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Toshimitsu Niwa - One of the best experts on this subject based on the ideXlab platform.
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3-Deoxyglucosone and AGEs in uremic complications: Inactivation of glutathione peroxidase by 3-Deoxyglucosone
Kidney International, 2020Co-Authors: Toshimitsu Niwa, Saori TsukudhiAbstract:3-Deoxyglucosone and AGEs in uremic complications: Inactivation of glutathione peroxidase by 3-Deoxyglucosone. 3-Deoxyglucosone (3-DG) is accumulated not only in uremic serum but also in uremic erythrocytes. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as imidazolone, pyrraline, and Nε-(carboxymethyl)lysine, among which imidazolone is the AGE that is most specific for 3-DG. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG that may be due to the loss of 3-DG reductase activity in the end-stage kidneys may lead to a high plasma 3-DG level. The elevated 3-DG levels in uremic patients may promote the formation of AGEs such as imidazolone in erythrocytes, aortas, and dialysis-related amyloid deposits. Treatment with an aldose reductase inhibitor reduced the erythrocyte levels of 3-DG and AGEs such as imidazolone in diabetic uremic patients. This finding demonstrates an important role of the polyol pathway in the formation of erythrocyte 3-DG and AGEs. The erythrocyte levels of 3-DG are elevated in not only diabetic uremic but also nondiabetic uremic patients. 3-DG showed some cytotoxicities by inducing intracellular oxidative stress. In contrast, oxidative stress was demonstrated to cause accumulation of intracellular 3-DG. Recently, we have demonstrated that 3-DG inactivates intracellular enzymes such as glutathione peroxidase, a key enzyme in the detoxification of hydrogen peroxide. Thus, intracellular accumulation of 3-DG may enhance oxidative stress by inactivating the antioxidant enzymes. In conclusion, 3-DG may play a principal role in the development of uremic complications, such as dialysis-related amyloidosis, atherosclerosis, and enhanced oxidative stress
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fate of the glucose degradation products 3 Deoxyglucosone and glyoxal during peritoneal dialysis
Molecular Nutrition & Food Research, 2005Co-Authors: Andreas Tauer, Toshimitsu Niwa, Thorsten O Bender, Erwin H Fleischmann, Achim Jorres, Monika PischetsriederAbstract:Conventional fluids for peritoneal dialysis (PD) contain reactive glucose degradation products (GDPs) as a result of glucose breakdown during heat-sterilization. GDPs in PD fluids (PDFs) have been associated with the progressive alteration of the peritoneal membrane during long-term PD by cytotoxic effects and formation of advanced glycation endproducts (AGEs). In this study, we investigated the possible fate of two characteristic GDPs, 3-Deoxyglucosone (3-DG) and glyoxal, during PD. In vivo, 3-DG and glyoxal concentrations, which were analyzed by high-performance liquid chromatography (HPLC), decreased in PDFs by 78% and 88% during 4 h of dwell time. The PDFs were then incubated in vitro in the presence of the most important reaction partners of GDPs in the peritoneal cavity. Neither human peritoneal mesothelial cells, human peritoneal fibroblasts, soluble protein, an insoluble collagen surface, nor components of spent dialysate led to a significant reduction of 3-DG or glyoxal after 6 h. Only after long-term incubation, a noticeable decrease of 3-DG was observed (-37% after three weeks), more likely due to spontaneous degradation reaction than formation of advanced glycation endproducts. These results suggest that in the course of PD, 3-DG, and glyoxal are absorbed into the organism and thus might contribute to the systemic pool of reactive carbonyl compounds.
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Gas chromatographic–mass spectrometric determination of erythrocyte 3-Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography-chemical ionization mass spectrometry using [ 13 C 6 ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbAlc (r=0.84, P
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gas chromatographic mass spectrometric determination of erythrocyte 3 Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography-chemical ionization mass spectrometry using [ 13 C 6 ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbAlc (r=0.84, P<0.001). However, no significant correlation could be found between erythrocyte 3-DG and age, onset age of diabetes, or duration of diabetes in our group of diabetic patients. In diabetes, the production of 3-DG in the erythrocytes is increased via the polyol pathway and/or the Maillard reaction due to hyperglycemia.
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Gas chromatographic–mass spectrometric determination of erythrocyte 3-Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography–chemical ionization 13 mass spectrometry using [ C ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in 6 diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbA1c (r50.84, P,0.001). However, no significant correlation could be found between erythrocyte 3-DG and age, onset age of diabetes, or duration of diabetes in our group of diabetic patients. In diabetes, the production of 3-DG in the erythrocytes is increased via the polyol pathway and/or the Maillard reaction due to hyperglycemia. 2002 Elsevier Science B.V. All rights reserved.
Carol M Artlett - One of the best experts on this subject based on the ideXlab platform.
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Two α-dicarbonyls downregulate migration, invasion, and adhesion of liver cancer cells in a p53-dependent manner.
Digestive and Liver Disease, 2013Co-Authors: Lorena Loarca, Sihem Sassi-gaha, Carol M ArtlettAbstract:Abstract Background Hepatocellular carcinoma accounts for more than 600,000 deaths per year due to it being a highly invasive tumor. The α-dicarbonyl, methylglyoxal demonstrates efficacy at reducing tumor burden, however the anti-cancerous activities of 3-Deoxyglucosone, have never been studied. Aims To determine the anti-cancerous potential of methylglyoxal and 3-Deoxyglucosone on liver tumor cells. Methods The in vitro effects of methylglyoxal and 3-Deoxyglucosone were studied by investigating migration, invasion, and adhesion of Huh-7, HepG2, and Hep3B cells. Results 3-Deoxyglucosone inhibited migration of Huh-7 and HepG2 cells. Methylglyoxal decreased migration of HepG2 cells. Additionally, 3-Deoxyglucosone and methylglyoxal impaired invasion, and adhesion of Huh-7 and HepG2 cells. In Hep3B cells, a p53 null cell line, 3-Deoxyglucosone and methylglyoxal had no effect on migration, invasion, or adhesion. However, both compounds inhibited invasion of wild-type p53 transfected Hep3B cells. Silencing of p53 in Huh-7 and HepG2 cells abrogated the effects of the α-dicarbonyls on cell invasion. 3DG and MG did not alter p53 total protein but promoted nuclear translocation of p53. Conclusions These studies suggest that 3-Deoxyglucosone and methylglyoxal impair invasion, migration, and adhesion of hepatocellular carcinoma. The effects of both compounds on cell invasion are dependent on p53 and imply that α-dicarbonyls could be efficacious in the treatment of p53-expressing invasive liver tumors.
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modification of collagen by 3 Deoxyglucosone alters wound healing through differential regulation of p38 map kinase
PLOS ONE, 2011Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:Background Wound healing is a highly dynamic process that requires signaling from the extracellular matrix to the fibroblasts for migration and proliferation, and closure of the wound. This rate of wound closure is impaired in diabetes, which may be due to the increased levels of the precursor for advanced glycation end products, 3-Deoxyglucosone (3DG). Previous studies suggest a differential role for p38 mitogen-activated kinase (MAPK) during wound healing; whereby, p38 MAPK acts as a growth kinase during normal wound healing, but acts as a stress kinase during diabetic wound repair. Therefore, we investigated the signaling cross-talk by which p38 MAPK mediates wound healing in fibroblasts cultured on native collagen and 3DG-collagen. Methodology/Principal Findings Using human dermal fibroblasts cultured on 3DG-collagen as a model of diabetic wounds, we demonstrated that p38 MAPK can promote either cell growth or cell death, and this was dependent on the activation of AKT and ERK1/2. Wound closure on native collagen was dependent on p38 MAPK phosphorylation of AKT and ERK1/2. Furthermore, proliferation and collagen production in fibroblasts cultured on native collagen was dependent on p38 MAPK regulation of AKT and ERK1/2. In contrast, 3DG-collagen decreased fibroblast migration, proliferation, and collagen expression through ERK1/2 and AKT downregulation via p38 MAPK. Conclusions/Significance Taken together, the present study shows that p38 MAPK is a key signaling molecule that plays a significantly opposite role during times of cellular growth and cellular stress, which may account for the differing rates of wound closure seen in diabetic populations.
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two dicarbonyl compounds 3 Deoxyglucosone and methylglyoxal differentially modulate dermal fibroblasts
Matrix Biology, 2010Co-Authors: Sihem Sassigaha, Danielle T Loughlin, Frank Kappler, Michael L Schwartz, Bangying Su, Annette Tobia, Carol M ArtlettAbstract:Abstract Advanced glycation endproducts accumulate on long-lived proteins such as collagens as a function of diet and age and mediate the cross-linking of those proteins causing changes in collagen pathophysiology resulting in the disruption of normal collagen matrix remodeling. Two commonly studied advanced glycation endproduct precursors 3-Deoxyglucosone and methylglyoxal were investigated for their role in the modification of collagen and on extracellular matrix expression. Fibroblasts cultured on methylglyoxal cross-linked matrices increased the expression of collagen, active TGF-beta1, beta1-integrin, and decreased Smad7; whereas 3-Deoxyglucosone decreased collagen, active TGF-beta1, beta1-integrin but increased Smad7. Purified collagen modified by 3-Deoxyglucosone or methylglyoxal had different molecular weights; methylglyoxal increased the apparent molecular weight by approximately 20 kDa, whereas 3-Deoxyglucosone did not. The differences in collagen expression by 3-Deoxyglucosone and methylglyoxal raise the provocative idea that a genetic or environmental background leading to the predominance of one of these advanced glycation endproduct precursors may precipitate a fibrotic or chronic wound in susceptible individuals, particularly in the diabetic.
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3 Deoxyglucosone collagen alters human dermal fibroblast migration and adhesion implications for impaired wound healing in patients with diabetes
Wound Repair and Regeneration, 2009Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:The interaction of fibroblasts with the extracellular matrix is critical for wound healing. Advanced glycation end products (AGEs) occur through nonenzymatic glycation of long-lived proteins such as collagens. One precursor to these modifications, 3-Deoxyglucosone (3DG), is elevated in patients with diabetes and contributes to the accumulation of AGEs on collagen with increasing chronological age. Because wound repair is dependent on fibroblast migration, proliferation, and expression of extracellular matrix proteins, we examined the role of 3DG-treated collagen and the subsequent response of fibroblasts to this modification. We found that fibroblasts adhere more strongly to 3DG-treated collagen and do not migrate efficiently into the wound site. We further show that 3DG-treated collagen induces perinuclear localization of focal adhesion kinase and paxillin, indicative of decreased association of these proteins with the cytoskeleton. Additionally, these cells expressed higher levels of the misfolded indicator protein growth arrest and DNA damage inducible gene 153. These data suggest that fibroblast/matrix interactions are altered as AGEs accumulate and affect focal adhesion formation. Furthermore, 3DG may be a factor mediating chronic wounds observed in patients with diabetes and in the elderly by altering the signaling within the fibroblast and inducing the misfolding of proteins.
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3‐Deoxyglucosone‐collagen alters human dermal fibroblast migration and adhesion: Implications for impaired wound healing in patients with diabetes
Wound Repair and Regeneration, 2009Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:The interaction of fibroblasts with the extracellular matrix is critical for wound healing. Advanced glycation end products (AGEs) occur through nonenzymatic glycation of long-lived proteins such as collagens. One precursor to these modifications, 3-Deoxyglucosone (3DG), is elevated in patients with diabetes and contributes to the accumulation of AGEs on collagen with increasing chronological age. Because wound repair is dependent on fibroblast migration, proliferation, and expression of extracellular matrix proteins, we examined the role of 3DG-treated collagen and the subsequent response of fibroblasts to this modification. We found that fibroblasts adhere more strongly to 3DG-treated collagen and do not migrate efficiently into the wound site. We further show that 3DG-treated collagen induces perinuclear localization of focal adhesion kinase and paxillin, indicative of decreased association of these proteins with the cytoskeleton. Additionally, these cells expressed higher levels of the misfolded indicator protein growth arrest and DNA damage inducible gene 153. These data suggest that fibroblast/matrix interactions are altered as AGEs accumulate and affect focal adhesion formation. Furthermore, 3DG may be a factor mediating chronic wounds observed in patients with diabetes and in the elderly by altering the signaling within the fibroblast and inducing the misfolding of proteins.
Guorong Jiang - One of the best experts on this subject based on the ideXlab platform.
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3 Deoxyglucosone induces glucagon like peptide 1 secretion from stc 1 cells via upregulating sweet taste receptor expression under basal conditions
International Journal of Endocrinology, 2019Co-Authors: Xiudao Song, Liang Zhou, Fei Wang, Guoqiang Liang, Lurong Zhang, Fei Huang, Heng Xu, Guorong JiangAbstract:3-Deoxyglucosone (3DG) is derived from D-glucose during food processing and storage and under physiological conditions. We reported that glucagon-like peptide-1 (GLP-1) secretion in response to an oral glucose load in vivo and high-glucose stimulation in vitro was decreased by acute 3DG administration. In this study, we determined the acute effect of 3DG on GLP-1 secretion under basal conditions and investigated the possible mechanisms. Normal fasting rats were given a single acute intragastric administration of 50 mg/kg 3DG. Plasma basal GLP-1 levels and duodenum 3DG content and sweet taste receptor expression were measured. STC-1 cells were acutely exposed to 3DG (80, 300, and 1000 ng/ml) for 1 h under basal conditions (5.6 mM glucose), and GLP-1 secretion, intracellular concentrations of cyclic adenosine monophosphate (cAMP) and Ca2+, and molecular expression of STR signaling pathway were measured. Under the fasted state, plasma GLP-1 levels, duodenum 3DG content, and duodenum STR expression were elevated in 3DG-treated rats. GLP-1 secretion was increased in 3DG-treated cells under either 5.6 mM glucose or glucose-free conditions. 3DG-induced acute GLP-1 secretion from STC-1 cells under 5.6 mM glucose was inhibited in the presence of the STR inhibitor lactisole, which was consistent with the observation under glucose-free conditions. Moreover, acute exposure to 3DG increased the protein expression of TAS1R2 and TAS1R3 under either 5.6 mM glucose or glucose-free conditions, with affecting other components of STR signaling pathway, including the upregulation of transient receptor potential channel type M5 TRPM5 and the increment of intracellular Ca2+ concentration. In summary, the glucose-free condition was used to first demonstrate the involvement of STR in 3DG-induced acute GLP-1 secretion. These results first showed that acute 3DG administration induces basal GLP-1 secretion in part through upregulation of STR expression.
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3 Deoxyglucosone reduces glucagon like peptide 1 secretion at low glucose levels through down regulation of sglt1 expression in stc 1 cells
Archives of Physiology and Biochemistry, 2019Co-Authors: Liang Zhou, Fei Wang, Xiudao Song, Guoqiang Liang, Lurong Zhang, Fei Huang, Guorong JiangAbstract:Context: Sodium glucose co-transporter 1 (SGLT1) triggers low glucose-induced glucagon-like peptide-1 (GLP-1) secretion. We reported that a two-week administration of 3-Deoxyglucosone (3DG), an ind...
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exogenous 3 Deoxyglucosone induced carbonyl and oxidative stress causes β cells dysfunction by impairing gut permeability in rats
Biochemistry, 2018Co-Authors: Liang Zhou, Fei Wang, Xiudao Song, Guoqiang Liang, Lurong Zhang, Fei Huang, Heng Xu, Guorong JiangAbstract:3-Deoxyglucosone (3DG) is a highly reactive dicarbonyl species, and its accumulation evokes carbonyl and oxidative stress. Our recent data reveal the role of 3DG as an independent factor for the development of prediabetes and suggest that intestine could be its novel target tissue. The present study investigated whether exogenous 3DG increases intestinal permeability by triggering carbonyl and oxidative stress, thus contributing to β-cell dysfunction. Rats were administered 3DG for two weeks by gastric gavage. Then levels of insulin, ROS, MDA, SOD, NLRP3, TNF-α and IL-1β in blood plasma as well as the ROS level and content of TNF-α and IL-1β in pancreas were assessed. Also, the expression of E-cadherin and ZO-1 as well as levels of 3DG, protein carbonylation, ROS, TNF-α and IL-1β in colon were determined. The 3DG-treated rats showed an elevation in systemic oxidative stress (ROS, MDA and SOD) and in inflammation (TNF-α and IL-1β), decreased plasma insulin level 15 min after the glucose load, and increased levels of TNF-α, IL-1β and ROS in pancreatic tissue. In colon tissues of the 3DG-treated rats, decreased E-cadherin expression and increased ROS production as well as an elevation of TNF-α and IL-1β levels were observed. Interestingly, elevation of colon protein carbonylation was observed in the 3DG-treated rats that displayed 3DG deposition in colon tissues. We revealed for the first time that 3DG deposition in colon triggers carbonyl and oxidative stress and, as a consequence, impairs gut permeability. The enhanced intestinal permeability caused by 3DG deposition in colon results in systemic and pancreatic oxidative stress and inflammatory process, contributing to the development of β-cell dysfunction.
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the downregulation of sweet taste receptor signaling in enteroendocrine l cells mediates 3 Deoxyglucosone induced attenuation of high glucose stimulated glp 1 secretion
Archives of Physiology and Biochemistry, 2018Co-Authors: Fei Wang, Liang Zhou, Xiudao Song, Guoqiang Liang, Fei Huang, Guorong Jiang, Lurong ZhangAbstract:AbstractContext: Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-Deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion.Objective: This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion.Methods: STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels.Results: Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reducti...
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involvement of exogenous 3 Deoxyglucosone in β cell dysfunction induces impaired glucose regulation
Molecular Medicine Reports, 2017Co-Authors: Lurong Zhang, Liang Zhou, Fei Wang, Xiudao Song, Guoqiang Liang, Fei Huang, Zhongrui Xu, Guorong JiangAbstract:Abstract β‑cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2‑dicarbonyl compounds, such as 3‑Deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair β‑cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre‑diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing β‑cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin‑PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ∆Ins30‑0/∆G30‑0. In 3DG‑treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased β‑cell function. This idea was further supported by these results that non‑cytotoxic 3DG concentration obviously decreased glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS‑1, PI3K‑p85 and Akt in high glucose‑induced INS‑1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from β‑cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing β‑cell dysfunction, at least in part, through impairing IRS‑1/PI3K/GLUT2 signaling.
Danielle T Loughlin - One of the best experts on this subject based on the ideXlab platform.
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modification of collagen by 3 Deoxyglucosone alters wound healing through differential regulation of p38 map kinase
PLOS ONE, 2011Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:Background Wound healing is a highly dynamic process that requires signaling from the extracellular matrix to the fibroblasts for migration and proliferation, and closure of the wound. This rate of wound closure is impaired in diabetes, which may be due to the increased levels of the precursor for advanced glycation end products, 3-Deoxyglucosone (3DG). Previous studies suggest a differential role for p38 mitogen-activated kinase (MAPK) during wound healing; whereby, p38 MAPK acts as a growth kinase during normal wound healing, but acts as a stress kinase during diabetic wound repair. Therefore, we investigated the signaling cross-talk by which p38 MAPK mediates wound healing in fibroblasts cultured on native collagen and 3DG-collagen. Methodology/Principal Findings Using human dermal fibroblasts cultured on 3DG-collagen as a model of diabetic wounds, we demonstrated that p38 MAPK can promote either cell growth or cell death, and this was dependent on the activation of AKT and ERK1/2. Wound closure on native collagen was dependent on p38 MAPK phosphorylation of AKT and ERK1/2. Furthermore, proliferation and collagen production in fibroblasts cultured on native collagen was dependent on p38 MAPK regulation of AKT and ERK1/2. In contrast, 3DG-collagen decreased fibroblast migration, proliferation, and collagen expression through ERK1/2 and AKT downregulation via p38 MAPK. Conclusions/Significance Taken together, the present study shows that p38 MAPK is a key signaling molecule that plays a significantly opposite role during times of cellular growth and cellular stress, which may account for the differing rates of wound closure seen in diabetic populations.
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two dicarbonyl compounds 3 Deoxyglucosone and methylglyoxal differentially modulate dermal fibroblasts
Matrix Biology, 2010Co-Authors: Sihem Sassigaha, Danielle T Loughlin, Frank Kappler, Michael L Schwartz, Bangying Su, Annette Tobia, Carol M ArtlettAbstract:Abstract Advanced glycation endproducts accumulate on long-lived proteins such as collagens as a function of diet and age and mediate the cross-linking of those proteins causing changes in collagen pathophysiology resulting in the disruption of normal collagen matrix remodeling. Two commonly studied advanced glycation endproduct precursors 3-Deoxyglucosone and methylglyoxal were investigated for their role in the modification of collagen and on extracellular matrix expression. Fibroblasts cultured on methylglyoxal cross-linked matrices increased the expression of collagen, active TGF-beta1, beta1-integrin, and decreased Smad7; whereas 3-Deoxyglucosone decreased collagen, active TGF-beta1, beta1-integrin but increased Smad7. Purified collagen modified by 3-Deoxyglucosone or methylglyoxal had different molecular weights; methylglyoxal increased the apparent molecular weight by approximately 20 kDa, whereas 3-Deoxyglucosone did not. The differences in collagen expression by 3-Deoxyglucosone and methylglyoxal raise the provocative idea that a genetic or environmental background leading to the predominance of one of these advanced glycation endproduct precursors may precipitate a fibrotic or chronic wound in susceptible individuals, particularly in the diabetic.
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3 Deoxyglucosone collagen alters human dermal fibroblast migration and adhesion implications for impaired wound healing in patients with diabetes
Wound Repair and Regeneration, 2009Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:The interaction of fibroblasts with the extracellular matrix is critical for wound healing. Advanced glycation end products (AGEs) occur through nonenzymatic glycation of long-lived proteins such as collagens. One precursor to these modifications, 3-Deoxyglucosone (3DG), is elevated in patients with diabetes and contributes to the accumulation of AGEs on collagen with increasing chronological age. Because wound repair is dependent on fibroblast migration, proliferation, and expression of extracellular matrix proteins, we examined the role of 3DG-treated collagen and the subsequent response of fibroblasts to this modification. We found that fibroblasts adhere more strongly to 3DG-treated collagen and do not migrate efficiently into the wound site. We further show that 3DG-treated collagen induces perinuclear localization of focal adhesion kinase and paxillin, indicative of decreased association of these proteins with the cytoskeleton. Additionally, these cells expressed higher levels of the misfolded indicator protein growth arrest and DNA damage inducible gene 153. These data suggest that fibroblast/matrix interactions are altered as AGEs accumulate and affect focal adhesion formation. Furthermore, 3DG may be a factor mediating chronic wounds observed in patients with diabetes and in the elderly by altering the signaling within the fibroblast and inducing the misfolding of proteins.
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3‐Deoxyglucosone‐collagen alters human dermal fibroblast migration and adhesion: Implications for impaired wound healing in patients with diabetes
Wound Repair and Regeneration, 2009Co-Authors: Danielle T Loughlin, Carol M ArtlettAbstract:The interaction of fibroblasts with the extracellular matrix is critical for wound healing. Advanced glycation end products (AGEs) occur through nonenzymatic glycation of long-lived proteins such as collagens. One precursor to these modifications, 3-Deoxyglucosone (3DG), is elevated in patients with diabetes and contributes to the accumulation of AGEs on collagen with increasing chronological age. Because wound repair is dependent on fibroblast migration, proliferation, and expression of extracellular matrix proteins, we examined the role of 3DG-treated collagen and the subsequent response of fibroblasts to this modification. We found that fibroblasts adhere more strongly to 3DG-treated collagen and do not migrate efficiently into the wound site. We further show that 3DG-treated collagen induces perinuclear localization of focal adhesion kinase and paxillin, indicative of decreased association of these proteins with the cytoskeleton. Additionally, these cells expressed higher levels of the misfolded indicator protein growth arrest and DNA damage inducible gene 153. These data suggest that fibroblast/matrix interactions are altered as AGEs accumulate and affect focal adhesion formation. Furthermore, 3DG may be a factor mediating chronic wounds observed in patients with diabetes and in the elderly by altering the signaling within the fibroblast and inducing the misfolding of proteins.
Saori Tsukushi - One of the best experts on this subject based on the ideXlab platform.
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Gas chromatographic–mass spectrometric determination of erythrocyte 3-Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography-chemical ionization mass spectrometry using [ 13 C 6 ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbAlc (r=0.84, P
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gas chromatographic mass spectrometric determination of erythrocyte 3 Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography-chemical ionization mass spectrometry using [ 13 C 6 ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbAlc (r=0.84, P<0.001). However, no significant correlation could be found between erythrocyte 3-DG and age, onset age of diabetes, or duration of diabetes in our group of diabetic patients. In diabetes, the production of 3-DG in the erythrocytes is increased via the polyol pathway and/or the Maillard reaction due to hyperglycemia.
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Gas chromatographic–mass spectrometric determination of erythrocyte 3-Deoxyglucosone in diabetic patients
Journal of Chromatography B, 2002Co-Authors: Saori Tsukushi, Mitsuharu Kajita, Sakurako Nakamura, Toshimitsu NiwaAbstract:To determine if the erythrocyte levels of 3-Deoxyglucosone (3-DG) are increased in diabetic patients, and if they correlate with glycemic status, they were measured in diabetic patients without renal disease as well as in healthy subjects. The erythrocyte levels of 3-DG were measured by a selected ion monitoring method of gas chromatography–chemical ionization 13 mass spectrometry using [ C ]-3-DG as an internal standard. The erythrocyte levels of 3-DG were significantly higher in 6 diabetic patients than in healthy subjects. The erythrocyte concentration of 3-DG was significantly and positively correlated with HbA1c (r50.84, P,0.001). However, no significant correlation could be found between erythrocyte 3-DG and age, onset age of diabetes, or duration of diabetes in our group of diabetic patients. In diabetes, the production of 3-DG in the erythrocytes is increased via the polyol pathway and/or the Maillard reaction due to hyperglycemia. 2002 Elsevier Science B.V. All rights reserved.
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3-Deoxyglucosone and AGEs in uremic complications: Inactivation of glutathione peroxidase by 3-Deoxyglucosone
Kidney International, 2001Co-Authors: Toshimitsu Niwa, Saori TsukushiAbstract:3-Deoxyglucosone (3-DG) is accumulated not only in uremic serum but also in uremic erythrocytes. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as imidazolone, pyrraline, and N(epsilon)-(carboxymethyl)lysine, among which imidazolone is the AGE that is most specific for 3-DG. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG that may be due to the loss of 3-DG reductase activity in the end-stage kidneys may lead to a high plasma 3-DG level. The elevated 3-DG levels in uremic patients may promote the formation of AGEs such as imidazolone in erythrocytes, aortas, and dialysis-related amyloid deposits. Treatment with an aldose reductase inhibitor reduced the erythrocyte levels of 3-DG and AGEs such as imidazolone in diabetic uremic patients. This finding demonstrates an important role of the polyol pathway in the formation of erythrocyte 3-DG and AGEs. The erythrocyte levels of 3-DG are elevated in not only diabetic uremic but also nondiabetic uremic patients. 3-DG showed some cytotoxicities by inducing intracellular oxidative stress. In contrast, oxidative stress was demonstrated to cause accumulation of intracellular 3-DG. Recently, we have demonstrated that 3-DG inactivates intracellular enzymes such as glutathione peroxidase, a key enzyme in the detoxification of hydrogen peroxide. Thus, intracellular accumulation of 3-DG may enhance oxidative stress by inactivating the antioxidant enzymes. In conclusion, 3-DG may play a principal role in the development of uremic complications, such as dialysis-related amyloidosis, atherosclerosis, and enhanced oxidative stress.
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gas chromatographic mass spectrometric analysis of erythrocyte 3 Deoxyglucosone in hemodialysis patients
Journal of Chromatography B: Biomedical Sciences and Applications, 1999Co-Authors: Saori Tsukushi, Kaoru Shimokata, Toshimitsu NiwaAbstract:The erythrocyte levels of 3-Deoxyglucosone (3-DG) were measured by a selected ion monitoring method of gas chromatography–chemical ionization mass spectrometry using [13C6]-3-DG as an internal standard. Because the erythrocyte levels of 3-DG measured after deproteinization using ethanol were 18 times higher than those using ultrafiltration, we used ethanol deproteinization for measurement of total 3-DG in the erythrocytes. The concentration of 3-DG was significantly elevated in hemodialysis (HD) patients compared with healthy subjects. Although HD treatment could remove the erythrocyte 3-DG efficiently, its post-HD levels were still elevated compared with the healthy subjects.
