ACS Chemical Neuroscience最新文献

Oxidative stress and neuroinflammation can synergistically accelerate dopaminergic neuronal degeneration in Parkinson's disease (PD). Small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) inhibit Nox4/ROS production by delivering specific miRNAs, regulate the EGR1/NOX4/p38MAPK axis to exert antioxidant effects, and can enhance antioxidant capacity by activating the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Additionally, at the same time, neuroinflammation can be alleviated by inhibiting the Sp1 signal and regulating pro-inflammatory/anti-inflammatory factors. MSC-sEVs can penetrate the blood-brain barrier, improve movement disorders, and relieve neuronal damage in PD models, providing a new anti-inflammatory and antioxidant strategy for PD treatment.

The application of terahertz waves in the field of neurological disease research has gradually attracted attention in recent years. Prior studies have indicated that terahertz waves are capable of alleviating the symptoms of Alzheimer's disease (AD) in mice, yet the underlying relevant mechanisms remain unclear. This study explores the therapeutic potential of terahertz (THz) radiation on AD using a transgenic Caenorhabditis elegans model expressing human tau protein. The nematodes were subjected to 0.1 THz radiation at varying power levels, and its impact on locomotion, tau protein aggregation, and associative learning was evaluated. Results indicate that 0.1 THz irradiation significantly improved the locomotor performance and associative learning of the tau transgenic nematodes, reduced tau aggregation, and increased the expression of SKN-1 and DAF-16. Molecular dynamics simulation revealed that THz waves inhibited the structural stability of tau protofibrils by reducing the protein compactness, altering the secondary structure, reducing hydrogen bond formation, and changing the hydrophobic interaction. Overall, this study demonstrates the potential of low-frequency THz radiation as a nonpharmacological therapy for AD, highlighting its ability to modulate neuronal function and alleviate disease symptoms.

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota in Alzheimer’s disease (AD) has garnered increasing attention, although the functional implications of these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, and gut microbiota interact in male 3 × Tg-AD and B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) and 12 months-old (12-MO). Employing a combination of behavioral assessments, diffusion kurtosis imaging (DKI), microbiota profiling, cytokine analysis, short-chain fatty acids (SCFAs), and immunohistochemistry, we explored the progression of AD-related pathology. Significant memory impairments in AD mice at both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation and microstructural damage. We observed elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, and IFN-γ, in the serum, which were associated with increased activity of microglia and astrocytes in brain regions critical for memory. Although gut microbiota analysis did not reveal significant changes in alpha diversity, it did show notable differences in beta diversity and a diminished Firmicutes/Bacteroidetes (F/B) ratio in AD mice at 12-MO. Furthermore, a reduction in six kinds of SCFAs were identified at two time points of 6-MO and 12-MO, indicating widespread disruption in gut microbial metabolism. These findings underscore a complex bidirectional relationship between systemic inflammation and gut dysbiosis in AD, highlighting the gut-brain axis as a crucial factor in disease progression. This study emphasizes the potential of integrating DKI metrics, microbiota profiling, and SCFA analysis to enhance our understanding of AD pathology and to identify new therapeutic targets.

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota in Alzheimer's disease (AD) has garnered increasing attention, although the functional implications of these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, and gut microbiota interact in male 3 × Tg-AD and B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) and 12 months-old (12-MO). Employing a combination of behavioral assessments, diffusion kurtosis imaging (DKI), microbiota profiling, cytokine analysis, short-chain fatty acids (SCFAs), and immunohistochemistry, we explored the progression of AD-related pathology. Significant memory impairments in AD mice at both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation and microstructural damage. We observed elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, and IFN-γ, in the serum, which were associated with increased activity of microglia and astrocytes in brain regions critical for memory. Although gut microbiota analysis did not reveal significant changes in alpha diversity, it did show notable differences in beta diversity and a diminished Firmicutes/Bacteroidetes (F/B) ratio in AD mice at 12-MO. Furthermore, a reduction in six kinds of SCFAs were identified at two time points of 6-MO and 12-MO, indicating widespread disruption in gut microbial metabolism. These findings underscore a complex bidirectional relationship between systemic inflammation and gut dysbiosis in AD, highlighting the gut-brain axis as a crucial factor in disease progression. This study emphasizes the potential of integrating DKI metrics, microbiota profiling, and SCFA analysis to enhance our understanding of AD pathology and to identify new therapeutic targets.

Engineered nanoparticles (ENPs) have widely revolutionized many fields, including medicine, technology, environmental science, and industry. However, with the wide use of ENPs in everyday life, concerns are increasingly being raised about their potential neurotoxic effects on the central nervous system (CNS), particularly in relation to neurodegeneration and neuroinflammation. The present systematic review focuses on reporting the current knowledge about the neurotoxic potential of ENPs, with particular attention to their mechanism of action in neuroinflammation and neurodegeneration. This PRISMA based systematic review encompassed studies from Pubmed, Embase, and Web of Science. Eligibility criteria included focusing on engineered NPs and their impacts on neuroinflammation, neurodegeneration, and neurotoxicity. Evidence shows that ENPs easily can cross the blood-brain barrier (BBB) inducing neuronal damage and neurotoxicity due to oxidative stress, inflammation, mitochondrial dysfunction, and cell death. Inflammation plays a crucial role in activating glial cells, such as microglia and astrocytes, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS). This increases the vulnerability of the brain to systemic inflammation. In conclusion, as ENP exposure continues to increase, understanding their long-term effects on the brain is fundamental to developing effective strategies to mitigate their impact on neuronal human health.

Parkinson’s disease (PD) poses a global menace, as the available treatment methods solely aim to mitigate symptoms. An effective strategy to address the pathogenesis of PD involves eliminating the accumulation of aggregated alpha-synuclein, emphasizing the role of epigenetics. Aberrant epigenetic changes significantly influence gene expression, which is pivotal in PD progression, impacting neuronal growth and degeneration. Epigenetic-related genes are regulated by histone modification and DNA methylation processes. Nevertheless, their significance in PD has not been confirmed. This research was carried out using both in vitro and in vivo approaches. In the in vitro investigations, N2A neuronal cell lines were utilized, and the neuroprotective effect of decitabine (DB) was observed at concentrations of 0.1 μM and 0.5 μM. In the in vivo study, PD induction led to significant motor deficits, which were notably ameliorated at the highest treatment dose. This improvement was accompanied by a marked attenuation of inflammatory mediators, including TNF-α, IL-6, IL-1β, and CRP levels. Additionally, there was a significant enhancement in antioxidative defense, evidenced by increased GSH (glutathione) levels and reduced oxidative stress marker NO (nitric oxide). Neurochemical analysis revealed a substantial rise in dopamine levels, a critical PD marker, alongside an elevation in BDNF, indicating neuroprotective effects. Furthermore, gene expression analysis indicated a notable upregulation in the mRNA expression of epigenetic genes and proteins linked to PD pathology. Histological assessments, including IHC, H&E, and CV staining of the substantia nigra, showed enhanced structural integrity following treatment. Collectively, these insights reveal DB’s promise as a therapeutic solution for mitigating PD symptoms and pathology exacerbated by 6-OHDA.

Engineered nanoparticles (ENPs) have widely revolutionized many fields, including medicine, technology, environmental science, and industry. However, with the wide use of ENPs in everyday life, concerns are increasingly being raised about their potential neurotoxic effects on the central nervous system (CNS), particularly in relation to neurodegeneration and neuroinflammation. The present systematic review focuses on reporting the current knowledge about the neurotoxic potential of ENPs, with particular attention to their mechanism of action in neuroinflammation and neurodegeneration. This PRISMA based systematic review encompassed studies from Pubmed, Embase, and Web of Science. Eligibility criteria included focusing on engineered NPs and their impacts on neuroinflammation, neurodegeneration, and neurotoxicity. Evidence shows that ENPs easily can cross the blood–brain barrier (BBB) inducing neuronal damage and neurotoxicity due to oxidative stress, inflammation, mitochondrial dysfunction, and cell death. Inflammation plays a crucial role in activating glial cells, such as microglia and astrocytes, leading to the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS). This increases the vulnerability of the brain to systemic inflammation. In conclusion, as ENP exposure continues to increase, understanding their long-term effects on the brain is fundamental to developing effective strategies to mitigate their impact on neuronal human health.

Receptor-interacting protein kinase 1 (RIPK1) serves as a critical mediator of cell necroptosis and represents a promising therapeutic target for various human neurodegenerative diseases and inflammatory diseases. Nonetheless, the RIPK1 inhibitors currently reported are inadequate for clinical research due to suboptimal inhibitory activities or lack of selectivity. Consequently, there is a need for the discovery of novel RIPK1 kinase inhibitors. In this study, we integrated a deep learning model, specifically the fingerprint graph attention network (FP-GAT), with molecular docking-based virtual screening to identify potential RIPK1 inhibitors from a library comprising 13 million compounds. Out of 43 compounds procured, two compounds (designated as 24 and 41) demonstrated enzyme inhibition activity exceeding 50% at a concentration of 10 μM against RIPK1. The half-maximal inhibitory concentrations (IC₅₀) for compounds 24 and 41 were determined to be 2.01 and 2.95 μM, respectively. Furthermore, these compounds exhibited protective effects in an HT-29 cell model of TSZ-induced necroptosis, with half-maximal effective concentrations (EC₅₀) of 6.77 μM for compound 24 and 68.70 μM for compound 41. Finally, molecular dynamics simulations and binding free energy calculations were conducted to elucidate the molecular mechanism of compounds 24 and 41 binding to RIPK1. The results show that Met92, Met95, Ala155, and Asp156 are key residues for novel RIPK1 inhibitors. In summary, this work discovered two hit compounds targeting RIPK1, which can be further structurally modified to become promising lead compounds.

Parkinson's disease (PD) poses a global menace, as the available treatment methods solely aim to mitigate symptoms. An effective strategy to address the pathogenesis of PD involves eliminating the accumulation of aggregated alpha-synuclein, emphasizing the role of epigenetics. Aberrant epigenetic changes significantly influence gene expression, which is pivotal in PD progression, impacting neuronal growth and degeneration. Epigenetic-related genes are regulated by histone modification and DNA methylation processes. Nevertheless, their significance in PD has not been confirmed. This research was carried out using both in vitro and in vivo approaches. In the in vitro investigations, N2A neuronal cell lines were utilized, and the neuroprotective effect of decitabine (DB) was observed at concentrations of 0.1 μM and 0.5 μM. In the in vivo study, PD induction led to significant motor deficits, which were notably ameliorated at the highest treatment dose. This improvement was accompanied by a marked attenuation of inflammatory mediators, including TNF-α, IL-6, IL-1β, and CRP levels. Additionally, there was a significant enhancement in antioxidative defense, evidenced by increased GSH (glutathione) levels and reduced oxidative stress marker NO (nitric oxide). Neurochemical analysis revealed a substantial rise in dopamine levels, a critical PD marker, alongside an elevation in BDNF, indicating neuroprotective effects. Furthermore, gene expression analysis indicated a notable upregulation in the mRNA expression of epigenetic genes and proteins linked to PD pathology. Histological assessments, including IHC, H&E, and CV staining of the substantia nigra, showed enhanced structural integrity following treatment. Collectively, these insights reveal DB's promise as a therapeutic solution for mitigating PD symptoms and pathology exacerbated by 6-OHDA.

Receptor-interacting protein kinase 1 (RIPK1) serves as a critical mediator of cell necroptosis and represents a promising therapeutic target for various human neurodegenerative diseases and inflammatory diseases. Nonetheless, the RIPK1 inhibitors currently reported are inadequate for clinical research due to suboptimal inhibitory activities or lack of selectivity. Consequently, there is a need for the discovery of novel RIPK1 kinase inhibitors. In this study, we integrated a deep learning model, specifically the fingerprint graph attention network (FP-GAT), with molecular docking-based virtual screening to identify potential RIPK1 inhibitors from a library comprising 13 million compounds. Out of 43 compounds procured, two compounds (designated as 24 and 41) demonstrated enzyme inhibition activity exceeding 50% at a concentration of 10 μM against RIPK1. The half-maximal inhibitory concentrations (IC₅₀) for compounds 24 and 41 were determined to be 2.01 and 2.95 μM, respectively. Furthermore, these compounds exhibited protective effects in an HT-29 cell model of TSZ-induced necroptosis, with half-maximal effective concentrations (EC₅₀) of 6.77 μM for compound 24 and 68.70 μM for compound 41. Finally, molecular dynamics simulations and binding free energy calculations were conducted to elucidate the molecular mechanism of compounds 24 and 41 binding to RIPK1. The results show that Met92, Met95, Ala155, and Asp156 are key residues for novel RIPK1 inhibitors. In summary, this work discovered two hit compounds targeting RIPK1, which can be further structurally modified to become promising lead compounds.