Role of the advanced glycation end products receptor in Crohn’s disease inflammation

AIM:To investigate the level of mucosal expression and the involvement of the receptor for the advanced glycation end products(RAGE)in delayed apoptosis and tumor necrosis factor(TNF)-αproduction in Crohn’s disease(CD).METHODS:Surgical and endoscopic specimens from both inflamed and non-inflamed areas of the ileum and/or colon were collected from 20 and 14 adult CD patients,respectively,and used for the assessment of RAGE expression by means of immunohistochemistry and western blotting analysis.Normal tissues from 21 control subjects were used for comparison.The same polyclonal anti-human RAGE antibody(R and D System)was used in all experimental conditions.RAGE staining was quantized by a score including both the amount of positive cells and intensity of immunoreactivity;cellular pattern was also described.The effects of RAGE blocking on apoptotic rate and TNF-αproduction were investigated on immune cells freshly isolated from CD mucosa and incubated both with and without the muramyl dipeptide used as antigenic stimulus.Statistical analysis was performed via the test for trend,with regression models to account for intra-patient correlations.A 2-sided P<0.05 was considered significant.RESULTS:In inflamed areas,RAGE expression in both the epithelial and lamina propria compartments was higher than control tissues(P=0.001 and 0.021,respectively),and a cluster of positive cells were usually found in proximity of ulcerative lesions.Similar results were obtained in the lamina propria compartment of non-inflamed areas(P=0.025).The pattern of staining was membranous and granular cytosolic at the epithelial level,while in the lamina propria it was diffuse cytosolic.When evaluating the amount of protein expression by immunoblotting,a significant increase of both surface area and band intensity(P<0.0001 for both)was observed in CD inflamed areas compared to control tissue,while in non-inflamed areas a significant increase was found only for band intensity(P<0.005).Moreover,a significantly lower expression in no     

Decreased levels of soluble receptor for advanced glycation end products in patients with primary Sjögren’s syndrome

The purpose of this study was to evaluate the levels of sRAGE in primary Sjögren’s syndrome (SS), and to assess whether there is an association between sRAGE levels and disease characteristics. Thirteen patients were randomly selected from three subgroups: primary SS, (n = 6), secondary Sjögren’s, (n = 4), and ANA(+) but lacking criteria for further disease classification (n = 3). Levels of serum sRAGE were measured in triplicate using an enzyme-linked immunosorbent assay kit. Mean sRAGE levels were significantly lower in the primary Sjögren’s group. Logistic regression analysis indicated that plasma sRAGE level was a significant predictor of diagnostic status. Analyses using routine serological tests for diagnosing autoimmune disorders failed to reach statistical significance. This preliminary study supports the hypothesis that the RAGE system might participate in the disease pathway of primary SS, and that sRAGE may be a potential biomarker to aid in the diagnosis of primary SS.     

Increased levels of advanced glycation end products positively correlate with iron overload and oxidative stress markers in patients with β-thalassemia major

The impaired biosynthesis of the β-globin chain in β-thalassemia leads to the accumulation of unpaired alpha globin chains, failure in hemoglobin formation, and iron overload due to frequent blood transfusion. Iron excess causes oxidative stress and massive tissue injuries. Advanced glycation end products (AGEs) are harmful agents, and their production accelerates in oxidative conditions. This study was conducted on 45 patients with major β-thalassemia who received frequent blood transfusions and chelation therapy and were compared to 40 healthy subjects. Metabolic parameters including glycemic and iron indices, hepatic and renal functions tests, oxidative stress markers, and AGEs (carboxymethyl-lysine and pentosidine) levels were measured. All parameters were significantly increased in β-thalassemia compared to the control except for glutathione levels. Blood glucose, iron, serum ferritin, non-transferrin-bound iron (NTBI), MDA, soluble form of low-density lipoprotein receptor, glutathione peroxidase, total reactive oxygen species (ROS), and AGE levels were significantly higher in the β-thalassemia patients. Iron and ferritin showed a significant positive correlation with pentosidine (P?<?0.01) but not with carboxymethyl-lysine. The NTBI was markedly increased in the β-thalassemia patients, and its levels correlated significantly with both carboxymethyl-lysine and pentosidine (P?<?0.05). Our findings confirm the oxidative status generated by the iron overload in β-thalassemia major patients and highlight the enhanced formation of AGEs, which may play an important role in the pathogenesis of β-thalassemia major.     

Immunohistochemical detection of β-amyloid and β-amyloid precursor protein in the canine brain and non-neuronal epithelial tissues

We examined the immunohistochemical localization of β-amyloid (Aβ) and β-amyloid precursor protein (AβPP) in the neuronal and non-neuronal tissues of 14 aged (over 10 years old) and 4 young (0–4 years old) dogs. Aβ was detected only in the senile plaque in the cerebrum of aged dogs. AβPP was expressed in the neuronal cell body, neuronal fiber, senile plaque and perimalacic tissue independent of age. In addition, epithelial cells in the bronchus, bronchial glands, gastric and intestinal mucosa, intrahepatic bile ducts, and pancreatic ducts and exocrine glands were immunopositive for AβPP. Thus, it is suggested that AβPP may be expressed in the non-neuronal epithelial tissues independent of age and of the presence of senile plaques, and the expression may depend on individual differences or physiological conditions.     

Advanced glycation end products of human β₂ glycoprotein I modulate the maturation and function of DCs

In chronic disorders related to endothelial cell dysfunction, plasma β? glycoprotein I (β?GPI) plays a role as a target antigen of pathogenetic autoimmune responses. However, information is still lacking to clarify why β?GPI triggers autoimmunity. It is possible that posttranslational modification of the protein, such as nonenzymatic glycosylation, leads to the formation of advanced glycation end products (AGEs). The aim of our study was to explore whether glucose-modified β?GPI is able to interact and activate monocyte-derived immature dendritic cells (iDCs) from healthy human donors. SDS-PAGE and spectrofluorometric analyses indicated that β?GPI incubated with glucose was sugar modified, and that this modification likely consisted of AGE formation, resulting in AGE-β?GPI. AGE-β?GPI caused phenotypical and functional maturation of iDCs involving the activation of p38 MAPK, ERK, and NF-κB. It also induced on DCs a significant up-regulation of RAGE, the receptor for AGEs. Evidence for RAGE involvement comes from blocking experiments with an anti-RAGE mAb, confocal analysis, and coimmunoprecipitation experiments. AGE-β?GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes toward a Th2 polarization. These findings might explain in part the interactive role of β?GPI, AGEs, and DCs in chronic disorders related to endothelial cell dysfunction.     

Inhibition of advanced glycation end products (AGEs): an implicit goal in clinical medicine for the treatment of diabetic nephropathy?

Several factors are incriminated in the genesis of diabetic nephropathy (DN). To elucidate their interplays, we utilized a diabetic rat model with nephropathy (SHR/NDmcr-cp). This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal AGE accumulation. Various therapeutic approaches were used to achieve renoprotection. Caloric restriction corrects metabolic abnormalities and protects the kidney without correcting hypertension. Anti-hypertensive agents, angiotensin II receptor blocker (ARB) and calcium channel blocker, lower blood pressure to the same extent, but only ARBs protect the kidney without changes in metabolic abnormalities. Glycemic control is better with insulin than with pioglitazone. The plasma insulin level is increased by insulin but decreased by pioglitazone which worsens the obesity. Nevertheless, pioglitazone provides renoprotection unlike insulin, perhaps as a result of the up-regulation of TGF-beta by hyperinsulinemia. Cobalt up-regulates the expression of a hypoxia-inducible factor (HIF) and its downstream genes (erythropoietin, VEGF, HO-1). It protects the kidney without correcting hypertension and metabolic abnormalities. Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with a decreased AGE formation. AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers.     

Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of β-amyloid

Standardized extracts of Bacopa monniera (BME) have been shown to exert a neuroprotective effect against mental diseases, such as depression, anxiety and Alzheimer''s disease (AD), in chronic administration studies. However, its mechanism of action has remained unclear. In this study, we evaluated the therapeutic effect of Bacopaside I (BS-I), a major triterpenoid saponin of BME, on the cognitive impairment and neuropathology in APP/PS1 transgenic mice and explored the possible mechanism from a biological systems perspective. We found that BS-I treatment significantly ameliorated learning deficits, improved long-term spatial memory, and reduced plaque load in APP/PS1 mice. We constructed BS-I''s therapeutic effect network by mapping the nodes onto the protein-protein interaction (PPI) network constructed according to their functional categories based on genomic and proteomic data. Because many of the top enrichment categories related to the processes of the immune system and phagocytosis were detected, we proposed that BS-I promotes amyloid clearance via the induction of a suitable degree of innate immune stimulation and phagocytosis. Our research may help to clarify the neuroprotective effect of BME and indicated that natural saponins target the immune system, which may offer new research avenues to discover novel treatments for AD.     

Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model

Metabolic Brain Disease - Hypertension (HT) is one of the main causes of vascular dementia, lead to cognitive decline. Here, we investigated the relationship between cerebral microvessels,...     

Reactive gliosis in Alzheimer’s disease: a crucial role for cognitive impairment and memory loss

Metabolic Brain Disease - Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Insulin resistance in central nervous system (CNS) is a...     

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Aims/hypothesis  

The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it.     

Plasma β-amyloid peptides in canine aging and cognitive dysfunction as a model of Alzheimer's disease

Aging dogs naturally demonstrate cognitive impairment and neuropathology that model early Alzheimer's disease (AD). In particular, there is evidence that canine cognitive dysfunction syndrome (CDS) in aged dogs is accompanied by cortical deposition of Aβ peptides and neurodegeneration. Plasma Aβ levels have been examined in humans as putative biomarkers for AD, but to date, no similar studies have been conducted for canine dementia. The aim of the present study was to assess plasma Aβ1-42 and Aβ1-40 levels in a blind study using pet dogs that were either successfully aging or exhibiting CDS. The severity of cognitive impairment was assessed using an owner-based questionnaire. On average, young dogs presented significantly higher plasma levels of Aβ1-42 and Aβ1-40 than aged, cognitively unimpaired dogs. Notably, among aged dogs, the levels of Aβ1-42 and the Aβ42/40 ratio were significantly higher in those showing mild cognitive impairment than in either cognitively unimpaired or severely affected dogs. These results suggest that increased plasma Aβ1-42 levels and Aβ42/40 ratio could be a biomarker for canine cognitive dysfunction, which is considered an excellent natural model of early AD.     

Bacille Calmette-Guérin inoculation induces chronic activation of peripheral and brain indoleamine 2,3-dioxygenase in mice

BACKGROUND: Activation of the indoleamine 2,3-dioxygenase (IDO) enzyme and the resulting decrease in plasma tryptophan (TRP) levels appears to be a crucial link in the relationship between cytokines and depression. We aimed to develop an experimental model of chronic IDO activation based on bacille Calmette-Guérin (BCG) infection that elicits a robust increase in levels of interferon (IFN)- gamma, a key cytokine in the activation of IDO. METHODS: Mice were inoculated intraperitoneally with BCG (10(7) cfu/mouse). Lung and brain IDO activity was measured over time, together with plasma levels of TRP and IFN- gamma. RESULTS: BCG induced, over the course of several weeks, a chronic increase in serum IFN- gamma levels that was associated with a sustained enhancement of lung and brain IDO activity and with decreases in peripheral (serum and lungs) and brain concentrations of TRP, with different time courses between tissues. CONCLUSIONS: The model of BCG-induced IDO activation will be useful for the study of the consequences of peripheral immune activation in the brain and the role of TRP metabolism in cytokine-induced mood alteration.     

Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA(y) mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA(y) mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.     

Morphological adaptation of muscle collagen and receptor of advanced glycation end product (RAGE) in osteoarthritis patients with 12 weeks of resistance training: influence of anti-inflammatory or glucosamine treatment

The aim of this study was to investigate the effect of 12-week resistance training on morphological presence of collagen and RAGE (receptor for advanced glycation end products) in skeletal muscle of patients with knee osteoarthritis (OA). Little is known about the influence of exercise on the skeletal muscle matrix that supports joints affected by OA mainly when it is associated with medication taken by OA patients (non-steroid anti-inflammatory drugs (NSAID) and glucosamine). A biopsy was collected from the vastus lateralis muscle in all patients before and after 12-week period of training. The patients (age 55–69 years) were divided into three groups, treated with NSAID, glucosamine or placebo. In addition, the muscle samples were analysed by immunohistochemistry for collagen types, RAGE and capillaries ratio. An increment in immunoreactivity for type IV collagen after the training period was observed in 72 % of all biopsies when compared with their respective baseline samples. Reduced immunoreactivity of collagen type I was observed in all patients treated with glucosamine. A significant increase with training in the amount of RAGE was detected in the placebo group only (p < 0.05). Comparison of post-treatment states indicated significant differences between the placebo and glucosamine group data, demonstrating increased levels in the placebo group (p < 0.05). These findings suggest a basement membrane remodelling in favour of a strengthened extracellular matrix surrounding individual muscle fibres after 12 weeks of resistance training. Glucosamine with training appeared to attenuate RAGE accumulation more than was seen with NSAID or placebo in skeletal muscle of OA patients.