Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 108 - 108

Published: Jan. 18, 2025

The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation reactive oxygen species (ROS), calcium homeostasis, and execution apoptotic processes. Disruptions function, driven by factors such as oxidative stress, excitotoxicity, altered ion balance, lead to neuronal death contribute cognitive impairments several brain diseases. Mitochondrial can arise from genetic mutations, ischemic events, hypoxia, other environmental factors. This article highlights critical role progression diseases discusses need targeted therapeutic strategies attenuate damage, restore enhance neuroprotection.

Language: Английский

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Mechanisms for Orofacial Pain: Roles of Immunomodulation, Metabolic Reprogramming, Oxidative Stress and Epigenetic Regulation

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 434 - 434

Published: Feb. 11, 2025

Background and Objectives: Orofacial pain corresponds to sensitization originating from the facial oral regions, often accompanied by diagnostic complexity due a multitude of contributory factors, leading significant patient distress impairment. Here, we have reviewed current mechanistic pathways biochemical aspects complex orofacial pathology, highlighting recent advancements in understanding its multifactorial regulation signaling thus providing holistic approach challenging it. Materials Methods: Studies were identified an online search PubMed database without any time range. Results: We discussed neuron–glia interactions glial cell activation terms immunomodulatory effects, metabolism reprogramming effects epigenetic modulatory response comprising different factors. highlighted fundamental role oxidative stress affecting cellular as well machinery, which renders pathology intricate multidimensional. Emerging research on modulation regulatory genes molecular environmental factors is also discussed, alongside updates novel treatment approaches. Conclusions: This review deliberates integrative perspectives implications immune system, glucose metabolism, lipid redox homeostasis mitochondrial dysfunction accommodating effect dysregulated non-coding RNAs for interdisciplinary at level, aiming improve outcomes with precise diagnosis offering improved management treatment.

Language: Английский

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Genetic regulation of the vascular endothelial growth factor receptor 1 during sepsis and association with ARDS susceptibility

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Background Acute respiratory distress syndrome (ARDS) is associated with high mortality in Intensive Care Units (ICU). A previous genome-wide association study (GWAS) identified the vascular endothelial growth factor receptor 1 ( VEGFR1 ) gene ARDS risk. We performed a GWAS on soluble (sVEGFR1) levels to identify protein quantitative trait loci (pQTLs) and genes of interest for ARDS. Methods Serum samples (n=292) within first 24 (T1), 72 hours (T2), 7 days (T7) after sepsis diagnosis were collected while ICU. sVEGFR1 measured tested association. combined fine mapping, colocalisation gene-set mapping analyses prioritise test low-frequency variation (n=822). analysed pQTLs susceptibility using polygenic scores (PGS). Finally, causality was assessed two-sample Mendelian randomisation (MR) analyses. Results found pQTL T2 at TCF20 (rs134871, p =4.66×10 -8 ). Fine prioritised rs762995 as likely pathogenic variant CYP2D6 most functional gene. The locus colocalised eQTLs . Low-frequency missense sepsis-associated =3.0×10 -3 PGS decreased mortality. MR did not evidence causality. Conclusions biologically relevant during more implicated. Low frequency models outcomes. What already known this topic an acute condition, characterised by failure, inflammatory response development non-cardiogenic oedema. There need target pharmacological strategies advances risk stratification methods that can improve patient management. adds patients sepsis. integration different complementary genomic approaches has allowed us reveal regulatory sepsis, suggesting role In exome-wide analyses, we novel How might affect research, practice or policy This emphasises value proteogenomic improving our understanding pathogenesis detecting advance stratification.

Language: Английский

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Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis

npj Biofilms and Microbiomes, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 13, 2025

Gut microbiota-derived metabolites play a crucial role in modulating the inflammatory response bowel disease (IBD). In this study, we identify gut succinate as driver of inflammation ulcerative colitis (UC) by activating succinate-responsive, colitogenic helper T (Th) cells that secrete interleukin (IL)-9. We demonstrate is associated with an increase succinate-producing bacteria and decrease succinate-metabolizing bacteria. Similarly, UC patients exhibit elevated levels luminal succinate. Intestinal colonization or increased availability, exacerbates colonic Th9 cells. contrast, intestinal bacteria, blocking receptor signaling antagonist, neutralizing IL-9 anti-IL-9 antibody alleviates reducing Our findings underscore driving suggesting its potential therapeutic target for treating IBD.

Language: Английский

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Effect of Fatty Acyl Composition for Lysophosphatidylinositol on Neuroinflammatory Responses in Primary Neuronal Cultures

Journal of Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 75(1)

Published: March 14, 2025

Language: Английский

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Effect of Fatty Acyl Composition for Lysophosphatidylinositol on Neuroinflammatory Responses in Primary Neuronal Cultures

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

Published: Jan. 8, 2025

Lysophosphatidylinositol (LPI) is an endogenous signaling molecule for the GPR55 receptor. Previous studies have shown that arachidonoyl-lysophosphatidylinositol (LPI-20:4) produced increase in inflammatory mediators NLPR3 (inflammasome - 3 marker) and IL-1b neurons from both rat dorsal root ganglion (DRG) hippocampal cultures. Because LPI comprised of a family lipid structures vary fatty acyl composition, current work examined neuroinflammatory responses to various DRG cultures as assessed by high content fluorescent imaging. Major consisting 16:0, 18:0, 18:1 or 20:4 were compared their effects on IL-1b, NLRP3 immunoreactive areas neurites cell bodies after 6-hour treatment. Among these four structures, only LPI-20:4 treatment increases GPR55, neurites. In contrast, all other tested decrease bodies. Additional with indicated IL-6, IL-18 TNF-a significantly increased However, oleoyl-lysophosphatidylinositol (LPI-18:1) decreases three cytokines. Using viability dye alamar blue, was produce concentration-dependent decreases, whereas this assay. These indicate structure major determinant cultures, showing pro-inflammatory LPIs exhibited anti-inflammatory responses.

Language: Английский

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Mutations of the Electron Transport Chain Affect Lifespan and ROS Levels in C. elegans

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 76 - 76

Published: Jan. 10, 2025

Mutations in highly conserved genes encoding components of the electron transport chain (ETC) provide valuable insights into mechanisms oxidative stress and mitochondrial ROS (mtROS) a wide range diseases, including cancer, neurodegenerative disorders, aging. This review explores structure function ETC context its role mtROS generation regulation, emphasizing dual roles cellular damage signaling. Using Caenorhabditis elegans as model organism, we discuss how mutations manifest developmental abnormalities, lifespan alterations, changes levels. We highlight utility redox sensors C. for vivo studies reactive oxygen species, offering both quantitative qualitative insights. Finally, examine potential platform testing ETC-targeting drug candidates, OXPHOS inhibitors, which represent promising avenues cancer therapeutics. underscores translational relevance research elegans, bridging fundamental biology therapeutic innovation.

Language: Английский

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Iron Drives Eosinophil Differentiation in Allergic Airway Inflammation Through Mitochondrial Metabolic Adaptation

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Abstract Eosinophils play a crucial role as effector cells in asthma pathogenesis, with their differentiation being tightly regulated by metabolic mechanisms. While the involvement of iron various cellular processes is well known, its specific eosinophil has largely remained unexplored. This study demonstrates that levels are increased during process from progenitors to mature and activated eosinophils context allergic airway inflammation. Through experiments involving chelators, supplements, iron‐deficient or iron‐enriched diets, indispensable lineage commitment both vitro vivo demonstrated. Remarkably, chelation effectively suppresses alleviates inflammation house dust mite(HDM)‐induced mouse model asthma. Mechanistically, promotes expression transcription factors enforce differentiation, maintains mitochondrial activities, leading shifts within tricarboxylic acid (TCA) cycle, succinate promoting differentiation. Overall, this highlights function underlying mechanisms providing potential therapeutic strategies for control.

Language: Английский

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Metabolomic Signatures in Adults with Metabolic Syndrome Indicate Preclinical Disruptions in Pathways Associated with High-Density Lipoprotein Cholesterol, Sugar Alcohols

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

Published: Feb. 14, 2025

Background Metabolic syndrome is a pressing public health issue and risk factor for the development of type 2 diabetes (T2D) cardiovascular disease (CVD), yet clinical practice lacking in biomarkers that represent pre-clinical perturbations heterogenous subtypes risk. This study aimed to characterize baseline metabolome relation known characteristics sample obese adults. Methods Untargeted data from N = 126 plasma samples with previously completed including adults metabolic syndrome. Metabolites were acquired using validated liquid chromatography mass spectrometry methods 15-25 internal standards quantified by peak heights. Pearson's correlations used determine relationships between metabolites, (e.g., age, body index (BMI)), atherosclerotic high-density lipoprotein cholesterol (HDL), low-density (LDL), triglycerides), adjusting multiple comparisons Benjamini-Hochberg False Discovery Rate (FDR) method. Differences metabolite levels classifications dysglycemia normal, prediabetes, diabetes) at assessed ANOVA adjusted covariates. Results The consisted primarily female (74%) participants, predominantly white (70%), an average age 56 years. After FDR adjustment, two metabolites significantly associated (xylose, threitol), BMI (shikimic acid, propane-1,3-diol), one LDL (tocopherol-alpha), 42 HDL cholesterol. Three fasting blood glucose (FBG) (glucose, gluconic acid lactone, pelargonic acid). Conclusions identified novel associations markers T2D CVD Specific such as alpha-tocopherol, branched-chain amino acids (BCAAs), sugar-derived like mannose xylose, BMI, lipid profiles, measures. Although most participants had normal baseline, branched chain HDL, suggesting biological pathways both comorbidities. Metabolomic signatures specific prediabetes can enhance stratification enable targeted prevention strategies T2D. Longitudinal studies are needed understand how these change over time at-risk individuals compared controls.

Language: Английский

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Impaired angiogenesis in gestational diabetes is linked to succinate/SUCNR1 axis dysregulation in late gestation

The Journal of Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

Abstract Recent research has highlighted the significance of succinate and its receptor in gestational diabetes (GDM) pathogenesis. However, a clear interconnection between placenta metabolism, levels, SUCNR1 signalling pregnancy pathologies remains elusive. Here, we set out to investigate potential role on labour placental mechanisms by combining clinical functional experimental data at same time as exploring specific SUCNR1‐mediated effects vascularization, addressing agonist actions. According our data, levels vary throughout postpartum, with natural increase during peripartum period. We also show that activation umbilical cord endothelium promotes angiogenesis under normal conditions. GDM, excessive impaired function may weaken this angiogenic response. In conclusion, present study underlines an emerging molecule placenta, regulating processes. The reduced sensitivity succinate/SUCNR1 pathway GDM environment serve protective physiological mechanism or could have pathogenic effect. image Key points Succinate delivery maternal fetal circulation. Gestational induces accumulation downregulation cords. compromises gene profile modulation endothelium. stimulates sprouting tube‐forming capacity human vein endothelial cells from healthy, but not pregnancies.

Language: Английский

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