Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia

Metabolism, Journal Year: 2025, Volume and Issue: unknown, P. 156161 - 156161

Published: Feb. 1, 2025

Language: Английский

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Rat models of postintracerebral hemorrhage pneumonia induced by nasal inoculation with Klebsiella pneumoniae or intratracheal inoculation with LPS

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 8, 2025

A stable and reproducible experimental bacterial pneumonia model postintracerebral hemorrhage (ICH) is necessary to help investigating the pathogenesis novel treatments of Stroke-associated (SAP). To establish a Gram-negative pneumonia-complicating ICH rat an acute lung injury (ALI)-complicating model. We established two standardized models post-ICH by nasal inoculation with Klebsiella pneumoniae (Kp) or intratracheal lipopolysaccharide (LPS). Survival neurological scores were monitored. Magnetic resonance imaging was performed evaluate hematoma volume. Abdominal aortic blood collected for leukocyte counting, serum isolated determine concentrations S100β proinflammatory cytokines using ELISAs. Histopathological changes brain, gut assessed hematoxylin-eosin staining. Lung immunofluorescence staining myeloperoxidase (MPO). Bronchoalveolar lavage fluid supernatant prepared measure MPO activity. Ileum tight junction proteins ZO-1 γδ TCRs/IL-17A Alcian blue-nuclear fast red acidic mucins. Feces collected, 16S rRNA sequencing, untargeted metabolomics Spearman's correlation analyses explore microbiota, metabolites their interactions. In Kp-induced rats, we demonstrated that Kp challenge caused more severe deficits, brain damage, neuroinflammation, aggravated injury. Disruptions intestinal structure barrier reductions protective IL-17A-producing γδT cells also observed. exacerbated microbiota dysbiosis fecal metabolic profile disorders, which characterized abnormal sphingolipid metabolism especially elevated ceramide levels; increased levels neurotoxic quinolinic acid upregulation tryptophan (Trp)-serotonin-melatonin pathway. further revealed reduction depletion some beneficial bacteria, such as Allobaculum Faecalitalea, blooming opportunistic pathogens, Turicibacter, Dietzia, Corynebacterium Clostridium_sensu_stricto_1 in SAP rats associated disordered Trp metabolism. Using LPS-induced ALI complicating model, SAP-induced histopathology injuries; peripheral immune disorders intense pulmonary inflammatory responses. These may be highly useful screening optimizing potential SAP. Moreover, differential genera identified above seem promising therapeutic targets.

Language: Английский

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Associations of Metabolites Related Salt Sensitivity of Blood Pressure and Essential Hypertension in Chinese Population: The EpiSS Study

Nutrients, Journal Year: 2025, Volume and Issue: 17(7), P. 1289 - 1289

Published: April 7, 2025

Salt sensitivity of blood pressure (SSBP) is an important risk factor for essential hypertension and cardiovascular diseases, its metabolic mechanisms remain poorly understood. This study aimed to identify SSBP-associated biomarkers investigate their potential mediating role in the SSBP-hypertension pathophysiology. Based on Systematic Epidemiological Study Sensitivity (EpiSS) conducted 2014-2016, we performed a case-control involving 54 matched pairs participants classified as salt-sensitive or salt-resistant with targeted metabolomics detected. Multivariable logistic regression analyses were assess metabolites associations SSBP hypertension. The diagnostic performance model was evaluated using receiver operating characteristic curve (ROC) analysis yielded area under (AUC) value, sensitivity, specificity. Furthermore, effects relationship between explored. Three demonstrated significant associations: L-Glutamine (OR = 0.998; 95% CI: 0.997, 0.999), PC (16:1/14:0) 1.039; 1.003, 1.077), ChE (22:4) 1.115; 1.002, 1.240). Among them, highest efficiency (AUC 0.766; 0.677, 0.855). combined three slightly improved 0.788; 0.703, 0.874). Cer (d18:0/24:1) identified protective factors against (p < 0.05). Mediation further indicated that partially mediated hypertension, demonstrating suppressive effect. both biomarker modulator attenuating risk, providing insights early screening pathways governing progression overt

Language: Английский

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Cerebral Small Vessel Disease: Current and Emerging Therapeutic Strategies

Aging and Disease, Journal Year: 2025, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2025

Cerebral small vessel disease (CSVD) is a common in older people, characterized by damage to intracranial microvessels, leading cognitive decline, increased risk of stroke, and dementia. This review reviews the current therapeutic approaches for CSVD latest research advances, encompassing traditional pharmacological therapies, emerging targeted interventions grounded pathophysiology, exploratory immune-related treatments, advances genetic research. In addition, role lifestyle modifications management discussed. The emphasizes importance holistic, personalized treatment strategy improve outcomes. More clinical trials are needed validate these treatments optimize individualized options patients.

Language: Английский

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Tongfu Xingshen Capsule Alleviates Stroke-Associated Pneumonia-Induced Multiple Organ Injuries by Modulating the Gut Microbiota and Sphingolipid Metabolism

Phytomedicine, Journal Year: 2025, Volume and Issue: 142, P. 156756 - 156756

Published: April 12, 2025

Language: Английский

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Ceramides may Play a Central Role in the Pathogenesis of Alzheimer’s Disease: a Review of Evidence and Horizons for Discovery

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Abstract While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders psychological stress, contribute this debilitating disease. Multiple lines evidence indicate that ceramides may be central pathogenesis Alzheimer’s Tumor necrosis factor-α, saturated fatty acids cortisol elevate brain levels ceramides, while mutations in APP , presenilin TREM2 APOE ε4, also ceramide synthesis. Importantly, displace sphingomyelin cholesterol from lipid raft-like membrane patches connect endoplasmic reticulum mitochondria, disturbing mitochondrial oxidative phosphorylation energy production. As a consequence, flattening rafts alters function γ-secretase, leading increased production Aβ 42 . Moreover, inhibit insulin-signaling cascade via at least three mechanisms, resulting activation glycogen synthase kinase-3 β. Activation kinase has multiple consequences, it further deteriorates insulin resistance, promotes transcription BACE1 causes hyperphosphorylation tau inhibits factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity improves blood–brain barrier function. Thus, various seemingly unrelated disease factors converge on production, whereas elevated give rise well-known pathological features Understanding targeting these provide promising foundation for development novel preventive therapeutic strategies.

Language: Английский

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Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control

Annals of Medicine, Journal Year: 2025, Volume and Issue: 57(1)

Published: April 28, 2025

Aging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked aging metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on biomarkers Cer profiles. This study explored association between SGLT2i use, plasma levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, CerC24:1), biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target rapamycin (mTOR), 5-Methylcytosine (5MC), Human H2AFX (Histone H2AX) patients with diabetes mellitus (T2DM). In this retrospective study, 95 participants were divided into three groups: (n = 34), non-SGLT2i anti-diabetic treatments 36), healthy controls 25). Plasma quantified using Liquid Chromatography tandem mass spectrometry (LC-MS-MS) ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences confounder adjustment. SGLT2i-treated showed significantly lower CerC16:0, CerC24:1 (p < 0.01) decreased 5MC H2AX 0.05) compared patients. IGF-1 was elevated 0.01), suggesting possible protective effect health. PCA distinguished control from diabetic groups but revealed overlap groups. Beyond glucose control, may improve markers patients, supporting their broader therapeutic potential age-related Further large-scale studies warranted confirm these effects underlying mechanisms.

Language: Английский

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Characterizing the gut microbiota composition in Taiwanese hypertensive patients using 16S rRNA sequencing analysis

International Journal of Medical Sciences, Journal Year: 2025, Volume and Issue: 22(10), P. 2460 - 2469

Published: April 28, 2025

Hypertension (HTN) is a significant risk factor for cardiovascular and cerebrovascular diseases. Accumulating evidence suggests close relationship between HTN alterations in the gut microbiota composition abundance. We recruited 23 patients 17 controls matched demographic characteristics. DNA extracted from fecal samples of was subjected to Illumina MiSeq sequencing, targeting V3-V4 region bacterial 16S rRNA gene analysis. compared diversity two groups. The α-diversity similar that control group. β-diversity analysis showed slight differences microbial used Welch's t-test evaluate difference top 20 ASVs group group, results Tyzzerella significantly increased, while Faecalibacterium decreased performed PCR using Faecalibacterium-specific primers analyzed their levels through agarose gel electrophoresis, confirming reduced abundance In addition, Tax4Fun2 employed examine functionality conclusion, we studied population Taiwan found has lower patients. This unique alteration may provide insights into pathogenesis aid development novel biomarkers therapeutic targets.

Language: Английский

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Lipidomic profiling of the cerebrospinal fluid in moyamoya angiopathy patients

Orphanet Journal of Rare Diseases, Journal Year: 2025, Volume and Issue: 20(1)

Published: May 23, 2025

Abstract Background Moyamoya angiopathy (MA) is a rare cerebrovascular disorder which can occur in both children and young adults, characterized by progressive occlusion of the intracranial carotid arteries, leading patients to ischemic haemorrhagic strokes. Despite decades research, mechanisms underlying MA remain poorly clarified current gaps understanding pathogenesis have hampered development suitable preventive strategies therapeutic options. Moreover, clinically approved biomarkers for patients’ stratification are missing. The unknown pathophysiology lack reliable prompted us investigate cerebrospinal fluid (CSF) lipidome through state-of-the-art lipidomics. Methods Intraoperative CSF from subgroup comparison age/sex matched controls (CTRL) was analysed LC–MS/MS, an untargeted lipidomic approach. Receiver operating characteristic (ROC) curve simple linear regression analyses were performed diagnostic use. We searched simultaneously altered lipids plasma patients. Results Overall, we observed significant increase sphingolipids ( p < 0.05) phospholipids CSF. A partial least squares discriminant analysis clearly separated CTRL 64% on Principal Component 1. identified lipid classes (n = 12) with Variance Importance Projection score ≥ 1.5, within those highly correlated 70). acylcarnitines, (sphingomyelins ceramides), (lysophosphatidylcholines; phosphatidylcholines; phosphatidylethanolamines; ether-phosphatidylethanolamines; ether-phosphatidylcholines) cholesterol esters found multivariate univariate analyses. Monoacylglycerols only class displaying markedly 0.001) decrease as compared subjects. ROC 10 out 12 biomarkers, mainly dealing phospholipids. then previous data profile. returned n 175 (in plasma) 70 CSF) respectively, phosphatidylcholines 10) resulted commonly decreased increased Conclusions Our findings highlighted strong pro-inflammatory environment These preliminary hallmarks could be helpful decipher complex pathogenesis, supplying candidate patient stratification.

Language: Английский

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Common lipidomic signatures across distinct acute brain injuries in patient outcome prediction

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 204, P. 106762 - 106762

Published: Dec. 10, 2024

Lipidomic alterations have been associated with various neurological diseases. Examining temporal changes in serum lipidomic profiles, irrespective of injury type, reveals promising prognostic indicators. In this longitudinal prospective observational study, samples were collected early (46 ± 24 h) and late (142 52 post-injury from 70 patients ischemic stroke, aneurysmal subarachnoid hemorrhage, traumatic brain that had outcomes dichotomized as favorable (modified Rankin Scores (mRS) 0-3) unfavorable (mRS 4-6) three months post-injury. profiling 1153 lipids, analyzed using statistical machine learning methods, identified 153 lipids late-stage significant outcome differences. Supervised pinpointed 12 key forming a combinatory equation high discriminatory power (AUC 94.7 %, sensitivity 89 specificity 92 %; p < 0.0001). Enriched functions the related to sphingolipid signaling, glycerophospholipid metabolism, necroptosis (p 0.05, FDR-corrected). The study underscores dynamic nature profiles acute injuries, emphasizing distinctions proposing markers, transcending types. These findings advocate further exploration for comprehensive understanding pathobiological roles enhanced prediction recovery trajectories.

Language: Английский

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