Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 8, 2024

The increasing life expectancy has led to a higher incidence of age-related neurodegenerative conditions. Within this framework, neuroinflammation emerges as significant contributing factor. It involves the activation microglia and astrocytes, leading release pro-inflammatory cytokines chemokines infiltration peripheral leukocytes into central nervous system (CNS). These instances result in neuronal damage neurodegeneration through activated nucleotide-binding domain leucine-rich repeat containing (NLR) family pyrin protein 3 (NLRP3) nuclear factor kappa B (NF-kB) pathways decreased erythroid 2-related 2 (Nrf2) activity. Due limited effectiveness regarding inhibition neuroinflammatory targets using conventional drugs, there is challenging growth search for innovative therapies alleviating CNS diseases or even before their onset. Our results indicate that interventions focusing on Interleukin-Driven Immunomodulation, Chemokine (CXC) Receptor Signaling Expression, Cold Exposure, Fibrin-Targeted strategies significantly promise mitigate processes. approaches demonstrate potential anti-neuroinflammatory effects, addressing conditions such Multiple Sclerosis, Experimental autoimmune encephalomyelitis, Parkinson’s Disease, Alzheimer’s Disease. While findings are promising, immunomodulatory often face limitations due Immune-Related Adverse Events. Therefore, conduction randomized clinical trials matter mandatory, will pave way promising future development new medicines with specific therapeutic targets.

Language: Английский

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

Biomolecules, Journal Year: 2024, Volume and Issue: 14(3), P. 305 - 305

Published: March 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.

Language: Английский

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Role of pyroptosis in the pathogenesis of various neurological diseases

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 117, P. 428 - 446

Published: Feb. 7, 2024

Language: Английский

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Mechanisms of immune response and cell death in ischemic stroke and their regulation by natural compounds

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

Ischemic stroke (IS), which is the third foremost cause of disability and death worldwide, has inflammation cell as its main pathological features. IS can lead to neuronal release factors such damage-related molecular patterns, stimulating immune system inflammatory mediators, thereby resulting in exacerbating brain damage. Currently, there are a limited number treatment methods for IS, fact necessitating discovery new targets. For this review, current research on ischemic was summarized. The complex roles pathways principal cells (microglia, astrocyte, neutrophils, T lymphocytes, monocytes/macrophage) after discussed. mechanisms interactions cytokines involved these Moreover, (pyroptosis, apoptosis, necroptosis, PANoptosis, ferroptosis) explored. Finally, summary provided mechanism action natural pharmacological active ingredients IS. Despite significant recent progress remain many challenges that need be overcome.

Language: Английский

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Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14771 - 14771

Published: Sept. 30, 2023

The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory can improve prognosis. In previous laboratory studies clinical trials, ursolic acid (UA) inhibited response, but whether it be administered to inhibit cerebral is unknown. aim this study was investigate effects hemorrhage. Online databases were used obtain potential therapeutic targets for treatment hemorrhage, possible mechanisms analyzed by KEGG, GO, molecular docking. A rat model established using collagenase, an in vitro constructed adding hemin BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, calcein/PI staining degree microglial M1 polarization, changes levels factors, activation NF-κB pathway, indicators cellular death treatment. addition, phorbol 12-myristate 13-acetate (PMA) activate pathway verify that exerts its anti-neuroinflammatory regulating NF-κB/NLRP3/GSDMD pathway. Network pharmacology bioinformatics analyses revealed may exert on through multiple pathways. Together, vivo experiments showed polarization significantly reduced p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, IL-1β, which use PMA. Ursolic inhibits pyroptosis via alleviate responses

Language: Английский

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Neutrophil extracellular traps in bacterial infections and evasion strategies

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 16, 2024

Neutrophils are innate immune cells that have a vital role in host defense systems. Neutrophil extracellular traps (NETs) one of neutrophils' mechanisms against pathogens. NETs comprise an ejected lattice chromatin associated with histones, granular proteins, and cytosolic proteins. They thought to be efficient strategy capture and/or kill bacteria received intensive research interest the recent years. However, soon after were identified, it was observed certain able evade NET entrapment through many different mechanisms. Here, we outline progress bacterial infections strategies employed by or withstand NETs. Identifying molecules modulate release will improve our understanding functions provide new avenues for prevention treatment diseases.

Language: Английский

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Gasdermin D triggers cardiolipin-driven mitochondrial damage and pyroptosis

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(2), P. 75 - 77

Published: Jan. 21, 2024

Language: Английский

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T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(5), P. 1277 - 1292

Published: April 16, 2024

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges an ischemic stroke, which promotes neuronal death and inhibits nerve tissue regeneration. As first immune cells to activated microglia play important immunomodulatory role in progression condition. After peripheral blood (mainly T cells) are recruited central nervous system by chemokines secreted brain, where they interact with microglia) trigger a neuroimmune response. This review summarizes interactions between immune-inflammatory processes stroke. We found that, during demonstrate more pronounced synergistic effect. Th1, Th17, M1 can co-secrete pro-inflammatory factors, such as interferon-γ, tumor necrosis factor-α, interleukin-1β, promote neuroinflammation exacerbate injury. Th2, Treg, M2 jointly secrete anti-inflammatory interleukin-4, interleukin-10, transforming growth factor-β, inhibit neuroinflammation, well factors brain-derived neurotrophic factor regeneration repair Immune influence direction subsequent turn determines prognosis stroke patients. Clinical trials have been conducted on ways modulate toward communication using immunosuppressant fingolimod or overdosing Treg neural reduce damage caused However, studies relatively infrequent, clinical experience is still insufficient. In summary, cell subsets act synergistically regulate inflammatory progression, mainly secreting factors. future, key research for treatment could rooted enhancement secretion promoting generation Th2 cells, along activation M2-type microglia. These approaches alleviate facilitate tissues.

Language: Английский

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NINJ1-mediated plasma membrane rupture of pyroptotic endothelial cells exacerbates blood-brain barrier destruction caused by neutrophil extracellular traps in traumatic brain injury

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 20, 2025

Abstract Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there lack research on underlying mechanisms after TBI. Here, excessive NETs were found in both contused tissue and circulation following We could activate TLR4/NF-κB pathway induce bEC pyroptosis, led disruption During this process, ninjurin-1 (NINJ1) was activated pyroptotic bECs, it mediated release high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) promote NET formation. NINJ1-mediated HMGB1 aggravated accumulation forming circle Knockdown NINJ1 rescued formation, attenuated leakage, improved neurological outcomes may represent promising target for alleviating NET-induced destruction other related injuries

Language: Английский

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Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1113 - 1113

Published: Jan. 17, 2024

Mucopolysaccharidoses (MPSs) are a group of inborn errors the metabolism caused by deficiency in lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time various tissues and disrupt multiple biological systems, including catabolism other substances, autophagy, mitochondrial function. pathological changes ultimately increase oxidative stress activate innate immunity inflammation. We have described pathophysiology MPS activated inflammation this paper, starting with accumulating primary storage materials, GAGs. At initial stage GAG accumulation, affected tissues/cells reversibly but progress irreversibly to: (1) disruption substrate degradation pathogenic function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), inflammatory process, (3) progressive tissue/organ damage cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current future treatment, several potential treatments for that can penetrate blood–brain barrier bone been proposed and/or clinical trials, targeting peptides molecular Trojan horses monoclonal antibodies attached via receptor-mediated transport. Gene therapy trials AAV, ex vivo LV, Sleeping Beauty transposon system underway innovative therapeutic options. In addition, possible immunomodulatory reagents suppress symptoms summarized review.

Language: Английский

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