Does dietary fat affect advanced glycation end products and their receptors? A systematic review of clinical trials.

CONTEXT: Dietary fat seems to affect advanced glycation end products (AGEs) and their receptors. This systematic review assesses studies that evaluated the effect of dietary fat on markers of glycation. OBJECTIVE: The aim of this systematic review was to analyze the effect of dietary fat on markers of glycation and to explore the mechanisms involved. DATA SOURCES: This study was conducted according to PRISMA guidelines. PubMed, Cochrane, and Scopus databases were searched, using descriptors related to dietary fat, AGEs, and the receptors for AGEs. STUDY SELECTION: Studies were selected independently by the 3 authors. Divergent decisions were resolved by consensus. All studies that evaluated the effects of the quantity and quality of dietary fat on circulating concentrations of AGEs and their receptors in adults and elderly adults with or without chronic diseases were included. Initially, 9 studies met the selection criteria. DATA EXTRACTION: Three authors performed data extraction independently. Six studies were included. RESULTS: Consumption of a Mediterranean diet rich in monounsaturated fatty acids (MUFAs) and low in dietary AGEs reduced serum concentrations of AGEs, reduced expression of the receptor for AGE (RAGE), and increased expression of the AGE receptor 1 (AGER1) when compared with consumption of a Western diet rich in saturated fatty acids and dietary AGEs. Supplementation with omega-3 polyunsaturated fatty acids (PUFAs) resulted in decreased concentrations of fluorescent AGEs and decreased expression of RAGE as well as increased expression of AGER1. CONCLUSIONS: Increased consumption of MUFAs and omega-3 PUFAs and reduced consumption of saturated fatty acids seem to be effective strategies to beneficially affect glycation markers, which in turn may prevent and control chronic diseases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42021220489.

A Novel Splice Variant of Human TGF-ß Type II Receptor Encodes a Soluble Protein and Its Fc-Tagged Version Prevents Liver Fibrosis in vivo.

We describe, for the first time, a new splice variant of the human TGF-ß type II receptor (TßRII). The new transcript lacks 149 nucleotides, resulting in a frameshift and the emergence of an early stop codon, rendering a truncated mature protein of 57 amino acids. The predicted protein, lacking the transmembrane domain and with a distinctive 13-amino-acid stretch at its C-terminus, was named TßRII-Soluble Endogenous (TßRII-SE). Binding predictions indicate that the novel 13-amino-acid stretch interacts with all three TGF-ß cognate ligands and generates a more extensive protein-protein interface than TßRII. TßRII-SE and human IgG1 Fc domain were fused in frame in a lentiviral vector (Lv) for further characterization. With this vector, we transduced 293T cells and purified TßRII-SE/Fc by A/G protein chromatography from conditioned medium. Immunoblotting revealed homogeneous bands of approximately 37 kDa (reduced) and 75 kDa (non-reduced), indicating that TßRII-SE/Fc is secreted as a disulfide-linked homodimer. Moreover, high-affinity binding of TßRII-SE to the three TGF-ß isoforms was confirmed by surface plasmon resonance (SPR) analysis. Also, intrahepatic delivery of Lv.TßRII-SE/Fc in a carbon tetrachloride-induced liver fibrosis model revealed amelioration of liver injury and fibrosis. Our results indicate that TßRII-SE is a novel member of the TGF-ß signaling pathway with distinctive characteristics. This novel protein offers an alternative for the prevention and treatment of pathologies caused by the overproduction of TGF-ß ligands.

Effects of the age/rage axis in the platelet activation.

Platelet activity is essential in cardiovascular diseases. Therefore our objective was to evaluate the main effects of activating RAGE in platelets which are still unknown. A search for RAGE expression in different databases showed poor or a nonexistent presence in platelets. We confirmed the expression in platelets and secreted variable of RAGE (sRAGE). Platelets from elderly adults expressed in resting showed 3.2 fold more RAGE from young individuals (p < 0.01) and 3.3 fold with TRAP-6 (p < 0.001). These results could indicate that the expression of RAGE is more inducible in older adults. Then we found that activating RAGE with AGE-BSA-derived from methylglyoxal and subthreshold TRAP-6, showed a considerable increase with respect to the control in platelet aggregation and expression of P-selectin (respectively, p < 0.01). This effect was almost completely blocked by using a specific RAGE inhibitor (FSP-ZM1), confirming that RAGE is important for the function and activation platelet. Finally, we predict the region stimulated by AGE-BSA is located in region V of RAGE and 13 amino acids are critical for its binding. In conclusion, the activation of RAGE affects platelet activation and 13 amino acids are critical for its stimulation, this information is crucial for future possible treatments for CVD.

Soluble Receptor for Advanced Glycation End Products and Its Correlation with Vascular Damage in Adolescents with Obesity.

OBJECTIVE: The aim of this study was to evaluate soluble receptor for advanced glycation end products (sRAGE) and advanced glycation end products (AGEs) in adolescents with and without obesity (OB) and their correlation with vascular damage. METHODS: This is a cross-sectional study with 15-19 years old adolescents: 33 with OB and 33 with normal weight (NW), each group included 17 male and 16 female. Lipid profile, insulin, carboxymethylysine (CML), sRAGE, total AGEs, and dietary AGEs intake (dAGEs) were evaluated. Vascular damage was measured by flow-mediated vasodilation (FMD) and arterial stiffness index (Iß). Homeostatic model assessment-insulin (HOMA-IR) and atherogenic index (AI) were calculated. RESULTS: The group with OB had higher triglycerides (TG; p < 0.0001), AI (p < 0.001), HOMA-IR (p < 0.0001), dAGEs intake (p < 0.0001), lower CML (p = 0.05), total AGEs (p < 0.01), sRAGE (p < 0.001), and FMD (p < 0.002). In the total group, sRAGE correlated with AI (r = -0.26 p = 0.037); in the NW group, CML correlated with Iß (r = -0.36; p = 0.037); and in the group of adolescents with OB, sRAGE correlated with FMD (r = -0.37; p = 0.037) and Iß (r = 0.47; p = 0.006), while CML and total AGEs correlated with AI, p = 0.007 and p < 0.01, respectively). CONCLUSIONS: The group of adolescents with OB showed higher cardiometabolic risk as shown by higher TG, AI, HOMA-IR, and lower sRAGE and FMD. sRAGE correlated negatively with FMD and positively with Iß, so it could be suggested as a biochemical marker of impaired endothelial function.

Inflammatory mediators, muscle and functional performance of community-dwelling elderly women.

The purpose of this study was to investigate the correlation and association between inflammatory mediators and muscle and functional performance in elderly women. We conducted a cross-sectional study. Plasma concentrations of interleukin-6 (IL-6) and soluble receptor for tumor necrosis factor alpha (sTNFR1) were determined by enzyme-linked immune sorbent assay. The muscle performance was measured using a isokinetic dynamometer and assessment of handgrip strength was performed using a Jamar® dynamometer. Functional performance was assessed through a walking speed test. Statistical analysis was performed using the Pearson or Spearman correlation. The association between the variables was determined by multiple regression analysis. 221 volunteers (71.07±4.93 years) participated in the study. Plasma levels of IL-6 (0.87pg/mL) correlated with the power of the knee extensors (r=0.14; p=0.03) and the power of the knee flexors (r=0.16; p=0.01); the plasma levels of sTNFR1 (1051.70pg/mL) did not correlate with any dependent variable. The regression models showed that the variables IL-6, level of physical activity and depressive status explained 5.5% (R(2)=0.055, p<0.01) of average power of knee extensors variability. For the average power of knee flexors, the final model showed that the factors IL-6 and level of physical activity explained 4.1% (R(2)=0.041, p<0.01). There was no negative correlation between inflammatory mediators and muscle or physical performance in elderly women. These results may be explained by the fact that the cytokine levels did not reach the threshold needed to influence the muscle tissue and functionality of the participants.