Pseudomonas aeruginosa significantly increases expression of receptor for advanced glycation endproducts (RAGE) in the septicemia suffering patients

Receptor for Advanced Glycation Endproducts (RAGE) is a cell surface receptor, which recognizes several endogenous and exogenous molecules and subsequently induces expression of several molecules including chemokines. Chemokines are members of the cytokine superfamily and participate in several immune system functions, including cell migration, inflammation, angiogenesis/angiostasis etc. CXC ligand 11 (CXCL11) is an important chemokine which participates in the induction of appropriate immune responses against microbes, including bacteria. The main mechanisms responsible to overcome septicemia are yet to be clarified. Thus, it has been hypothesized that RAGE may participate in induction of CXCL11 in response to the microbial agents. Due to the fact that immune responses play key roles in limitation of infection, it has been proposed that RAGE may inhibit spread of septicemia. Therefore, in this project mRNA levels of RAGE and CXCL11 were explored in the patients suffering from septicemia versus healthy controls. RAGE and CXCL11 expression levels in the 80 subjects, including 40 septicemia patients and 40 healthy controls were explored using Real-Time PCR technique. Accordingly, by using the specific primer against RAGE and CXCL11 in a Rotorgene vehicle the mRNA levels have been determined. The septicemia and the sources of the bacteria in the blood were diagnosed using microbial cultures. The results demonstrated that although mRNA levels for RAGE and CXCL11 did not change in the septicemia patients vs. healthy controls, mRNA levels of RAGE were significantly higher in the patients infected by Pseudomonas aeruginosa compared to those infected by other bacteria, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii. RAGE and CXCL11 mRNA levels did not differ among male and female patients. Based on the results it seems that RAGE is a critical receptor against P. aeruginosa during septicemia and more investigations, especially on the RAGE down-stream molecules can clarify its main roles against P. aeruginosa.

Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: The Maastricht Study

Background Dicarbonyls are highly reactive compounds and major precursors of advanced glycation endproducts (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously, but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown. Objective To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs. Design In 2566 individuals of the population based Maastricht Study (age: 60±8 yrs, 50% males, 26% type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), by combining Food Frequency Questionnaires with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in >200 commonly-consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by UPLC-MS/MS. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE-Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardio-metabolic risk factors and lifestyle. Results Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/day, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β = 0.08, 95%CI [0.02,0.13]) and SAF (β = 0.12 [0.07,0.17]). Dietary GO was associated with plasma GO (β = 0.10 [0.04,0.16]) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF. Conclusions Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. Clinical Trial Registry number: The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems

Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems.

Natural Products as a Source of Inspiration for Novel Inhibitors of Advanced Glycation Endproducts (AGEs) Formation

Protein glycation, a post-translational modification found in biological systems, is often associated with a core defect in glucose metabolism. In particular, advanced glycation endproducts are complex heterogeneous sugar-derived protein modifications implicated in the progression of pathological conditions such as atherosclerosis, diabetic complications, skin diseases, rheumatism, hypertension, and neurodegenerative diseases. Undoubtedly, there is the need to expand the knowledge about antiglycation agents that can offer a therapeutic approach in preventing and treating health issues of high social and economic importance. Although various compounds have been under consideration, little data from clinical trials are available, and there is a lack of approved and registered antiglycation agents. Next to the search for novel synthetic advanced glycation endproduct inhibitors, more and more the efforts of scientists are focusing on researching antiglycation compounds from natural origin. The main purpose of this review is to provide a thorough overview of the state of scientific knowledge in the field of natural products from plant origin (e.g., extracts and pure compounds) as inhibitors of advanced glycation endproduct formation in the period between 1990 and 2019. Moreover, the objectives of the summary also include basic chemistry of AGEs formation and classification, pathophysiological significance of AGEs, mechanisms for inhibiting AGEs formation, and examples of several synthetic anti-AGEs drugs.

O-026 Advanced Glycation Endproducts: A new player in obesity related infertility

text Globally, 39% of the adult population is overweight or obese, with the prevalence of obesity following an upward trajectory over the recent decades (WHO). Up to 30% of women of reproductive age in Western countries are obese before conception, and obese women experience higher rates of infertility and pregnancy complications than lean women; however, the mechanisms underpinning obesity-related infertility are poorly understood. Advanced Glycation Endproducts (AGEs) are a proinflammatory modification of proteins exposed to sugars, formed through the Maillard reaction. AGEs are elevated four-fold in the uterine fluid of obese, infertile women, compared to lean. AGEs equimolar to those in the obese microenvironment negatively impact the functions of endometrial epithelial and stromal cells, and adhesion and invasion of trophoblast cells, reducing the potential for successful maternal-fetal interactions (Antoniotti et al., 2018). This research further investigated preimplantation embryo development and endometrial cell functions in the presence of AGEs equimolar to those in obese uterine fluid. Altered local environments in very early life can set offspring up for a lifetime of health or disease (DoHAD); thus, uterine AGEs may contribute to the prevalence of non-communicable disease in children of obese parents. Preimplantation mouse embryos were cultured in vitro with AGEs equimolar with uterine fluid concentrations from lean and obese women, and their development and implantation potential assessed. “Obese” AGEs did not impact the proportion of embryos reaching blastocyst stage by day 4, but significantly reduced the proportion of blastocysts hatching by day 5 (P < 0.01). AGEs equimolar with the obese uterine environment detrimentally impacted trophectoderm formation and function: reduced trophectoderm cell number (P < 0.01), reduced outgrowth on fibronectin (indicative of reduced implantation potential, (P < 0.01), but did not increase cell apoptosis (TUNEL assay). RAGE antagonism, but neither metformin nor antioxidants, improved trophectoderm cell number. Thus, obesity-associated AGEs link obesity and reduced fertility through poor placentation potential of embryos (Hutchison et al, 2020). Endometrial epithelial cell function was examined in the presence of lean and obese concentrations of AGEs. Obese AGEs significantly reduced the rate of proliferation (xCelligence real time cell analysis) of the endometrial epithelial cell line ECC-1 versus lean AGEs (P = 0.04). Antioxidants successfully restored the rate of proliferation in the presence of obese AGEs (P = 0.7 versus lean AGEs). Subsequently, human endometrial epithelial organoid culture was utilised as a more physiologically relevant experimental paradigm. When cultured as organoids, primary endometrial epithelial cells were functionally responsive to obesity-associated AGEs, expressing both RAGE and TLR4. The morphology of organoids in culture was not impacted by the presence of obese AGEs versus lean; however, the proliferation of epithelial cells retrieved from organoid culture was altered by obese AGEs versus lean. Obese AGEs also increased the secretion of proinflammatory CXCL16 versus vehicle control (P = 0.04) while increased secretion of other proinflammatory cytokines and chemokines including TNFa approached significance in the presence of obese AGEs. As the inflammatory milieu is altered in the uterine fluid of infertile women, elevated AGEs may promote an infertile endometrial inflammatory environment. AGEs link obesity and reduced fertility, being detrimental to preimplantation embryo development and endometrial cell function when present at concentrations equal to those in obese uterine fluid. Antioxidants and RAGE antagonism provide beneficial effects to cell function in the presence of obesity-associated AGEs. This research provides evidence supporting AGEs as a factor contributing to obesity related infertility, and as an emerging frontier for reproductive health. Clinically, reduction of uterine AGEs may improve fertility for obese couples wishing to conceive. Antoniotti et al (2018). Hum Rep. 33(4), 654-665. PMID: 29471449 Hutchison et al (2020). RBMO. 41(5), 757-766. PMID: 32972872