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Fibronectin glycation increases IGF-I induced proliferation of human aortic smooth muscle cells

Giannella, Maria Lucia Cardillo Correa; Andrade de Azevedo, Maria Regina; LeRoith, Derek; Giannella-Neto, Daniel
Fonte: BIOMED CENTRAL LTD; LONDON Publicador: BIOMED CENTRAL LTD; LONDON
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
56.09%
The advanced glycation end products, namely AGEs, contribute to long-termed complications of diabetes mellitus, including macroangiopathy, where smooth muscle cells (SMC) proliferation stimulated by platelet-derived growth factor (PDGF) isoforms and insulin-like growth factor-I (IGF-I) plays an important role. The objective of the present study was to investigate the effect of an AGE-modified extracellular matrix protein on IGF-I induced SMC proliferation and on the IGF-I-IGF binding protein 4 (IGFBP-4) axis under basal conditions and after stimulation with PDGF-BB. IGF-I resulted in significantly higher thymidine incorporation in SMC seeded on AGE-modified fibronectin (AGE-FN) in comparison to cells seeded on fibronectin (FN). This augmented proliferation could not be accounted for by increased expression of IGF-IR, by decreased secretion of IGFBP-4, a binding protein that inhibits IGF-I mitogenic effects or by increased IGF-IR autophosphorylation. PDGF-BB did not modulate IGF-IR and IGFBP-4 mRNA expression in any of the substrata, however, this growth factor elicited opposite effects on the IGFBP-4 content in the conditioned media, increasing it in cells plated on FN and diminishing it in cells plated on AGE-FN. These findings suggest that one mechanism by which AGE-modified proteins is involved in the pathogenesis of diabetes-associated atherosclerosis might be by increasing SMC susceptibility to IGF-I mitogenic effects.; FAPESP...

Albumina modificada por glicação avançada no diabete melito tipo 1 e 2 prejudica o transporte reverso de colesterol e favorece o acúmulo de lípides em macrófagos; Impairment in reverse cholesterol transport and macrophage lipid accumulation induced by advanced glycated albumin drawn from uncontrolled type 1 and type 2 diabetes mellitus patients

Lima, Adriana Machado Saldiba de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 24/02/2011 PT
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55.88%
Produtos de glicação avançada (AGE) são prevalentes no diabete melito e alteram o metabolismo de lípides e lipoproteínas. Neste estudo, avaliou-se a influência da albumina, isolada do soro de indivíduos controles (C, n =12) e de portadores de diabete melito tipo 1 (DM 1, n=13) e tipo 2 (DM 2, n=11), com controle glicêmico inadequado, sobre a remoção de colesterol de macrófagos, o acúmulo intracelular de lípides, o conteúdo do receptor de HDL, ABCA-1 e a captação seletiva de colesterol esterificado de HDL. Além disso, foi determinada a expressão diferencial de genes em macrófagos tratados com albumina C, DM 1 ou DM 2. A concentração plasmática de albumina glicada foi superior no grupo DM 1 e DM 2 em relação ao C e correlacionou-se positivamente com glicemia, hemoglobina glicada e frutosamina. Albumina sérica foi isolada por cromatografia para separação rápida de proteínas e purificada por extração alcoólica. Albumina DM 1 e DM 2 apresentaram maior conteúdo de carboximetil-lisina e apo A-I quando comparada à albumina C. Macrófagos enriquecidos com LDL acetilada e 14C-colesterol foram tratados com albumina C, DM 1 ou DM 2 e, a seguir, incubados na presença ou ausência de apo A-I, HDL3 ou HDL2 para determinação do efluxo de colesterol. Apesar de removerem maior quantidade de colesterol celular...

O efeito pró-apoptótico de oligômeros da amilina humana não é potencializado pela lipotoxicidade em ilhotas pancreáticas de rato em cultura; The pro-apoptotic effect of human amylin oligomers is not potentiated by lipotoxicity in rat pancreatic islets in culture

Oliveira, Érika Rodrigues de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 25/07/2012 PT
Relevância na Pesquisa
55.96%
O depósito de amilina é um achado histopatológico frequente em pacientes portadores de diabetes mellitus tipo 2 (DM 2) e parece estar relacionado à disfunção da célula beta pancreática característica desta doença. Um estudo previamente desenvolvido em nosso laboratório verificou que oligômeros de amilina humana provocam diminuição na expressão do mRNA do gene que codifica o receptor do hormônio incretínico peptídeo insulinotrópico dependente de glicose (Gipr) e aumento do índice de apoptose em ilhotas pancreáticas de rato mantidas em cultura. Considerando o importante papel do depósito amilóide e das incretinas na fisiopatologia do DM 2, os objetivos deste trabalho foram investigar (1) o efeito da amilina humana sobre a expressão dos receptores de incretinas e (2) a modulação de seu efeito tóxico por outras condições concomitantes presentes no DM, como a lipotoxicidade e os produtos finais de glicação avançada (AGEs). Para isto, foi realizada a avaliação da expressão do mRNA dos genes Gipr e Glp1r (receptor do peptídeo semelhante ao glucagon) por PCR em tempo real em ilhotas expostas apenas aos oligômeros de amilina humana (10 M) por 4 e 8 h e em ilhotas expostas aos oligômeros e ao palmitato (0...

N-acetilcisteína reduz o estresse de retículo endoplasmático e afeta seletivamente o efluxo de colesterol de macrófagos mediado por ABCA-1 e ABCG-1 na doença renal crônica; -

Machado, Juliana Tironi
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 01/09/2014 PT
Relevância na Pesquisa
55.92%
Produtos de glicação avançada, carbamilação e estresse oxidativo contribuem como fatores de risco não tradicionais para a aterosclerose na doença renal crônica (DRC), em parte, por prejudicarem o metabolismo lipídico e por representarem um mecanismo de injúria memorizado ao longo do desenvolvimento da doença renal. A albumina sérica, isolada de animais com DRC, reduz a remoção de colesterol mediado por apoA-I e subfrações de HDL, prejudicando o fluxo de colesterol de macrófagos arteriais ao fígado por meio do transporte reverso de colesterol. Objetivo: Avaliou-se a influência do tratamento com N-acetilcisteína (NAC) em ratos com DRC sobre a concentração plasmática de produtos de oxidação e glicação avançada e o reflexo sobre os efeitos da albumina sérica sobre o efluxo de colesterol e o estresse de retículo endoplasmático em macrófagos. Métodos: Ratos Wistar com 2 meses de idade, pesando aproximadamente 200-250g foram submetidos à nefrectomia 5/6 e mantidos por 60 dias (grupo DRC) com ou sem tratamento com N-acetilcisteína na água (600mg/L), após o 7° dia de indução da DRC (grupo DRC + NAC). Animais controles foram falso-operados (grupo C) e um subgrupo submetido ao tratamento com NAC (C + NAC). No início e no final do estudo foram determinadas as concentrações plasmáticas de glicose...

A menor expressão do RNA mensageiro do receptor 1 de produtos finais de glicação avançada (AGER1) em células linfomononucleares de sangue periférico está associada à doença renal em portadores de diabetes mellitus tipo 1; Lower expression of advanced glycation endproduts receptor-1 (AGER1) in peripheral blood mononuclear cells is associated with renal disease in type 1 diabetes patients

Santos, Daniele Pereira dos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 03/07/2015 PT
Relevância na Pesquisa
55.88%
O papel da hiperglicemia na patogênese das complicações crônicas do diabetes mellitus tipo 1 (DM1) está bem estabelecido; um dos mecanismos propostos para explicar seus efeitos deletérios é o aumento da formação dos produtos finais de glicação avançada (AGEs). Os AGEs alteram irreversivelmente a estrutura de macromoléculas, comprometendo sua função biológica. Além disso, a interação com receptores para AGE (RAGEs) favorece vias de transdução de sinal que culminam na geração de espécies reativas de oxigênio (EROs). Um segundo tipo de receptor de AGEs, o AGER1 contrapõe-se à toxicidade dos AGEs, graças ao estímulo à atividade antioxidante e à redução do estresse inflamatório. Uma enzima de potencial interesse é a sirtuína 1, uma desacetilase que desempenha importante papel na resposta ao estresse e a compostos tóxicos e que parece ter sua atividade diminuída no DM, sendo negativamente modulada pelos AGEs. O sistema tiorredoxina (TXN) é um dos principais sistemas antioxidantes endógenos; a TXN é capaz de interagir com várias proteínas, tal como a TXN interacting protein (TXNIP), implicada na patogênese do DM e de suas complicações. Há poucos estudos na literatura abordando a expressão de receptores de AGEs e sua associação com complicações crônicas microvasculares no DM1. Os objetivos deste trabalho foram avaliar a expressão do mRNA dos genes que codificam o RAGE (AGER)...

Avaliação dos produtos finais de glicosilação e o fator nuclear K-B em glandulas lacrimais e superficie ocular de modelos animais de diabetes e envelhecimento; Advanced glycation end-products and Nuclear Factor K-B in lacrimal glands and ocular surface of diabetes and aging animal models

Monica de Cassia Alves
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/07/2006 PT
Relevância na Pesquisa
76%
Este estudo avaliou as possíveis vias comuns na fisiopatogênese da síndrome do olho seco no Diabetes Mellitus (DM) e no envelhecimento, envolvendo o acúmulo dos produtos de glicosilação ("Advanced Glycation End-products" - AGEs), seu receptor RAGE e a ativação do Fator Nuclear-?B (NF-?B) na glândula lacrimal (GL) e alterações do filme lacrimal nessas condições. Modelos animais de DM induzido com estreptozotocina e animais senis (24 meses de vida) foram comparados a animais controle tratados com tampão citrato e adultos jovens (2 meses de vida). Foram avaliadas vias de sinalização, envolvendo AGEs, RAGE e a ativação do NF-?B na GL e alterações no filme lacrimal em ratos Wistar de todos os grupos. A análise do filme lacrimal foi realizada através de medidas de volume de secreção basal e dosagem de citocinas como a Interleucina-1 ß (IL-1 ß) e Fator de Necrose Tumoral - a (TNF- a). A capacidade secretória da GL foi avaliada através de medidas da atividade de peroxidase. Técnicas de "western blot" foram utilizadas para avaliar a expressão e ativação do NF-?B na GL. A expressão de AGE, RAGE e NF-?B na GL e córnea nos grupos estudados, foi avaliada através de microscopia confocal com imunofluorescência. O volume lacrimal foi significativamente menor nos animais diabéticos e senis (P=0...

Advanced glycation end products contribute to amyloidosis in Alzheimer disease.

Vitek, M P; Bhattacharya, K; Glendening, J M; Stopa, E; Vlassara, H; Bucala, R; Manogue, K; Cerami, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 24/05/1994 EN
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55.88%
Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble beta AP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated beta-amyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified beta AP-nucleation seeds further accelerated aggregation of soluble beta AP compared to non-modified "seed" material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of posttranslational covalent adducts on long-lived proteins in vivo. In a standardized competitive ELISA, plaque fractions of AD brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of beta-amyloid is prolonged in AD...

Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor.

Doi, T; Vlassara, H; Kirstein, M; Yamada, Y; Striker, G E; Striker, L J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/04/1992 EN
Relevância na Pesquisa
66.01%
Renal disease is one of the most common and severe complications of diabetes mellitus. The hallmark of the disease, glomerulosclerosis, is characterized by an accumulation of extracellular matrix in the mesangial areas, leading to progressive obliteration of the vascular spaces. The role of the metabolic derangements of diabetes mellitus in the development of these lesions is incompletely understood. One of the consequences of hyperglycemia is the formation of advanced glycosylation end products (AGEs), which result from a series of rearrangements secondary to nonenzymatic reaction of glucose with proteins. Specific receptors for proteins modified by AGEs, present in several cell types, were recently described in human and rat mesangial cells. Furthermore, exposure of mesangial cells to AGEs was followed by an increase in fibronectin production. In the present study we show evidence that mouse mesangial cells exhibit an increase in collagen type IV mRNA and peptide synthesis after exposure to AGEs. Antibodies to AGE receptors prevent this increase, indicating that the response is AGE-receptor-mediated. In addition, anti-platelet-derived growth factor abrogates the AGE response, suggesting that platelet-derived growth factor acts as an intermediate factor. Transcription assay reveals that the elevated mRNA levels are due to an increase in the transcription rate...

Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications.

Vlassara, H; Fuh, H; Makita, Z; Krungkrai, S; Cerami, A; Bucala, R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/12/1992 EN
Relevância na Pesquisa
66.11%
Advanced glycosylation end products (AGEs) have been implicated in many of the complications of diabetes and normal aging. Markedly elevated vascular tissue and circulating AGEs were linked recently to the accelerated vasculopathy of end-stage diabetic renal disease. To determine the pathogenic role of AGEs in vivo, AGE-modified albumin was administered to healthy nondiabetic rats and rabbits alone or in combination with the AGE-crosslink inhibitor aminoguanidine. Within 2-4 weeks of AGE treatment, the AGE content of aortic tissue samples rose to six times the amount found in controls (P < 0.001). Cotreatment with aminoguanidine limited tissue AGE accumulation to levels two times that of control. AGE administration was associated with a significant increase in vascular permeability, as assessed by 125I label tracer methods. This alteration was absent in animals that received aminoguanidine in addition to AGE. Significant mononuclear cell migratory activity was observed in subendothelial and periarteriolar spaces in various tissues from AGE-treated rats compared to normal cellularity noted in tissues from animals treated with aminoguanidine. Blood pressure studies of AGE-treated rats and rabbits revealed markedly defective vasodilatory responses to acetylcholine and nitroglycerin compared to controls (P < 0.001)...

Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy.

Beisswenger, P J; Moore, L L; Brinck-Johnsen, T; Curphey, T J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1993 EN
Relevância na Pesquisa
66.01%
RATIONALE: Advanced glycosylation end products (AGEs) may play an important role in the development of diabetic vascular sequelae. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs. OBJECTIVES: To evaluate the role of AGEs in the development of diabetic nephropathy and retinopathy, we studied pentosidine levels and the clinical characteristics of 48 subjects with insulin-dependent diabetes mellitus. Diabetic nephropathy was classified as normal, microalbuminuria, or gross proteinuria, and retinopathy was graded as none, background, or proliferative. NEWLY OBSERVED FINDINGS: Significant elevation of pentosidine (P = 0.025) was found in subjects with microalbuminuria or gross proteinuria (73.03 +/- 9.47 vs 76.46 +/- 6.37 pmol/mg col) when compared with normal (56.96 +/- 3.26 pmol/mg col). Multivariate analysis to correct for age, duration of diabetes, and gender did not modify the results. Elevated pentosidine levels were also found in those with proliferative when compared with those with background retinopathy (75.86 +/- 5.66 vs 60.42 +/- 5.98 pmol/mg col) (P < 0.05). CONCLUSIONS: Microalbuminuria is associated with elevated levels of pentosidine similar to those found in overt diabetic nephropathy suggesting that elevated AGE levels are already present during the earliest detectable phase of diabetic nephropathy.

Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.

Bucala, R; Tracey, K J; Cerami, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1991 EN
Relevância na Pesquisa
46.16%
Nitric oxide (an endothelium-derived relaxing factor) induces smooth muscle relaxation and is an important mediator in the regulation of vascular tone. Advanced glycosylation end products, the glucose-derived moieties that form nonenzymatically and accumulate on long-lived tissue proteins, have been implicated in many of the complications of diabetes and normal aging. We demonstrate that advanced glycosylation products quench nitric oxide activity in vitro and in vivo. Acceleration of the advanced glycosylation process in vivo results in a time-dependent impairment in endothelium-dependent relaxation. Inhibition of advanced glycosylation with aminoguanidine prevents nitric oxide quenching, and ameliorates the vasodilatory impairment. These results implicate advanced glycosylation products as important modulators of nitric oxide activity and endothelium-dependent relaxation.

Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins.

Kirstein, M; Aston, C; Hintz, R; Vlassara, H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1992 EN
Relevância na Pesquisa
55.93%
Normal tissue homeostasis requires a finely balanced interaction between phagocytic scavenger cells (such as monocytes and macrophages) that degrade senescent material and mesenchymal cells (such as fibroblasts and smooth muscle cells), which proliferate and lay down new extracellular matrix. Macrophages and monocytes express specific surface receptors for advanced glycosylation end products (AGEs), which are covalently attached adducts resulting from a series of spontaneous nonenzymatic reactions of glucose with tissue proteins. Receptor-mediated uptake of AGE-modified proteins induces human monocytes to synthesize and release cytokines (TNF and IL-1), which are thought to contribute to normal tissue remodeling by mechanisms not entirely understood. We now report that AGEs also induce human monocytes to generate the potent progression growth factor insulin-like growth factor I (IGF-I), known to stimulate proliferation of mesenchymal cells. After in vitro stimulation with AGE-modified proteins, normal human blood monocytes express IGF-IA mRNA leading to the secretion of IGF-IA prohormone. The signal for IGF-IA mRNA induction seems to be initiated via the monocyte AGE-receptor, and to be propagated in an autocrine fashion via either IL-1 beta or PDGF. These data introduce a novel regulatory system for IGF-I...

Early and advanced glycosylation end products. Kinetics of formation and clearance in peritoneal dialysis.

Friedlander, M A; Wu, Y C; Elgawish, A; Monnier, V M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/02/1996 EN
Relevância na Pesquisa
55.88%
The chronic contact of glucose-containing dialysate and proteins results in the deposition of advanced glycation end products (AGEs) on peritoneal tissues in patients treated by peritoneal dialysis (PD), yet plasma levels of the AGE pentosidine are significantly lower in PD than in hemodialysis (HD). We measured glycation of peritoneal proteins in patients on PD over the time course of intraperitoneal equilibration of fresh peritoneal dialysate. The glycated content of peritoneal proteins (furosine method) was initially identical to plasma but increased 200% within 4 h due to in situ glycation as also demonstrated in vitro. In contrast, peritoneal proteins contained a 2-4 x greater content of the AGE pentosidine at all equilibrium time points. Plasma protein furosine content was identical in patients on PD and on HD. Fractionation by gel filtration of serum from patients on PD and HD revealed that > 95% of the pentosidine was linked to proteins > 10,000 mol wt; < 1% to proteins < 10,000 mol wt; and < 1%, free. Neither HD nor PD affected protein-bound pentosidine. The HD treatment decreased free and < 10,000 mol wt bound pentosidine. However clearance of protein-associated pentosidine by the peritoneal membrane may explain lower steady state levels in patients treated by PD.

Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus.

Nakamura, Y.; Horii, Y.; Nishino, T.; Shiiki, H.; Sakaguchi, Y.; Kagoshima, T.; Dohi, K.; Makita, Z.; Vlassara, H.; Bucala, R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1993 EN
Relevância na Pesquisa
66.08%
Advanced glycosylation end products (AGEs) accumulate on long-lived extracellular matrix proteins and have been implicated in the micro- and macrovascular complications of diabetes mellitus. Within the arterial wall, AGE-modified proteins increase vascular permeability, inactivate nitric oxide activity, and induce the release of growth-promoting cytokines. Recently developed anti-AGE antibodies were used in an immunohistochemical analysis of coronary arteries obtained from type II diabetic and nondiabetic patients. High levels of AGE reactivity were observed within the atherosclerotic plaque present in vessels from selected patients with diabetes. Considered together with the pathological effects of AGEs on vascular wall homeostasis, these data support the role of advanced glycosylation in the rapidly progressive atherosclerosis associated with diabetes mellitus.

Hyperglycemia and advanced glycosylation end products suppress adipocyte apoE expression: implications for adipocyte triglyceride metabolism

Espiritu, Doris Joy; Huang, Zhi Hua; Zhao, Yong; Mazzone, Theodore
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.11%
Endogenous adipocyte apolipoprotein E (apoE) plays an important role in adipocyte lipoprotein metabolism and lipid flux. A potential role for hyperglycemia in regulating adipocyte apoE expression and triglyceride metabolism was examined. Exposure of adipocytes to high glucose or advanced glycosylation end product-BSA significantly suppressed apoE mRNA and protein levels. This suppression was significantly attenuated by antioxidants or inhibitors of the NF-κB transcription pathway. Hyperglycemia in vivo led to adipose tissue oxidant stress and significant reduction in adipose tissue and adipocyte apoE mRNA level. Incubation with antioxidant in organ culture completely reversed this suppression. Hyperglycemia also reduced adipocyte triglyceride synthesis, and this could be completely reversed by adenoviral-mediated increases in apoE. To more specifically evaluate an in vivo role for adipocyte apoE expression on organismal triglyceride distribution in vivo, WT or apoE knockout (EKO) adipose tissue was transplanted in EKO recipient mice. After 12 wk, WT adipocytes transplanted in EKO mice accumulated more triglyceride compared with transplanted EKO adipocytes. In addition, EKO recipients of WT adipose tissue had reduced hepatic triglyceride content compared with EKO recipients transplanted with EKO adipose tissue. Our results demonstrate that hyperglycemia and advanced glycosylation end products suppress the expression of adipocyte apoE in vitro and in vivo and thereby reduce adipocyte triglyceride synthesis. In vivo results using adipose tissue transplantation suggest that reduction of adipocyte apoE...

The G82S Polymorphism Promotes Glycosylation of the Receptor for Advanced Glycation End Products (RAGE) at Asparagine 81: COMPARISON OF WILD-TYPE RAGE WITH THE G82S POLYMORPHIC VARIANT*

Park, Sun Jin; Kleffmann, Torsten; Hessian, Paul A.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.2%
Interaction between the receptor for advanced glycation end products (RAGE) and its ligands amplifies the proinflammatory response. N-Linked glycosylation of RAGE plays an important role in the regulation of ligand binding. Two potential sites for N-linked glycosylation, at Asn25 and Asn81, are implicated, one of which is potentially influenced by a naturally occurring polymorphism that substitutes Gly82 with Ser. This G82S polymorphic RAGE variant displays increased ligand binding and downstream signaling. We hypothesized that the G82S polymorphism affects RAGE glycosylation and thereby affects ligand binding. WT or various mutant forms of RAGE protein, including N25Q, N81Q, N25Q/G82S, and N25Q/N81Q, were produced by transfecting HEK293 cells. The glycosylation patterns of expressed proteins were compared. Enzymatic deglycosylation showed that WT RAGE and the G82S polymorphic variant are glycosylated to the same extent. Our data also revealed N-linked glycosylation of N25Q and N81Q mutants, suggesting that both Asn25 and Asn81 can be utilized for N-linked glycosylation. Using mass spectrometry analysis, we found that Asn81 may or may not be glycosylated in WT RAGE, whereas in G82S RAGE, Asn81 is always glycosylated. Furthermore, RAGE binding to S100B ligand is affected by Asn81 glycosylation...

Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE)

Baba, Shahid P.; Hellmann, Jason; Srivastava, Sanjay; Bhatnagar, Aruni
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.96%
Diabetes results in enhanced chemical modification of proteins by advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) precursors. These modifications have been linked to the development of several secondary diabetic complications. Our previous studies showed that aldose reductase (AR; AKR1B3) catalyzes the reduction of ALEs and AGEs precursors; however, the in vivo significance of this metabolic pathway during diabetes and obesity has not been fully assessed. Therefore we examined the role of AR in regulating ALEs and AGEs formation in murine models of diet-induced obesity and streptozotocin-induced diabetes. In comparison with wild-type (WT) and AR-null mice fed normal chow, mice fed a high-fat (HF) diet (42% kcal fat) showed increased accumulation of AGEs and protein–acrolein adducts in the plasma. AGEs and acrolein adducts were also increased in the epididymal fat of WT and AR-null mice fed a HF diet. Deletion of AR increased the accumulation of 4-hydroxy-trans-2-nonenal (HNE) protein adduct in the plasma and increased the expression of the AGE receptor (RAGE) in HF fed mice. No change in AGEs formation was observed in the kidneys of HF-fed mice. In comparison, renal tissue from AR-null mice treated with streptozotocin showed greater AGE accumulation than streptozotocin-treated WT mice. These data indicated that AR regulated the accumulation of lipid peroxidation derived aldehydes and AGEs under conditions of severe...

Non-specific binding of advanced-glycosylation end-products to macrophages outweighs specific receptor-mediated interactions.

Shaw, S M; Crabbe, M J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/11/1994 EN
Relevância na Pesquisa
55.88%
On binding to murine peritoneal macrophages, maleylated BSA exhibited saturable-binding kinetics, with about 24000 sites/cell. Prolonged incubation of BSA with > 20 mM glucose or 2 months incubation with > or = 0.5 M glucose induced the modified protein to readily bind non-specifically to both cell and tube surfaces. Kinetic studies on the binding of advanced glycated end-products (AGEs) and other modified proteins to macrophages and hepatocytes showed no evidence for specific receptor binding, as neither binding saturation nor cross-competition (homologous or heterologous) was detected. Although there was evidence for uptake of BSA which had been incubated with 0.5 M glucose for 2 months, there was no uptake or degradation of AGEs which had been produced at physiological concentrations of glucose. This has implications for the role of macrophages in the recognition of AGEs, and suggests that the non-specific binding may be important in adhesion of AGEs, particularly in poorly controlled diabetics, and might act as a 'damage limitation' mechanism in the potential development of diabetic complications, while low macrophage levels in the blood could seriously potentiate the long-term effects of non-enzymic post-translational protein modifications.

Aterogênese induzida por albumina modificada por glicação avançada em camundongos dislipidêmicos é previnida pelo tratamento com losartana ; Atherogenesis induced by advanced glycated albumin in dyslipidemic mice is prevented by losartan

Gomes, Diego Juvenal
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 02/09/2015 PT
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INTRODUÇÃO: Produtos de glicação avançada (AGE) encontram-se aumentados no diabete melito e contribuem independentemente para o risco cardiovascular. O reconhecimento dos AGE pelo receptor para produtos de glicação avançada (RAGE) potencializa vias de sinalização pró-aterogênicas. Antagonistas do receptor de angiotensina II (ANGII) do tipo 1 (AT-1) diminuem a expressão de RAGE em área de lesão aterosclerótica. No presente projeto, avaliou-se, na aorta de camundongos dislipidêmicos (knockout para apoE) tratados ou não com inibidor do receptor AT-1 (losartana, LOS), o efeito do tratamento crônico com albumina-AGE sobre o infiltrado de lípides, a expressão de mRNA e proteínas envolvidas no eixo AGE/RAGE, ANGII/AT-1, modulação da resposta inflamatória e fluxo de lípides, além da secreção de citocinas inflamatórias por macrófagos tratados com albumina controle ou AGE, concomitantemente ou não a losartana, isolados da cavidade peritoneal de camundongos apoE knockout. MÉTODOS: Camundongos machos knockout para apoE de 12 semanas de idade foram mantidos em dieta padrão e divididos, aleatoriamente, em quatro grupos experimentais (n = 20/grupo): grupo Controle (C), C+LOS, albumina-AGE (AGE) e AGE+LOS. Os animais receberam injeção intraperitoneal diária...

Lower limb ulcers in diabetic patients: molecular and cellular mechanisms; Úlceras nos membros inferiores de pacientes diabéticos: mecanismos moleculares e celulares

Ladeira, Pedro Ribeiro Soares de; Isaac, Cesar; Paggiaro, Andre Oliveira; Hosaka, Elisabeth Mie; Ferreira, Marcus Castro
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; Formato: application/pdf
Publicado em 11/09/2011 POR
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Diabetes depictures a heterogeneous group of metabolic disorders that arise as a result of hyperglycemia due to the deficit of secretion and/or insulin action. Its prevalence and related costs have been growing around the world. Among its long-term complications, foot ulcer is the one that generates more hospital admissions. These wounds often become chronic due to a series of molecular and cellular aberrations of the healing process, being the main mechanisms the following: high concentrations of matrix metalloproteinases (MMPs), neuropathy, high probability of infection and non-physiological inflammatory response, oxidative stress, excessive formation of AGEs (advanced glicoxidation end-products), deficient neoangiogenesis, imbalance between metabolism and nutrient delivery, inadequate concentrations of growth factors and gene expression regulators, and cellular abnormalities. With better scientific understanding of these events and physiological healing, new approaches to disease can provide more satisfactory results to the treatment; Diabetes mellitus representa um grupo de desordens metabólicas heterogêneas que surge como resultado de hiperglicemia por déficit na secreção e/ou ação da insulina. Sua prevalência e gastos relacionados vêm crescendo no mundo todo. Entre suas complicações de longo prazo...