TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2

Journal of Inflammation Research, Год журнала: 2023, Номер Volume 16, С. 3699 - 3714

Опубликована: Авг. 1, 2023

Objective: Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Materials and Methods: Mice were fed 0.12% for 16 weeks. Then, mice made into MCAO/R models. Neurological score, infarct volume, neuronal damage markers associated inflammation assessed. Since microglia played crucial role in ischemic stroke, isolated high-throughput sequencing identify the most differentially expressed gene following treatment. Afterward, downstream pathways investigated using primary microglia. Results: promoted release inflammatory cytokines brain activation OGD/R microglial inflammasome, thereby exacerbating outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome by downregulating m6A level NLRP3. can inhibit expression FTO IGF2BP2, thus promoting In conclusion, these results demonstrated that promotes aggravating neurological injury through FTO/IGF2BP2. Conclusion: Our These findings explained molecular detail provided clinical Keywords: TMAO, OGD/R, microglia, FTO, IGF2BP2

Язык: Английский

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The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Cardiovascular Diabetology, Год журнала: 2024, Номер 23(1)

Опубликована: Фев. 29, 2024

Abstract Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in recovery. However, the potential efficacy of to improve recovery T2D has not been investigated. Therefore, we determined whether a intervention with Empagliflozin could mice. was induced C57BL6J mice by 8 months high-fat diet feeding. Hereafter, animals were subjected transient middle cerebral artery occlusion treated vehicle or SGLTi (10 mg/kg/day) starting from 3 days after stroke. A similar study non diabetic conducted. Stroke assessed using forepaw grip strength test. To identify mechanisms involved Empagliflozin-mediated effects, metabolic parameters assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis vascularization analyzed immunohistochemistry/quantitative microscopy. significantly improved but non-diabetic Improvement functional associated lowered glycemia, increased serum levels fibroblast growth factor-21 (FGF-21), normalization T2D-induced aberration parenchymal pericyte density. The global T2D-epidemic fact is major risk factor for drastically increasing number people need efficacious Our data provide strong incentive use treatment sequelae T2D.

Язык: Английский

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Systemic-inflammatory indices and clinical outcomes in patients with anterior circulation acute ischemic stroke undergoing successful endovascular thrombectomy

Heliyon, Год журнала: 2024, Номер 10(10), С. e31122 - e31122

Опубликована: Май 1, 2024

BackgroundThere is a lack of comprehensive profile assessment on complete blood count (CBC)-derived systemic-inflammatory indices, and their correlations with clinical outcome in patients anterior circulation acute ischemic stroke (AIS) who achieved successful recanalization by endovascular thrombectomy (EVT).MethodsPatients AIS caused large vessel occlusion (AIS-LVO) were retrospectively screened from December 2018 to 2022. Systemic-inflammatory indices including ratios neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR), platelet-to-neutrophil (PNR), systemic immune-inflammation index (SII), inflammation response (SIRI), aggregate (AISI) admission the first day post-EVT calculated. Their symptomatic intracranial hemorrhage (sICH) unfavorable 90-day functional (modified Rankin Scale score 3-6) analyzed.ResultsA total 482 [65 (IQR, 56-72) years; 33% female] enrolled, which 231 (47.9%) had 50 (10.4%) developed sICH. Day 1 neutrophil monocyte counts, NLR, MLR, PLR, SII, SIRI, AISI increased, while lymphocyte PNR decreased compared levels. In multivariate analyses, count, independently associated outcome. Moreover, PNR, SIRI linked occurrence No variables identified as independent risk factors for patient outcomes.ConclusionCBC-derived measured after EVT are predictive sICH AIS-LVO.

Язык: Английский

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Mechanisms of inflammation after ischemic stroke in brain-peripheral crosstalk

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Июнь 12, 2024

Stroke is a devastating disease with high morbidity, disability, and mortality, among which ischemic stroke more common. However, there still lack of effective methods to improve the prognosis reduce incidence its complications. At present, evidence that peripheral organs are involved in inflammatory response after stroke. Moreover, interaction between central inflammation includes activation resident immune cells, as well inflammation-related signaling pathways, all play an important role pathophysiology In this review, we discuss mechanisms stroke, interactions through circulatory pathways (such gut, heart, lung spleen) brain mediate regulate We also propose potential meningeal lymphatic vessels (MLVs)-cervical lymph nodes (CLNs) brain-peripheral crosstalk pathway addition, summarize anti-inflammatory drugs treatment

Язык: Английский

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Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer

Stem Cell Research & Therapy, Год журнала: 2025, Номер 16(1)

Опубликована: Март 12, 2025

Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umbilical mesenchymal stem cells (UMSCs) offer therapeutic potential due to their immunomodulatory properties. They can regulate reduce neuroinflammation, potentially enhancing recovery by fostering pro-regenerative environment. However, the effect of UMSCs dynamics AIS remains underexplored. This study investigates following examines how may mitigate dysregulation develop better treatment strategies. patients (NIHSS scores 0–15) were recruited within 72 h onset, blood samples collected Day 0 (enrollment) 7. compartments identified flow cytometry, plasma cytokine levels quantified using cytometric bead array (CBA). Mitochondria labeled MitoTracker. Peripheral mononuclear isolated, treated lipopolysaccharide (LPS), cocultured both direct contact Transwell systems. Flow CBA, RT-qPCR, immunofluorescence assays used detect compartments, gene expression markers for helper T (Th) cell differentiation, profiles, mitochondrial transfer, reactive oxygen species (ROS) production, membrane potential. Additionally, DNA was depleted. The effects mitochondria-depleted mice compared through behavioral assessments analysis microenvironment. In AIS, underwent phenotypic shift naïve effector or memory states, specific increase Th17 decrease regulatory cells, leading alterations T-cell-mediated functions. an ex vivo co-culture system, LPS stimulation further amplified these disparities, inducing dysfunction oxidative stress cells. Notably, restored function reversed transfer. Critically, UMSC significantly improved deficits disorders mice, whereas failed produce this effect. Our comprehensive insights into attributes acute mechanisms provide crucial theoretical foundation understanding treatment.

Язык: Английский

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Protective effects of melatonin on stroke in diabetic mice: central and peripheral inflammation modulation

Stroke and Vascular Neurology, Год журнала: 2025, Номер unknown, С. svn - 003442

Опубликована: Фев. 24, 2025

Background Melatonin protects against ischaemic stroke in diabetic animal models, though the mechanisms involving brain and peripheral immune responses remain underexplored. We aimed to clarify how melatonin interacts with these protect mice. Methods Type 1 diabetes mellitus (T1DM) was induced mice using streptozotocin. RNA sequencing of tissue blood mononuclear cells (PBMCs) performed 24 hours poststroke. Inflammatory were evaluated 72 after ischaemia/reperfusion. Results reduced infarction improved neurological function T1DM In brain, downregulated inflammatory factor expression, bioinformatics identifying 62 differentially expressed genes (DEGs) related inflammation 11 associated inflammasomes. Western blotting confirmed reductions NLRP3, HMGB1 Cleaved Caspase-1 expression. Flow cytometry showed infiltration CD8+T neutrophils. decreased IL-6, IL-1β IL-4 levels. PBMCs, revealed 939 DEGs following treatment. Kyoto Encyclopaedia Genes Genomes analysis indicated that involved metabolic pathways, upregulated enriched Jak-STAT signalling pathway. GO cytosol, macromolecule modification. Protein–protein interaction affected 38 inflammation-associated linked key cytokines (Il6, Il1b, Ifng, Il4). increased cells, monocytes neutrophils blood, suggesting a reversal immunosuppression. Multiplex cytokine assays IL-6 IFN-γ Conclusion Poststroke therapy reduces damage by modulating central responses.

Язык: Английский

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Autonomic dysfunction after stroke: an overview of recent clinical evidence and perspectives on therapeutic management

Clinical Autonomic Research, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Central autonomic dysfunction is common in acute stroke and associated with cardiovascular complications increased mortality. The aim of this review to present novel diagnostic therapeutic approaches the management disorder latest data on its impact clinical outcome after stroke. We performed a narrative recent literature, particular focus articles related underlying pathophysiological mechanisms cardiac dysregulation, role dysregulation activation neuroinflammatory response development cardiovascular, respiratory metabolic patients ischemic hemorrhagic assessment central by non-invasive techniques, including heart rate variability baroreflex sensitivity, has gained wide practical application years, they may have predictive for evaluating disease prognosis. emerging evidence derived from trials demonstrates that presence imbalance lead mortality an adverse effect post-stroke rehabilitation. early detection treatment system improved survival Among available approaches, neuromodulatory techniques pharmacological interventions are promising strategies which be implemented as part standard care improve patient recovery. Future studies warranted address long-term effects potential agents modulation function survivors.

Язык: Английский

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Differences in the post-stroke innate immune response between young and old

Seminars in Immunopathology, Год журнала: 2023, Номер 45(3), С. 367 - 376

Опубликована: Апрель 12, 2023

Aging is associated to progressive changes impairing fundamental cellular and tissue functions, the relationships amongst them through vascular immune systems. factors are key understanding pathophysiology of stroke since they increase its risk worsen functional outcome. Most currently recognised hallmarks aging also involved in cerebral responses stroke. Notably, age-associated chronic low-grade inflammation related innate highlighted by induction type-I interferon. The interferon program prominent microglia where it interrelates cell damage, danger signals, phagocytosis with immunometabolic disturbances inflammation. Microglia engulfment damaged myelin debris may overwhelm capacity for waste removal inducing intracellular lipid accumulation. Acute interferon-stimulated gene expression typical features acute stroke, signal recognition trigger alterations underscored droplet biogenesis. reduces control these causing increased persistent inflammation, metabolic dysregulation, impaired disposal. In turn, peripheral during induces immunosenescence further worsening stroke-induced immunodepression, thus increasing post-stroke infection. alters gut microbiota composition dysbiosis. These enhanced age-related diseases, such as atherosclerosis type-II diabetes, that promote aging, predispose exacerbate brain after Current advances research suggest some be reversed. Future work will unravel whether evolving anti-aging enable designing strategies improve outcome elderly.

Язык: Английский

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MiRNAs as potential therapeutic targets and biomarkers for non-traumatic intracerebral hemorrhage

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Фев. 2, 2024

Abstract Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, often occurring between ages 45 and 60. Hypertension cause ICH. Less often, atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication, vitamin deficiencies, other reasons hemorrhages. Cerebral can occur by diapedesis or as a result ruptured vessel. This very dangerous disease difficult to treat, requires surgery lead disability death. MicroRNAs (miRNAs) are class non-coding RNAs (about 18-22 nucleotides) that involved variety biological processes including cell differentiation, proliferation, apoptosis, etc., through gene repression. A growing number studies have demonstrated miRNAs deregulation various cardiovascular In addition, given computed tomography (CT) and/or magnetic resonance imaging (MRI) either not available do show clear signs possible vessel rupture, accurate reliable analysis circulating fluids help early diagnosis for prevention ICH prognosis patient outcome after hemorrhage. this review, we highlight up-to-date findings on deregulated ICH, potential use clinical settings, such therapeutic targets non-invasive diagnostic/prognostic biomarker tools.

Язык: Английский

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Efficacy of a Rehabilitation Program Using Mirror Therapy and Cognitive Therapeutic Exercise on Upper Limb Functionality in Patients with Acute Stroke

Healthcare, Год журнала: 2024, Номер 12(5), С. 569 - 569

Опубликована: Фев. 29, 2024

Applying evidence-based therapies in stroke rehabilitation plays a crucial role this process, as they are supported by studies and results that demonstrate their effectiveness improving functionality, such mirror therapy (MT), cognitive therapeutic exercise (CTE), task-oriented training. The aim of study was to assess the MT CTE combined with training on sensitivity, range, pain affected upper limb patients acute stroke. A longitudinal multicenter recruited sample 120 randomly consecutively, meeting specific inclusion exclusion criteria. They were allocated into three groups: control group only for (TOT) two groups undergoing either or CTE, both TOT. overall functionality limb, range motion, assessed using Fugl–Meyer Assessment Upper Extremity (FMA-UE) scale validated Spanish population. An initial assessment conducted before intervention, second after completing 20 sessions, another months later. ANCOVA analysis revealed statistically significant differences between assessments experimental compared group, indicating improvement these patients. However, no observed groups. conclusion drawn techniques equally effective treating following

Язык: Английский

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