Role Of Advanced Glycation End Products Research Articles

Role of advanced glycation endproducts in bone fragility in type 1 diabetes

The excess fracture risk observed in adults with type 1 diabetes (T1D) is inexplicable in the presence of only modest reductions in areal bone mineral density (BMD). Accumulation of advanced glycation endproducts (AGEs) in bone has been invoked as one explanation for the increased bone fragility in diabetes. The evidence linking AGEs and fractures in individuals with T1D is sparse, although the association has been observed in individuals with type 2 diabetes. Recent data show that in T1D, AGEs as measured by skin intrinsic fluorescence, are a risk factor for lower BMD. Further research in T1D is needed to ascertain whether there is a causal relationship between fractures and AGEs. If confirmed, this would pave the way for finding interventions that can slow AGE accumulation and thus reduce fractures in T1D.

Increased dietary intake of ultraprocessed foods and mitochondrial metabolism alterations in pediatric obesity

The increased intake of ultraprocessed foods (UPFs) in the pediatric age paralleled with the risen prevalence of childhood obesity. The Ultraprocessed Foods in Obesity (UFO) Project aimed at investigating the potential mechanisms for the effects of UPFs in facilitating pediatric obesity, focusing on the direct role of advanced glycation end-products (AGEs) on mitochondrial function, the key regulator of obesity pathophysiology. We comparatively investigated the daily dietary intake of UPFs, energy, nutrients, dietary AGEs [Nε -(carboxymethyl)lysine (CML), Nε -(1-carboxyethyl)lysine (CEL), and Nδ -(5-hydro-5- methyl-4-imidazolon-2-yl)-ornithine (MG-H1)] in 53 obese patients and in 100 healthy controls visiting the Tertiary Center for Pediatric Nutrition of the Department of Translational Medical Science at the University of Naples “Federico II”. AGEs skin accumulation and mitochondrial function in peripheral blood mononuclear cells (PBMCs) were also assessed. A higher intake of UPFs and AGEs, energy, protein, fat, and saturated fatty acids was observed in obese patients. Obese children presented significantly higher skin AGEs accumulation and alterations in mitochondrial metabolism. PBMCs from healthy controls exposed to AGEs showed the same mitochondrial alterations observed in patients. These findings support the UPFs role in pediatric obesity, and the need for dietary strategies limiting UPFs exposure for obesity prevention and treatment.

Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification.

Type 2 diabetes (T2D) and osteoporosis (OP) are major causes of morbidity and mortality that have arelevant health and economic burden. Recent epidemiological evidence suggests that both of these disorders are often associated with each other and that T2D patients have an increased risk of fracture, making bone an additional target of diabetes. As occurs for other diabetic complications, the increased accumulation of advanced glycation end-products (AGEs) and oxidative stress represent the major mechanisms explaining bone fragility in T2D. Both of these conditions directly and indirectly (through the promotion of microvascular complications) impair the structural ductility of bone and negatively affect bone turnover, leading to impaired bone quality, rather than decreased bone density. This makes diabetes-induced bone fragility remarkably different from other forms of OP and represents a major challenge for fracture risk stratification, since either the measurement of BMD or the use of common diagnostic algorithms for OP have a poor predictive value. We review and discuss the role of AGEs and oxidative stress on the pathophysiology of bone fragility in T2D, providing some indications on how to improve fracture risk prediction in T2D patients.

Impact of elevated serum advanced glycation end products and exercise on intact and injured murine tendons

ABSTRACT Overview: Delayed tendon healing is a significant clinical challenge for those with diabetes. We explored the role of advanced glycation end-products (AGEs), a protein modification present at elevated levels in serum of individuals with diabetes, on injured and intact tendons using a mouse model. Cell proliferation following tissue injury is a vital component of healing. Based on our previous work demonstrating that AGEs limit cell proliferation, we proposed that AGEs are responsible for the delayed healing process commonly observed in diabetic patients. Further, in pursuit of interventional strategies, we suggested that moderate treadmill exercise may support a healing environment in the presence of AGEs as exercise has been shown to stimulate cell proliferation in tendon tissue. Materials and Methods: Mice began receiving daily intraperitoneal injections of bovine serum albumin (BSA)-Control or AGE-BSA injections (200μg/ml) at 16-weeks of age. A tendon injury was created in the central third of both patellar tendons. Animals assigned to an exercise group began a moderate treadmill protocol one week following injury. The intact Achilles tendon and soleus muscle were also evaluated to assess the effect of BSA and AGE-BSA on un-injured muscle and tendon. Results: We demonstrate that our injection dosing and schedule lead to an increase in serum AGEs. Our findings imply that AGEs indeed modulate gene expression following a patellar tendon injury and have modest effects on gene expression in intact muscle and tendon. Conclusions: While additional biomechanical analysis is warranted, these data suggest that elevated serum AGEs in persons with diabetes may impact tendon health.

Causative or associative: A critical review of the role of advanced glycation end-products in bone fragility.

The accumulation of advanced glycation end-products (AGEs) in the organic matrix of bone with aging and chronic disease such as diabetes is thought to increase fracture risk independently of bone mass. However, to date, there has not been a clinical trial to determine whether inhibiting the accumulation of AGEs is effective in preventing low-energy, fragility fractures. Moreover, unlike with cardiovascular or kidney disease, there are also no pre-clinical studies demonstrating that AGE inhibitors or breakers can prevent the age- or diabetes-related decrease in the ability of bone to resist fracture. In this review, we critically examine the case for a long-standing hypothesis that AGE accumulation in bone tissue degrades the toughening mechanisms by which bone resists fracture. Prior research into the role of AGEs in bone has primarily measured pentosidine, an AGE crosslink, or bulk fluorescence of hydrolysates of bone. While significant correlations exist between these measurements and mechanical properties of bone, multiple AGEs are both non-fluorescent and non-crosslinking. Since clinical studies are equivocal on whether circulating pentosidine is an indicator of elevated fracture risk, there needs to be a more complete understanding of the different types of AGEs including non-crosslinking adducts and multiple non-enzymatic crosslinks in bone extracellular matrix and their specific contributions to hindering fracture resistance (biophysical and biological). By doing so, effective strategies to target AGE accumulation in bone with minimal side effects could be investigated in pre-clinical and clinical studies that aim to prevent fragility fractures in conditions that bone mass is not the underlying culprit.

Wound Healing Impairment in Type 2 Diabetes Model of Leptin-Deficient Mice-A Mechanistic Systematic Review.

Type II diabetes mellitus (T2DM) is one of the most prevalent diseases in the world, associated with diabetic foot ulcers and impaired wound healing. There is an ongoing need for interventions effective in treating these two problems. Pre-clinical studies in this field rely on adequate animal models. However, producing such a model is near-impossible given the complex and multifactorial pathogenesis of T2DM. A leptin-deficient murine model was developed in 1959 and relies on either dysfunctional leptin (ob/ob) or a leptin receptor (db/db). Though monogenic, this model has been used in hundreds of studies, including diabetic wound healing research. In this study, we systematically summarize data from over one hundred studies, which described the mechanisms underlying wound healing impairment in this model. We briefly review the wound healing dynamics, growth factors’ dysregulation, angiogenesis, inflammation, the function of leptin and insulin, the role of advanced glycation end-products, extracellular matrix abnormalities, stem cells’ dysregulation, and the role of non-coding RNAs. Some studies investigated novel chronic diabetes wound models, based on a leptin-deficient murine model, which was also described. We also discussed the interventions studied in vivo, which passed into human clinical trials. It is our hope that this review will help plan future research.

Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression.

To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.

Fracture behavior of human cortical bone: Role of advanced glycation end-products and microstructural features

Diabetes is associated with increased fracture risk in human bone, especially in the elderly population. In the present study, we investigate how simulated advanced glycation end-products (AGEs) and materials heterogeneity affect crack growth trajectory in human cortical bone. We used a phase field fracture framework on 2D models of cortical microstructure created from human tibias to analyze crack propagation. The increased AGEs level results in a higher rate of crack formation. The simulations also indicate that the mismatch between the fracture properties (e.g., critical energy release rate) of osteons and interstitial tissue can alter the post-yielding behavior. The results show that if the critical energy release rate of cement lines is lower than that of osteons and the surrounding interstitial matrix, cracks can be arrested by cement lines. Additionally, activation of toughening mechanisms such as crack merging and branching depends on bone microstructural morphology (i.e., osteons geometrical parameters, canals, and lacunae porosities). In conclusion, the present findings suggest that materials heterogeneity of microstructural features and the crack-microstructure interactions can play important roles in bone fragility.

Altered hepatic sphingolipid metabolism in insulin resistant mice: Role of advanced glycation endproducts

High plasma levels of the sphingolipid intermediates ceramide (Cer) and sphingosine-1-phosphate (S1P) are suggested to be involved in the development of insulin resistance (IR). Recent evidence indicates that advanced glycation endproducts (AGEs) can alter the sphingolipids metabolism equilibrium. Since enzymes responsible for sphingolipid rheostat maintenance are highly expressed in liver, we thus investigated whether AGEs accumulation can affect hepatic sphingolipids metabolism in insulin resistant mice.Two different models of IR were examined: genetically diabetic LeptrDb-/- (DbDb) and diet-induced insulin resistant C57Bl/6J mice fed a 60% trans-fat diet (HFD). In addition, a group of HFD mice was supplemented with the anti-AGEs compound pyridoxamine. AGEs were evaluated in the liver by western blotting. Cer and S1P were measured by UHPLC-MS/MS. The expression of RAGE and of enzymes involved in sphingolipid metabolism were assessed by RT-PCR and western blotting. HepG2 cells were used to study the effect of the major AGE Nε-(carboxymethyl)lysine (CML)-albumin on sphingolipid metabolism and the role of the receptor of AGEs (RAGE).High levels of AGEs and RAGE were detected in the liver of both DbDb and HFD mice in comparison to controls. The expression of enzymes of sphingolipid metabolism was altered in both models, accompanied by increased levels of Cer and S1P. Specifically, ceramide synthase 5 and sphingosine kinase 1 were increased, while neutral ceramidase was reduced. Pyridoxamine supplementation to HFD mice diminished hepatic AGEs and prevented alterations of sphingolipid metabolism and the development of IR. CML administration to HepG2 cells evoked alterations similar to those observed in vivo, that were in part mediated by the binding to RAGE.The present study shows a direct involvement of AGEs in alterations of sphingolipid metabolism associated to the development of IR. The modulation of sphingolipids metabolism through the prevention of AGEs accumulation by pyridoxamine may reduce the development of IR.

Commentary on Some Recent Theses Relevant to Combating Aging: February 2021.

Theses reviewed in this issue include "Developing the Next Generation of Universal Immune Receptors," "From Synthesis to Pathology: A Bottom-Up Approach to Studying the Role of Advanced Glycation End-Products in Diabetes and Aging," "Hybrid Bioactive Nanoparticles for Modulation of Tumor Microenvironment and Enhancing Radiation and Chemotherapy Efficacy," "In Situ Bioprinting of Planar Biomaterials and Tissues," "Novel AAV Engineering Technology: Identification of Improved AAV Variants for Gene Addition and Genome Engineering in Primary Human Cells," and "Substrate Reduction Therapy for Krabbe Disease and a New Murine Model for Cell-Autonomous Expression of Lysosomal Hydrolases."

Advanced glycation end products (AGEs) and their soluble receptors (sRAGE) as early predictors of reno-vascular complications in patients with uncontrolled type 2 diabetes mellitus

AimTo evaluate the role of advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) expression levels as predictors of vascular complications in uncontrolled type 2 diabetes mellitus (T2DM). MethodsCross-sectional study was conducted on T2DM adults of both sexes who attended the outpatient service of Al-Karak Teaching Hospital, Jordan during the period from June 2017 to August 2018. Participants were categorized in two groups according to their glycemic control and the presence of reno-vascular complications. Twenty healthy subjects were recruited as control group. Blood sample was obtained from all participants and used for the assessment of FBG, HbA1c, serum AGEs and sRAGE, serum urea and creatinine; 24 h urine was also collected for the determination of urinary albumin. ResultsDiabetic subjects with vascular complication had a significantly higher serum AGEs 50.3 ± 13 vs. 28.9 ± 8 pg/ml) and AGEs/sRAGE ratio (0.058 ± 0.02 vs. 0.037 ± 0.02) associated with significantly lower serum sRAGE (868.7 ± 50.8 vs. 912.8 ± 294.3) compared to those with no complications. Serum AGEs and sRAGE showed weak negative and non-significant association in both groups of patients. However, the AGEs/sRAGE ration was inversely and significantly associated with the urinary albumin/creatinine ratio (r = − 0.51, P = 0.009) only in DM patients with reno-vascular complications. ConclusionWe found an association between AGEs/sRAGE ratio and urinary albumin/serum creatinine ratio in T2DM patients with reno-vascular complications; providing evidence that serum AGEs and sRAGE can be considered as predictors of vascular complications in uncontrolled T2DM patients.

Retracted: Advanced glycation end-products induce oxidative stress through the Sirt1/Nrf2 axis by interacting with the receptor of AGEsunder diabetic conditions.

Despite the administration of exogenous insulin and other medications used to control many aspects of diabetes mellitus (DM), increased oxidative stress has been increasingly acknowledged in DM development and complications. Therefore, this study aims to investigate the role of advanced glycation end-products (AGEs) in oxidative stress (OS) of thyroid cells in patients with DM. Patients with DM with or without thyroid dysfunction (TD) were enrolled. Thyroid toxic damage was induced by adding AGE-modified bovine serum albumin (AGE-BSA) to normal human thyroid follicular epithelial cells. The cell viability, cell cycle, and cell apoptosis, as well as the content of reactive oxygen species (ROS), catalase (CAT), and malondialdehyde (MDA) in cells were measured. Thyroid hormones, T3, T4, FT3, and FT4 levels were measured by enzyme-linked immunosorbent assay. Receptor for advanced glycation end products (RAGE), sirtuin1 ( Sirt1), and NF-E2-related factor 2 ( Nrf2) expressions were detected, and the mitochondrial membrane potential was measured. We found increased AGEs in the serum of DM patients with TD. By increasing AGE-BSA concentration, cell viability; the thyroid hormones T3, T4, FT3, and FT4 levels; and mitochondrial membrane potential all significantly decreased. However, the increase in AGE-BSA concentration led to an increase in cell apoptosis, RAGE, and nuclear factor-κB expressions but produced the opposite effect on Sirt1, Nrf2, and heme oxygenase-1 expressions, as well as a decrease in antioxidant response element protein levels. The AGE-BSA increased ROS and MDA levels and reduced CAT level in normal human thyroid follicular epithelial cells on a dose independence basis. Our results demonstrated that AGEs-mediated direct increase of RAGE produced OS in thyroid cells of DM by inactivating the Sirt1/Nrf2 axis.

The possible role of advanced glycation endproducts (AGEs) in experimentally-induced ischemic brain damage.

Stroke is the second leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. Advanced glycation endproducts (AGEs) are known to be increased in several chronic diseases and induce inflammation and protein intercalation. The only drug approved for the treatment ischemic stroke is recombinant tissue plasminogen activator (r-TPA). The current study was designed to investigate the protective effect of benfotiamine (70 mg/kg/day), perindopril (2 mg/kg/day) and alagebrium (2 mg/kg/day) on experimentally-induced ischemic brain damage. All drugs were administered daily for one week before and 2 days after middle cerebral artery occlusion (MCAO). Benfotiamine, perindopril and alagebrium ameliorated the deleterious effects of MCAO as indicated by the improvement in the performance of the animals in initiation of walking test and improvement of the deteriorated brain histology. This was associated with normalization of the level of AGEs that was increased following MCAO. The result of the current study represent a new indication for benfotiamine, perindopril, alagebrium in the management of ischemic stroke.

Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease.

The rapid increase in metabolic diseases, which occurred in the last three decades in both industrialized and developing countries, has been related to the rise in sugar-added foods and sweetened beverages consumption. An emerging topic in the pathogenesis of metabolic diseases related to modern nutrition is the role of Advanced Glycation Endproducts (AGEs). AGEs can be ingested with high temperature processed foods, but also endogenously formed as a consequence of a high dietary sugar intake. Animal models of high sugar consumption, in particular fructose, have reported AGE accumulation in different tissues in association with peripheral insulin resistance and lipid metabolism alterations. The in vitro observation that fructose is one of the most rapid and effective glycating agents when compared to other sugars has prompted the investigation of the in vivo fructose-induced glycation. In particular, the widespread employment of fructose as sweetener has been ascribed by many experimental and observational studies for the enhancement of lipogenesis and intracellular lipid deposition. Indeed, diet-derived AGEs have been demonstrated to interfere with many cell functions such as lipid synthesis, inflammation, antioxidant defences, and mitochondrial metabolism. Moreover, emerging evidence also in humans suggest that this impact of dietary AGEs on different signalling pathways can contribute to the onset of organ damage in liver, skeletal and cardiac muscle, and the brain, affecting not only metabolic control, but global health. Indeed, the most recent reports on the effects of high sugar consumption and diet-derived AGEs on human health reviewed here suggest the need to limit the dietary sources of AGEs, including added sugars, to prevent the development of metabolic diseases and related comorbidities.

Diverging effects of diabetes mellitus in patients with peripheral artery disease and abdominal aortic aneurysm and the role of advanced glycation end-products: ARTERY study — protocol for a multicentre cross-sectional study

IntroductionDiabetes mellitus is a well-defined risk factor for peripheral artery disease (PAD), but protects against the development and growth of abdominal aortic aneurysm (AAA). Diabetes mellitus is associated with arterial...

The Role of Advanced Glycation End-Products in Cancer Disparity.

While the socioeconomic and environmental factors associated with cancer disparity have been well documented, the contribution of biological factors is an emerging field of research. Established disparity factors such as low income, poor diet, drinking alcohol, smoking, and a sedentary lifestyle may have molecular effects on the inherent biological makeup of the tumor itself, possibly altering cell signaling events and gene expression profiles to profoundly alter tumor development and progression. Our understanding of the molecular and biological consequences of poor lifestyle is lacking, but such information may significantly change how we approach goals to reduce cancer incidence and mortality rates within minority populations. In this review, we will summarize the biological, socioeconomic, and environmental associations between a group of reactive metabolites known as advanced glycation end-products (AGEs) and cancer health disparity. Due to their links with lifestyle and the activation of disease-associated pathways, AGEs may represent both a biological consequence and a bio-behavioral indicator of poor lifestyle which may be targeted within specific populations to reduce disparities in cancer incidence and mortality.

Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases.

Advanced glycation end products (AGEs) have been implicated in vision loss associated with macula degeneration, cataract formation, diabetic retinopathy and glaucoma. This pathogenic potential is mainly attributed to their accumulation in ocular tissues where they mediate aberrant crosslinking of extracellular matrix proteins and disruption of endothelial junctional complexes that affects cell permeability, mediates angiogenesis and breakdown of the inner blood-retinal barrier. Furthermore, AGEs severely affect cellular metabolism by disrupting ATP production, enhancing oxidative stress and modulating gene expression of anti-angiogenic and anti-inflammatory genes. Elucidation of AGE-induced mechanisms of action in different eye compartments will help in the understanding of the complex cellular and molecular processes associated with eye diseases. Several pharmaceutical agents with anti-glycating and anti-oxidant properties as well as AGE crosslink 'breakers' have been currently applied to eye diseases. The role of diet and the beneficial effects of certain nutriceuticals provide an alternative way to manage chronic visual disorders that affect the quality of life of millions of people.

Cytotoxic role of advanced glycation end-products in PC12 cells treated with β-amyloid peptide

Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. Recent studies have increasingly suggested that a high concentration of advanced glycation end products (AGEs) may be important in AD pathogenesis. However, the mechanisms and pathways involved remain unknown. The aim of this study was to explore whether the mechanism of the effect of AGEs on Aβ‑PC12 cells [PC12 cells treated with β‑amyloid (Aβ) peptide] was associated with oxidative stress; and to study whether inhibiting the activity of the receptor for AGE (RAGE) attenuated the toxic effect of AGEs and Aβ on PC12 cells. Several PC12 cells were pretreated with Aβ, and were then treated with different concentrations of AGEs. Other PC12 cells were treated with trypsin, a pancreatic protein enzyme and an inhibitor of RAGE, and were then treated with Aβ and AGEs. Apoptosis was measured by flow cytometry (FCM) and cell viability was measured by MTT assay. RAGE and nuclear factor‑κB (NF‑κB) were measured by reverse transcription-polymerase chain reaction (RT‑PCR) assay. With an increase in AGE concentration, the viability of Aβ‑PC12 cells treated with AGEs decreased. However, the Aβ‑PC12 cell viability was greater in the trypsin group than in the non‑trypsin group. Cell apoptosis rates and mRNA expression of RAGE and NF‑κB in Aβ‑PC12 cells treated with AGEs were significantly higher than in the Aβ‑PC12 cells. AGEs and Aβ were neurotoxic, and RAGE triggered the neural cytotoxic role of AGEs in Aβ‑PC12 cells. The molecular mechanisms may be connected with the expression of NF‑κB and apoptosis mediated by RAGE. Inhibiting the activity of RAGE may mitigate the toxic effect of AGEs and Aβ on neural cells.

AGE-LDL Activates Toll Like Receptor 4 Pathway and Promotes Inflammatory Cytokines Production in Renal Tubular Epithelial Cells

Background/Aims:Accumulation of advanced glycation end-products, the well-recognized pro-inflammatory molecules, has been detected in renal tissues including tubules. The aim of the present study was to investigate the role of advanced glycation end-products modified low density lipoprotein (AGE-LDL) in inflammatory cytokines production in human proximal tubular epithelial cells and the underlying mechanism. Methods: The Interleukin-6 (IL-6) and Interleukin-8 (IL-8) production was examined by real-time PCR and ELISA. The expression of Toll-like receptor 2 and 4 (TLR2/4) was detected by flow cytometry and western blot. The interaction of TLR2/4 with AGE-LDL was examined by co-immunoprecipitation assay. The involvement of MyD88 and the downstream molecules in inflammatory cytokines production was examined by siRNA and pharmacologic inhibitors, respectively. Results: AGE-LDL interacted with TLR2 and TLR4. TLR4 siRNA showed stronger inhibition on AGE-LDL-induced IL-6 and IL-8 production than that of TLR2 siRNA. Silencing MyD88, but not TRIF, inhibited AGE-LDL-induced IL-6 and IL-8 production. AGE-LDL stimulation led to phosphorylation of JNK, p38, Akt and the p65 subunit of nuclear factor-κB (NF-κB). Pharmacologic inhibitor of Akt suppressed AGE-LDL-induced activation of NF-κB, but the inhibitor of JNK, p38 or ERK1/2 had no effect. Blocking MyD88, p38, JNK, Akt or NF-κB attenuated AGE-LDL-triggered IL-6 production. Conclusion: AGE-LDL induced IL-6 and IL-8 production via TLR2/4-MyD88-dependent pathway in tubular epithelial cells. These data suggest that activation of TLRs signaling in tubular epithelial cells by AGE-LDL might be a novel mechanism for the tubulointerstitial inflammation.

Altered profile of circulating endothelial progenitor cells in obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) is independently associated with endothelial dysfunction, which may be perpetuated by alteration in endothelial repair capacity. Our study evaluates changes in endothelial progenitor cell (EPC) profile in relation to OSA and the role of advanced glycation end-products (AGE) in this relationship.MethodsConsecutive Chinese adults undergoing sleep studies, who had no medical illnesses or regular medications, were enrolled. Subjects with morbid obesity or grossly elevated lipoprotein levels were excluded from analysis. Circulating EPC was measured with flow cytometry analysis.ResultsSeventy-two subjects, 64 % with OSA defined by apnea–hypopnea index (AHI) ≥ 5, were analyzed. CD34+ cell counts were positively correlated with oxygen desaturation index (ODI) (r = 0.250, p = 0.041) and duration of oxygen desaturation <90 % (T90) (r = 0.261, p = 0.033) and negatively with minimal oxygen saturation (r = −0.247, p = 0.044) after adjusting for age, glucose, body weight, and smoking status. AGE was positively correlated with indices of OSA severity (AHI, r = 0.249, p = 0.042; ODI, r = 0.244, p = 0.047; T90, r = 0.243, p = 0.047; minimal oxygen saturation, r = −0.251, p = 0.041) and negatively with CD133+ cells (r = −0.281, p = 0.021). On stepwise multiple linear regression analysis, minimal oxygen saturation (p = 0.013) and CD133+ cell counts (p = 0.029) were found to be significant determinants of AGE level (R 2 = 0.147).ConclusionsNocturnal hypoxemia in OSA subjects was associated with increase in endothelial cells (CD34+) which may promote vascular repair. Accumulation of AGE in OSA may lead to diminution in early EPC (CD133+) and endothelial repair capacity over time, thus contributing to vascular pathogenesis.