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The NF-κB-mediated neuroinflammatory cascade. Pro-inflammatory factors like TNF-α, IL-1β, IL-6, and CD-40L activate the cell surface receptor. The cell surface receptor consists of two pathways, first is canonical pathway in which inhibitor of κB kinase (IKK) β is necessary for NF-κB activation that phosphorylates IκB, while NF-κB essential modulator (NEMO) is regulatory subunit of IKK complex. IκB undergoes proteasomal degradation in the cytosol and then phosphorylated heterodimer of NF-κB (p50-p65) goes to the nucleus via nuclear membrane and binds to the NF-κB response element activating the associated pro-inflammatory mediators like TNF-α, IL-1β, IL-6, iNOS, and ICAM and ultimately causes NF-κB-mediated neuroinflammation that leads to the progressive degeneration of the DA neurons in PD. In alternate or non-canonical pathway, NEMO along with NF-κB inducing kinase (NIK) phosphorylates IKK-α and causes the proteasomal degradation along with the proteasomal processing of p100 which is a subunit of NF-κB heterodimer and forms the p52-RELB active heterodimer. The p52-RELB active heterodimer goes into the nucleus through nuclear membrane and similar to the canonical pathway binds to the NF-κB response element regulating the expression of pro-inflammatory factors like TNF-α, IL-1β, IL-6, iNOS, and ICAM, ultimately causing the NF-κB-mediated neuroinflammation via progressive neurodegeneration in PD
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Different animal and human studies from last two decades in the case of Parkinson’s disease (PD) have concentrated on oxidative stress due to increased inflammation and cytokine-dependent neurotoxicity leading to induction of dopaminergic (DA) degeneration pathway in the nigrostriatal region. Chronic inflammation, the principle hallmark of PD, form...
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Central nervous system (CNS) infections occur more commonly in young children than in adults and pose unique challenges in the developing brain. This review builds on the distinct vulnerabilities in children's peripheral immune system (outlined in part 1 of this review series) and focuses on how the developing brain responds once a CNS infection oc...
Citations
... PFN1 is also a target of Artenimol, a drug originally used to treat malaria 37 . Gao et al. 38 proved that Artenimol could be used for treating neuroinflammatory diseases by inactivating the PI3K/AKT and NF-κ B signalling pathways, two pathways that are dysregulated in PD 39,40 , suggesting that the Artenimol-PFN1 drug-target interaction could be exploited for treating PD. We highlight six gene predictions (APLP2, RRBP1, RCN1, SEC63, KDELR1, SSR4) for their role in maintaining the proper functioning of ER (see Supplementary Table 4). ...
Parkinson’s disease (PD) is a complex neurodegenerative disorder without a cure. The onset of PD symptoms corresponds to 50% loss of midbrain dopaminergic (mDA) neurons, limiting early-stage understanding of PD. To shed light on early PD development, we study time series scRNA-seq datasets of mDA neurons obtained from patient-derived induced pluripotent stem cell differentiation. We develop a new data integration method based on Non-negative Matrix Tri-Factorization that integrates these datasets with molecular interaction networks, producing condition-specific “gene embeddings”. By mining these embeddings, we predict 193 PD-related genes that are largely supported (49.7%) in the literature and are specific to the investigated PINK1 mutation. Enrichment analysis in Kyoto Encyclopedia of Genes and Genomes pathways highlights 10 PD-related molecular mechanisms perturbed during early PD development. Finally, investigating the top 20 prioritized genes reveals 12 previously unrecognized genes associated with PD that represent interesting drug targets.
... Caspase-3 is involved in cell apoptosis pathways and may influence the quality of sleep by regulating neuronal apoptosis and synaptic remodeling. [76] It is reported that ginsenoside Rg1 contributes to the amelioration of sleep deprivationinduced learning and memory deficits, which might be mediated by the Bcl-2/Bax/caspase-3 apoptosis signaling pathway. [77] In this study, we validated the binding ability of β-sitosterol and caspase-3 by molecular docking and molecular dynamics simulations, which revealed that the complex exhibited excellent stability. ...
The purpose of this study is to investigate the potential mechanisms of Chinese herbs for the treatment of insomnia using a combination of data mining, network pharmacology, and molecular-docking validation. All the prescriptions for insomnia treated by the academician Qi Wang from 2020 to 2022 were collected. The Ancient and Modern Medical Case Cloud Platform v2.3 was used to identify high-frequency Chinese medicinal herbs and the core prescription. The Traditional Chinese Medicine Systems Pharmacology and UniProt databases were utilized to predict the effective active components and targets of the core herbs. Insomnia-related targets were collected from 4 databases. The intersecting targets were utilized to build a protein–protein interaction network and conduct gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using the STRING database, Cytoscape software, and clusterProfiler package. Gene chip data (GSE208668) were obtained from the Gene Expression Omnibus database. The limma package was applied to identify differentially expressed genes (DEGs) between insomnia patients and healthy controls. To create a “transcription factor (TF)-miRNA-mRNA” network, the differentially expressed miRNAs were entered into the TransmiR, FunRich, Targetscan, and miRDB databases. Subsequently, the overlapping targets were validated using the DEGs, and further validations were conducted through molecular docking and molecular dynamics simulations. Among the 117 prescriptions, 65 herbs and a core prescription were identified. Network pharmacology and bioinformatics analysis revealed that active components such as β-sitosterol, stigmasterol, and canadine acted on hub targets, including interleukin-6, caspase-3, and hypoxia-inducible factor-1α. In GSE208668, 6417 DEGs and 7 differentially expressed miRNAs were identified. A “TF-miRNA-mRNA” network was constructed by 4 “TF-miRNA” interaction pairs and 66 “miRNA-mRNA” interaction pairs. Downstream mRNAs exert therapeutic effects on insomnia by regulating circadian rhythm. Molecular-docking analyses demonstrated good docking between core components and hub targets. Molecular dynamics simulation displayed the strong stability of the complex formed by small molecule and target. The core prescription by the academician Qi Wang for treating insomnia, which involves multiple components, targets, and pathways, showed the potential to improve sleep, providing a basis for clinical treatment of insomnia.
... Indeed, activation of microglia has been reported in animal models of PD induced by 6-OHDA [49]. The NF-κB signaling pathway is a key player in this process [50]. Ghosh and co-workers demonstrated that selective inhibition of NF-κB prevents the degeneration of DA neurons in the SN in a mouse model of PD [51]. ...
This study aimed to elucidate the role of O -GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD)-like neurodegeneration and the underlying mechanisms. We observed dose-dependent downregulation of O -GlcNAcylation, accompanied by an increase in O -GlcNAcase following 6-OHDA treatment in both mouse brain and Neuro2a cells. Interestingly, elevating O -GlcNAcylation through glucosamine (GlcN) injection provided protection against PD pathogenesis induced by 6-OHDA. At the behavioral level, GlcN mitigated motor deficits induced by 6-OHDA, as determined using the pole, cylinder, and apomorphine rotation tests. Furthermore, GlcN attenuated 6-OHDA-induced neuroinflammation and mitochondrial dysfunction. Notably, augmented O-GlcNAcylation, achieved through O -GlcNAc transferase (OGT) overexpression in mouse brain, conferred protection against 6-OHDA-induced PD pathology, encompassing neuronal cell death, motor deficits, neuroinflammation, and mitochondrial dysfunction. These collective findings suggest that O -GlcNAcylation plays a crucial role in the normal functioning of dopamine neurons. Moreover, enhancing O -GlcNAcylation through genetic and pharmacological means could effectively ameliorate neurodegeneration and motor impairment in an animal model of PD. These results propose a potential strategy for safeguarding against the deterioration of dopamine neurons implicated in PD pathogenesis.
... Excessive cytokine production, which leads to the elevation of various cytokine-regulated signaling systems involved in inflammation, apoptosis, and autophagy, underlies the disturbed communication balance between the brain and the immune system. One of these signaling systems is the nuclear factor-κB (NF-κB) pathway, whose deregulation has already been connected to the pathophysiology of PD and AD [64,65]. Further, it is well understood that the neurophysiological function of the CNS is critically dependent on astrocytes. ...
Neuroinflammation is the major cause of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Currently available drugs present relatively low efficacy and are not capable of modifying the course of the disease or delaying its progression. Identifying well-tolerated and brain-penetrant agents of plant origin could fulfil the pressing need for novel treatment techniques for neuroinflammation. Attention has been drawn to a large family of flavonoids in citrus fruits, which may function as strong nutraceuticals in slowing down the development and progression of neuroinflammation. This review is aimed at elucidating and summarizing the effects of the flavonoid tangeretin (TAN) in the management of neuroinflammation-mediated neurodegenerative disorders. A literature survey was performed using various resources, including ScienceDirect, PubMed, Google Scholar, Springer, and Web of Science. The data revealed that TAN exhibited immense neuroprotective effects in addition to its anti-oxidant, anti-diabetic, and peroxisome proliferator-activated receptor-γ agonistic effects. The effects of TAN are mainly mediated through the inhibition of oxidative and inflammatory pathways via regulating multiple signaling pathways, including c-Jun N-terminal kinase, phosphoinositide 3-kinase, mitogen-activated protein kinase, nuclear factor erythroid-2-related factor 2, extracellular-signal-regulated kinase, and CRE-dependent transcription. In conclusion, the citrus flavonoid TAN has the potential to prevent neuronal death mediated by neuroinflammatory pathways and can be developed as an auxiliary therapeutic agent in the management of neurodegenerative disorders.
... Chronic NMDA administration up-regulates proinflammatory markers, including IL-1β, TNF-α, and iNOS, suggesting a cross-talk between neuroinflammation and excitotoxicity involving NO release and iNOS up-regulation in the brain (Brown and Bal-Price, 2003). Furthermore, the transcriptional regulation of iNOS, a key player in neuroinflammatory processes, involves nuclear factor-κB (NF-κB) (Singh, Rai et al. 2020). This NF-κB-mediated iNOS expression triggers pathways related to RONS formation, leading to oxidative stress and brain damage (Oh et al. 2009;Shaked et al., 2012). ...
Epilepsy poses a significant challenge, especially for drug-resistant cases, necessitating novel treatment avenues. This study explores the potential interplay between nitric oxide (NO) and the anticonvulsant effects of betulin, a triterpene with promising neuroprotective properties. While betulin exhibits anticonvulsant effects, the specific involvement of NO remains inadequately understood, constituting a pivotal gap in current knowledge. One hundred NMRI mice were randomly assigned to diverse treatment groups, with seizures induced by pentylenetetrazol (PTZ). Parameters such as seizure threshold, nitrite levels, total antioxidant capacity (TAC), malondialdehyde (MDA) levels, and iNOS/nNOS gene expressions were assessed. Betulin significantly increased seizure thresholds and mitigated PTZ-induced NO levels. These findings suggest a potential modulation of NO-related pathways, emphasizing betulin's anti-inflammatory and antioxidant attributes. The study sheds light on betulin's multifaceted impact on oxidative stress, NO regulation, and iNOS/nNOS gene expressions. The ability of betulin to suppress iNOS/nNOS gene expressions, leading to reduce NO production, underscores its potential as an anticonvulsant.
... The release of TNF-α also activates the apoptotic pathway [2]. Further, free radicals activate nuclear factor kappa B (NF-κB) which has deleterious effects on brain cells [3]. Notably, toll like reseptor-4 (TLR-4) is one of the most studied receptors among TLRs and is capable of producing proinflammatory cytokines and stimulating the inflammatory response [4]. ...
... NF-kB activation has been shown to mediate inflammation and plays a critical role in the regulation of cell survival in various diseases [3]. Increased NF-kB activation in microglia stimulates the secretion of proinflammatory cytokines and downregulation of NF-kB suppresses the expression of proinflammatory cytokines [24]. ...
Background
Subarachnoid hemorrhage (SAH) is one of the most prevalent brain injuries in humans which has poor prognosis and high mortality rates. Due to several medical or surgical treatment methods, a gold standard method doesn’t exist for SAH treatment. Piceatannol (PCN), a natural analog of resveratrol, was reported to reduce inflammation and apoptosis promising a wide range of therapeutic alternatives. In this study, we aimed to investigate the effects of PCN in an experimental SAH model. The alleviating effects of PCN in the hippocampus in an experimental SAH model were investigated for the first time.
Methods and results
In this study, 27 Wistar Albino male rats (200–300 g; 7–8 week) were used. Animals were divided into three groups; SHAM, SAH, and SAH + PCN. SAH model was created with 120 µl of autologous arterial tail blood to prechiasmatic cisterna. 30 mg/kg PCN was administered intraperitoneally at 1st h after SAH. Neurological evaluation was performed with Garcia's score. RT-PCR was performed for gene expression levels in the hippocampus. Pyknosis, edema, and apoptosis were evaluated by H&E and TUNEL staining. Our results indicated that PCN administration reduced apoptosis (P < 0.01), cellular edema, and pyknosis (P < 0.05) in the hippocampus after SAH. Moreover, PCN treatment significantly decreased the expression levels of TNF-α (P < 0.01), IL-6 (P < 0.05), NF-κB (P < 0.05), and Bax (P < 0.05) in the hippocampus.
Conclusions
Our results demonstrated that PCN might be a potential therapeutic adjuvant agent for the treatment of early brain injury (EBI) following SAH. Further studies are required to clarify the underlying mechanisms and treatment options of SAH.
... NF-κB is a transcription factor that regulates the expression of genes involved in inflammatory responses, cell survival, and immune reactions. Its activation occurs through two distinct mechanisms [51,52]: ...
Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood–brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.
... GPX4 has a significant contribution in eliminating peroxides by suppressing the NF-κB activation and decreasing ROS accumulation. NF-κB is closely linked with inflammation, which has been found to be expressed in nearly all cell tissues including astrocytes, neurons, and microglia [92]. In addition, it controls several functional target genes and plays roles in several biological mechanisms including tumorigenesis, apoptosis, inflammation, and immune response. ...
Ferroptosis is a newly discovered non-apoptotic and iron-dependent type of cell death. Ferroptosis mainly takes place owing to the imbalance of anti-oxidation and oxidation in the body. It is regulated via a number of factors and pathways both inside and outside the cell. Ferroptosis is closely linked with brain and various neurological disorders (NDs). In the human body, the brain contains the highest levels of polyunsaturated fatty acids, which are known as lipid peroxide precursors. In addition, there is also a connection of glutathione depletion and lipid peroxidation with NDs. There is growing evidence regarding the possible link between neuroinflammation and multiple NDs, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and stroke. Recent studies have demonstrated that disruptions of lipid reactive oxygen species (ROS), glutamate excitatory toxicity, iron homeostasis, and various other manifestations linked with ferroptosis can be identified in various neuroinflammation-mediated NDs. It has also been reported that damage-associated molecular pattern molecules including ROS are generated during the events of ferroptosis and can cause glial activation via activating neuroimmune pathways, which subsequently leads to the generation of various inflammatory factors that play a role in various NDs. This review summarizes the regulation pathways of ferroptosis, the link between ferroptosis as well as inflammation in NDs, and the potential of a range of therapeutic agents that can be used to target ferroptosis and inflammation in the treatment of neurological disorders.
... Therefore, these findings suggest that NF-κB has potential as a therapeutic target for mitigating neurodegeneration in the dopaminergic system. However, additional research is required to ascertain the most appropriate strategy and medication for treating NDs [40]. ...
... PD, the 2nd most prevalent ND, affects around 2% of those aged 65 and above, impacting dopaminergic neurons located in the substantia nigra (SN), which leads to a reduction in dopamine levels [40,75]. Polyphenols have been extensively researched for their effectiveness in treating PD. ...
Polyphenolic compounds have shown promising neuroprotective properties, making them a valuable resource for identifying prospective drug candidates to treat several neurological disorders (NDs). Numerous studies have reported that polyphenols can disrupt the nuclear factor kappa B(NF-κB) pathway by inhibiting the phosphorylation or ubiquitination of signaling molecules, which further prevents the degradation of IκB. Additionally, they prevent NF-κB translocation to the nucleus and pro-inflammatory cytokine production. Polyphenols such as curcumin, resveratrol, and pterostilbene had significant inhibitory effects on NF-κB, making them promising candidates for treating NDs. Recent experimental findings suggest that polyphenols possess a wide range of pharmacological properties. Notably, much attention has been directed towards their potential therapeutic effects in NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety, depression, autism, and spinal cord injury (SCI). Much preclinical data supporting the neurotherapeutic benefits of polyphenols has been developed. Nevertheless, this study has described the significance of polyphenols as potential neurotherapeutic agents, specifically emphasizing their impact on the NF-κB pathway. This article offers a comprehensive analysis of the involvement of polyphenols in NDs, including both preclinical and clinical perspectives.
... NF-κB activation is linked to a number of disorders of the human neurological system. The NF-κB pathway has been linked to a number of diseases and conditions, including headaches (Burstein et al., 2017), migraine (Reuter et al., 2002), aging (Csiszar et al., 2008), stroke (Harari & Liao, 2010), traumatic brain injury (Sullivan et al., 1999), Parkinson's disease (Singh et al., 2020), Alzheimer's disease (Srinivasan & Lahiri, 2015), Huntington's disease (Yu et al., 2000), and brain tumors (Wang et al., 2019). The polyphenols of Curcumin and tea inhibit the NF-κB pathway for neuroprotection (Mandal et al., 2020). ...
Phenolic compounds are those bioactive compounds that contain an aromatic ring with one or more hydroxyl groups or their derivatives such as esters, ethers, and glycosides. In nomenclature terms, these are hydroxybenzene and hydroxycinnamic acid derivatives. These vary from single-ring compounds to complex multiple-ring and polyhydroxyl compounds
