male diabetic patients may also have reproductive dysfunction, and this dysfunction may result from the oxidative stress induced by AGE-mediated the receptor for AGEs (RAGE) activation. Sustained intake of food rich in AGEs may lead to an increase in endogenous AGEs and chronic oxidative damage. Taken together, it is interesting to clarify the effect of AGE diet on function of testes, kidney and pancreas in normal and diabetic anamals. Silymarin is a flavonoid with hepatoprotective characteristics and powerful antioxidant activity.Therefore, the other section of study was further investigated to clarify the biological actions of silymarin in animals fed an AGE diet. Our study is divided into two sections as follows: In part 1, we assessed the effect of different formula of AGE diet on testes, kidney and pancreas in male BALB/c mice and Sprague-Dawley rats, respectively, and the effect of the biological actions of silymarin. The results showed that AGE diet may lead to accumulation of AGEs in vivo, resulting in oxidative damage of testes and epididymis as well as a decrease in sperm count and motility. To investigate the intervention effect of silymarin, we found that silymarin had potential for prevention of AGE diet-induced oxidative damage. Based on the results of first part, AGE diet was shown to cause accumulation of AGEs. Because the circulating AGEs are closely related to the progression of diabetic complications, it is speculated that diabetic damage of testes and epididymis may be augmented by AGE diet. In part 2, we investigated the effect of AGE diet on STZ-induced type 1 diabetes mellitus (DM) SD rat as well as the intervention effect of silymarin. The results showed that DM-induced oxidative damage led to a decrease of sperm count and motility, and AGE diet may aggravate related lesions, such as an increase of abnormal sperm rate. However, silymarin elevated activity of antioxidant enzymes of testes and ameliorated the lipid peroxidation in pancreas. Silymarin showed the potential for improving DM-induced oxidative damage in vivo; however, it did not significantly improve the STZ and AGE diet-induced decline of sperm count and diffuse spermatic degeneration/necrosis of epididymis. We speculate that the related damage of animals may be difficult to restore; thus, we cannot observe the expected results in related analyses. In conclusion, diversity and preparation method of diet, experimental models, and animal strain might be the reasons why partial results are inconsistent. Based on all results, we summerize that AGE diet-induced oxidative stress are closely related to abnormalities of sperm in rodents. Additionally, administration of silymarin indeed significantly promoted antioxidant actions within testes, kidney and pancreas in rodents, suggesting that silymarin has potential to inhibit the generation of lipid peroxides and improvement of oxidative damage in vivo.
Friess, Ulrich [Verfasser]. "Formation, distribution, and pathophysiological relevance of the 'advanced glycation end-product' Nε-(carboxymethyl)-lysine [N-epsilon-(carboxymethyl)-lysine] in target tissues of diabetic organ damage and in degenerative and chronic inflammatory tissue lesions = Bildung, Verteilung and pathophysiologische Bedeutung von N(epsilon)-Carboxymethyllysin bei diabetischer Organschädigung und in chronisch degenerativen und chronisch entzündlichen Gewebeläsionen / vorgelegt von Ulrich Friess." 2004. http://d-nb.info/97204292X/34.
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