The receptor for advanced glycation endproducts: A potential role in systemic sclerosis

Systemic sclerosis (SSc) is a very heterogeneous disease; every patient with SSc is unique, with variable presentation of clinical features. Furthermore, the disease can show variable activity within one patient. Therefore, correctly characterising the pathophysiological processes that contribute to the early disease course is crucial. In this thesis, we showed that the receptor for advanced glycation endproducts (RAGE) is involved as one of the multiple pathways, and we attempted to make translational steps to clinical application in patients with SSc. RAGE is a cell surface receptor and can bind molecules such as advanced glycation endproducts (AGEs) and high mobility group box 1 (HMGB1), leading to inflammation. The AGE-RAGE axis can be assessed non-invasively using the AGE Reader, as well as measuring the soluble form of RAGE (sRAGE) as a potential serum biomarker for pulmonary arterial hypertension and its outcome. Furthermore, we showed that detecting active calcification in calcinosis cutis is feasible, further characterising specific disease activity in individual patients. The studies presented in this thesis should be considered proofs of concepts that underline the need for further validation of these methods, thereby paving the way for better personalised medicine in patients with SSc

Multidiameter single-fiber reflectance spectroscopy of heavily pigmented skin:modeling the inhomogeneous distribution of melanin

When analyzing multidiameter single-fiber reflectance (MDSFR) spectra, the inhomogeneous distribution of melanin pigments in skin tissue is usually not accounted for. Especially in heavily pigmented skins, this can result in bad fits and biased estimation of tissue optical properties. A model is introduced to account for the inhomogeneous distribution of melanin pigments in skin tissue. In vivo visible MDSFR measurements were performed on heavily pigmented skin of type IV to VI. Skin tissue optical properties and related physiological properties were extracted from the measured spectra using the introduced model. The absorption of melanin pigments described by the introduced model demonstrates a good correlation with the co-localized measurement of the well-known melanin index. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License

The soluble receptor for advanced glycation end products is potentially predictive of pulmonary arterial hypertension in systemic sclerosis

IntroductionPulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications.MethodsOne hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants.ResultsAt baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001).ConclusionsHigh systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc

Release of High-Mobility Group Box-1 after a Raynaud’s Attack Leads to Fibroblast Activation and Interferon-γ Induced Protein-10 Production: Role in Systemic Sclerosis Pathogenesis

Raynaud’s Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-β1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-β1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc

Microbial Phenolic Metabolites Are Associated with Improved Cognitive Health<br />

Scope: Diets rich in polyphenols has been associated with better cognitive performance. The aim of this study is toassess the relationship between microbial phenolic metabolites (MPM) in urine and cognition in the context of an olderpopulation at high cardiovascular risk.Methods and results: A cross-sectional analysis is conducted in 400 individuals of the PREDIMED-Plus study. Liquidchromatography coupled to mass spectrometry is used to identify urinaryMPM.Mediterranean diet (MedDiet) adherenceis estimated with a 17-item questionnaire and cognitive function is evaluated with a battery of neuropsychological tests.Multivariable-adjusted linear regression models are fitted to assess the relationship of urinary MPM with the MedDietand cognitive tests. Protocatechuic acid and enterolactone glucuronide are associated with higher adherence to theMedDiet. Regarding cognitive function, protocatechuic acid, vanillic acid glucuronide, 3-hydroxybenzoic acid, enterodiolglucuronide, and enterolactone glucuronide are directly associated with a global composite score of all the cognitive tests.Furthermore, protocatechuic acid and enterolactone glucuronide are associated with higher scores in the Mini-MentalState Examination, whereas enterodiol glucuronide is associated with improved Clock Drawing Test scores.Conclusions: These results suggest that the MedDiet is linked to MPM associated with better cognitive performance inan older population.</p