GSK-3β: An exuberating neuroinflammatory mediator in Parkinson's disease

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 210, P. 115496 - 115496

Published: March 11, 2023

Neuroinflammation is a critical degradative condition affecting neurons in the brain. Progressive neurodegenerative conditions such as Alzheimer's disease and Parkinson's (PD) have been strongly linked to neuroinflammation. The trigger point for inflammatory cells body physiological immune system. response mediated by glial astrocytes can rectify alterations occurring cell time being but prolonged activation leads pathological progression. proteins mediating an response, per available literature, are undoubtedly GSK-3β, NLRP3, TNF, PPARγ, NF-κB, along with few other mediatory proteins. NLRP3 inflammasome undeniably principal instigator of neuroinflammatory regulatory pathways controlling its still unclear, besides less clarity interplay between different Recent reports suggested involvement GSK-3β regulating activation, exact mechanistic pathway remains vague. In current review, we attempt provide elaborate description crosstalk markers neuroinflammation progression, linking it transcription factors posttranslational modification recent clinical therapeutic advances targeting these also discussed parallel comprehensive view progress made PD management lacunas existing field.

Language: Английский

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Akt signaling pathway: a potential therapy for Alzheimer’s disease through glycogen synthase kinase 3 beta inhibition

The Egyptian Journal of Neurology Psychiatry and Neurosurgery, Journal Year: 2023, Volume and Issue: 59(1)

Published: Nov. 7, 2023

Abstract Alzheimer’s disease (AD) is a form of dementia marked by the accumulation neuritic plaques and neurofibrillary tangles through action GSK-3β with both significant epidemiological clinical impact. Current pharmacological treatment approaches are focused on symptomatic relief aims to suppress AD’s progression rather than modification. This issue has triggered further investigations about tau pathology as an important component in pathophysiology, one them being Akt signaling pathway. Based problem served AD, combined non-existence conclusive therapy for this disease; hence, study strives investigate potential therapeutical benefit towards AD. A total 82 studies included, consisting national international articles creating narrative review based PRISMA checklist. Variables searched study, include (AD), signaling, serine-9 phosphorylation, GSK-3β. Tau protein been mainstay physiopathology which largely influenced expression. shown inactivate phosphorylation. Thus, modulating optimizing pathway present encouraging prospects development innovative efficacious therapeutic strategies addressing Several have tried estimate harm well dose–effect relationship between concluding promising beneficial effect AD therapy. Here, we show effects theoretical empirical standpoints.

Language: Английский

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Recent Advances in the Mechanisms of Postoperative Neurocognitive Dysfunction: A Narrative Review

Biomedicines, Journal Year: 2025, Volume and Issue: 13(1), P. 115 - 115

Published: Jan. 7, 2025

Postoperative neurocognitive dysfunction (PND) is a prevalent and debilitating complication in elderly surgical patients, characterized by persistent cognitive decline that negatively affects recovery quality of life. As the aging population grows, rising number patients has made PND an urgent clinical challenge. Despite increasing research efforts, pathophysiological mechanisms underlying remain inadequately characterized, underscoring need for more integrated framework to guide targeted interventions. To better understand molecular therapeutic targets PND, this narrative review synthesized evidence from peer-reviewed studies, identified through comprehensive searches PubMed, Embase, Cochrane Library, Web Science. Key findings highlight neuroinflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalances, microvascular changes, white matter lesions as central pathophysiology, with particular parallels encephalocele- sepsis-associated impairments. Among these, mediated pathways such NLRP3 inflammasome blood-brain barrier disruption, emerges pivotal driver, triggering cascades exacerbate neuronal injury. Oxidative stress synergistically amplify these effects, while imbalances alterations, including lesions, contribute synaptic decline. Anesthetic agents modulate interconnected pathways, exhibiting both protective detrimental effects. Propofol dexmedetomidine demonstrate neuroprotective properties suppressing neuroinflammation microglial activation, whereas inhalational anesthetics like sevoflurane intensify inflammatory responses. Ketamine, its anti-inflammatory potential, offers promise but requires further evaluation determine long-term safety efficacy. By bridging insights practice, highlights critical role personalized anesthetic strategies mitigating improving patients. It aims inform future decision-making address multifaceted

Language: Английский

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The Importance of Phosphoinositide 3-Kinase in Neuroinflammation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(21), P. 11638 - 11638

Published: Oct. 30, 2024

Neuroinflammation, characterised by the activation of immune cells in central nervous system (CNS), plays a dual role both protecting against and contributing to progression neurodegenerative diseases, such as Alzheimer's disease (AD) multiple sclerosis (MS). This review explores phosphoinositide 3-kinase (PI3K), key enzyme involved cellular survival, proliferation, inflammatory responses, within context neuroinflammation. Two PI3K isoforms interest, PI3Kγ PI3Kδ, are specific regulation CNS cells, microglia, astrocytes, neurons, oligodendrocytes, influencing pathways, Akt, mTOR, NF-κB, that control cytokine production, cell activation, neuroprotection. The dysregulation signalling is implicated chronic neuroinflammation, exacerbation diseases. Preclinical studies show promise targeting neuronal disorders using inhibitors, AS605240 (PI3Kγ) idelalisib (PI3Kδ), which have reduced inflammation, microglial death vivo models AD. However, clinical translation these inhibitors faces challenges, including blood-brain barrier (BBB) permeability, isoform specificity, long-term safety concerns. highlights therapeutic potential modulation neuroinflammatory identifying gaps current research, particularly need for brain-penetrating isoform-specific inhibitors. These findings underscore importance future research develop targeted therapies can effectively modulate activity provide neuroprotection disorders.

Language: Английский

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Gas6 induces AIM to suppress acute lung injury in mice by inhibiting NLRP3 inflammasome activation and inducing autophagy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 17, 2025

Introduction Growth arrest-specific 6 (Gas6) protein signaling plays a critical role in maintaining immune homeostasis and regulating inflammation. However, novel mechanisms for modulating macrophage activity through the Gas6 axis are being identified. enhances production of apoptosis inhibitor macrophages (AIM), with potent anti-inflammatory properties. This study investigates whether Gas6-induced AIM suppresses acute lung injury (ALI) mice by key inflammatory pathways, including inflammasome activation, autophagy, reactive oxygen species (ROS) generation, efferocytosis. Methods ALI was induced wild-type (WT) −/− via intratracheal administration LPS. To evaluate effects Gas6-AIM on inflammation, recombinant (rGas6) treated intraperitoneally. Inflammatory responses were evaluated using enzyme-linked immunosorbent assay, cell-sizing analyzer, Bicinchoninic acid assays. Lung pathology assessed hematoxylin-eosin staining. NLRP3 activation autophagy western blot, quantitative real-time PCR, immunofluorescence. Reactive levels alveolar measured fluorescence microscopy, while efferocytosis cytospin-stained BAL cells cultured co-cultured apoptotic Jurkat cells. Additionally, rGas6-mediated validated mouse bone marrow-derived (BMDMs) siRNAs targeting AIM, Axl, LXRα, or LXRβ. Results Proinflammatory cytokine production, neutrophil infiltration, BALF significantly reduced rGas6 WT but not mice. Specifically, IL-1β IL-18 levels, caspase-1 activity, apoptosis-associated speck-like containing caspase recruitment domain (ASC) macrophages. promoted reducing ROS production. These protective absent Furthermore, siRNA-mediated silencing LXRβ, reversed inhibitory BMDMs, essential rGas6-induced autophagy. Conclusion protects against LPS-induced inhibiting enhancing efferocytosis, oxidative stress. findings highlight Gas6–AIM as potential therapeutic target mitigating diseases.

Language: Английский

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Bioactive Carbon Dots from Clove Residue: Synthesis, Characterization, and Osteogenic Properties

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 527 - 527

Published: Feb. 19, 2025

Background/Objectives: Bone regeneration using nanomaterial-based approaches shows promise for treating critical bone defects. However, developing sustainable and cost-effective therapeutic materials remains challenging. This study investigates the osteogenic potential of clove-derived carbon dots (C-CDs) applications. Methods: C-CDs were synthesized a green hydrothermal method. The was evaluated in human marrow-derived mesenchymal stem cells (hBM-MSCs) validated ectopic formation calvarial defect models. Results: demonstrated uniform morphology (~10 nm) with efficient cellular uptake. In vitro studies showed successful differentiation through upregulation RUNX2, ALP, COL1A1, BMP-2 mediated by Wnt/β-catenin/GSK3β BMP signaling pathways. vivo models have also that are effective promoting regeneration. Conclusions: These findings establish as promising candidates therapy, offering alternative to current treatments. While optimization is needed, their properties warrant further development regenerative medicine

Language: Английский

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Rutin protects hemorrhagic stroke development via supressing oxidative stress and inflammatory events in a zebrafish model

European Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 925, P. 174973 - 174973

Published: April 22, 2022

Language: Английский

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GSK3-Driven Modulation of Inflammation and Tissue Integrity in the Animal Model

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8263 - 8263

Published: July 29, 2024

Nowadays, GSK3 is accepted as an enzyme strongly involved in the regulation of inflammation by balancing pro- and anti-inflammatory responses cells organisms, thus influencing initiation, progression, resolution inflammatory processes at multiple levels. Disturbances within its broad functional scope, either intrinsically or extrinsically induced, harbor risk profound disruptions to regular course immune response, including formation severe inflammation-related diseases. Therefore, this review aims summarizing contextualizing current knowledge derived from animal models further shape our understanding GSK3α β their roles process occurrence tissue/organ damage. Following a short recapitulation structure, function, GSK3, we will focus on lessons learned GSK3α/β knock-out knock-in/overexpression models, both conventional conditional, well variety (predominantly rodent) disease reflecting defined pathologic conditions with significant proportion tissue injury. In summary, literature suggests that acts crucial switch driving pro-inflammatory destructive contributes significantly pathogenesis inflammation-associated

Language: Английский

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Spaceflight alters host-gut microbiota interactions

npj Biofilms and Microbiomes, Journal Year: 2024, Volume and Issue: 10(1)

Published: Aug. 29, 2024

The ISS rodent habitat has provided crucial insights into the impact of spaceflight on mammals, inducing symptoms characteristic liver disease, insulin resistance, osteopenia, and myopathy. Although these physiological responses can involve microbiome Earth, host-microbiota interactions during are still being elucidated. We explore murine gut microbiota host gene expression in colon after 29 56 days using multiomics. Metagenomics revealed significant changes 44 species, including relative reductions bile acid butyrate metabolising bacteria like Extibacter muris Dysosmobacter welbionis. Functional prediction indicate over-representation fatty metabolism, extracellular matrix interactions, antibiotic resistance genes. Host described corresponding to energy immune suppression. These imply that at host-gut interface contribute pathology might critically influence human health long-duration feasibility.

Language: Английский

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JAC4 Alleviates Rotenone-Induced Parkinson’s Disease through the Inactivation of the NLRP3 Signal Pathway

Antioxidants, Journal Year: 2023, Volume and Issue: 12(5), P. 1134 - 1134

Published: May 20, 2023

Parkinson’s disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) common widely used pesticide which can directly inhibit mitochondrial complex I, leading neurons. Our previous studies proved that JWA gene (arl6ip5) may play prominent role resisting aging, oxidative stress inflammation, knockout astrocytes increases susceptibility mice 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced JWA-activating compound 4 (JAC4) small-molecule activator gene, but its mechanism against PD have not yet been clarified. In present study, we showed expression level strongly related tyrosine hydroxylase (TH) different growth periods mice. Additionally, constructed models with Rot vivo vitro observe neuroprotective effects JAC4. results demonstrated JAC4 prophylactic intervention improved motor dysfunction neuron Mechanistically, reduced damage reversing I damage, reducing nuclear factor kappa-B (NF-κB) translocation repressing nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing-3 (NLRP3) inflammasome activation. Overall, our provide proof could serve as novel agent for prevention.

Language: Английский

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