晚期糖基化终末产物与纤维化

晚期糖基化终末产物形成增多是糖尿病的重要特征。目前多个研究显示，其在糖尿病并发症中的发生、发展起了重要作用。晚期糖基化终末产物能促进肾脏、血管、腹膜等组织纤维化。其促纤维化作用可通过直接修饰细胞外基质、促进细胞外基质分泌、促进致纤维化细胞因子的产生、促进间质细胞转化及抑制细胞外基质降解等环节实现。本文对晚期糖基化终末产物的促纤维化作用进行综述。     

晚期糖基化终末产物与动脉粥样硬化

晚期糖基化终末产物(AGEs)是一种伴随糖尿病出现的重要的生化异常,本文将总结AGEs在动脉粥样硬化形成及进展过程中的分子学、细胞学机制以及最新的相关基础与临床研究结果,包括AGEs在细胞外基质、低密度脂蛋白修饰、血管损伤、氧化应激、免疫炎症反应中的作用机制,尤其是AGEs与其受体相互作用激活下游信号转导通路,促进活性氧产生及相关基因表达改变从而加速动脉粥样硬化进程。因此,更好地理解AGEs致动脉粥样硬化的生化机制,将有助于我们制定相应的预防及治疗糖尿病相关动脉粥样硬化的策略。     

晚期糖基化终末产物与糖尿病性骨质疏松

晚期糖基化终末产物(AGEs)是由蛋白质经非酶催化的Maillard反应所形成,糖尿病时AGEs的形成和积累加速.AGEs与其受体(RAGE)结合后,引起氧化应激及炎性反应,继而导致成骨细胞、破骨细胞及骨髓间充质干细胞功能改变;同时AGEs与骨基质中胶原蛋白交联还可使骨强度下降,是造成糖尿病性骨质疏松的主要原因.检测血清及尿液中的AGEs成分,可作为评估糖尿病患者骨折发生风险的有效指标.     

Advanced glycation end products and cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Advanced glycation end products [AGEs] seem to play an important role for the development and/or progression of CVD mainly through induction of oxidative stress and inflammation. AGEs are a heterogenous group of molecules formed by the nonenzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. Recent studies suggest that in addition to those endogenously formed, diet constitutes an important exogenous source of AGEs. Diet-derived AGEs contribute to the whole body AGE pool and the AGE-related pathology. Recent in vitro and in vivo studies revealed significant correlations between diet-derived AGEs and several risk factors and/or markers of CVD, suggesting the dietary AGEs restriction as a promising therapeutic intervention.     

糖基化终末产物与肝病

肝脏是糖基化终末产物的主要代谢部位,肝病时伴随的氧化应激、糖耐量损害以及肝肾功能降低导致糖基化终末产物增加,而糖基化终末产物可通过促进氧应激/脂质过氧化、炎症反应以及纤维化等途径,加重肝脏损伤。     

Advanced glycation end products induce angiogenesis in vivo

Advanced glycation end products (AGEs) have been thought to participate in diabetic microangiopathy. However, the effects of AGEs on angiogenesis have so far been mainly examined either in vitro or by using cultured cells. In the present study, we have analyzed whether AGEs induce angiogenesis in vivo by using the chorioallantoic membrane (CAM) assay. The CAM assay was carried out in embryonated hen eggs to determine the effects of AGEs. Following generation of AGEs based on bovine serum albumin (BSA), either AGE-BSA or nonglycated BSA was administered to the CAM and their effects on angiogenesis were assessed, together with an inhibitory effect of an anti-AGE antibody against AGE-BSA-induced angiogenesis. The histological features of AGE-induced vascular lumens were examined by immunohistochemical analysis for Factor VIII and smooth muscle alpha-actin. AGE-BSA induced angiogenesis in CAM in a dose- and time-dependent manner. AGE-induced angiogenesis on CAM was neutralized by the anti-AGE antibody. Immunohistochemical analysis demonstrated that AGE-induced vascular lumens were devoid of pericytes. Our data demonstrated that AGEs are an angiogenetic factor and that our system of AGE-induced abnormal vessels in CAMs is useful in further investigations of the mechanism of diabetic retinal angiogenesis and can also be used to provide a therapeutic model for diabetic angiopathy.     

Advanced glycation end products and diabetic foot disease

Diabetic foot disease is an important complication of diabetes. The development and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease.The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide and impaired function of growth factors. In the last decade, many experimental studies have shown that these effects of AGE formation may play a role in the pathogenesis of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired wound healing. In recent years also, several clinical studies have shown that glycation is an important pathway in the pathophysiology of those complications that predispose to the development of foot ulcers. Currently, there are a number of ways to prevent or decrease glycation and glycation-induced tissue damage. Although not in the area of neuropathy or wound healing, recent clinical studies have shown that the AGE-breakers may be able to decrease adverse vascular effects of glycation with few side effects.     

Advanced glycation end products and diabetic cardiovascular disease

Advanced glycation end products (AGEs) are formed by a nonenzymatic reaction of sugar moieties (eg, glucose, fructose, glycolytic adducts) with the free amino groups on amino acid residues of proteins. A growing body of data demonstrate that AGEs are intimately involved in the pathophysiology of cardiovascular disease by stimulating inflammation, contributing to atheroma formation, and modulating vascular stiffness. The role of AGEs as potential biomarkers for disease presence and prognosis in patients with diabetes mellitus remains an active area of study. Epidemiologic and angiographic studies suggest that AGE levels may be related to the presence and extent of atherosclerosis, and may predict future outcomes in select populations. The present review summarizes the relevant evidence supporting the role of advanced glycation in promoting atherosclerosis and the epidemiologic studies demonstrating an association between AGEs and diabetic cardiovascular disease.     

Advanced glycation end products, diabetes and ageing

Advanced glycation end products (AGEs) are formed in vivo by a non-enzymatic reaction of proteins with carbohydrates and accumulate in many tissues during ageing. They are discussed as being responsible for many age- and diabetes-related diseases. On the other hand, AGEs are formed by the heating of food and are taken up by the nutrition. The contribution of endogenously formed versus exogenous intake of AGEs to age-related diseases is still under discussion.     

Advanced glycation end products and vascular structure and function

Diabetes mellitus has now reached epidemic proportions in the Western world. The associated microvascular and macrovascular complications are a result of severe metabolic derangement, which leads to chronic tissue injury. Although there are a number of proposed pathophysiologic mechanisms for the vascular complications associated with diabetes, this review focuses predominantly on the role of advanced glycation end products (AGEs) in the pathogenesis of diabetes-associated atherosclerosis. The potential role of AGEs in enhancing arterial stiffness, an entity occurring with a greater prevalence in populations known to have higher-than-normal AGE levels, is also examined. Pharmacologic interventions aimed at reducing the level of these chemical compounds or interrupting their action provide hope for the future treatment of both atherosclerotic vascular disease and systolic hypertension, particularly in the setting of diabetes.     

Advanced glycation end products and advanced oxidation protein products in hemodialyzed patients

Chronic renal failure is associated with increased oxidative and carbonyl stresses that contribute to long-term uremic complications. In our study, we determined two markers of these stresses--AGEs (advanced glycation end products) and AOPP (advanced oxidation protein products)--in chronic hemodialysis patients in order to find out their relationship to the dialysis treatment. Plasmas of 20 hemodialyzed patients treated with modified cellulose membranes were examined at 0 and 15 min and at the end (i.e. after 4 h) of the dialysis session. AGEs were estimated using a spectrofluorometric method (excitation 350 nm, emission 440 nm) and are expressed in AU (arbitrary units)/g protein. AOPP were determined spectrophotometrically (absorbance at 340 nm) and are expressed in chloramine units per gram of protein (micromol/g). AOPP decrease slightly from 0 to 15 min of the dialysis procedure (4.0 +/- 1.5 vs. 3.0 +/- 0.9 micromol/g, p < 0.01). However, they are increased at the end of the session (5.0 +/- 2.1 micromol/l vs. 15 min, p < 0.01, not significant vs. beginning). On the other hand, AGEs decrease continuously from the beginning to the end of the session (mainly in the first minutes of the dialysis) (1.52 +/- 0.34 x 10(4) AU/g at 0 min, 1.39 +/- 0.33 x 10(4) AU/g at 15 min, p < 0.001 vs. beginning, 1.30 +/- 0.33 x 10(4) AU/g at the end, p < 0.001 vs. beginning, not significant vs. 15 min). Neither AGEs nor AOPP correlate with the age of hemodialyzed patients and with the number of years of the dialysis treatment. AOPP correlate with AGEs before the dialysis session (r = 0.62, p < 0.05) but not after the session (r = 0.29, not significant). According to our results, AGEs may serve more as a marker of chronic damage while AOPP may better describe acute oxidative stress during the dialysis treatment.     

Advanced glycation end products in the skin are enhanced in COPD

Background

Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity.

Methods

202 mild-to-very-severe COPD patients and 83 old (40–75 years) and 110 young (18–40 years) healthy smokers and never-smokers were included. AGEs were measured by skin autofluorescence (SAF). Demographic variables, smoking habits, co-morbidities and lung function values were obtained.

Results

COPD patients (FEV₁ = 55% predicted) had significantly higher SAF values than old and young healthy controls: 2.5 vs. 1.8 and 1.2 (arbitrary units, p < 0.05). No differences in SAF values were found between GOLD stages I-IV (2.4, 2.3, 2.5, 2.5 respectively). Lower function (FEV₁/FVC, MEF₅₀/FVC, RV/TLC) and higher number of packyears were significantly associated with SAF (p < 0.05).

Conclusions

SAF is increased in mild-to-very severe COPD patients compared with healthy controls. Interestingly, SAF was not associated with disease severity as values were comparable between different GOLD stages (stage I-IV) of COPD. This may suggest that AGEs play a role in the induction phase of COPD in susceptible smokers. Future studies should further investigate the mechanisms underlying AGEs formation and accumulation in COPD.     

Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury

Summary Advanced glycation end products (AGEs) are believed to play an important role in the development of diabetic complications. AGEs are increased in experimental diabetes and treatment with the inhibitor of advanced glycation end products, aminoguanidine, has been shown to attenuate the level of these products in tissues undergoing complications. Recently, an AGE-binding protein has been isolated from bovine lung endothelial cells and termed the receptor for advanced glycated end products (RAGE). The present study sought to determine the distribution of AGE and RAGE in tissues susceptible to the long-term complications of diabetes including the kidney, eye, nerve, arteries as well as in a tissue resistant to such complications, the lung. Using polyclonal antisera both AGE and RAGE were found to co-localize in the renal glomerulus. AGE staining was clearly increased with age and was further increased by diabetes. Aminoguanidine treatment reduced AGE accumulation in the kidney. Co-localisation of AGE and RAGE was demonstrated in the inner plexiform layer and the inner limiting membrane of the retina and in nerve bundles from mesenteric arteries. In the aorta, both AGE and RAGE were found in the intima, media and adventitia. Medial staining was increased in diabetes and was reduced by aminoguanidine treatment. A similar pattern was observed for RAGE in the aorta. In the lung, RAGE was found widely distributed throughout the lung whereas the distribution of AGE staining was more limited, primarily localising to macrophages. The co-localisation of AGEs and RAGE in sites of diabetic microvascular injury suggests that this ligand-receptor interaction may represent an important mechanism in the genesis of diabetic complications. [Diabetologia (1997) 40: 619–628] Received: 16 October 1996 and in final revised form: 17 February 1997     

Advanced glycation end products contribute to amyloidosis in Alzheimer disease.

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, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.     

Advanced glycation end products: role in pathology of diabetic cardiomyopathy

Increasing evidence demonstrates that advanced glycation end products (AGEs) play a pivotal role in the development and progression of diabetic heart failure, although there are numerous other factors that mediate the disease response. AGEs are generated intra- and extracellularly as a result of chronic hyperglycemia. Then, following the interaction with receptors for advanced glycation end products (RAGEs), a series of events leading to vascular and myocardial damage are elicited and sustained, which include oxidative stress, increased inflammation, and enhanced extracellular matrix accumulation resulting in diastolic and systolic dysfunction. Whereas targeting glycemic control and treating additional risk factors, such as obesity, dyslipidemia, and hypertension, are mandatory to reduce chronic complications and prolong life expectancy in diabetic patients, drug therapy tailored to reducing the deleterious effects of the AGE–RAGE interactions is being actively investigated and showing signs of promise in treating diabetic cardiomyopathy and associated heart failure. This review shall discuss the formation of AGEs in diabetic heart tissue, potential targets of glycation in the myocardium, and underlying mechanisms that lead to diabetic cardiomyopathy and heart failure along with the use of AGE inhibitors and breakers in mitigating myocardial injury.     

Advanced glycation end products induce moesin phosphorylation in murine retinal endothelium

Increase in vascular permeability is the most important pathological event during the development of diabetic retinopathy. Deposition of advanced glycation end products (AGEs) plays a crucial role in the process of diabetes. This study was to investigate the role of moesin and its underlying signal transduction in retinal vascular hyper-permeability induced by AGE-modified mouse serum albumin (AGE-MSA). Female C57BL/6 mice were used to produce an AGE-treated model by intraperitoneal administration of AGE-MSA for seven consecutive days. The inner blood–retinal barrier was quantified by Evans blue leakage assay. Endothelial F-actin cytoskeleton in retinal vasculature was visualized by fluorescence probe staining. The expression and phosphorylation of moesin in retinal vessels were detected by RT–PCR and western blotting. Further studies were performed to explore the effects of Rho kinase (ROCK) and p38 MAPK pathway on the involvement of moesin in AGE-induced retinal vascular hyper-permeability response. Treatment with AGE-MSA significantly increased the permeability of the retinal microvessels and induced the disorganization of F-actin in retinal vascular endothelial cells. The threonine (T558) phosphorylation of moesin in retinal vessels was enhanced remarkably after AGE administration. The phosphorylation of moesin was attenuated by inhibitions of ROCK and p38 MAPK, while this treatment also prevented the dysfunction of inner blood–retinal barrier and the reorganization of F-actin in retinal vascular endothelial cells. These results demonstrate that moesin is involved in AGE-induced retinal vascular endothelial dysfunction and the phosphorylation of moesin is triggered via ROCK and p38 MAPK activation.