“…7 K–L). These results confirm the dependence of the expression of some cytokines on the export of mitochondrial citrate to maintain acetyl-CoA levels and NAD + /NADH redox balance [ 40 , 41 ]. Fig.…”
“…7 K–L). These results confirm the dependence of the expression of some cytokines on the export of mitochondrial citrate to maintain acetyl-CoA levels and NAD + /NADH redox balance [ 40 , 41 ]. Fig.…”
“…The generation of pyruvate and the translocation of PDH to the nucleus was identified as a pivotal step, indispensable for producing acetyl-CoA, which, in turn, is essential for the remodeling of enhancers triggered by T cell activation. PDH has also been found to be essential for histone acetylation and subset-specific gene expression in Th17 cells 4 . In this study, we demonstrate that PDH inhibition abrogates the expression of SF-induced genes ( Figure 5b ).…”
Section: Discussionmentioning
confidence: 99%
“…Upon activation of the T-cell receptor (TCR), a metabolic program is initiated that not only enhances mitochondrial function but also engages aerobic glycolysis 3 . Recent studies have identified an essential role for glycolysis in orchestrating epigenetic and transcriptional changes during T-cell activation and differentiation [4][5][6][7] . However, it remains unclear how this is impacted when considering inflammatory environments.…”
Juvenile Idiopathic Arthritis (JIA) describes a heterogeneous group of autoimmune conditions with an unknown cause and childhood onset. It is characterized by the accumulation of mononuclear cells, notably activated CD4+ memory/effector T (Tmem/Teff) cells, within the synovial fluid of affected joints. JIA CD4+ T cells exhibit a unique epigenomic signature linked to inflammation, however, the molecular mechanisms driving this remain unclear. Here we show that CD4+ T cells isolated from JIA synovial fluid (SF) exhibit abnormal intracellular metabolism marked by heightened glycolysis after activation driving transcriptional reprogramming. Epigenetic profiling between activated healthy controls and JIA patients allowed the definition of specific disease-related enhancers upregulated in SF-derived JIA CD4+ T cells. Pharmacological inhibition of glycolytic flux affected the expression of genes associated with these enhancers. When activated in the presence of JIA SF, CD4+ T cells obtained from healthy control (HC) subjects, displayed heightened glycolytic activity compared to paired plasma. Moreover, this also led to increased H3K27ac at JIA-specific genes. Increased H3K27ac was dependent on glycolytic flux, but not oxidative phosphorylation. Inhibition of glycolysis also specifically affected the transcription of genes upregulated during T cell activation in the presence of SF. Inhibiting the glycolytic enzyme pyruvate dehydrogenase (PDH) reduced JIA-associated gene expression. Taken together, these findings demonstrate that for JIA, the inflammatory microenvironment can modulate T cell activation-driven transcriptional programs through a glycolysis-mediated pathway. Specific targeting of this T cell metabolism-epigenetic axis may provide avenues for intervention during the development of autoinflammatory disease.
“…In Chinese medicine, UC is believed to affect not only the intestine but also the liver, spleen, kidney, lung, and other organs. Some patients with prolonged illness, poor qi flow, and anxiety develop liver qi stagnation and dysregulation (Soriano-Baguet et al, 2023). Cysteine, a sulfhydryl-containing intermediate produced during the metabolism of methionine and cysteine, acts as an antioxidant to scavenge free radicals, promoting UC recovery and preventing recurrence (Fu et al, 2020).…”
The current study utilizes a comprehensive network pharmacology and metabolomics analysis to investigate the mechanism of action of Ma‐Mu‐Ran Antidiarrheal Capsules (MMRAC) for the treatment of ulcerative colitis (UC). In this study, we established a mouse model of UC using dextran sulfate sodium. Colonic tissues were collected from mice and then subjected to hematoxylin and eosin staining, as well as histopathological analysis, to assess the therapeutic effect of MMRAC. Furthermore, we assessed the mechanisms through which MMRAC combats UC by employing integrated metabolomics and network pharmacology strategies. Lastly, we validated the key targets identified through western blot and molecular docking. An integrated network of metabolomics and network pharmacology was constructed using Cytoscape to identify eight endogenous metabolites involved in the therapeutic action of MMRAC on UC. Further comprehensive analyses were focused on four key targets and their associated core metabolites and pathways. The results of western blot and molecular docking demonstrated that MMRAC could modulate key targets and their expression levels. The cumulative results indicated that MMRAC restored intestinal function in UC, reduced inflammatory responses, and alleviated oxidative stress by influencing the methionine and cysteine metabolic pathways, as well as the urea cycle. In addition, it had an impact on arginine, proline, glutamate, aspartate, and asparagine metabolic pathways and their associated targets.
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