Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions

Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis

\ua9 2024 The Author(s). Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL+ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7+ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints

Antioxidants and the Inhibition of Gastric Luminal Nitrosative Stress; A Mechanism Relevant to Upper Gastrointestinal Malignancies

No abstract available

Antioxidants and the Inhibition of Gastric Luminal Nitrosative Stress; A Mechanism Relevant to Upper Gastrointestinal Malignancies

No abstract available

Dietary phenolic acids and ascorbic acid: influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids

Acid-catalyzed nitrosation and production of potentially carcinogenic nitrosative species is focused at the gastroesophageal junction, where salivary nitrite, derived from dietary nitrate, encounters the gastric juice. Ascorbic acid provides protection by converting nitrosative species to nitric oxide (NO). However, NO may diffuse into adjacent lipid, where it reacts with O2 to re-form nitrosative species and N-nitrosocompounds (NOC). In this way, ascorbic acid promotes acid nitrosation. Using a novel benchtop model representing the gastroesophageal junction, this study aimed to clarify the action of a range of water-soluble antioxidants on the nitrosative mechanisms in the presence or absence of lipids. Caffeic, ferulic, gallic, or chlorogenic and ascorbic acids were added individually to simulated gastric juice containing secondary amines, with or without lipid. NO and O2 levels were monitored by electrochemical detection. NOC were measured in both aqueous and lipid phases by gas chromatography-tandem mass spectrometry. In the absence of lipids, all antioxidants tested inhibited nitrosation, ranging from 35.9 Ý 7.4% with gallic acid to 93 Ý 0.6% with ferulic acid. In the presence of lipids, the impact of each antioxidant on nitrosation was inversely correlated with the levels of NO they generated (R2 = 0.95, p < 0.01): gallic, chlorogenic, and ascorbic acid promoted nitrosation, whereas ferulic and caffeic acids markedly inhibited nitrosation

24-Hour Movement Behaviors in Children with Chronic Disease and Their Healthy Peers: A Case-Control Study

Background: Time spent in 24-h movement behaviors is important to health and wellbeing in childhood, but levels of these behaviors in children with chronic disease are unknown. Methods: A case-control-study included 80 children with chronic disease; 20 with type 1 diabetes mellitus (T1DM), 20 with juvenile idiopathic arthritis (JIA), 20 with congenital heart disease (CHD), 20 with cystic fibrosis (CF); pair-matched individually for age, sex, and timing of measures with 80 healthy children. Habitual time spent in movement behaviors and step counts were all measured with an activPAL accelerometer over 7 days. Comparisons against recommendations and differences between the groups were made. Results: Time spent in physical activity and step counts/day were significantly lower in T1DM and CHD groups compared to controls. Only 20/80 children with chronic disease and 29/80 controls met step count recommendations. Sedentary time was significantly higher in children with CF compared to controls. Time spent asleep was slightly greater in children with chronic disease, significant only for the JIA group. Sleep disruption was consistently greater in those with chronic disease, reaching significance for T1DM, CHD, and CF groups. Conclusions: For some groups of children with chronic disease, 24-h movement behaviors may differ substantially from recommendations, and slightly but systematically from their healthy peers. Optimizing levels of 24-h movement behaviors should confer a number of benefits for child health, development, and wellbeing.</jats:p

24-hour movement behaviors in children with chronic disease and their healthy peers: a case-control study

Background: Time spent in 24-h movement behaviors is important to health and wellbeing in childhood, but levels of these behaviors in children with chronic disease are unknown. Methods: A case-control-study included 80 children with chronic disease; 20 with type 1 diabetes mellitus (T1DM), 20 with juvenile idiopathic arthritis (JIA), 20 with congenital heart disease (CHD), 20 with cystic fibrosis (CF); pair-matched individually for age, sex, and timing of measures with 80 healthy children. Habitual time spent in movement behaviors and step counts were all measured with an activPAL accelerometer over 7 days. Comparisons against recommendations and differences between the groups were made. Results: Time spent in physical activity and step counts/day were significantly lower in T1DM and CHD groups compared to controls. Only 20/80 children with chronic disease and 29/80 controls met step count recommendations. Sedentary time was significantly higher in children with CF compared to controls. Time spent asleep was slightly greater in children with chronic disease, significant only for the JIA group. Sleep disruption was consistently greater in those with chronic disease, reaching significance for T1DM, CHD, and CF groups. Conclusions: For some groups of children with chronic disease, 24-h movement behaviors may differ substantially from recommendations, and slightly but systematically from their healthy peers. Optimizing levels of 24-h movement behaviors should confer a number of benefits for child health, development, and wellbeing