26 stricturing and penetrating disease complications. Recent technological advances have facilitated biomarker discovery by enabling high-throughput, high-resolution characterization of circulating proteins (proteomics) as well as circulating antibodies (immunosequencing). In this part, we continue our exploration of biomarkers by leveraging proximity extension assay technology, which was used to quantify 92 different inflammation-related plasma proteins in over 1,000 patients with IBD. Furthermore, we aimed to study the impact of genetics, disease phenotypes and dietary habits on protein variation in patients with IBD, since these factors may potentially affect inflammatory protein levels and thereby reveal relevant pathophysiological pathways and drug targets.82 In Chapter 11, we study the influence of phenotypic patient characteristics and patient genotypes on plasma inflammatory proteins in patients with IBD. In Chapter 12, we use the same technology to search for potential inflammatory biomarkers for fatigue in patients with clinically and biochemically quiescent IBD, and in Chapter 13 we study the influence of dietary habits of patients with IBD on their plasma inflammatory protein profile. PART III: OXIDATIVE STRESS BIOMARKERS IN IBD In Part III of this thesis, we shift our focus to the role of oxidative stress and hypoxia in IBD, with special attention for the role of systemic sulfhydryl groups (R-SH, reduced or “free” thiols) and HIF pathway activity as markers for systemic oxidative stress and hypoxia, respectively. In Chapter 14, we review the current knowledge on the role of oxidative stress in IBD, present a novel theoretical framework of redox signalling - referred to as the Reactive Species Interactome -, and discuss the potential of oxidative stress biomarkers and redox-modulating therapeutics in the context of IBD. In terms of biomarkers, systemic free thiol levels are mainly highlighted, as they represent the central components of the extracellular antioxidant machinery, form important transducers of redox-regulated events and capture the balance between total oxidant burden and antioxidant capacity in humans. Since free thiols rapidly scavenge ROS, lower levels of free thiols are generally associated with oxidative stress, whereas higher levels represent a favourable “healthy” redox status. In Chapter 15, we show that serum free thiols comprise a useful predictive tool with regard to the occurrence of future oxidative stress-mediated disease, in this case cardiovascular disease and all-cause mortality, in individuals from the general population. In Chapter 16, we test the hypothesis that serum free thiols may be reduced in patients with IBD and are associated with inflammatory disease activity. In Chapter 17, we further build on these findings by examining the discriminative capacity of serum free thiols with regard to endoscopic disease activity in patients with IBD. Finally, in Chapter 18, we zoom in on the interplay between HIF pathway activation and systemic iron status, as this may be underlying iron deficiency in patients with IBD. In this study, we investigate associations between serum iron status and activation of the HIF pathway and related target genes in mucosal biopsies of patients with IBD. Chapter 1
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