Dysregulation of Receptor for Advanced Glycation End Products (RAGE) Expression as a Biomarker of Keratoconus

Background. Because of the implications of Receptor for Advanced Glycation End Products (RAGE) in keratoconus (KC), we describe a differential expression of RAGE transcripts and proteins in corneal tissues and tears of KC and healthy patients. Methods. Using a case-controlled study, corneal epitheliums and tears of KC and healthy subjects were obtained during corneal collagen cross-linking and photorefractive keratectomy (PKR) and during usual consultations. Quantitative reverse transcription (RT-qPCR) and Western-Blot were performed to analyze RAGE transcripts and proteins’ expression in corneal tissues and tears. Results. One hundred and six patients were included in this study. The characteristics of the patients were as follows: 56 KC (25 corneal epithelium and 31 tears) and 50 control subjects (25 corneal epithelium and 25 tears). Transcripts of RAGE, HMGB1, and S100 family ligands were quantified by RT-qPCR, identifying a significantly higher expression of RAGE and HMGB1 in the healthy group than in the KC group ( p = 0.03 and 0.04, respectively). Western Blot showed a significantly higher fl-RAGE expression in KC corneal epithelium than control ( p < 0.001 ) and lower s-RAGE expression in KC tears than control ( p = 0.04 ). Conclusions. Linked with the inflammatory process occurring in KC pathophysiology, we propose for the first time that the RAGE expression (total and truncated forms of receptor and ligands) in KC corneal tissues and tear samples provides viable biomarkers.

In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration

Advanced glycation end products (AGEs) can be present in food or be endogenously produced in biological systems. Their formation has been associated with chronic neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. The implication of AGEs in neurodegeneration is related to their ability to bind to AGE-specific receptors and the ability of their precursors to induce the so-called “dicarbonyl stress”, resulting in cross-linking and protein damage. However, the mode of action underlying their role in neurodegeneration remains unclear. While some research has been carried out in observational clinical studies, further in vitro studies may help elucidate these underlying modes of action. This review presents and discusses in vitro methodologies used in research on the potential role of AGEs in neuroinflammation and neurodegeneration. The overview reveals the main concepts linking AGEs to neurodegeneration, the current findings, and the available and advisable in vitro models to study their role. Moreover, the major questions regarding the role of AGEs in neurodegenerative diseases and the challenges and discrepancies in the research field are discussed.

Receptor Mediated Effects of Advanced Glycation End Products (AGEs) on Innate and Adaptative Immunity: Relevance for Food Allergy

As of late, evidence has been emerging that the Maillard reaction (MR, also referred to as glycation) affects the structure and function of food proteins. MR induces the conformational and chemical modification of food proteins, not only on the level of IgG/IgE recognition, but also by increasing the interaction and recognition of these modified proteins by antigen-presenting cells (APCs). This affects their biological properties, including digestibility, bioavailability, immunogenicity, and ultimately their allergenicity. APCs possess various receptors that recognize glycation structures, which include receptor for advanced glycation end products (RAGE), scavenger receptors (SRs), galectin-3 and CD36. Through these receptors, glycation structures may influence the recognition, uptake and antigen-processing of food allergens by dendritic cells (DCs) and monocytes. This may lead to enhanced cytokine production and maturation of DCs, and may also induce adaptive immune responses to the antigens/allergens as a result of antigen uptake, processing and presentation to T cells. Here, we aim to review the current literature on the immunogenicity of AGEs originating from food (exogenous or dietary AGEs) in relation to AGEs that are formed within the body (endogenous AGEs), their interactions with receptors present on immune cells, and their effects on the activation of the innate as well as the adaptive immune system. Finally, we review the clinical relevance of AGEs in food allergies.

Intracellular Toxic Advanced Glycation End-Products in 1.4E7 Cell Line Induce Death with Reduction of Microtubule-Associated Protein 1 Light Chain 3 and p62

Background: The death of pancreatic islet β-cells (β-cells), which are the insulin-producing cells, promote the pathology in both Type 1 and Type 2 diabetes mellitus (DM) (T1DM and T2DM), and they are protected by autophagy which is one of the mechanisms of cell survival. Recently, that some advanced glycation end-products (AGEs), such as methylglyoxial-derived AGEs and Nε-carboxymethyllysine, induced the death of β-cells were revealed. In contrast, we had reported AGEs derived from glyceraldehyde (GA, the metabolism intermediate of glucose and fructose) are considered to be toxic AGEs (TAGE) due to their cytotoxicity and role in the pathogenesis of T2DM. More, serum levels of TAGE are elevated in patients with T1 and T2DM, where they exert cytotoxicity. Aim: We researched the cytotoxicity of intracellular and extracellular TAGE in β-cells and the possibility that intracellular TAGE were associated with autophagy. Methods: 1.4E7 cells (a human β-cell line) were treated with GA, and analyzed viability, quantity of TAGE, microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, and p62. We also examined the viability of 1.4E7 cells treated with TAGE-modified bovine serum albumin, a model of TAGE in the blood. Results: Intracellular TAGE induced death of 1.4E7 cells, decrease of LC3-I, LC3-II, and p62. Extracellular TAGE didn’t show cytotoxicity in the physiological concentration. Conclusion: Intracellular TAGE induced death of β-cells more strongly than extracellular TAGE, and may suppress autophagy via reduction of LC3-I, LC3-II, and p62 to inhibit the degradation of them.

Biochemical analyses for dental age estimation: a review

Background For various legal and forensic scenarios, establishing an individual’s age, both living and dead, plays a crucial role. Various morphological, radiographic, and molecular methods can be used for age estimation. In children and adolescents, age estimation is based on the established developmental stages. However, in adults, where the development ceases into maturation, the degenerative changes play a role in determining the age. Main body of the abstract In the natural aging process, several molecular changes occur most commonly in the long-living proteins and hard tissues like the teeth and bone. These molecular changes gradually lead to alterations in several organs and organ systems, which can be quantified and correlated with age, including aspartic acid racemization, collagen crosslinks, advanced glycation-end products, and mitochondrial DNA mutations. Short conclusion Among the above methods, the racemization of aspartic acid can be considered as the most precise method. The main advantage of using aspartic acid racemization is that the sample can be collected from tissues (teeth) protected from various environmental and nutritional factors. If all the confounding factors are stable, the utilization of advanced glycation-end products can also be considered valuable. Environmental factors like lead accumulations may also help determine the age. However, further studies need to be conducted, focusing on providing a more standardized method. This review provides a concise summary of the biochemical techniques that can be used for estimation of age.

Advanced Glycation End-products Are Associated With Limited Range of Motion of the Shoulder Joint Following Rotator Cuff Tears

Background: Most degenerative rotator cuff tears (RCTs) are associated with a limited range of motion (ROM) of the shoulder joint. Additionally, patients with diabetes mellitus (DM) show a higher frequency of limited ROM. Recently, advanced glycation end products (AGEs) of proteins have been observed to cause tissue fibrosis, primarily through abnormal collagen cross-linking and oxidative stress. In this study, we investigated the effect of AGEs on ROM limitation in the shoulder capsule and its relationship with DM.Methods: 16 patients (8 each in the DM and non-DM groups) who underwent arthroscopic surgery for RCT with limited shoulder ROM were included in this study. AGE-related pathologies in both groups were compared, and the relationship between AGE accumulation and shoulder joint ROM was evaluated. Shoulder capsule tissue was harvested and subjected to histological and in vitro evaluation. Results: The DM group displayed high levels of AGEs and reactive oxygen species (ROS), and reduced cell viability. There was a significant positive correlation between ROS expression, apoptosis, and preoperative hemoglobin A1c. ROS expression, apoptosis, and ROM of the shoulder joint showed a negative correlation. The NADPH oxidase (NOX) expression and collagen III/I ratio were significantly higher in the DM group than in the non-DM group.Conclusions: The DM group showed significant AGE deposition in the shoulder capsule. Additionally, there was a significant association between AGEs and ROM limitation. The oxidative stress induced by AGE deposition, which leads to fibrosis and local inflammation, might contribute to the limited ROM of the shoulder joint.

The role of advanced glycation end products in patogenesis of diabetic nephropathy

Diabetes mellitus (DM) and chronic kidney disease are the diseases that have exceeded epidemic thresholds in terms of prevalence all over the world. That made it possible to classify them as non-communicable epidemics of the XXI century. Diabetic nephropathy (DN) is implicated with high levels of disablement and mortality. Advanced glycation end products (AGE) play a key role in the progression of DN. Increased formation of AGE occurs due to hyperglycemia under the conditions of diabetes. Moreover, there are additional factors in DN that increase the elaboration of AGE, such as high levels of oxidative stress and decreased renal clearance which slows down the AGE excretion. Both immediate effects of AGE and interaction of AGE with its cell-bound receptor (RAGE) result in a сascade of events that lead to further progression of DN. Thus, the research of the new therapeutic approaches targeted on the AGE-RAGE system is of great interest to slow progression of DN and improve the prognosis.