Accumulation Of Advanced Glycation End Products Research Articles

MicroRNA-96 targets the INS/AKT/GLUT4 signaling axis: Association with and effect on diabetic retinopathy

BackgroundmiR-96-5p is a highly expressed microRNA in the retina of subjects with diabetes. The INS/AKT/GLUT4 signaling axis is the main cell signaling pathway of glucose uptake in cells. Here, we investigated the role of miR-96-5p in this signaling pathway. MethodsExpression levels of miR-96-5p and its target genes were measured under high glucose conditions, in the retina of streptozotocin-induced diabetic mice, in the retina of AAV-2-eGFP-miR-96 or GFP intravitreal injected mice and in the retina of human donors with diabetic retinopathy (DR). MTT, wound healing, tube formation, Western blot, TUNEL, angiogenesis assays and hematoxylin-eosin staining of the retinal sections were performed. ResultsmiR-96-5p expression was increased under high glucose conditions in mouse retinal pigment epithelial (mRPE) cells, in the retina of mice receiving AAV-2 carrying miR-96 and STZ-treated mice. Expression of the miR-96-5p target genes related to the INS/AKT/GLUT4 signaling pathway was reduced following miR-96-5p overexpression. mmu-miR-96-5p expression decreased cell proliferation and thicknesses of retinal layers. Cell migration, tube formation, vascular length, angiogenesis, and TUNEL-positive cells were increased. ConclusionsIn in vitro and in vivo studies and in human retinal tissues, miR-96-5p regulated the expression of the PIK3R1, PRKCE, AKT1, AKT2, and AKT3 genes in the INS/AKT axis and some genes involved in GLUT4 trafficking, such as Pak1, Snap23, RAB2a, and Ehd1. Because disruption of the INS/AKT/GLUT4 signaling axis causes advanced glycation end product accumulation and inflammatory responses, the inhibition of miR-96-5p expression could ameliorate DR.

Diphlorethohydroxycarmalol, a phlorotannin contained in brown edible seaweed Ishige okamurae, prevents AGE-related diabetic nephropathy by suppression of AGE-RAGE interaction

Advanced glycation end-products (AGEs) are complex and heterogeneous compounds generated through various steps and are naturally produced during the glycation reaction. Excessively generated AGEs bind to long-lived proteins such as collagen and cause renal dysfunction, leading to AGE-related diabetic nephropathy (DN). In this study, we aimed to confirm the therapeutic potential of marine biological resources by evaluating the role of diphlorethohydroxycarmalol (DPHC), a major phlorotannin compound contained in edible brown algae Ishige okamurae, in the key mechanisms involved in the pathogenesis and progression of AGE-induced DN. The AGE formation inhibitory and AGE-collagen cross-link inhibiting/breaking ability assay were performed to evaluate the anti-glycation effect of DPHC. The AGE-RAGE interaction inhibitory effect was evaluated through molecular docking study. The renoprotective effect of DPHC was confirmed in mouse glomerular mesangial cells. DPHC treatment exhibited anti-glycation ability through suppression of AGE formation and AGE-collagen cross-linking generation, and disruption of cross-links formed between AGE-collagen. In addition, DPHC pre-treatment significantly suppressed reactive oxygen species (ROS) production, intracellular methylglyoxal (MGO)/AGEs accumulation, and activation of apoptosis cascade by MGO. Moreover, DPHC suppressed AGE-receptor for AGE (RAGE) interaction by competing with MG-H1 for the binding site of RAGE. Furthermore, DPHC pre-treatment regulated apoptosis-related protein expression and increased Nrf2, Glo-1, HO-1, CAT, NQO1, and SOD1. These findings prove that the chemical structural characteristics of DPHC have the potential to prevent or manage AGE-induced DN by effectively mediating the key mechanisms responsible for its pathogenesis.

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.

Clinical Manifestation of AGE-RAGE Axis in Neurodegenerative and Cognitive Impairment Disorders.

The receptor of Advanced Glycation Endproducts (RAGE) and Advanced Glycation Endproducts (AGE) have multiple functions in our body and their restraint are being observed in neurodegenerative and memory impairment disorders. The review of different pathways allows an understanding of the probable mechanism of neurodegeneration and memory impairment involving RAGE and AGE. Commonly we observe AGE accumulation in neural cells and tissues but the extent of accumulation increases with the presence of memory impairment disorder. The presence of AGEs can also be seen in morbid accumulation, pathological structures in the form of amyloid clots, and nervous fibrillary tangles in Alzheimer's Disease (AD) and memory impairment disease.Many neuropathological and biochemical aspects of AD are explained by AGEs, including widespread protein crosslinking, glial activation of oxidative stress, and neuronal cell death. Oxidative stress is due to different reasons and glycation end products set in motion and form or define various actions which are normally due to AGE changes in a pathogenic cascade. By regulating the transit of ß-amyloid in and out of the brain or altering inflammatory pathways, AGE and it's ensnare receptor such as soluble RAGE may function as blockage or shield AD development. RAGE activates the transcription-controlling factor Necrosis Factor (NF-κB) and increases the protraction of cytokines, like a higher number of Tumor Necrosis Factor (TNF-α) and Interleukin (IL-I) by inducing several signal transduction cascades. Furthermore, binding to RAGE can pro-activate reactive oxygen species (ROS), which is popularly known to cause neuronal death.

Impaired pulp healing associated with underlying disorders in the dental pulp of rats with type 2 diabetes

Background/purposeType 2 diabetes mellitus (T2DM), characterized by hyperglycemia, is a systematic disease affecting structure and healing ability in various tissues. This study aimed to investigate whether T2DM could impair the dental pulp healing and cause underlying pathological changes in the dental pulp before an injury occurred. Materials and methodsGoto-Kakizaki rats were used as T2DM model animals and performed with direct pulp capping procedures on the first maxillary molars. The molars at 1, 2, 4 weeks after operation and non-injured molars were examined using hematoxylin and eosin staining, immunohistochemical staining, immunofluorescence staining, and Masson's trichrome staining. The fresh dental pulp of maxillary incisors was collected for transmission electron microscopy and glucose content evaluation. ResultsThe T2DM rats showed deficient reparative dentin formation compared with the healthy rats. Before the occurrence of an injury, underlying pathological changes of major components in the pulp tissue were observed in T2DM rats, including vasculopathy; collagen abnormalities; decreased proliferation, decreased odontogenetic differentiation and damaged ultrastructure of dental pulp cells. High glucose content and advanced glycation end products accumulation were further found in the pulp tissue in T2DM rats. ConclusionT2DM can impede pulp healing process in rats, which is associated with underlying pathological changes in the non-injured pulp caused by the advanced glycation end products accumulation under high-glucose conditions.

Osteosarcopenia in the Spine Beyond Bone Mineral Density: Association Between Paraspinal Muscle Impairment and Advanced Glycation Endproducts.

Prospective cross-sectional study. To determine if an accumulation of advanced glycation endproducts (AGEs) is associated with impaired paraspinal muscle composition. Impaired bone integrity and muscle function are described as osteosarcopenia. Osteosarcopenia is associated with falls, fragility fractures, and reduced quality of life. Bone integrity is influenced by bone quantity (bone mineral density) and quality (microarchitecture and collagen). The accumulation of AGEs stiffens collagen fibers and increases bone fragility. The relationship between paraspinal muscle composition and bone collagen properties has not been evaluated. Intraoperative bone biopsies from the posterior superior iliac spine were obtained and evaluated with multiphoton microscopy for fluorescent AGE cross-link density (fAGEs). Preoperative magnetic resonance imaging measurements at level L4 included the musculus (m.) psoas and combined m. multifidus and m. erector spinae (posterior paraspinal musculature, PPM). Muscle segmentation on axial images (cross-sectional area, CSA) and calculation of a pixel intensity threshold method to differentiate muscle (functional cross-sectional area, fCSA) and intramuscular fat (FAT). Quantitative computed tomography was performed at the lumbar spine. Univariate and multivariable regression models were used to investigate associations between fAGEs and paraspinal musculature. One hundred seven prospectively enrolled patients (50.5% female, age 60.7y, BMI 28.9kg/m 2 ) were analyzed. In all, 41.1% and 15.0% of the patients demonstrated osteopenia and osteoporosis, respectively. Univariate linear regression analysis demonstrated a significant association between cortical fAGEs and CSA in the psoas (ρ=0.220, P =0.039) but not in the PPM. Trabecular fAGEs revealed no significant associations to PPM or psoas musculature. In the multivariable analysis, higher cortical fAGEs were associated with increased FAT (β=1.556; P =0.002) and CSA (β=1.305; P =0.005) in the PPM after adjusting for covariates. This is the first investigation demonstrating that an accumulation of nonenzymatic collagen cross-linking product fAGEs in cortical bone is associated with increased intramuscular fat in the lumbar paraspinal musculature.

Evaluation of Dry Fasting Effect during Ramadan on Protein Glycation in Saudi Individuals

Introduction: The non-enzymatic protein glycation alters protein function and contributes to many biochemical disorders. The accumulation of advanced glycation end-products (AGEs) is associated with the complications of diabetes, kidney disease, metabolic disorders and degenerative diseases. 
 Objectives: This study was designed to measure the level of some glycated proteins such as glycated insulin and glycated hemoglobin in Saudi volunteers before and after dry fasting in Ramadan.
 Methods: Blood samples were collected twice; first sample (before) and second sample (after) dry fasting. The study included 45 Saudi male volunteers, whose ages ranged between23 and 52 years They were divided into four groups: healthy, type II diabetic patients, smokers, and obese individuals. Plasma glucose level and HbA1c were measured immediately using (Beckman coulter). Assessment of insulin resistance was determined using the equation of homeostasis model for insulin resistance (HOMA-IR). Plasma insulin level and glycated insulin % were assayed by TSQ Vantage Triple Stage Quadruple LC/MS Mass Spectrometer from Thermo Scientific.
 Results: Level of HbA1c, HOMA IR and glycated insulin in healthy, type II diabetic patients, smokers, and obese individuals showed significant decrease in the second sample. The level of HbA1c showed a significant decrease (p-value <0.0001) after dry fasting (5.69 ± 1.55 %), (6.14 ± 1.77%). The level of HOMA IR showed significant decrease (p-value <0.0001) after dry fasting (1.97 ± 1), (2.46 ± 1.28). The level of glycated insulin showed significant decrease (p-value <0.0001) after dry fasting (6.25 ± 2%), (7.71 ± 2.48%).
 Conclusion: Glucose, HbA1c, HOMA IR, and glycated insulin levels showed a significant decrease after dry fasting. Reduced protein glycation and formation of advanced glycation end products, can improve the clinical course of many medical disorders. More researches are needed to understand the molecular mechanisms behind glycation-induced clinical disorders and diseases, as well as to correlate these mechanisms to the diagnosis and prevention of lifestyle-related diseases.

Galectin-3 and RAGE differentially control advanced glycation endproduct-induced collagen damage in murine intervertebral disc organ culture.

Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE-induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE-induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration.

Camellia oleifera shells polyphenols inhibit advanced glycation end-products (AGEs) formation and AGEs-induced inflammatory response in RAW264.7 macrophages

Cammelia oleifera C.Abel (C. oleifera), a characteristic tropical economic crop, which is widely cultivated in Southern China. The fruit shells are a main by-product in the C. oleifera industry without high-value utilization. This work optimized the ultrasound-microwave synergistic extraction (UMSE) process of C. oleifera shells crude polyphenols (CSCP). The impacts of C. oleifera shells pure polyphenols (CSPP) on the advanced glycation end-products (AGEs) accumulation and AGEs-triggered inflammation were assessed. The results showed that the highest yield of CSCP reached 125.85 ± 5.34 mg extract/g dry shells under the optimum condition. Furthermore, CSPP exhibited intense anti-glycation action by scavenging free radicals and glycated intermediates, chelating transition metals, attenuating molecular aggregation, and conformational modification of BSA. Moreover, CSPP was found to dose-dependently block the AGEs-induced secretions of pro-inflammatory cytokines by inhibiting the downstream iNOS and COX-2 related MAPK/NF-κB pathway. These findings indicated that C. oleifera shells polyphenols could be a functional ingredient for preventing AGEs production and AGEs-induced inflammation.

Chemical Composition of Hazelnut Skin Food Waste and Protective Role against Advanced Glycation End-Products (AGEs) Damage in THP-1-Derived Macrophages.

Glycation and the accumulation of advanced glycation end-products (AGEs) are known to occur during aging, diabetes and neurodegenerative diseases. Increased glucose or methylglyoxal (MGO) levels in the blood of diabetic patients result in increased AGEs. A diet rich in bioactive food compounds, like polyphenols, has a protective effect. The aim of this work is to evaluate the capacity of hazelnut skin polyphenolic extract to protect THP-1-macrophages from damage induced by AGEs. The main polyphenolic subclass was identified and quantified by means of HPLC/MS and the Folin-Ciocalteu method. AGEs derived from incubation of bovine serum albumin (BSA) and MGO were characterized by fluorescence. Cell viability measurement was performed to evaluate the cytotoxic effect of the polyphenolic extract in macrophages. Reactive oxygen species' (ROS) production was assessed by the H2-DCF-DA assay, the inflammatory response by real-time PCR for gene expression, and the ELISA assay for protein quantification. We have shown that the polyphenolic extract protected cell viability from damage induced by AGEs. After treatment with AGEs, macrophages expressed high levels of pro-inflammatory cytokines and ROS, whereas in co-treatment with polyphenol extract there was a reduction in either case. Our study suggests that hazelnut skin polyphenol-rich extracts have positive effects and could be further investigated for nutraceutical applications.

Bone collagen quality in lumbar fusion patients: the association between volumetric bone mineral density and advanced glycation endproducts.

The sole determination of volumetric bone mineral density (vBMD) is insufficient to evaluate overall bone integrity. The accumulation of advanced glycation endproducts (AGEs) stiffens and embrittles collagen fibers. Despite the important role of AGEs in bone aging, the relationship between AGEs and vBMD is poorly understood. We hypothesized that an accumulation of AGEs, a marker of impaired bone quality, is related to decreased vBMD. Prospectively collected data of 127 patients undergoing lumbar fusion were analyzed. Quantitative computed tomography (QCT) measurements were performed at the lumbar spine. Intraoperative bone biopsies were obtained and analyzed with confocal fluorescence microscopy for fluorescent AGEs, both trabecular and cortical. Spearman's correlation coefficients were calculated to examine relationships between vBMD and fAGEs, stratified by sex. Multivariable linear regression analysis with adjustments for age, sex, body mass index (BMI), race, diabetes mellitus and HbA1c was used to investigate associations between vBMD and fAGEs. One-hundred and twenty-seven patients (51.2% female, 61.2years, BMI of 28.7kg/m2) with 107 bone biopsies were included in the final analysis, excluding patients on anti-osteoporotic drug therapy. In the univariate analysis, cortical fAGEs increased with decreasing vBMD at (r = -0.301; p = 0.030), but only in men. In the multivariable analysis, trabecular fAGEs increased with decreasing vBMD after adjusting for age, sex, BMI, race, diabetes mellitus and HbA1c (β = 0.99;95%CI=(0.994,1.000); p = 0.04). QCT-derived vBMD measurements were found to be inversely associated with trabecular fAGEs. Our results enhance the understanding of bone integrity by suggesting that spine surgery patients with decreased bone quantity may also have poorer bone quality.

In vitro glycation of a tissue-engineered wound healing model to mimic diabetic ulcers.

Diabetic foot ulcers are a major complication of diabetes that occurs following minor trauma. Diabetes-induced hyperglycemia is a leading factor inducing ulcer formation and manifests notably through the accumulation of advanced glycation end-products (AGEs) such as N-carboxymethyl-lysin. AGEs have a negative impact on angiogenesis, innervation, and reepithelialization causing minor wounds to evolve into chronic ulcers which increases the risks of lower limb amputation. However, the impact of AGEs on wound healing is difficult to model (both in vitro on cells, and in vivo in animals) because it involves a long-term toxic effect. We have developed a tissue-engineered wound healing model made of human keratinocytes, fibroblasts, and endothelial cells cultured in a collagen sponge biomaterial. To mimic the deleterious effects induced by glycation on skin wound healing, the model was treated with 300 µM of glyoxal for 15 days to promote AGEs formation. Glyoxal treatment induced carboxymethyl-lysin accumulation and delayed wound closure in the skin mimicking diabetic ulcers. Moreover, this effect was reversed by the addition of aminoguanidine, an inhibitor of AGEs formation. This in vitro diabetic wound healing model could be a great tool for the screening of new molecules to improve the treatment of diabetic ulcers by preventing glycation.

Effect of ribose incubation on physical, chemical, and mechanical properties of human cortical bone

Raman spectroscopy (RS) is sensitive to the accumulation of advanced glycation end-products (AGEs), and it measures matrix-sensitive properties that correlate with the fracture toughness of human cortical bone. However, it is unclear whether sugar-mediated accumulation of AGEs affects the fracture toughness of human cortical bone in a manner that is consistent with the negative correlations between amide I sub-peak ratios and fracture toughness. Upon machining 64 single-edge notched beam (SENB) specimens from cadaveric femurs (8 male and 7 female donors between 46 years and 61 years of age), pairs of SENB specimens were incubated in 15 mL of phosphate buffered saline with or without 0.1 M ribose for 4 weeks at 37 °C. After acquiring 10 Raman spectra per bone specimen (n = 32 per incubation group), paired SENB specimens were loaded in three-point bending at a quasi-static or a high loading rate approximating 10−4 s−1 or 10−2 s−1, respectively (n = 16 per incubation group per loading rate). While 2 amide I sub-peak ratios, I1670/I1640 and I1670/I1610, decreased by 3–5% with a 100% increase in AGE content, as confirmed by fluorescence measurements, the ribose incubation to accumulate AGEs in bone did not affect linear elastic (KIc) nor non-linear elastic (KJc) measurements of bone's ability to resist crack growth. Moreover, AGE accumulation did not affect the change in these properties when the loading rate changed. Increasing the loading rate increased KIc but decreased KJc. Ribose incubation did not affect mineral-related RS properties such as mineral-to-matrix ratios, Type B carbonate substitutions, and crystallinity. It did however increase the thermal stability of demineralized bone (differential scanning calorimetry), without affecting the network connectivity of the organic matrix (i.e., maximum slope during a hydrothermal isometric tension test of demineralized bone). In conclusion, RS is sensitive to AGE accumulation via the amide I band (plus the hydroxyproline-to-proline ratio), but the increase in AGE content due to ribose incubation was not sufficient to affect the fracture toughness of human cortical bone.

Advanced Glycation End Products and Bone Metabolism in Patients with Chronic Kidney Disease.

Advanced glycation end products (AGEs) accumulation may be involved in the progression of CKD-bone disorders. We sought to determine the relationship between AGEs measured in the blood, skin, and bone with histomorphometry parameters, bone protein, gene expression, and serum biomarkers ofbone metabolism in patients with CKD stages 3 to 5D patients. Serum levels of AGEs were estimated by pentosidine, glycated hemoglobin (A1c), and N-carboxymethyl lysine (CML). The accumulation of AGEs in the skin was estimated from skin autofluorescence (SAF). Bone AGEs accumulation and multiligand receptor for AGEs (RAGEs) expression were evaluated by immunohistochemistry; bone samples were used to evaluate protein and gene expression and histomorphometric analysis. Data are from 86 patients (age: 51 ± 13 years; 60 [70%] on dialysis). Median serum levels of pentosidine, CML, A1c, and SAF were 71.6pmol/mL, 15.2ng/mL, 5.4%, and 3.05 arbitrary units, respectively. AGEs covered 3.92% of trabecular bone and 5.42% of the cortical bone surface, whereas RAGEs were expressed in 0.7% and 0.83% of trabecular and cortical bone surfaces, respectively. AGEs accumulation in bone was inversely related to serum receptor activator of NF-κB ligand/parathyroid hormone (PTH) ratio (R=-0.25; p=0.03), and RAGE expression was negatively related to serum tartrate-resistant acid phosphatase-5b/PTH (R=-0.31; p=0.01). Patients with higher AGEs accumulation presented decreased bone protein expression (sclerostin [1.96 (0.11-40.3) vs. 89.3 (2.88-401) ng/mg; p=0.004]; Dickkopf-related protein 1 [0.064 (0.03-0.46) vs. 1.36 (0.39-5.87) ng/mg; p=0.0001]; FGF-23 [1.07 (0.4-32.6) vs. 44.1 (6-162) ng/mg; p=0.01]; and osteoprotegerin [0.16 (0.08-2.4) vs. 6.5 (1.1-23.7) ng/mg; p=0.001]), upregulation of the p53 gene, and downregulation of Dickkopf-1 gene expression. Patients with high serum A1c levels presented greater cortical porosity and Mlt and reduced osteoblast surface/bone surface, eroded surface/bone surface, osteoclast surface/bone surface, mineral apposition rate, and adjusted area. Cortical thickness was negatively correlated with serum A1c (R=-0.28; p=0.02) and pentosidine levels (R=-0.27; p=0.02). AGEs accumulation in the bone of CKD patients was related to decreased bone protein expression, gene expression changes, and increased skeletal resistance to PTH; A1c and pentosidine levels were related to decreased cortical thickness; and A1c levels were related to increased cortical porosity and Mlt. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

DF-5 COMPOUND DELAYS DEVELOPMENT OF DIABETIC NEPHROPATHY IN RATS

Advanced glycation end-products play an important role in the development of diabetic complications, so slowing down of glycated proteins’ cross-links formation have been suggested as a potential therapeutic option for the treatment of vascular diabetic complications and preventing their progression.The aim of the work was to assess the influence of novel anticrosslinking agent DF-5 on the renal advanced glycation end-products and collagen contents, body weight, blood glucose and glycated hemoglobin levels and the development of early renal disease in streptozotocin-induced diabetic rats.Materials and methods. 40 male Sprague-Dawley rats were used in the study. Two months after inducing diabetes, the study substance was administered intragastrically once a day for 28 days (12.5 mg/kg). Measurements included the assessment of blood glucose and HbA1c levels, the evaluation of the renal function, and the results of histology and immunohistochemical staining of kidneys.Results. A repeated intragastric administration of DF-5 for 30 days significantly reduced the level of HbA1c in the blood, but did not affect the level of fasting blood glucose. DF-5 compound significantly reduced proteinuria and prevented kidney damage in experimental animals by limiting damage of the glomeruli and tubules. It was found that DF-5 inhibits the progression of an early renal dysfunction in rats with streptozotocin-induced diabetic nephropathy. This was associated with a decreased accumulation of advanced glycation end-products in the kidney, accompanied by the improvement of both renal morphology and function.Conclusion. The results obtained provide investigators with additional therapeutic options for the treatment of diabetic nephropathy and possibly other complications of diabetes.

Advanced Glycation End-Products and Their Effects on Gut Health.

Dietary advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed when reducing sugars are heated with proteins, amino acids, or lipids at high temperatures for a prolonged period. The presence and accumulation of AGEs in numerous cell types and tissues are known to be prevalent in the pathology of many diseases. Modern diets, which contain a high proportion of processed foods and therefore a high level of AGE, cause deleterious effects leading to a multitude of unregulated intracellular and extracellular signalling and inflammatory pathways. Currently, many studies focus on investigating the chemical and structural aspects of AGEs and how they affect the metabolism and the cardiovascular and renal systems. Studies have also shown that AGEs affect the digestive system. However, there is no complete picture of the implication of AGEs in this area. The gastrointestinal tract is not only the first and principal site for the digestion and absorption of dietary AGEs but also one of the most susceptible organs to AGEs, which may exert many local and systemic effects. In this review, we summarise the current evidence of the association between a high-AGE diet and poor health outcomes, with a special focus on the relationship between dietary AGEs and alterations in the gastrointestinal structure, modifications in enteric neurons, and microbiota reshaping.

Modulation of the biophysical and biochemical properties of collagen by glycation for tissue engineering applications.

The structural and functional properties of collagen are modulated by the presence of intramolecular and intermolecular crosslinks. Advanced Glycation End-products (AGEs) can produce intermolecular crosslinks by bonding the free amino groups of neighbouring proteins. In this research, the following hypothesis is explored: The accumulation of AGEs in collagen decreases its proteolytic degradation rates while increasing its stiffness. Fluorescence Lifetime Imaging (FLIM) and Fourier-transform infrared spectroscopy (FTIR) detect biochemical changes in collagen scaffolds during the glycation process. The accumulation of AGEs increases exponentially in the collagen scaffolds as a function of Methylglyoxal (MGO) concentration by performing autofluorescence measurement and competitive ELISA. Glycated scaffolds absorb water at a much higher rate confirming the direct affinity between AGEs and interstitial water within collagen fibrils. In addition, the topology of collagen fibrils as observed by Atomic Force Microscopy (AFM) is a lot more defined following glycation. The elastic modulus of collagen fibrils decreases as a function of glycation, whereas the elastic modulus of collagen scaffolds increases. Finally, the enzymatic degradation of collagen by bacterial collagenase shows a sigmoidal pattern with a much slower degradation rate in the glycated scaffolds. This study identifies unique variations in the properties of collagen following the accumulation of AGEs. STATEMENT OF SIGNIFICANCE: In humans, Advanced Glycation End-products (AGEs) are naturally produced as a result of aging process. There is an evident lack of knowledge in the basic science literature explaining the biomechanical impact of AGE-mediated crosslinks on the functional and structural properties of collagen at both the nanoscale (single fibrils) and mesoscale (bundles of fibrils). This research, demonstrates how it is possible to harness this natural phenomenon in vitro to enhance the properties of engineered collagen fibrils and scaffolds. This study identifies unique variations in the properties of collagen at nanoscale and mesoscale following accumulation of AGEs. In their approach, they investigate the unique properties conferred to collagen, namely enhanced water sorption, differential elastic modulus, and finally sigmoidal proteolytic degradation behavior.

Phenolic Compounds as Preventive and Therapeutic Agents in Diabetes-Related Oxidative Stress, Inflammation, Advanced Glycation End-Products Production and Insulin Sensitivity.

Diabetes mellitus and its complications represent an extremely concerning health problem across the world. The extraordinary worldwide increase of the disease incidence highlights a challenging need for the development of new, safe, effective, and affordable therapeutic approaches. This complex disease, characterized by high blood sugar levels, involves numerous pathogenic processes in its etiology. Even though the molecular mechanisms behind are not clear, it is broadly recognized that oxidative stress, the accumulation of advanced glycation end-products (AGEs) and inflammation are implicated in the development, the progression and the related complications of the disease. In this regard, phenolic compounds represent a valuable therapeutic perspective. Thus, this review is focused on the role of phenolic compounds in diabetes-related oxidative stress, AGEs production and inflammation. In particular, we summarized recent results of in vitro and in vivo studies concerning antioxidant and antiglycative properties of phenolic compounds and also the modulation of activity on inflammation and inflammation-related pathways relevant in diabetes, namely arachidonic acid, nuclear factor-κB, mitogen-activated protein kinases and phosphatidylinositol 3‑kinase/protein kinase B signaling pathways, were described. Highlighting thus the anti-diabetic potential of phenolic compounds in the development of preventive or therapeutic strategies for the management of diabetes and its related complications.

Effect of non-enzymatic glycation on collagen nanoscale mechanisms in diabetic and age-related bone fragility.

Age and diabetes have long been known to induce an oxidative reaction between glucose and collagen, leading to the accumulation of advanced glycation end-products (AGEs) cross-links in collagenous tissues. More recently, AGEs content has been related to loss of bone quality, independent of bone mass, and increased fracture risk with aging and diabetes. Loss of bone quality is mostly attributed to changes in material properties, structural organization, or cellular remodeling. Though all these factors play a role in bone fragility disease, some common recurring patterns can be found between diabetic and age-related bone fragility. The main pattern we will discuss in this viewpoint is the increase of fibrillar collagen stiffness and loss of collagen-induced plasticity with AGE accumulation. This study focused on recent related experimental studies and discusses the correlation between fluorescent AGEs content at the molecular and fibrillar scales, collagen deformation mechanisms at the nanoscale, and resistance to bone fracture at the macroscale.

Advances in Research on the Mechanism of Association Between Periodontitis and Diabetes Mellitus

Periodontitis and diabetes mellitus are both chronic diseases with a rather high prevalence and they are closely associated with each other. On one hand, diabetes mellitus poses as a risk factor for periodontitis. On the other hand, periodontitis has a negative impact on glucose control in diabetic patients. The two-way relationship has aroused a lot of research interest in recent years. Herein, approaching the issue by looking at the effect of periodontitis on diabetes, we summarized the mechanism of the traditional periodontal pocket-blood circulation pathway and reviewed the role of the oral-gut axis in the mechanism, which has been proposed in recent years. In addition, regarding the impact of diabetes on periodontitis, we summarized new findings concerning changes in oral microbiota, abnormal levels of cytokines and adipokines, oxidative stress, unbalanced osteogenic and osteoclastic activities, and the accumulation of advanced glycation end-products. We hope this paper will be helpful for further studies on the mechanism of association between periodontitis and diabetes.