医学最新文献

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

JOURNAL/nrgr/04.03/01300535-202504000-00031/figure1/v/2024-07-06T104127Z/r/image-tiff Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia. Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia. Currently, studies have reported increased oscillation power in cases of levodopa-induced dyskinesia. However, little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia. Furthermore, the role of the dopamine D3 receptor, which is implicated in levodopa-induced dyskinesia, in movement disorder-related changes in neural oscillations is unclear. We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson's disease. Furthermore, levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components, as well as bidirectional primary motor cortex (M1) ↔ dorsolateral striatum gamma flow. Administration of PD128907 (a selective dopamine D3 receptor agonist) induced dyskinesia and excessive gamma oscillations with a bidirectional M1 ↔ dorsolateral striatum flow. However, administration of PG01037 (a selective dopamine D3 receptor antagonist) attenuated dyskinesia, suppressed gamma oscillations and cortical gamma aperiodic components, and decreased gamma causality in the M1 → dorsolateral striatum direction. These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity, and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1β, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson's disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson's disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography-tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Astrocytes are the most abundant type of glial cell in the central nervous system. Upon injury and inflammation, astrocytes become reactive and undergo morphological and functional changes. Depending on their phenotypic classification as A1 or A2, reactive astrocytes contribute to both neurotoxic and neuroprotective responses, respectively. However, this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries. Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles, which emphasizes the heterogeneous nature of their reactivity. Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types, releasing cytokines, and influencing the immune response. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior, as evidenced by in silico , in vitro , and in vivo results. In astrocytes, inflammatory cues trigger a cascade of molecular events, where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses. Here, we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation. We highlight the involvement of various signaling pathways that regulate astrocyte reactivity, including the PI3K/AKT/mammalian target of rapamycin (mTOR), α v β 3 integrin/PI3K/AKT/connexin 43, and Notch/PI3K/AKT pathways. While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage, evidence suggests that activating this pathway could also yield beneficial outcomes. This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation. The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior. The findings should then be validated using in vivo models to ensure real-life relevance. The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage, although further studies are required to fully comprehend its role due to varying factors such as different cell types, astrocyte responses to inflammation, and disease contexts. Specific strategies are clearly necessary to address these variables effectively.