Modification of the glyoxalase system in streptozotocin-Induced diabetic rats and the effect of the aldose reductase Inhibitor Statil

Sa, Phillips; Mirrlees, Donald J.; Pj, Thronalley

doi:10.1042/bst021162s

Cited by 44 publications

(55 citation statements)

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“…Most detoxification of MG is catalyzed by the oxidative glyoxalase system, leading to the production of the inert end product D-lactate (46). Previous studies to investigate the effect of diabetes on the activity of glyoxalase have produced mixed results: some showed a modest increase in activity in red blood cells and leukocytes (21,47), whereas others found reduced activity in renal cortex and liver in diabetic animals (48). Optimal activity of the glyoxalase system is dependent on adequate levels of reduced glutathione (GSH) (49), and the known association of hyperglycemia and depletion of GSH (50,51) could lead to impaired MG detoxification.…”

Section: Figure 2-mean ϯ Sd Integrated Postprandial Excursions Of Metmentioning

confidence: 87%

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

Beisswenger

Howell

O’Dell³

et al. 2001

Diabetes Care

165

125

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OBJECTIVE -Chronic hyperglycemia is known to increase tissue glycation and diabetic complications, but controversy exists regarding the independent role of increased postprandial glucose excursions. To address this question, we have studied the effect of postprandial glycemic excursions (PPGEs) on levels of methylglyoxal (MG) and 3-deoxyglucosone (3-DG), two highly reactive precursors of advanced glycation end products (AGEs).RESEARCH DESIGN AND METHODS -We performed 4-month crossover studies on 21 subjects with type 1 diabetes and compared the effect of premeal insulin lispro or regular insulin on PPGEs and MG/3-DG excursions. PPGE was determined after standard test meal (STMs) and by frequent postprandial glucose monitoring. HbA 1c and postprandial MG and D-lactate were measured by HPLC, whereas 3-DG was determined by gas chromatography/mass spectroscopy.RESULTS -Treatment with insulin lispro resulted in a highly significant reduction in PPGEs relative to the regular insulin-treated group (P ϭ 0.0005). However, HbA 1c levels were similar in the two groups, and no relationship was observed between HbA 1c and PPGE (P ϭ 0.93). Significant postprandial increases in MG, 3-DG, and D-lactate occurred after the STM. Excursions of MG and 3-DG were highly correlated with levels of PPGE (R ϭ 0.55, P ϭ 0.0002 and R ϭ 0.61, P ϭ 0.0004; respectively), whereas a significant inverse relationship was seen between PPGE and D-lactate excursions (R ϭ 0.40, P ϭ 0.01). Conversely, no correlation was observed between HbA1c and postprandial MG, 3-DG, or D-lactate levels.CONCLUSIONS -Increased production of MG and 3-DG occur with greater PPGE, whereas HbA1c does not reflect these differences. Reduced PPGE also leads to increased production of D-lactate, indicating a role for increased detoxification in reducing MG levels. The higher postprandial levels of MG and 3-DG observed with greater PPGE may provide a partial explanation for the adverse effects of glycemic lability and support the value of agents that reduce glucose excursions. Diabetes Care 24:726 -732, 2001

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Section: Figure 2-mean ϯ Sd Integrated Postprandial Excursions Of Metmentioning

confidence: 87%

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

Beisswenger

Howell

O’Dell³

et al. 2001

Diabetes Care

165

125

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“…The concentration of MG in human cells can be elevated under various pathological conditions (e.g., diabetes) (19)(20)(21). It was found recently that MG induces modifications in calf thymus DNA mainly on dG to give N 2 -CEdG (22).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, treatment of human red blood cells with increasing concentrations of glucose in vitro can result in increases of intracellular MG concentration (19). The MG concentration was also found to be elevated in the kidney (cortex and medulla), lens, and blood of streptozotocin-induced diabetic rats (20) and in blood samples of diabetic patients (21).…”

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confidence: 95%

Efficient and accurate bypass of N ² -(1-carboxyethyl)-2′-deoxyguanosine by DinB DNA polymerase in vitro and in vivo

Yuan¹,

Cao²,

Jiang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

135

153

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DinB, a Y-family DNA polymerase, is conserved among all domains of life; however, its endogenous substrates have not been identified. DinB is known to synthesize accurately across a number of N 2 -dG lesions. Methylglyoxal (MG) is a common byproduct of the ubiquitous glycolysis pathway and induces the formation of N 2 -(1-carboxyethyl)-2-deoxyguanosine (N 2 -CEdG) as the major stable DNA adduct. Here, we found that N 2 -CEdG could be detected at a frequency of one lesion per 10 7 nucleosides in WM-266-4 human melanoma cells, and treatment of these cells with MG or glucose led to a dose-responsive increase in N 2 -CEdG formation. We further constructed single-stranded M13 shuttle vectors harboring individual diastereomers of N 2 -CEdG at a specific site and assessed the cytotoxic and mutagenic properties of the lesion in wild-type and bypass polymerase-deficient Escherichia coli cells. Our results revealed that N 2 -CEdG is weakly mutagenic, and DinB (i.e., polymerase IV) is the major DNA polymerase responsible for bypassing the lesion in vivo. Moreover, steady-state kinetic measurements showed that nucleotide insertion, catalyzed by E. coli pol IV or its human counterpart (i.e., polymerase ), opposite the N 2 -CEdG is both accurate and efficient. Taken together, our data support that N 2 -CEdG, a minor-groove DNA adduct arising from MG, is an important endogenous substrate for DinB DNA polymerase.glycolysis ͉ mutagenesis ͉ polymerase ͉ translesion synthesis

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“…In addition, increased AR activity contributes to oxidative-nitrosative stress indirectly, via other pathways, such as nonenzymatic glycation and activation of PKC. In particular, AR is involved in generation of fructose, a 10 times more potent glycation agent than glucose, as well as other AGE precursors, i.e., methylglyoxal and 3-deoxyglucosone [74,75]. ARI treatment suppresses formation of the AGE pentosidine and carboxymethyllysine [76,77] known to generate oxidative stress via interaction with their receptors [57].…”

Section: Discussionmentioning

confidence: 99%

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Drel

Pacher²,

Stevens

et al. 2006

Free Radical Biology and Medicine

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Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADPribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg −1 day −1 ) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetesinduced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM Lglucose or 30 mM D-glucose plus 10 μM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.

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Modification of the glyoxalase system in streptozotocin-Induced diabetic rats and the effect of the aldose reductase Inhibitor Statil

Cited by 44 publications

References 0 publications

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

Efficient and accurate bypass of N ² -(1-carboxyethyl)-2′-deoxyguanosine by DinB DNA polymerase in vitro and in vivo

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

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Modification of the glyoxalase system in streptozotocin-Induced diabetic rats and the effect of the aldose reductase Inhibitor Statil

Cited by 44 publications

References 0 publications

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

α-Dicarbonyls Increase in the Postprandial Period and Reflect the Degree of Hyperglycemia

Efficient and accurate bypass of N 2 -(1-carboxyethyl)-2′-deoxyguanosine by DinB DNA polymerase in vitro and in vivo

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

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Efficient and accurate bypass of N ² -(1-carboxyethyl)-2′-deoxyguanosine by DinB DNA polymerase in vitro and in vivo