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1.
Am J Physiol Endocrinol Metab ; 320(3): E539-E550, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459180

RESUMO

Association between receptor for advanced glycation end products (RAGE) and postmyocardial infarction (MI) ventricular arrhythmias (VAs) in diabetes was investigated. Correlation between premature ventricular contractions (PVCs) and serum advanced glycation end products (AGEs) content was analyzed in a cohort consisting of 101 patients with ST-segment elevated MI (STEMI). MI diabetic rats were treated with anti-receptor for AGE (RAGE) antibody. Electrocardiography was used to record VAs. Myocytes were isolated from adjacent area around infracted region. Immunofluorescent stains were used to evaluate the association between FKBP12.6 (FK506-bindingprotein 12.6) and ryanodine receptor 2 (RyR2). Calcium sparks were evaluated by confocal microscope. Protein expression and phosphorylation were assessed by Western blotting. Calcineurin (CaN) enzymatic activity and RyR2 channel activity were also determined. In the cohort study, significantly increased amount of PVC was found in STEMI patients with diabetes (P < 0.05). Serum AGE concentration was significantly positively correlated with PVC amount in patients with STEMI (r = 0.416, P < 0.001). Multivariate analysis showed that serum AGE concentration was independently and positively related to frequent PVCs (adjusted hazard ratio, 1.86; 95% CI, 1.09-3.18, P = 0.022). In the animal study, increased glucose-regulated protein 78 (GRP78) expression, protein kinase RNA-like ER kinase (PERK) phosphorylation, CaN enzymatic activity, FKBP12.6-RyR2 disassociation, RyR2 channel opening, and endoplasmic reticulum (ER) calcium releasing were found in diabetic MI animals, which were attenuated by anti-RAGE antibody treatment. This RAGE blocking also significantly lowered the VA amount in diabetic MI animals. Activation of RAGE-dependent ER stress-mediated PERK/CaN/RyR2 signaling participated in post-MI VAs in diabetes.NEW & NOTEWORTHY In this study, we proposed a possible mechanism interpreting the clinical scenario that after myocardial infarction (MI) patients were more vulnerable to ventricular arrhythmias (VAs) when complicated with diabetes. A cohort study revealed that advanced glycation end products (AGEs) accumulated in patients with diabetes and closely associated post-MI VAs. In vivo and in vitro studies indicated that receptor for AGEs (RAGE)-dependent endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK) pathway triggered VAs, via ER calcium releasing, through calcineurin/RyR2 mechanism.


Assuntos
Arritmias Cardíacas/patologia , Diabetes Mellitus , Estresse do Retículo Endoplasmático/fisiologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST , Animais , Anticorpos/farmacologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/terapia , Estudos de Casos e Controles , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/terapia , Progressão da Doença , Chaperona BiP do Retículo Endoplasmático , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/imunologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia
2.
Front Immunol ; 11: 1800, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973755

RESUMO

White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, ex vivo fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors TLR4 and receptor for advanced glycation end products (RAGE) were reduced with age (TLR4/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Biglicano/farmacologia , Citocinas/metabolismo , Proteína HMGB1/farmacologia , Lipopolissacarídeos/farmacologia , Receptores Toll-Like/agonistas , Tecido Adiposo Marrom/imunologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Fatores Etários , Animais , Masculino , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Via Secretória , Transdução de Sinais , Técnicas de Cultura de Tecidos , Receptores Toll-Like/metabolismo
3.
Pharmacol Res ; 158: 104879, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32413483

RESUMO

Advanced glycation end products (AGEs) are destructive molecules in the body that, at high levels, contribute to the progression of various chronic diseases. Numerous studies have suggested a modifying effect of vitamin D on AGEs and their receptors. This study sought to summarize the effects of vitamin D on AGEs and their receptors, including receptor for AGEs (RAGE) and soluble receptor for AGEs (sRAGE). The search method initially identified 484 articles; 331 remained after duplicate removal. Thirty-five articles were screened and identified as relevant to the study topic. After critical analysis, 27 articles were included in the final analysis. Vitamin D treatment may possibly be beneficial to reduce AGE levels and to augment sRAGE levels, particularly in vitamin D-deficient situations. Treatment with this vitamin may be effective in reducing RAGE expression in some disease conditions, but might be even harmful under normal conditions. The inhibitory or stimulatory effects of vitamin D on AGE receptors are mediated by various signaling pathways, MAPK/NF-κB, ADAM10/MMP9 and AT1R. In populations with chronic diseases and concomitant hypovitaminosis D, vitamin D supplementation can be used as a strategy to ameliorate AGE-mediated complications by modifying the AGE-RAGE and sRAGE systems.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/metabolismo , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Animais , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Receptor para Produtos Finais de Glicação Avançada/agonistas
4.
Diab Vasc Dis Res ; 16(6): 556-561, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31375034

RESUMO

OBJECTIVE: Advanced glycation end products and their receptor - RAGE - in the adipose tissues contribute to metabolic derangements in fructose-fed rats. However, it remains unclear whether fructose could cause endothelial cell damage via the activation of AGE-RAGE. METHODS: Intracellular advanced glycation end products were evaluated by dot blot analysis. Fructose-derived advanced glycation end products (Fruc-AGEs) were prepared by incubating bovine serum albumin with fructose for 8 weeks. Reactive oxygen species generation was measured using a fluorescent probe. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription-polymerase chain reaction. Binding affinities of Fruc-AGEs to DNA-aptamer raised against Fruc-AGEs (Fruc-AGE-aptamer) or RAGE were measured with a quartz crystal microbalance. RESULTS: Fructose increased the advanced glycation end product-specific fluorescence intensity in assay medium, while it stimulated intracellular formation of advanced glycation end products in human umbilical vein endothelial cells. Furthermore, 0.3 mM fructose for 4 days significantly increased reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. Fruc-AGE-aptamer, but not Control-aptamer, bound to Fruc-AGEs with Kd value of 5.60 × 10-6 M and dose-dependently inhibited the binding of Fruc-AGEs to RAGE. Moreover, Fruc-AGE-aptamer prevented the Fruc-AGE- and fructose-induced reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. CONCLUSION: This study suggests that fructose may elicit endothelial cell damage partly via the activation of AGE-RAGE axis.


Assuntos
Frutose/toxicidade , Produtos Finais de Glicação Avançada/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/agonistas , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Vascul Pharmacol ; 118-119: 106559, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954689

RESUMO

Receptors for advanced glycation end-product (RAGE) play a pivotal role in the progression of proliferative vascular diseases. However, the precise mechanisms regulating RAGE expression in vascular smooth muscle cells (VSMCs) of the injured vasculatures is unclear. Given the potential importance of 5-lipoxygenase (5-LO) derived mediators in cellular responses mediated by RAGE, this study aimed to evaluate in VSMCs treated with high mobility group box 1 (HMGB1): 1) the RAGE expression; 2) the AGE-induced VSMC proliferation; 3) the role of 5-LO signaling in HMGB1-induced RAGE expression. In cultured human VSMCs stimulated with HMGB1 (100 ng/ml), RAGE mRNA and protein expression were markedly increased along with an increase in AGE-mediated VSMC proliferation. Both of these effects were markedly attenuated in cells pretreated with zileuton (1-10 µM), a 5-LO inhibitor, as well as in cells transfected with 5-LO siRNA, suggesting a potential involvement of 5-LO signaling in HMGB1-mediated RAGE expression in VSMCs. Moreover, 5-LO expression, accompanied by production of leukotrienes was markedly increased in HMGB1-stimulated VSMCs, which was attenuated in cells deficient of TLR2 or RAGE. Taken together, our results suggest that HMGB1-induced increase in 5-LO expression enhances RAGE expression in VSMCs, which stimulates AGE-mediated VSMC proliferation. Thus, the 5-LO-RAGE signaling axis in VSMCs might serve as a potential therapeutic target for vascular remodeling in the injured vasculature.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Proliferação de Células/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Proteína HMGB1/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/agonistas , Soroalbumina Bovina/farmacologia , Araquidonato 5-Lipoxigenase/genética , Células Cultivadas , Humanos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais
6.
Microvasc Res ; 120: 90-93, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30056058

RESUMO

We have previously shown that albuminuria and renal levels of advanced glycation end products (AGEs), receptor for AGEs (RAGE), and oxidative stress are suppressed in dipeptidyl peptidase-4 (DPP-4)-deficient diabetic rats, thus suggesting the crosstalk between AGE-RAGE axis and DPP-4 in experimental diabetic nephropathy. Therefore, we examined here the role of DPP-4 in AGE-evoked inflammatory reactions in human proximal tubular cells. Proteins were extracted from proximal tubular cells, and conditioned medium was collected, both of which were subjected to western blot analysis using anti-DPP-4 antibody. RAGE-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. NF-κB p65 and monocyte chemoattractant protein-1 (MCP-1) gene expression was analyzed by reverse transcription-polymerase chain reaction. AGEs significantly increased DPP-4 expression and soluble DPP-4 production by tubular cells, the latter of which was attenuated by RAGE-aptamer or an anti-oxidant, N-acetylcysteine. AGEs or DPP-4 up-regulated NF-κB p65 or MCP-1 mRNA levels in tubular cells, which were suppressed by linagliptin, an inhibitor of DPP-4. AGEs stimulated NF-κB p65 gene expression in tubular cells isolated from control rats, but not from DPP-4-deficient rats. Our present results suggest that the AGE-RAGE-mediated oxidative stress could evoke inflammatory reactions in proximal tubular cells via autocrine production of DPP-4.


Assuntos
Comunicação Autócrina/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Produtos Finais de Glicação Avançada/toxicidade , Mediadores da Inflamação/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Soroalbumina Bovina/toxicidade , Animais , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dipeptidil Peptidase 4/deficiência , Dipeptidil Peptidase 4/genética , Humanos , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Transgênicos , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
7.
J Am Heart Assoc ; 7(1)2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29301761

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease. The accumulation of uremic solutes in this patient population is associated with endothelial dysfunction and accelerated cardiovascular disease. In this study, we examined the impact of the uremic milieu on the endothelial transcription factor, Krüppel-like factor 2 (KLF2), a key regulator of endothelial function and activation. METHODS AND RESULTS: Using serum from uremic pigs with chronic renal insufficiency, our results show that KLF2 expression is suppressed by the uremic milieu and individual uremic solutes in vitro. Specifically, KLF2 expression is significantly decreased in human umbilical vein endothelial cells after treatment with uremic porcine serum or carboxymethyllysine-modified albumin, an advanced glycation end product (AGE) known to induce endothelial dysfunction. AGE-mediated suppression of KLF2 is dependent on activation of the receptor for AGE, as measured by small interfering RNA knockdown of the receptor for AGE. Furthermore, KLF2 suppression promotes endothelial dysfunction, because adenoviral overexpression of KLF2 inhibits reactive oxygen species production and leukocyte adhesion in human umbilical vein endothelial cells. In addition, the application of hemodynamic shear stress, prolonged serum dialysis, or treatment with the receptor for AGE antagonist azeliragon (TTP488) is sufficient to prevent KLF2 suppression in vitro. To decipher the mechanism by which uremic AGEs suppress KLF2 expression, we assessed the role of the receptor for AGE in activation of nuclear factor-κB signaling, a hallmark of endothelial cell activation. Using a constitutively active form of IκBα, we show that translocation of p65 to the nucleus is necessary for KLF2 suppression after treatment with uremic AGEs. CONCLUSIONS: These data identify KLF2 suppression as a consequence of the uremic milieu, which may exacerbate endothelial dysfunction and resultant cardiovascular disease.


Assuntos
Proteínas Sanguíneas/metabolismo , Produtos Finais de Glicação Avançada/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/metabolismo , Insuficiência Renal Crônica/sangue , Soroalbumina Bovina/toxicidade , Uremia/sangue , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Diálise Renal , Insuficiência Renal Crônica/terapia , Sus scrofa , Fator de Transcrição RelA/metabolismo , Uremia/terapia
8.
Crit Rev Food Sci Nutr ; 58(2): 208-226, 2018 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26980434

RESUMO

Food allergens have a notable potential to induce various health concerns in susceptible individuals. The majority of allergenic foods are usually subjected to thermal processing prior to their consumption. However, during thermal processing and long storage of foods, Maillard reaction (MR) often takes place. The MR is a non-enzymatic glycation reaction between the carbonyl group of reducing sugars and compounds having free amino groups. MR may sometimes be beneficial by damaging epitope of allergens and reducing allergenic potential, while exacerbation in allergic reactions may also occur due to changes in the motifs of epitopes or neoallergen generation. Apart from these modulations, non-enzymatic glycation can also modify the food protein(s) with various type of advance glycation end products (AGEs) such as Nϵ-(carboxymethyl-)lysine (CML), pentosidine, pyrraline, and methylglyoxal-H1 derived from MR. These Maillard products may act as immunogen by inducing the activation and proliferation of various immune cells. Literature is available to understand pathogenesis of glycation in the context of various diseases but there is hardly any review that can provide a thorough insight on the impact of glycation in food allergy. Therefore, present review explores the pathogenesis with special reference to food allergy caused by non-enzymatic glycation as well as AGEs.


Assuntos
Imunidade Adaptativa , Antígenos/efeitos adversos , Proteínas Alimentares/efeitos adversos , Hipersensibilidade Alimentar/etiologia , Produtos Finais de Glicação Avançada/efeitos adversos , Imunidade Inata , Modelos Imunológicos , Antígenos/química , Antígenos/metabolismo , Proteínas Alimentares/química , Proteínas Alimentares/metabolismo , Epitopos , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/metabolismo , Hipersensibilidade Alimentar/patologia , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Fenômenos Imunogenéticos , Lectinas Tipo C/agonistas , Lectinas Tipo C/metabolismo , Reação de Maillard , Receptor de Manose , Lectinas de Ligação a Manose/agonistas , Lectinas de Ligação a Manose/metabolismo , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/metabolismo , Receptores Depuradores/agonistas , Receptores Depuradores/metabolismo , Transdução de Sinais
9.
Diab Vasc Dis Res ; 14(5): 450-453, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28631505

RESUMO

OBJECTIVE: Glyceraldehyde-derived advanced glycation end products contribute to vascular inflammation in diabetes. However, what advanced glycation end product structure could evoke inflammatory reactions remains unknown. We examined whether and how methylglyoxal-derived hydroimidazolone 1, one of the advanced glycation end products formed from glyceraldehyde, elicits inflammatory reactions in human umbilical vein endothelial cells. MATERIALS AND METHODS: Glyceraldehyde-advanced glycation end products-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. The binding affinities of methylglyoxal-derived hydroimidazolone 1 to receptor for advanced glycation end products or advanced glycation end product-aptamer were measured with a quartz crystal microbalance. Intracellular reactive oxygen species generation and THP-1 cell adhesion were evaluated using fluorescent probes. Gene expression was analysed by reverse transcription polymerase chain reaction. RESULTS: Methylglyoxal-derived hydroimidazolone 1 bound to receptor for advanced glycation end products and advanced glycation end product-aptamer with a dissociation constant ( Kd) of 56.7 µM and 1.51 mM, respectively. Methylglyoxal-derived hydroimidazolone 1 at 100 µg/mL significantly increased reactive oxygen species generation in human umbilical vein endothelial cells, which were attenuated by anti-receptor for advanced glycation end products antibody or advanced glycation end product-aptamer. In all, 100 µg/mL methylglyoxal-derived hydroimidazolone 1 significantly increased receptor for advanced glycation end products and intercellular adhesion molecule-1 messenger RNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were blocked by anti-receptor for advanced glycation end products antibody. CONCLUSION: Our present results indicate that methylglyoxal-derived hydroimidazolone 1 evokes inflammatory reactions in human umbilical vein endothelial cells via receptor for advanced glycation end products, although apparently limited to supraphysiological levels of methylglyoxal-derived hydroimidazolone 1. Methylglyoxal-derived hydroimidazolone 1 is a distinct advanced glycation end product structure that could mediate harmful effects of methylglyoxal and glyceraldehyde-mediated glycation processes.


Assuntos
Produtos Finais de Glicação Avançada/toxicidade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Imidazóis/toxicidade , Mediadores da Inflamação/metabolismo , Inflamação/induzido quimicamente , Aldeído Pirúvico/toxicidade , Receptor para Produtos Finais de Glicação Avançada/agonistas , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Produtos Finais de Glicação Avançada/metabolismo , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imidazóis/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Ligação Proteica , Aldeído Pirúvico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
10.
Diabetes Metab Syndr ; 11(4): 305-309, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27612394

RESUMO

Advanced glycation end products (AGE) resulted from a reaction between free amino group of proteins and carbohydrates. This reaction is followed by oxidation and molecular rearrangement. Alternatively AGEs can be produced by glycolysis and oxidation. AGEs bind to a cellular receptor RAGE. RAGE engagement by ligands AGE, ß-amyloid peptide, and S100 calgranulin induces a stimulation of NADPH oxidase, reactive oxygen intermediate formation, NFκB activation and gene transcription. This cascade of reaction leads to an inflammatory reaction responsible for alteration of microvessels in the retina and the kidney. Blockade of RAGE by antibodies anti-RAGE, TTP488 (azeliragon), or rRAGE prevents or limits the deleterious effect of AGEs.


Assuntos
Produtos Finais de Glicação Avançada/efeitos adversos , Produtos Finais de Glicação Avançada/metabolismo , Saúde , Receptor para Produtos Finais de Glicação Avançada/agonistas , Animais , Humanos , Inflamação/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais
11.
Nutrients ; 8(8)2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27463726

RESUMO

Diabetic retinopathy (DR), the most ordinary and specific microvascular complication of diabetes, is a disease of the retina. Zerumbone (ZER) is a monocyclic sesquiterpene compound, and based on reports, it is the predominant bioactive compound from the rhizomes of Zingiber zerumbet. The aim of the current study is to evaluate the protective effect of zerumbone against DR in streptozotocin (STZ)-induced diabetic rats. STZ-diabetic rats were treated with ZER (40 mg/kg) once a day orally for 8 weeks. ZER administration significantly (p < 0.05) lowered the levels of plasma glucose (32.5% ± 5.7% lower) and glycosylated hemoglobin (29.2% ± 3.4% lower) in STZ-diabetic rats. Retinal histopathological observations indicated that disarrangement and reduction in thickness of retinal layers were reversed in ZER-treated diabetic rats. ZER downregulated both the elevated levels of advanced glycosylated end products (AGEs) and the higher levels of the receptors for AGEs (RAGE) in retinas of diabetic rats. What's more, ZER significantly (p < 0.05) ameliorated diabetes-induced upregulation of tumor necrosis factor-α, interleukin (IL)-1 and IL-6. ZER also attenuated overexpression of vascular endothelial growth factor and intercellular adhesion molecule-1, and suppressed activation of nuclear factor (NF)-κB and apoptosis in the retinas of STZ-diabetic rats. Our results suggest ZER possesses retinal protective effects, which might be associated with the blockade of the AGEs/RAGE/NF-κB pathway and its anti-inflammatory activity.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Retinopatia Diabética/prevenção & controle , Suplementos Nutricionais , Hipoglicemiantes/uso terapêutico , Rizoma/química , Sesquiterpenos/uso terapêutico , Zingiberaceae/química , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Citocinas/antagonistas & inibidores , Citocinas/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/imunologia , Hemoglobinas Glicadas/análise , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/sangue , Hiperglicemia/prevenção & controle , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Distribuição Aleatória , Ratos Wistar , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Retina/imunologia , Retina/metabolismo , Retina/patologia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Br J Nutr ; 115(4): 629-36, 2016 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-26824730

RESUMO

Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague-Dawley rats were fed a diet containing 20% milk powder with different proportions of this being given as heated milk powder (0, 40 or 100%), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of N ε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.


Assuntos
Dieta/efeitos adversos , Produtos Finais de Glicação Avançada/efeitos adversos , Hexosiltransferases/metabolismo , Receptor para Produtos Finais de Glicação Avançada/agonistas , Regulação para Cima , Animais , Biomarcadores/sangue , Biomarcadores/urina , Ingestão de Energia , Produtos Finais de Glicação Avançada/administração & dosagem , Produtos Finais de Glicação Avançada/química , Produtos Finais de Glicação Avançada/urina , Hexosiltransferases/sangue , Hexosiltransferases/química , Hexosiltransferases/genética , Temperatura Alta/efeitos adversos , Imidazóis/urina , Imidazolinas/urina , Lisina/análogos & derivados , Lisina/urina , Masculino , Proteínas do Leite/administração & dosagem , Proteínas do Leite/efeitos adversos , Proteínas do Leite/química , Peso Molecular , Proteólise , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Eliminação Renal , Testes de Toxicidade Subaguda , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
J Biol Chem ; 291(7): 3174-83, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26719327

RESUMO

Several different receptor proteins have been identified that bind monomeric, oligomeric, or fibrillar forms of amyloid-ß (Aß). "Good" receptors internalize Aß or promote its transcytosis out of the brain, whereas "bad" receptors bind oligomeric forms of Aß that are largely responsible for the synapticloss, memory impairments, and neurotoxicity that underlie Alzheimer disease. The prion protein both removes Aß from the brain and transduces the toxic actions of Aß. The clustering of distinct receptors in cell surface signaling platforms likely underlies the actions of distinct oligomeric species of Aß. These Aß receptor-signaling platforms provide opportunities for therapeutic intervention in Alzheimer disease.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Receptores de Superfície Celular/agonistas , Transdução de Sinais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Animais , Apoptose/efeitos dos fármacos , Humanos , Ligantes , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/agonistas , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Neurônios/efeitos dos fármacos , Neurônios/patologia , Nootrópicos/farmacologia , Nootrópicos/uso terapêutico , Proteínas PrPC/agonistas , Proteínas PrPC/antagonistas & inibidores , Proteínas PrPC/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/tratamento farmacológico , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/prevenção & controle , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Agregação de Receptores/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcitose/efeitos dos fármacos
14.
J Biol Chem ; 291(3): 1481-91, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26586913

RESUMO

Advanced glycation end products (AGE) accumulate in diabetic patients and aging people because of high amounts of three- or four-carbon sugars derived from glucose, thereby causing multiple consequences, including inflammation, apoptosis, obesity, and age-related disorders. It is important to understand the mechanism of AGE-mediated signaling leading to the activation of autophagy (self-eating) that might result in obesity. We detected AGE as one of the potent inducers of autophagy compared with doxorubicin and TNF. AGE-mediated autophagy is inhibited by suppression of PI3K and potentiated by the autophagosome maturation blocker bafilomycin. It increases autophagy in different cell types, and that correlates with the expression of its receptor, receptor for AGE. LC3B, the marker for autophagosomes, is shown to increase upon AGE stimulation. AGE-mediated autophagy is partially suppressed by inhibitor of NF-κB, PKC, or ERK alone and significantly in combination. AGE increases sterol regulatory element binding protein activity, which leads to an increase in lipogenesis. Although AGE-mediated lipogenesis is affected by autophagy inhibitors, AGE-mediated autophagy is not influenced by lipogenesis inhibitors, suggesting that the turnover of lipid droplets overcomes the autophagic clearance. For the first time, we provide data showing that AGE induces several cell signaling cascades, like NF-κB, PKC, ERK, and MAPK, that are involved in autophagy and simultaneously help with the accumulation of lipid droplets that are not cleared effectively by autophagy, therefore causing obesity.


Assuntos
Autofagia , Produtos Finais de Glicação Avançada/metabolismo , NF-kappa B/agonistas , Receptor para Produtos Finais de Glicação Avançada/agonistas , Transdução de Sinais , Regulação para Cima , Quinases raf/metabolismo , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Produtos Finais de Glicação Avançada/efeitos adversos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Lipogênese/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/química , NF-kappa B/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Albumina Sérica/efeitos adversos , Albumina Sérica/metabolismo , Albumina Sérica Humana , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Quinases raf/antagonistas & inibidores , Quinases raf/química
16.
Am J Physiol Endocrinol Metab ; 309(10): E829-39, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26394662

RESUMO

Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic ß-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGE-damaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with well-organized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSA-induced mitophage formation. Our study demonstrated that CML-BSA induced mitochondrial dysfunction and mitophagy in pancreatic ß-cells. The findings from this study suggest that increased concentration of AGEs may damage ß-cells and reduce insulin secretion.


Assuntos
Diabetes Mellitus/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Lisina/análogos & derivados , Dinâmica Mitocondrial , Mitofagia , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Diabetes Mellitus/dietoterapia , Diabetes Mellitus/patologia , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Produtos Finais de Glicação Avançada/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/ultraestrutura , Lisina/antagonistas & inibidores , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Fagossomos/efeitos dos fármacos , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Ratos , Receptor para Produtos Finais de Glicação Avançada/agonistas , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Soroalbumina Bovina/antagonistas & inibidores , Soroalbumina Bovina/farmacologia , Ácido Tióctico/metabolismo , Ácido Tióctico/uso terapêutico
17.
Diabetes ; 64(12): 4046-60, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26253613

RESUMO

Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator-activated receptor-γ (PPARG)-responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68(+) macrophages from atherosclerotic plaques of Ldlr(-/-) mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr(-/-) mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Colesterol/metabolismo , Angiopatias Diabéticas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Macrófagos/metabolismo , Receptor para Produtos Finais de Glicação Avançada/agonistas , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Transporte Biológico , Linhagem Celular , Células Cultivadas , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/patologia , Produtos Finais de Glicação Avançada/sangue , Humanos , Ligantes , Lipoproteínas/antagonistas & inibidores , Lipoproteínas/genética , Lipoproteínas/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos Knockout , PPAR gama/genética , PPAR gama/metabolismo , Placa Aterosclerótica/sangue , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Regiões Promotoras Genéticas , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
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