Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress

Loske, Claudia; Neumann, Arne; Cunningham, Anne M.; Nichol, K.A.; Schinzel, Reinhard; Riederer, Peter; Münch, Gerald

doi:10.1007/s007020050108

Cited by 134 publications

(87 citation statements)

References 22 publications

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“…The AGE have been implicated in nerve damage with much work done on the aetiology of Alzheimer's disease and the glycation of amyloid-b protein, which is a precursor of the senile plaque seen in this condition [116]. As with diabetic retinopathy there is evi-dence of vascular dysfunction and that includes accumulation of AGE in the vasa nervorum leading to wall thickening, ischaemia, occlusion [117] and myelin damage with segmental demyelination [35].…”

Section: Thrombosis and Fibrinolysis Tissue Factor Thrombomodulinmentioning

confidence: 99%

Advanced glycation end-products: a review

et al. 2001

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Diabetes is a common condition with multiple complications. There has been much work done to elaborate on the aetiology, prevention and treatment of diabetes related complications. The DCCT [1] and UKPDS [2] studies have emphasised the role of tight glucose control as being important in reducing diabetic microvascular disease in Type I (insulin-dependent) diabetes mellitus (DCCT) and Type II (non-insulin-dependent) diabetes mellitus (UKPDS). The relation between tight glucose control and macrovascular complications is, however, not clear [3]. Recently the importance of blood pressure control in reducing diabetic microvascular complications has been shown [4]. Apart from these factors, damage induced by hyperglycaemia involves a complex interaction between many influences including genetic predisposition, smoking, BMI, dyslipidaemia and alterations in coagulation factors [3]. The presence of advanced glycation end-products (AGE) is closely related to Diabetologia (2001) AbstractAdvanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occuring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications. [Diabetologia (2001) 44: 129±146]Keywords Advanced glycated end-products, diabetes mellitus, microvascular disease, carbonyl stress, aminoguanidine.Corresponding author: Dr R. Singh MRCP (UK), FRACP, University Dept of Medicine, Royal Perth Hospital, PO Box X2213, Perth 6847, Western Australia Abbreviations: ESRD, End-stage renal disease; 3-DG, 3-deoxyglucosone; MGO, methylglyoxal; DOLD, deoxyglucosone-lysine dimer; MOLD, methyl glyoxal-lysine dimer; CML, N e -[carboxymethyl]-lysine; FFI, furoyl-furanyl imidazole; PTB, phenacyl thiozolium bromide; RAGE, receptor for AGE; NF-kB, nuclear factor-kB; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular adhesion molecule-1; PECAM-1, platelet endothelial cell adhesion molecule-1; ELAM-1, endothelial leucocyte adhesion molecule-1; MSR, macrophage scavenger recepto...

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Section: Thrombosis and Fibrinolysis Tissue Factor Thrombomodulinmentioning

confidence: 99%

Advanced glycation end-products: a review

et al. 2001

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“…However, it could be prevented by treatment with an antioxidant, pointing to oxidative stress as a cause of cell death. Since AGEs and oxidative stress have been linked [30] and endogenous NO is known to contribute to intracellular oxidative stress [31], we investigated oxidative stress markers in SH-SY5Y cells. Indeed we have found that the highest increase in ROS upon exposure to AGEs occurred in nNOS-positive cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

et al. 2004

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Aims/hypothesis. We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression. Methods. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose. Results. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase. Conclusions/interpretation. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes. [Diabetologia (2004) 47: 331-339]

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“…MTT enters the cells by endocytosis and is reduced to formazan by NADH reductase and other enzymes in a reaction that can be measured spectrophotometrically. The amount of formazan reflects the reductive potential of the cytoplasm and the cell viability and generally shows good correlation with other viability tests (30,39,40). Live/dead assays were performed following the protocol provided by the kit (live/dead viability/cytotoxicity kit for mammalian cells; Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Prion Protein Complexed to N2a Cellular RNAs through Its N-terminal Domain Forms Aggregates and Is Toxic to Murine Neuroblastoma Cells

Gomes¹,

Millen²,

Ferreira³

et al. 2008

Journal of Biological Chemistry

123

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Conversion of the cellular prion protein (PrP C ) into its altered conformation, PrPSc , is believed to be the major cause of prion diseases. Although PrP is the only identified agent for these diseases, there is increasing evidence that other molecules can modulate the conversion. We have found that interaction of PrP with double-stranded DNA leads to a protein with higher ␤-sheet content and characteristics similar to those of PrP Sc . RNA molecules can also interact with PrP and potentially modulate PrP C to PrP Sc conversion or even bind differentially to both PrP isoforms. Here, we investigated the interaction of recombinant murine PrP with synthetic RNA sequences and with total RNA extracted from cultured neuroblastoma cells (N2aRNA). We found that PrP interacts with N2aRNA with nanomolar affinity, aggregates upon this interaction, and forms species partially resistant to proteolysis. RNA does not bind to N-terminal deletion mutants of PrP, indicating that the N-terminal region is important for this process. Cell viability assays showed that only the N2aRNA extract induces PrP-RNA aggregates that can alter the homeostasis of cultured cells. Small RNAs bound to PrP give rise to nontoxic small oligomers. Nuclear magnetic resonance measurements of the PrP-RNA complex revealed structural changes in PrP, but most of its native fold is maintained. These results indicate that there is selectivity in the species generated by interaction with different molecules of RNA. The catalytic effect of RNA on the PrP C 3 PrP Sc conversion depends on the RNA sequence, and small RNA molecules may exert a protective effect.Prion diseases can be infectious, sporadic, or inherited (1). Regardless of their origin, they are related to modifications of a ubiquitous membrane-anchored protein, the prion protein (PrP).3 Through a poorly understood process, the cellular PrP isoform (PrP C ), an ␣-helix-rich protein, undergoes a profound conformational change, acquiring higher ␤-sheet content; the latter isoform is known as PrP Sc (Sc from scrapie) and is the only known component of the infectious prion particle (1-4).The protein-only hypothesis postulates that PrP Sc "multiplies" by catalyzing the conversion of PrP C into a likeness of itself, thus becoming responsible for its own propagation (5). This hypothesis is based strongly on the fact that PrP knock-out mice are resistant to prion infection, suggesting that endogenous PrP is necessary for prion propagation and infection (6). It was also suggested, however, that an additional unknown factor could influence the PrP C to PrP Sc conversion (7-10). This molecule would act by lowering the free energy barrier between PrP C and PrP Sc and triggering conversion (11,12). In this field, a great number of biological macromolecules have emerged as candidates for conversion catalysts. Cellular adhesion molecules, nucleic acids (NAs), basal membrane molecules, and sulfated glycans, among other biological macromolecules, have been reported to interact with PrP C and to induce its conversion in...

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Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress

Cited by 134 publications

References 22 publications

Advanced glycation end-products: a review

Advanced glycation end-products: a review

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

Prion Protein Complexed to N2a Cellular RNAs through Its N-terminal Domain Forms Aggregates and Is Toxic to Murine Neuroblastoma Cells

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