Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

Biomolecules, Год журнала: 2024, Номер 14(3), С. 305 - 305

Опубликована: Март 4, 2024

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital the successful development clinically useful medications. Stroke is generally accepted as leading cause adult disability globally and ischemic stroke accounts most common form two main types. Despite its health socioeconomic burden, there still minimal availability effective pharmacological treatment. In this review, we take an in-depth look at etiology stroke, including molecular cellular changes. This followed by a highlight drugs, therapies, complementary medicines that or undergoing clinical trials treatment management stroke. We also identify unexplored potential targets in pathogenesis can be exploited increase pool anti-stroke neuroprotective agents through de novo drug repurposing.

Язык: Английский

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Role of microglia in stroke

Glia, Год журнала: 2024, Номер 72(6), С. 1016 - 1053

Опубликована: Янв. 4, 2024

Abstract Microglia play key roles in the post‐ischemic inflammatory response and damaged tissue removal reacting rapidly to disturbances caused by ischemia working restore lost homeostasis. However, modified environment, encompassing ionic imbalances, disruption of crucial neuron–microglia interactions, spreading depolarization, generation danger signals from necrotic neurons, induce morphological phenotypic shifts microglia. This leads them adopt a proinflammatory profile heighten their phagocytic activity. From day three post‐ischemia, macrophages infiltrate core while microglia amass at periphery. Further, inflammation prompts metabolic shift favoring glycolysis, pentose‐phosphate shunt, lipid synthesis. These shifts, combined with intake, drive droplet biogenesis, fuel anabolism, enable proliferation. Proliferating release trophic factors contributing protection repair. some accumulate lipids persistently transform into dysfunctional potentially harmful foam cells. Studies also showed that either display impaired apoptotic cell clearance, or eliminate synapses, viable endothelial Yet, it will be essential elucidate viability engulfed cells, features local extent damage, temporal sequence. Ischemia provides rich variety region‐ injury‐dependent stimuli for microglia, evolving time generating distinct phenotypes including those exhibiting traits others showing pro‐repair features. Accurate profiling phenotypes, alongside more precise understanding associated conditions, is necessary step serve as potential foundation focused interventions human stroke.

Язык: Английский

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HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation

Translational Stroke Research, Год журнала: 2024, Номер unknown

Опубликована: Май 14, 2024

Abstract Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration rtPA essential for restoring perfusion acute ischemic stroke, though it concurrently elevates the risk hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player neuroinflammation after brain ischemia ischemia–reperfusion. Released passively necrotic cells actively secreted, including direct secretion HMGB1 into extracellular space packaging intracellular vesicles immune cells, glial platelets, endothelial represents prototypical damage-associated molecular pattern (DAMP). It intricately involved pathogenesis atherosclerosis, thromboembolism, detrimental inflammation during early phases stroke. Moreover, significantly contributes to neurovascular remodeling functional recovery later stages. Significantly, mediates transformation facilitating neuroinflammation, directly compromising integrity blood–brain barrier, enhancing MMP9 through interaction with rtPA. As systemic inflammatory factor, also implicated post-stroke depression an elevated stroke-associated pneumonia. role extends influencing polarizing various subtypes cells. This includes mediating excitotoxicity due excitatory amino acids, autophagy, release, NET formation, autocrine trophic pathways. Given multifaceted role, recognized crucial therapeutic target prognostic marker stroke In this review, we summarize structure redox properties, pathways, regulation cell activity, pathophysiological mechanisms hemorrhage HMGB1, which will pave way developing new neuroprotective drugs, reduction expansion thrombolysis time window.

Язык: Английский

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Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force?

Frontiers in Bioengineering and Biotechnology, Год журнала: 2023, Номер 11

Опубликована: Фев. 28, 2023

Neurological disorders are recognized as major causes of death and disability worldwide. Because this, they represent one the largest public health challenges. With awareness massive burden associated with these disorders, came recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; which cell-based therapies. In this review, we present a critical analysis features, challenges, prospects stem cell types can be employed numerous disorders—mesenchymal cells (MSCs). Despite fact several studies have already established safety MSC-based approaches, there still some reservations within field regarding their immunocompatibility, heterogeneity, stemness stability, range adverse effects—one tumor-promoting ability. We additionally examine MSCs’ mechanisms action respect in vitro vivo well detail findings past ongoing clinical trials for Parkinson’s Alzheimer’s disease, ischemic stroke, glioblastoma multiforme, multiple sclerosis. Finally, review discusses therapeutics form biomaterials, use electromagnetic fields enhance proliferation differentiation neuronal cells.

Язык: Английский

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Gut microbiota and its metabolic products in acute respiratory distress syndrome

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 16, 2024

The prevalence rate of acute respiratory distress syndrome (ARDS) is estimated at approximately 10% in critically ill patients worldwide, with the mortality ranging from 17% to 39%. Currently, ARDS usually higher COVID-19, giving another challenge for treatment. However, treatment efficacy far satisfactory. relationship between gut microbiota and has been substantiated by relevant scientific studies. not only changes distribution microbiota, but also influences intestinal mucosal barrier through alteration microbiota. modulation can impact onset progression triggering dysfunctions inflammatory response immune cells, oxidative stress, cell apoptosis, autophagy, pyroptosis, ferroptosis mechanisms. Meanwhile, may influence metabolic products In this review, we focus on how further function, cellular functions related signaling pathways during ARDS. roles microbiota-derived metabolites development occurrence are discussed.

Язык: Английский

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Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives

Biomedicines, Год журнала: 2024, Номер 12(4), С. 812 - 812

Опубликована: Апрель 7, 2024

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects ischemic research, emphasizing crucial mechanisms, therapeutic approaches, the role clinical imaging in disease management. It discusses multifaceted Netrin-1, highlighting potential promoting neurovascular repair mitigating post-stroke neurological decline. also examines impact blood–brain barrier permeability on outcomes explores alternative targets such as statins sphingosine-1-phosphate signaling. Neurocardiology investigations underscore contribution cardiac factors to mortality, importance understanding brain–heart axis for targeted interventions. Additionally, advocates early reperfusion neuroprotective agents counter-time-dependent excitotoxicity inflammation, aiming preserve tissue viability. Advanced techniques, including DWI, PI, MR angiography, are discussed their evaluating penumbra evolution guiding decisions. By integrating molecular insights with modalities, this interdisciplinary approach enhances our offers promising avenues future research interventions improve patient outcomes.

Язык: Английский

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Advances of phytotherapy in ischemic stroke targeting PI3K/Akt signaling

Phytotherapy Research, Год журнала: 2023, Номер 37(12), С. 5509 - 5528

Опубликована: Авг. 28, 2023

Abstract The pathogenesis of ischemic stroke is complex, and PI3K/Akt signaling considered to play a crucial role in it. pathway regulates inflammation, oxidative stress, apoptosis, autophagy, vascular endothelial homeostasis after cerebral ischemia; therefore, drug research targeting the has become focus scientists. In this review, we analyzed reports antiischemic drugs past two decades. Because rich sources natural products, increasing studies have explored value compounds, including Flavonoids, Quinones, Alkaloids, Phenylpropanoids, Phenols, Saponins, Terpenoids, alleviating neurological impairment achieved satisfactory results. Herbal extracts medicinal formulas been applied treatment for thousands years East Asian countries. These precious clinical experiences provide new avenue drugs. Finally, summarize discuss characteristics shortcomings current put forward prospects further in‐depth exploration.

Язык: Английский

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Knockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Янв. 12, 2024

Abstract Background Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration autophagy in multiple neurological disorders. However, knowledge to how NEAT1 modulates the formation associated signaling pathways is limited. Methods In this study, primary microglia were isolated from newborn mice exposed oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, antisense oligonucleotide (ASO) was adopted silence under vitro conditions. Studying interactions regard hypoxic conditions, inhibitor activator 3-methyladenine (3-MA) rapamycin (RAPA) used, respectively. preclinical stroke model, received intraventricular injections ASO or control vectors order yield knockdown. Analysis readout parameters included qRT-PCR, immunofluorescence, western blot assays, behavioral tests. Results Microglia OGD/R displayed temporal pattern expression, peaking at four hours hypoxia followed by six reoxygenation. After effectively silencing NEAT1, autophagy-related proteins significantly repressed microglia. Stimulating conditions means RAPA reversed downregulation perilipin 2 (PLIN2) expression. On contrary, application 3-MA promoted repression expression LD-associated protein PLIN2. Under vivo increased 24 h post-stroke. Knockdown alleviated inhibited autophagy, resulting improved cerebral perfusion, reduced brain injury recovery. Conclusion key player stimulation, knockdown provides promising therapeutic value against stroke. Graphical abstract

Язык: Английский

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USP10 is a potential mediator for vagus nerve stimulation to alleviate neuroinflammation in ischaemic stroke by inhibiting NF-κB signalling pathway

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Апрель 20, 2023

Vagus nerve stimulation (VNS) has a protective effect on neurological recovery in ischaemic stroke. However, its underlying mechanism remains to be clarified. Ubiquitin-specific protease 10 (USP10), member of the ubiquitin-specific family, been shown inhibit activation NF-κB signalling pathway. Therefore, this study investigated whether USP10 plays key role VNS against ischemic stroke and explore mechanism. Ischaemic model was constructed by transient middle cerebral artery occlusion (tMCAO) mice. performed at 30 min, 24hr, 48hr after establishment tMCAO model. expression induced measured. LV-shUSP10 used establish with low stereotaxic injection technique. The effects or without silencing deficits, infarct volume, pathway activation, glial cell release pro-inflammation cytokines were assessed. enhanced following tMCAO. ameliorated deficits reduced but inhibited USP10. Activation inflammatory suppressed VNS. Moreover, promoted pro-to-anti-inflammatory response microglia astrocytes, while prevented neuroprotective anti-neuroinflammatory is potential mediator for alleviate neuroinflammation, inhibiting

Язык: Английский

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Understanding the role of cGAS-STING signaling in ischemic stroke: a new avenue for drug discovery

Expert Opinion on Drug Discovery, Год журнала: 2023, Номер 18(10), С. 1133 - 1149

Опубликована: Авг. 4, 2023

ABSTRACTIntroduction Ischemic stroke is a significant global health challenge with limited treatment options. Neuroinflammation, driven by microglial activation, plays critical role in pathophysiology. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as key player sterile neuroinflammation, and cell death following stroke. Understanding the interplay between this pathophysiology crucial for exploring newer therapeutics patients.Areas Covered This review discusses pivotal cGAS-STING ischemic It explores microglia M2 polarization, neutrophil infiltration, cytokine release. Additionally, authors examine its contributions to various programs (pyroptosis, apoptosis, necroptosis, lysosomal death, autophagy, ferroptosis). summarizes recent studies on targeting stroke, highlighting therapeutic potential small molecule inhibitors RNA-based approaches mitigating preventing improving patient outcomes.Expert opinion offers an exciting avenue drug discovery. Targeting holds promise developing novel that effectively mitigate prevent enhance outcomes. Further research development strategies are warranted fully exploit target stroke.KEYWORDS: cGASSTINGneuroinflammationstrokeneurodegenerative disordersimmune response Article highlights cGAS cytosolic enzyme senses dsDNA orchestrates innate immune activating cGAMP-dependent STING signaling.Accumulation cytosol or extracellularly during triggers cascade, contributing significantly stroke.Activation regulates polarization release, shaping post-ischemic neuroinflammatory response.The involved programs, including pyroptosis, ferroptosis.Targeting treatment, selective RNA demonstrating efficacy reducing inflammation outcomes.Continued into essential advancing outcomes stroke.AcknowledgmentsThe corresponding author would like acknowledge express gratitude Science Engineering Research Board, Department Technology, Government India, financial support provided conducted his laboratory.Declaration interestThe have no other relevant affiliations involvement any organization entity interest conflict subject matter materials discussed manuscript apart from those disclosed.Reviewer disclosuresOne reviewer declares they former employee consultant Evotec who their own discovery consultancy company. Peer reviewers relationships otherwise disclose.Additional informationFundingRK Kaundal been granted funds division Technology India.

Язык: Английский

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