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Congenital hypothyroidism
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Genetic causes of thyroid hormone biosynthesis (dyshormonogenesis) encompass roughly 10–15% of PH and are usually AR/homozygous at presentation. Mild heterozygous variants can cause hypothyroidism that may or may not be detected by NBS. The thyroid hormone biosynthetic process requires several sequential steps that, if lacking, may cause PH. First, iodide in the blood accumulates in the thyroid cell via the basal membrane sodium/iodide symporter (NIS) and, subsequently, by the apical membrane pendrin complex (SLC26A4/PDS). Thyroid peroxidase (TPO) catalyzed the iodination of tyrosine residues on thyroglobulin (TG) as well as the coupling of these iodinated tyrosines to form 3,5,5’-triiodothyronine (T3) and 3,5,3’5’, tetraiodothyronine (T4). The organification process of TPO requires hydrogen peroxide produced by dual oxidase 1 (DUOX1) and dual oxidase 2 (DUOX2). The iodotyrosine dehalogenase 1 (DEHAL1) rescues and recycles iodotyrosines that are not incorporated into free thyroid hormone. A palpable goiter and familial history of CH are often present with disorders of thyroid hormone biosynthesis.
The Influence of Dietary Protein Modification During Food Processing on Food Allergy
Published in Andreas L. Lopata, Food Allergy, 2017
Additional to exogenous nitration also the acidic environment of the stomach has been discussed to support several pathways leading to protein nitration. Recirculation of nitrate and nitrite between gut and saliva might play a major role in the process of nitration. Ingestion of nitrate contained in green leafy vegetables such as spinach or lettuce may even increase salivary levels of nitrite as a considerable proportion of nitrate can be reduced by facultative anaerobe bacteria in the oral cavity (Oldreive and Rice-Evans 2001, Lundberg et al. 2004). Protonation of nitrite in the stomach yields nitrous acid that can be decomposed to NO and NO2 giving rise to other potent reactive nitrogen species (RNS). High concentrations of NO and O2, a condition which might exclusively occur in the stomach, enable NO auto-oxidation to NO2 (Rocha et al. 2012). Furthermore, dual oxidase 2 expressed in epithelial cells of the gastrointestinal tract (El Hassani et al. 2005) can provide O2- for the formation of peroxynitrite. Peroxynitrite exists in equilibrium with its protonated conjugate peroxynitrous acid (ONOOh, pKa = 6.8) at a pH dependent ratio (Radi et al. 2001). Homolytic cleavage of peroxynitrous acid results in formation of the strong nitrating species NO2 and hydroxyl radicals (Yeo et al. 2008). Even in the gastric lumen, peroxynitrite could react with carbon dioxide that is present in the gastric headspace to form the intermediate nitroso-peroxocarbonate (ONOOCO2-). ONOOCO2- is decomposed to NO2 and a carbonate radical (CO3-) contributing to tyrosine nitration (Radi et al. 2001, Rocha et al. 2012). As a result, physiological conditions in the stomach allow the presence of both, oxidants and nitrating species, which might interact with proteins to form 3-NT.
Drug discovery strategies for modulating oxidative stress in gastrointestinal disorders
Published in Expert Opinion on Drug Discovery, 2020
Taraneh Mousavi, Nastaran Hadizadeh, Shekoufeh Nikfar, Mohammad Abdollahi
Across the GI tract, immune cells, particularly macrophages, neutrophils, and polymorphonuclear cells, are considered as the primary and main sources of free radicals generation, followed by epithelial cells as the secondary factor. Under acute or chronic inflammatory conditions, an increment in the generation of cytokines and chemokines leads to the accumulation of phagocytic cells, i.e., neutrophils, and macrophages in the submucosal layer. A large amount of oxygen is consumed during phagocytosis, which is then converted to superoxide radical (O2− .) through phagocytic NADPH oxidase or NOX-2. Besides NOX-2, 6 other subtypes of NADPH are expressed in the GI tract, among which NOX-1 and dual oxidase-2 (DUOX-2) are the most abundant; the first is known as ‘colon NADPH oxidase’, and the latter is mostly expressed in the colon and the cecum.
Neuroblast Differentiation-Associated Protein Derived Polypeptides: AHNAK(5758-5775) Induces Inflammation by Activating Mast Cells via ST2
Published in Immunological Investigations, 2023
Xiangjin Song, Lei Zhang, Xueshan Du, Yi Zheng, Tao Jia, Tong Zhou, Delu Che, Songmei Geng
The inflammatory waterfall in psoriasis can be caused by both endogenous and exogenous factors. Short-chain fatty acids from gut are reported to activate GPR43 on immune cells and induce dual oxidase 2/reactive oxygen species and IL-6 signaling in psoriasis-like inflammation (Nadeem et al. 2017). Other endogenous substances, such as polypeptides and cathelicidin, can also trigger and enhance psoriatic inflammation. Therefore, it remains to be determined whether AHNAK or AHNAK-derived peptides act as ligands that activate innate immune cells and participate in the psoriatic inflammatory response.
Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes
Published in Gut Microbes, 2022
Jacob M. Allen, Amy R. Mackos, Robert M. Jaggers, Patricia C. Brewster, Mikaela Webb, Chia-Hao Lin, Chris Ladaika, Ronald Davies, Peter White, Brett R. Loman, Michael T. Bailey
Despite no transcriptional changes of key IEC stress-response genes in GF mice, we deemed it reasonable that endogenous host stress signals may still play a role in mediating IEC physiology, albeit in combination with microbial signals. To explore this hypothesis, we exposed another cohort of GF mice to an identical social disruption paradigm (Str) followed by IEC isolation and culture for 2 h. Cultured IECs were then subjected to an additional 2 h of immune challenge with bacterial-derived lipopolysaccharide (LPS) or flagellin (FLG) before RNA isolation and gene expression analysis. In analyzing a subset of 6 genes in IECS that were altered by Str in CONV-R, we found that dual oxidase 2 (Duox2) and nitric oxide synthase 2 (Nos2), two genes involved in ROS production, were primed by Str to over-respond to FLG and LPS challenges, respectively (Stress x LPS/FLG p < .05, Figure 4(a),). Stress exposure did not affect the response of other selected genes (Fut2, Saa1, Il18, RegIIIb) to an ex vivo challenges (Str x LPS/FLG, p > .05; Figure 4(a), Table S1). We reasoned that a Str-induced increase in the expression of toll-like receptor-4 (TLR)-4 (the canonical host receptor for LPS) or toll-like receptor-5 (TLR)-5 (the canonical host receptor for FLG) may underlie the potentiation of Duox2 or Nos2 expression by Str. However, we failed to find any significant Str-induced changes to IEC expression of Tlr4 or Tlr5 at baseline or in response to an ex vivo bacterial challenge in GF mice (Str x LPS/FLG p > .05; Figure S5a). To determine if these host-microbiota interactions were dependent on an intact microbiota in-vivo, we next used identical stress and ex vivo methods in CONV-R mice, focused on IEC expression of the same target genes described above. Unlike in GF mice, we did not observe any interactions of Str and ex vivo immune challenge on IEC gene expression in CONV-R mice. Nevertheless, we again observed strong main effects of Str on expression of Duox2 and Nos2 (as well as Fut2, Saa1 and Reg3b) across all ex vivo conditions (p < .05; Figure S5b and Table S2). We deemed it possible that the difference in GF and CONV-R mice responses to FLG and LPS challenge may be related to Toll-like receptor expression in IECs. However, we failed to find any differences in IEC Tlr4 or Tlr5 expression in GF vs CONV-R mice (Figure S5c). In light of the unique sensitivity of Duox2 to Str and ex vivo challenges, we next investigated whether colonic DUOX2 protein mimicked gene expression changes. Indeed, immunofluorescence of colonic tissue revealed higher levels of colonic DUOX2 protein expression in Str mice, with notable fluorescence signaling observed on the luminal side of the epithelium (p < .05; Figure 4(b)).