Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect the response. Metabolic intermediates accumulate a result adaptations mediate functions outside metabolism regulation immunity inflammation. In macrophages, there been major focus on 3 metabolites linked to Krebs cycle, itaconate, succinate, fumarate, which have shown regulate multiple processes. Here, we discuss recent progress these with regard their effect macrophages host defense inflammatory diseases. We also consider therapeutic opportunities presented from mimicry or by targeting enzymes that make metabolize them order leverage body's own anti-inflammatory

Language: Английский

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Resolution of long-term severe irritable bowel syndrome following fecal microbiota transplantation: A case report and microbiota analysis

Gut Microbes Reports, Journal Year: 2025, Volume and Issue: 2(1)

Published: April 20, 2025

Language: Английский

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Mitochondrial Oxidative Phosphorylation Alterations in Placental Tissues from Early- and Late-Onset Preeclampsia

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 3951 - 3951

Published: April 22, 2025

Preeclampsia (PE), a pregnancy complication characterized by high blood pressure and organ damage, has been suggested to be associated with mitochondrial dysfunction, although evidence remains limited. This study aimed investigate the activity of oxidative phosphorylation (OXPHOS) enzymes expression related proteins in placental tissues from women diagnosed early-onset preeclampsia (eoPE, <34 weeks gestation), late-onset (loPE, ≥34 normotensive controls. Placental samples were analyzed using immunohistochemistry, western blotting, enzymatic assays assess OXPHOS complexes. Complex I was increased 80% eoPE 56% loPE, positive correlations between normalized complex expression, gestational age at delivery (r = 0.85, p 0.01), birth weight 0.88, 0.004) loPE. Relative II loPE showed duration 0.76, 0.03) 0.77, 0.03), while controls, correlated 0.64, 0.03). Additionally, IV enzyme negatively maternal −0.69, The observed highlight metabolism as promising biomarker for predicting disease progression guiding therapeutic interventions preeclampsia. Unraveling its precise role PE pathogenesis is critical advancing diagnostic precision improving maternal-fetal outcomes.

Language: Английский

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Cellular crosstalk in fibrosis: insights into macrophage and fibroblast dynamics

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 110203 - 110203

Published: May 1, 2025

Language: Английский

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Dietary Succinic Acid Enhances High-Starch Diet Utilization in Largemouth Bass (Micropterus salmoides) Through Gut-Liver Axis Modulation

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

A 10-week feeding trial was conducted to investigate the effects of succinic acid (SUA) supplementation in high-starch diets (HSD) on growth performance and enterohepatic health largemouth bass (Micropterus salmoides; initial weight 11.96 ± 0.71 g). Six isocaloric isolipidic were formulated, comprising: a standard diet containing 10% corn starch 40% fish meal, an HSD with 15% 36% HSDs supplemented 0.5%, 1.0%, 1.5%, or 2.0% SUA. Compared diet, exhibited adverse including impaired feed utilization, retardation, diminished antioxidant capacity immune response, along metabolic dysregulation gut microbiota disturbances. Significant linear quadratic dose-responses (P < 0.05) detected for multiple parameters: conversion ratio, hepatosomatic index, viscerosomatic glycogen content, amylase protease activities, hepatic status. The 0.5% SUA group demonstrated: enhanced intestinal morphology; upregulated expression tight junction proteins (ZO-1, Claudin-4) anti-apoptotic Bcl2; increased abundance beneficial microbiota; suppressed endoplasmic reticulum stress markers (GRP78, PERK, IRE1, ATF6, eIF2α, Chopα). Additionally, dietary anti-inflammatory mediators (Nrf2, TGFβ1, IL10), glycolytic genes (PK, PFKL2, GK), β-oxidation-related CPT1, Bag, glucose transporter GLUT2, while downregulating pro-inflammatory TNFα, gluconeogenic enzymes (PEPCK, G6Pase), lipogenic (ACC1, FASN), pro-apoptotic Bad. Broken-line regression analysis identified 0.46–0.50% as optimal inclusion level based parameters. This study demonstrates that appropriate alleviates HSD-induced oxidative stress, enhances barrier function, modulates microbiota, maintains homeostasis, thereby improving utilization bass.

Language: Английский

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Physiologic relevance of the transpulmonary metabolome in connective tissue disease–associated pulmonary vascular disease

JCI Insight, Journal Year: 2025, Volume and Issue: 10(9)

Published: May 7, 2025

Pathologic implications of dysregulated pulmonary vascular metabolism to arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients pathobiologically relevant metabolites, an exercise stage-specific manner. Sixty-three CTD patients with established or suspected underwent right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified plasma samples simultaneously collected from and radial arteries at baseline during resistance-free wheeling, peak exercise, recovery. identified uptake excretion bed, unique distinct single site analysis. demonstrated physiological relevance previously shown promote disease animal models end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, tryptophan catabolites. Notably, handling was stage specific. Transpulmonary correlated hemodynamic endpoints largely free-wheeling. Glycolytic intermediates physiologic significance net lactate those more advanced disease. Contribution CTD-PAH pathogenesis therapeutic candidacy modulation must be considered context stress.

Language: Английский

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Excessive palmitic acid disturbs macrophage α-ketoglutarate/succinate metabolism and causes adipose tissue insulin resistance associated with gestational diabetes mellitus

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 222, P. 424 - 436

Published: July 2, 2024

Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development diabetes. However, underlying mechanisms that regulate ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed determine effects abnormal fatty acids on macrophage GDM. Levels were assessed serum samples tissues patients An vitro cell model treated palmitic acid was established, regulating clarified. The excessive regulation histone methylations IR also explored high-fat diet induced GDM mice model. We found pregnancies increased levels acids, tissues. Increased could induce mitochondrial dysfunction ROS macrophages, leading cytoplasmic nuclear metabolism succinate α-ketoglutarate (αKG). Specifically, a decreased αKG/succinate ratio attenuate enrichment H3K27me3 at promoters pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, cytokine secretion. Importantly, GSK-J4, an inhibitor lysine demethylase, protected from production cytokines. Our findings highlight importance αKG transcriptional modulators sensitivity tissue, ensuring normal pregnancy. This novel insight sheds new light epigenetic alterations

Language: Английский

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Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside

Neurotherapeutics, Journal Year: 2024, Volume and Issue: unknown, P. e00515 - e00515

Published: Dec. 1, 2024

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role mitochondrial dysfunction in pathophysiology TBI, making mitochondria an attractive target for intervention. This review comprehensively examines advancements mitochondrial-targeted therapies bridging gap from basic to clinical applications. We discuss underlying mechanisms damage including oxidative stress, impaired bioenergetics, dynamics, apoptotic pathways. Furthermore, we highlight complex interplay between dysfunction, inflammation, blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate impede recovery. also evaluate various preclinical studies exploring pharmacological agents, gene therapy, novel drug delivery systems designed protect restore function. Clinical trials their outcomes are assessed translational potential TBI. By integrating findings bench bedside, this emphasizes promising avenues addresses remaining challenges. It provides guidance future pave way innovative treatments that improve patient

Language: Английский

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The Warburg Effect: Is it Always an Enemy?

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(12)

Published: Nov. 27, 2024

The Warburg effect, also known as 'aerobic' glycolysis, describes the preference of cancer cells to favor glycolysis over oxidative phosphorylation for energy (adenosine triphosphate-ATP) production, despite having high amounts oxygen and fully active mitochondria, a phenomenon first identified by Otto Warburg. This metabolic pathway is traditionally viewed hallmark cancer, supporting rapid growth proliferation supplying biosynthetic precursors. However, emerging research indicates that effect not just strategy proliferate at higher rates compared normal cells; thus, it should be considered an 'enemy' since plays complex roles in cellular functions and/or under stress conditions, prompting reconsideration its purely detrimental characterization. Moreover, this review highlights distinguishing 'anaerobic' exist, lactate likely final product regardless presence oxygen. Finally, explores nuanced contributions beyond oncology, including regulatory various environments potential effects on systemic physiological processes. By expanding our understanding these mechanisms, we can uncover novel therapeutic strategies target reprogramming, offering new avenues treating other diseases characterized dysregulation. comprehensive reevaluation only challenges traditional views but enhances metabolism's adaptability implications health disease.

Language: Английский

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Tremella fuciformis Berk Alleviated Atherosclerosis Symptoms via Nuclear Factor-Kappa B-Mediated Inflammatory Response in ApoE−/− Mice

Nutrients, Journal Year: 2024, Volume and Issue: 17(1), P. 160 - 160

Published: Dec. 31, 2024

Background: Atherosclerosis, a persistent inflammatory disease marked by the presence of atherosclerotic plaques or fibrous plaques, is significant contributor to onset development cardiovascular disease. Tremella fuciformis Berk contains various active ingredients that have anti-inflammatory, antioxidant, and hypolipidemic properties. Nevertheless, potential effects T. on atherosclerosis not been systematically reported. Method: In this study, ApoE−/− mice were employed as models caused high-fat diet (HFD) investigate effect fuciformis. Gut microbiota serum metabolism analysis performed elucidate mechanism for its anti-atherosclerosis effects. Results: significantly decreased aortic root wall thickness area lipid droplets, regulated levels, inhibited fat accumulation improve lesions. Furthermore, altered metabolite (including diethyl phthalate succinate) abundance microbiota, such Coriobacteriaceae_UCG-002 Alistipes, suppressed response ameliorate via nuclear factor-kappa B (NF-κB)-mediated in HFD-induced mice. Conclusions: These results offer theoretical basis data support strategy treating atherosclerosis.

Language: Английский

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