Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer.

Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the "cancer hallmarks" of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.

Plasma advanced glycation end products and soluble receptor for advanced glycation end products as indicators of sterol content in human carotid atherosclerotic plaques.

Advanced glycation end products (AGEs) are independently related to cardiovascular disease (CVD) and favor cholesterol and oxysterol accumulation in macrophage foam cells. Soluble RAGE (sRAGE) impairs cellular AGE signaling alleviating the deleterious effects of AGE in atherogenesis. The association between plasma AGEs and sRAGE with the content of cholesterol, markers of cholesterol synthesis and absorption, and oxysterols in atherosclerotic plaques was evaluated in subjects undergoing carotid endarterectomy.Plasma and carotid plaques were obtained from symptomatic (n = 23) and asymptomatic subjects (n = 40). Lipids from plaques were extracted and sterols (oxysterols, cholesterol, desmosterol, lathosterol, sitosterol, and campesterol) were determined by using gas chromatography/mass spectrometry. Plasma total AGEs and pentosidine were measured by using fluorimetry and sRAGE by using ELISA.In symptomatic subjects´ atherosclerotic plaques, an increased amount of cholesterol (3x) and oxysterols [7 α-hydroxycholesterol (1.4x); 7 ß-hydroxycholesterol (1.2x); 25-hydroxycholesterol (1.3x); 24-hydroxycholesterol (2.7x), and 27-hydroxycholesterol, (1.15x)], with exception to 7 ketocholesterol, were found in comparison to asymptomatic individuals. Plasma total AGEs and pentosidine significantly and positively correlated to sterols accumulated in the atherosclerotic lesion, including cholesterol, desmosterol, campesterol, sitosterol, and oxysterols. On the other hand, sRAGE inversely correlated to total AGEs and pentosidine in plasma, and with major species of oxysterols, cholesterol, and markers of cholesterol synthesis and absorption in the atherosclerotic lesion. In multiple regression analyses, it was observed a significant inverse correlation between sRAGE and 24-hydroxycholesterol and desmosterol, and a positive significant correlation between pentosidine and 24-hydroxycholesterol, 27-hydroxycholesterol, and campesterol.In conclusion, the plasma concentration of AGEs and sRAGE is a tool to predict the accumulation of sterols in atherosclerotic lesions in symptomatic and asymptomatic individuals, helping to prevent and improve the management of acute cardiovascular complications.

Diabetic nephropathy patients show hyper-responsiveness to N6-carboxymethyllysine

The aim of this study was to evaluate the impact of N6-carboxymethyllysine (CML) on NF-κB gene expression and tumor necrosis factor (TNF) production in diabetic nephropathy. This was an observational study comprised of three groups: diabetic nephropathy (n=30), type II diabetes mellitus (n=28), and healthy volunteers (n=30). Blood samples collected from the study participants were cultured for 24 h in the presence of CML or an appropriate control. After incubation, the cultures were centrifuged to separate the cells from the conditioned media. cDNA was prepared from the cell pellet and used to quantify NF-κB gene expression by quantitative real-time polymerase chain reaction (PCR). The conditioned media were used to measure TNF production by enzyme-linked immunosorbent assay (ELISA). The CML-induced fold change in NF-κB gene expression was significantly different among the study groups (P=5.4×10-5). Also, the CML-induced fold change in TNF levels was significantly different among the three groups (P=4.3×10-8). These results imply that patients with diabetic nephropathy and type II diabetes mellitus showed an elevated response to CML.

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus.

In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM.

Can advanced glycation end-products and their receptors be affected by weight loss? A systematic review.

Advanced glycation end products (AGEs) have been implicated in the pathogenesis of most chronic diseases. Therefore, identification of treatments that can attenuate the effects of these compounds and prevent cardiometabolic complications is of extreme public health interest. Recently, body weight management interventions showed positive results on reducing serum AGE concentrations. Moreover, the soluble receptor for advanced glycation end products (sRAGE) is considered to be a novel biomarker to identify patients with obesity most likely to benefit from weight management interventions. This systematic review aimed to critically analyze papers evaluating the effects of weight loss on serum AGEs and its receptors in adults with excess body weight. MEDLINE, Cochrane, Scopus, and Lilacs databases were searched. Three studies evaluating the response of AGEs to energy-restricted diets and six assessing sRAGE as the primary outcome were included. Energy-restricted diets and bariatric surgery reduced serum AGE concentrations, but effects on endogenous secretory RAGE (esRAGE) and sRAGE concentrations are conflicting. These results may be associated with mechanisms related to changes in dietary intake and limiting endogenous AGE formation. Therefore, the role of energy-restricted diets and bariatric surgery on lowering serum AGE concentrations, as well as its effects on AGEs receptors, deserves further investigation.

Effect of reducing dietary advanced glycation end products on obesity-associated complications: a systematic review.

CONTEXT: Consumption of dietary advanced glycation end products (AGEs) is associated with oxidative stress, inflammation, and other chronic conditions commonly associated with obesity. OBJECTIVE: To analyze the effects of dietary AGEs on complications associated with obesity. DATA SOURCES: This systematic review was conducted and reported according to PRISMA guidelines. The PubMed, Cochrane, and Scopus databases were searched, using the terms "advanced glycation end products," "overweight," and "obesity." The last search was performed in October 2018. DATA EXTRACTION: Six studies that evaluated the effects of low-AGE and high-AGE diets were included in the review. The duration of the studies ranged from 1 day to 12 weeks. A comparison of all the compiled data was conducted by the authors. DATA ANALYSIS: Circulating and urinary AGE markers, besides soluble receptor for AGEs, were considered as the primary outcomes. The secondary outcomes were cardiometabolic, inflammatory, glycemic, anthropometric, and renal markers. CONCLUSIONS: AGE-RAGE interactions can activate the NF-κB (nuclear factor kappa B) signaling pathway and inhibit the PI3K-AKT pathway in adipocytes, which may explain their association with chronic diseases. This interaction can be considered as a novel explanation for the pathogenesis of obesity. AGEs can also be used as a biomarker for monitoring responses to dietary interventions in overweight and obese people. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018082745.

3'-O-ß-d-glucopyranosyl-α,4,2',4',6'-pentahydroxy-dihydrochalcone, from Bark of Eysenhardtia polystachya Prevents Diabetic Nephropathy via Inhibiting Protein Glycation in STZ-Nicotinamide Induced Diabetic Mice.

Previous studies have shown that accumulation of advanced glycation end products (AGEs) can be the cause of diabetic nephropathy (DN) in diabetic patients. Dihydrochalcone 3'-O-ß-d-glucopyranosyl α,4,2',4',6'-pentahydroxy⁻dihydrochalcone (1) is a powerful antiglycation compound previously isolated from Eysenhardtia polystachya. The aim was to investigate whether (1) was able to protect against diabetic nephropathy in streptozotocin (STZ)-induced diabetic mice, which displayed renal dysfunction markers such as body weight, creatinine, uric acid, serum urea, total urinary protein, and urea nitrogen in the blood (BUN). In addition, pathological changes were evaluated including glycated hemoglobin (HbA1c), advanced glycation end products (AGEs) in the kidney, as well as in circulation level and pro-inflammatory markers ICAM-1 levels in diabetic mice. After 5 weeks, these elevated markers of dihydrochalcone treatment (25, 50 and 100 mg/kg) were significantly (p < 0.05) attenuated. In addition, they ameliorate the indices of renal inflammation as indicated by ICAM-1 markers. The kidney and circulatory AGEs levels in diabetic mice were significantly (p < 0.05) attenuated by (1) treatment. Histological analysis of kidney tissues showed an important recovery in its structure compared with the diabetic group. It was found that the compound (1) attenuated the renal damage in diabetic mice by inhibiting AGEs formation.

Dietary advanced glycated end-products and medicines influence the expression of SIRT1 and DDOST in peripheral mononuclear cells from long-term type 1 diabetes patients.

Quantitative polymerase chain reaction was employed to quantify expression of two genes coding for advanced glycation end-product receptors [RAGE ( AGER) and AGER1 ( DDOST)] and of the gene coding the deacetylase SIRT1 ( SIRT1) in peripheral blood mononuclear cells from type 1 diabetes patients without [Group A, n = 35; 28.5 (24-39) years old; median (interquartile interval)] or with at least one microvascular complication [Group B, n = 117; 34.5 (30-42) years old]; 31 healthy controls were also included. In a subgroup of 48 patients, daily advanced glycation end-products intake before blood collection was assessed. Lower expression of DDOST was found in patients than in controls after adjustment for sex, age, use of statins, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Higher expressions of AGER, DDOST and SIRT1 were observed in Group A. Stratifying by complications, AGER and DDOST expressions were higher in those without retinopathy and without diabetic kidney disease, respectively, compared to patients with these complications. Patients using statins or angiotensin receptor blockers presented higher expression of DDOST. Expression of SIRT1 was higher in patients consuming ≥12,872 KU daily of advanced glycation end-products. Although AGER, DDOST and SIRT1 are differently expressed in peripheral blood mononuclear cells from type 1 diabetes patients with and without microvascular complications, they are also influenced by dietary advanced glycation end-products and by statins and angiotensin receptor blockers.

Dietary Advanced Glycation End Products and Cardiometabolic Risk.

PURPOSE OF REVIEW: This report analyzes emerging evidence about the role of dietary advanced glycation end products (AGEs) as a cardiometabolic risk factor. Two important aspects are discussed: First, the modulation of AGE load by dietary AGEs; second, if the evidence of clinical and observational studies is enough to make dietary recommendations towards lowering AGE intake. RECENT FINDINGS: Clinical studies in subjects with diabetes mellitus have shown that high intake of dietary AGEs increases inflammation markers, oxidative stress, and could impair endothelial function. In subjects at risk for cardiometabolic diseases (with overweight, obesity, or prediabetes), dietary AGE restriction decreases some inflammatory molecules and improves insulin sensitivity. However, studies in healthy subjects are limited, and not all of the studies have shown a decrease in circulating AGEs. Therefore, it is still unclear if dietary AGEs represent a health concern for people potentially at risk for cardiometabolic diseases. The evidence shows that dietary AGEs are bioavailable and absorbed, and the rate of excretion depends on dietary intake. The metabolic fate of most dietary AGEs remains unknown. Regardless, most studies have shown that by diminishing AGE intake, circulating levels will also decrease. Thus, dietary AGEs can modulate the AGE load at least in patients with DM, overweight, or obesity. Studies with specific clinical outcomes and large-scale observational studies are needed for a better risk assessment of dietary AGEs and to establish dietary recommendations accordingly.

Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

Apocynin decreases AGEs-induced stimulation of NF-κB protein expression in vascular smooth muscle cells from GK rats.

CONTEXT: Elevated oxidative stress plays a key role in diabetes-associated vascular disease. Excessive production of reactive oxygen species via advanced glycation end products (AGEs) activates peroxisome proliferator-activated receptor gamma (PPARγ) and the transcription factor nuclear factor-kB (NF-κB) in aortic vascular smooth muscle cells (VSMCs). Apocynin, a drug with an antioxidant effect, has also been proposed as a therapeutic agent for atherosclerotic disease. OBJECTIVES: This work investigates the effects of apocynin on the PPARγ and NF-κB protein expression evoked by AGEs in cultured VSMCs from Goto-Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. MATERIALS AND METHODS: VSMCs, isolated from aortas of GK and non-diabetic rats, were cultured. The expression of proteins was evaluated by Western blot. The blood glucose concentration was measured with a blood glucose test meter. The diabetes of GK rats was controlled by blood glucose and insulin determinations (non-fasting values). The serum insulin concentration was determined by radioimmunoassay. RESULTS: In VSMCs from non-diabetic and GK rats, apocynin (1 and 10 µM) abolished the protein overexpression of NF-κB induced by glycated bovine serum albumin (AGEs-BSA) incubation. However, apocynin (1 and 10 µM) enhanced the expression of PPARγ protein in the presence of AGEs-BSA (100 µg/mL) in VSMCs from non-diabetic, but not from GK rats. CONCLUSION: These findings suggest that apocynin decreases the incidence of alterations in VSMCs induced by AGEs through the reduction of NF-κB and may represent an attractive therapeutic approach to treat diabetes mellitus.

Glicação não enzimática de proteínas na gênese da nefropatia diabética / Glycation end products of proteins in the pathogenesis of diabetic nephropathy

Realizou-se uma pesquisa em base de dados para avaliar os produtos finais da glicação de proteínas na patogênese da nefropatia diabética. Diabetes melito é uma doença crônico-degenerativa, com uma incidência crescente em todo o mundo. Sua principal característica é a hiperglicemia, que está associada com complicações micro e macrovasculares aumentando o risco de morte cardiovascular, nefropatia,retinopatia e neuropatia. A nefropatia diabética afeta até 40% dos pacientes com diabetes melito tipo 1 e tipo 2 e é a principal causa de insuficiência renal crônica e necessidade de diálise. Os principais fatores de risco para o seu desenvolvimento são predisposição genética, falta de controle da glicemia e hipertensão. Nesta revisão, aponta-se os produtos de glicação avançada (AGEs) produzidos pela falta de controle glicêmico como sendo um fator de risco adicional atuando em conjunto com os tradicionais. Os AGEs podem causar esclerose glomerular, fibrose intersticial e atrofia tubular. Novos tratamentos que visam a prevenir a formação e deposição de AGEs pode ser uma nova alternativa para a prevenção ou tratamento da nefropatia diabética.

A search in medical data banks for glycation end products of proteins in the pathogenesis of diabetic nephropathy was done. Diabetes Mellitus is a chronic degenerative disorder with an increasing incidence throughout the world. Its main feature is hyperglycemia that is associated with micro and macrovascular complications increasing the risk of cardiovascular death,nephropaty, retinopathy and neuropathy. Diabetic nephropathy affects up to 40% of patients with Diabetes Mellitus Type 1 and type 2 and is the leading cause of chronic renal failure and need of dialysis. The main risk factors for its development are genetic predisposition, poor glycemic control and hypertension. In this review, the advanced glycation end products (AGEs) produced by poor glycemic control was found to be an additional risk factor acting together with the traditional ones. The AGEs can cause glomerular sclerosis, interstitial fibrosis and tubular atrophy. New treatments aiming prevent formation and deposition of AGEs could be an new alternative for prevention or treatment of diabetic nephropathy.