| 1. |
- Stadler, Krisztian, et al.
(författare)
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Aminoguanidin-kezeles pozitiv hatasa a peroxinitrit-termelodesre es szivhipertrofiara streptozotocinnal indukalt diabeteses patkanyokban
- 2004
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Ingår i: Orvosi Hetilap. - 0030-6002. ; 145:49, s. 2491-2496
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Tidskriftsartikel (refereegranskat)abstract
- The effect and possible mechanisms of action of aminoguanidine (a preferential iNOS inhibitor) has been studied on cardiovascular damages and overproduction of reactive nitrogen species in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: 40 rats were divided into five groups (control and diabetic, with or without aminoguanidine treatment, diabetic with insulin treatment) and oxidative stress parameters were examined. Tissue nitric oxide levels were determined by EPR spectroscopy, while peroxynitrite generation by a chemiluminescence method. Cardiac hypertrophy, blood metabolic parameters (blood glucose, HbA1c, fructosamine), as well as tissue protein carbonyl levels were also determined. RESULTS: Diabetic animals showed increased nitric oxide and peroxynitrite generation in the aorta along with a significant hypertrophy and protein carbonylation of the cardiac tissue. Both aminoguanidine and insulin treatment suppressed high levels of nitric oxide and peroxynitrite in the vasculature, but only aminoguanidine was able to prevent hypertrophic alterations and to reduce protein carbonylation in the heart. CONCLUSIONS: The results show that (1) aminoguanidine reduces nitric oxide production and prevents cardiac hypertrophy, (2) insulin therapy improves carbohydrate metabolism, reduces nitrosative stress but has no effect on cardiac hypertrophy. Cardiac hypertrophy in diabetes is strongly correlated with non-enzymatic glycation. Aminoguanidine prevented hypertrophy by blocking the formation of advanced glycation end products rather than via other mechanisms.
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| 2. |
- Stadler, Krisztian, et al.
(författare)
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Beneficial effects of aminoguanidine on the cardiovascular system of diabetic rats
- 2005
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 21:2, s. 189-196
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The study focused on investigating the effect of aminoguanidine on cardiovascular damages in diabetes and the possible mechanisms of its action. METHODS: Aminoguanidine (AMNG) was used to treat streptozotocin-induced diabetic rats, and the effects were compared to those obtained under insulin treatment. Blood metabolic parameters, *NO and ONOO- as well as protein carbonyl levels and cardiac hypertrophy were determined. RESULTS: Diabetic animals showed increased *NO levels and markedly increased ONOO- generation in the aorta, along with a significant hypertrophy and protein carbonylation in the cardiac tissue. Both AMNG and insulin treatment suppressed the levels of overproduced *NO or ONOO- in the vasculature, but only AMNG was able to prevent hypertrophic alterations and reduce protein carbonylation in the cardiac tissue. CONCLUSIONS: Oxidative protein modification, together with cardiac hypertrophy and high generation of *NO and ONOO-, are important early events in the development of cardiovascular complications in diabetes. Aminoguanidine could prevent hypertrophy through inhibition of production of nonenzymatic glycation products rather than via inhibition of *NO production.
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| 3. |
- Stadler, Krisztian, et al.
(författare)
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Szabadgyokok es reaktiv nitrogen speciesek szerepe a diabetes kesoi szovodmenyeinek kialakulasaban patkanyban
- 2004
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Ingår i: Orvosi Hetilap. - 0030-6002. ; 145:21, s. 1135-1140
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Tidskriftsartikel (refereegranskat)abstract
- In this time-course study the levels of different reactive species, especially those of nitric oxide and peroxynitrite were determined in streptozotocin-induced diabetic rat tissues at different time-points after the onset of the disease, before the development of histopathological damages. Significantly higher steady state free radical concentrations were found in the liver 3 weeks after the onset of diabetes, compared to age matched control groups. Increased nitric oxide levels in diabetic vasculature and kidney, and its rapid reaction with reactive oxygen species, resulted in high peroxynitrite generation. This suggested the onset of processes characteristic to premature aging of the endothelium. According to the histopathological results, there were no signs of late complications in the tissues up to seven weeks after induction of diabetes. In conclusion, the authors' experimental evidences support the idea of a complex role for nitric oxide, reactive oxygen species and peroxynitrite in the development of early diabetic tissue injury before the evolution of late complications. This study showed for the first time a time-course dependence for changes in nitric oxide production in diabetic tissues compared to age-matched controls at an early stage of the disease. These results suggest that oxidative stress in increased at a very early stage of diabetes and, in particular, that high levels of nitric oxide and peroxynitrite could play a decisive role in the development of late complications in the diabetic vasculature and kidney.
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| 4. |
- Wang, Qin, et al.
(författare)
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Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR
- 2023
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Ingår i: NATURE METABOLISM. - 2522-5812. ; 5, s. 607-625
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime risk of kidney disease in people with diabetes is 10-30%, implicating genetic predisposition in the cause of diabetic kidney disease (DKD). Here we identify an expression quantitative trait loci (QTLs) in the cis-acting regulatory region of the xanthine dehydrogenase, or xanthine oxidoreductase (Xor), a binding site for C/EBP beta, to be associated with diabetes-induced podocyte loss in DKD in male mice. We examine mouse inbred strains that are susceptible (DBA/2J) and resistant (C57BL/6J) to DKD, as well as a panel of recombinant inbred BXD mice, to map QTLs. We also uncover promoter XOR orthologue variants in humans associated with high risk of DKD. We introduced the risk variant into the 5 '-regulatory region of XOR in DKD-resistant mice, which resulted in increased Xor activity associated with podocyte depletion, albuminuria, oxidative stress and damage restricted to the glomerular endothelium, which increase further with type 1 diabetes, high-fat diet and ageing. Therefore, differential regulation of Xor contributes to phenotypic consequences with diabetes and ageing. Wang et al. identify a promoter variant in xanthine oxidoreductase associated with diabetic kidney disease through increased podocyte depletion and glomerular injury.
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