Microglia serve as the principal instigators of neuroinflammatory cascades following ischemic stroke. We here demonstrated that PRMT2IP (previously named as 1700017B05Rik in mice and C15orf39 in humans) is essential for modulating microglial activation and functional responses in ischemic stroke. Mendelian randomization (MR) analysis demonstrated a causal relationship between downregulation of human PRMT2IP expression and an elevated risk of ischemic stroke. Mouse PRMT2IP expression was downregulated in ischemic microglia. Critically, PRMT2IP overexpression provided a protective role in reducing cerebral ischemia injury, while PRMT2IP knockout showed significantly worsened outcomes. Mechanistically, PRMT2IP interacts with PRMT2 and inhibits the activation of the NF-κB signaling pathway by PRMT2-IκBα signaling axis, ultimately reducing the expression of inflammatory factors IL-6 and TNFα. In conclusion, our results suggest that microglial PRMT2IP, as a key negative regulator of microglial inflammatory response, alleviates ischemia-induced brain injury. Thus, up-regulation of PRMT2IP expression may provide a therapeutic strategy to attenuate deleterious neuroinflammation post-stroke.

BACKGROUND:The circadian rhythm is an intrinsic, approximately 24-h cycle of physiological, behavioral, and psychological changes formed through organisms' long-term evolutionary adaptation to the 24-h light-dark cycle on Earth. It regulates the body's homeostatic processes according to a daily schedule, ensuring the proper execution of physiological processes and the stability of the internal environment. In recent years, numerous studies have indicated crosstalk between the circadian rhythm and neuroinflammation. Disruption of the circadian rhythm can influence the onset and progression of various acute and chronic central nervous system diseases. SUMMARY:This review outlines the basic components and mechanisms of the circadian timing system and divides the development of neuroinflammation into several parts: initiation of neuroinflammation, glial cell activation, disruption of the neurovascular unit, oxidative stress response, and cellular energy metabolism. By revealing the role of circadian mechanisms in each part, the relationship between the biological clock and neuroinflammation is analyzed from a molecular biology perspective, aiming to provide a new theoretical basis for the clinical intervention of neuroinflammation and the treatment of related diseases. KEY MESSAGES:Disrupted circadian rhythms participate in various stages of neuroinflammation through "crosstalk," making them a factor that cannot be ignored in the treatment of neurological disorders.

The potential role of diacylglycerol acyltransferase 1(DGAT1) in regulating dendritic cell (DC) function and apoptosis in sepsis and its associated mechanisms is still unknown. Levels of very low-density lipoproteins (VLDLs), which transport endogenous triglycerides, are elevated in sepsis, leading to hypertriglyceridemia. Triacylglyceride (triacylglycerol, TAG) is the main energy storage material in life. DGAT 1 is a key enzyme in triglyceride synthesis, responsible for TAG synthesis during fat absorption and storage. This study explored the effect of the regulation of DGAT 1 expression on the immune function of dendritic cells in sepsis and associated mechanisms. Downregulation of DGAT 1 expression improved the function and apoptosis of bone marrow-derived dendritic cells in sepsis and may have activated pathway signaling proteins (JAK 2 and STAT 3) to alleviate oxidative stress and inflammation. These suggest that DGAT 1 may have a role in improving immune function in sepsis.

The current management of neurological disorders remains largely symptomatic. In recent years, stem cell–derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell–derived exosomes across several neurological disorders. In Alzheimer’s disease models, stem cell–derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson’s disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell–derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.

Gene editing (GE) technology is a genetic manipulation technique based on artificial nucleases that enables the precise modification of DNA or RNA. With the development of technology, GE in disease treatment is becoming increasingly widespread, playing an essential role in haematology, cancer, and neurological disorders (ND). This review describes the principles, advantages, and limitations of four GE technologies, focusing on the fourth generation of GE (next-generation GE). The next-generation GE technology breaks the limitations of traditional GE technology, makes GE more precise and stable, and broadens the scope of gene technology applications. Additionally, this review explores the latest gene therapy strategies for ND, focusing on the application of next-generation GE technologies to examine the prospects for the application of GE technologies. This study discusses and analyses the great advantages and potential of GE technology for treating ND and elucidates the shortcomings of GE in this field.

Phosphoglycerate dehydrogenase (PHGDH) is a key molecule in the progression of Alzheimer's disease. Herein, we report that PHGDH exerts a significant influence on cerebral ischemia-reperfusion injury (CIRI). Ischemia-reperfusion injury is predominantly triggered by oxidative stress and inflammatory responses; however, the underlying molecular mechanisms remain incompletely understood. Our findings demonstrate that PHGDH displays predominant expression in brain astrocytes and undergoes time-dependent alterations in reactive astrocytes following cerebral ischemia-reperfusion. Specifically, targeted knockdown of PHGDH expression in astrocytes substantially exacerbates pathological damage and neurological deficits post cerebral ischemia-reperfusion. Subsequent mechanistic analyses unveiled that PHGDH knockdown predominantly facilitates astrocyte pyroptosis and neuroinflammation. Specifically, downregulation of PHGDH in astrocytes induces oxidative stress, augments ROS production, and diminishes antioxidant levels of GSH and NADPH. Moreover, PHGDH downregulation disrupts the mitochondrial respiratory chain, triggering mitochondrial damage and dsDNA release during ischemia-reperfusion, thereby exacerbating oxidative stress. Collectively, these mechanisms culminate in AIM2 inflammasome activation, as evidenced by substantial increases in AIM2, ASC, and Cleaved Caspase-1 expression. Notably, exogenous depletion of serine and glycine fails to fully explain the astrocyte pyroptosis triggered by PHGDH knockdown. In conclusion, downregulation of PHGDH in astrocytes post cerebral ischemia-reperfusion predominantly drives astrocyte pyroptosis via oxidative stress, resulting in the release of pro-inflammatory cytokines (e.g., IL-1β and IL-18) and subsequent exacerbation of ischemia-reperfusion injury. These novel insights into the role of PHGDH may inform the development of targeted therapeutic strategies for cerebral ischemia-reperfusion.

There is a common mechanism in the pathogenesis of central nervous system diseases: Neuronal damage causes a dissipation of the intermediate metabolites, triggering a wider range of injury and inflammation. Due to the selective permeability of the blood-brain barrier, the drug treatment of neurological diseases is not effective. Nanomedicine, with good biocompatibility and high plasticity, can pass through the blood-brain barrier through various mechanisms and targeted the lesion: The nano-delivery system helps drugs cross the blood-brain barrier while taking advantage of its high drug-loading capacity to achieve combined treatment; Nano-enzymes can simulate the enzymatic reaction in biological body to remove metabolic substances, and are more stable and economical than biological enzymes; Individual nanomedicine can regulate the differentiation process of neural stem cells from the genetic level, increase the number of neurons, and repair injured nerves. Nanomaterials can not only improve the pharmacokinetics and pharmacodynamics, but also play the function of focal location to monitor and evaluate the disease and condition during the treatment of nervous system diseases. In this paper, the mechanism of nanomaterials penetrating the blood-brain barrier (BBB) and locating lesions in various nervous system diseases is reviewed, which opens up new ideas for further exploring the application of nanotechnology in central nervous system diseases.

BACKGROUND:The blood-brain barrier (BBB) is essential for central nervous system (CNS) homeostasis, yet neuroinflammatory mechanisms driving BBB disruption remain poorly understood. PURPOSE:To explore the oxygen-glucose deprivation/reoxygenation (OGD/R)-induced BBB dysfunction and evaluate the therapeutic effects of Guanxinning injection (GXNI), a Danshen-Chuanxiong herbal combination, targeting neuroinflammatory pathways. METHODS:A 3D-BBB organoid composed of human brain microvascular endothelial cells, human astrocytes, and primary human brain microvascular pericytes was constructed, and conditions for OGD/R that simulate ischemic stroke were established. Structure and function of the in vitro BBB were evaluated by morphology, paracellular permeability, and tight junction proteins ZO-1, claudin-5, and occludin expression. In vivo, infarct volume and BBB leakage were measured in a mid-cerebral artery occlusion-induced cerebral ischemia-reperfusion injury model. RNA-seq and network pharmacology analysis were used to identify key genes and pathways for ischemic BBB disruption. HPLC-MS was performed to identify and quantify active components. Molecular docking, SPR, and molecular dynamics were performed to predict and confirm the interaction of active compounds and target proteins. RESULTS:A Danshen-Chuanxiong double herbal medicine, GXNI, mitigated these effects, restoring transport capacity, reducing oxidative stress (ROS), and enhancing basement membrane components (laminin, collagen IV). In vivo, GXNI alleviated cerebral ischemia-reperfusion injury (CIRI), decreasing BBB leakage, infarct volume, and neurological deficits. The pivotal role of TLR4/NF-κB/MMP9 neuroinflammatory axis for GXNI BBB protection was identified through transcriptomic analysis and validated via immunofluorescence in BBB spheroids. Molecular docking revealed Danshen-derived salvianolic acid B (SAB) as a high-affinity MMP9 binder, confirmed by quantitative binding assays. The SAB and Chuanxiong-derived senkyunolide I (SI) combination achieved more prominent upregulation of tight junction proteins and suppression of MMP9. CONCLUSION:Our findings further confirm neuroinflammation as a central driver of ischemic BBB damage and demonstrate that GXNI preserves BBB integrity by targeting TLR4/NF-κB/MMP9 signaling in 3D models and CIRI mice, with SAB-SI synergistically contributing to enhanced therapeutic efficacy.

Optogenetics is an emerging technology that uses the light-responsive effects of photosensitive proteins to regulate the function of specific cells. This technique combines genetics with optics, allowing for the precise inhibition or activation of cell functions through the introduction of photosensitive proteins into target cells and subsequent light stimulation to activate these proteins. In recent years, numerous basic and clinical studies have demonstrated the unique advantages of this approach in the research and treatment of neurological disorders. This review aims to introduce the fundamental principles and techniques of optogenetics, as well as its applications in the research and treatment of neurological diseases.

Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer’s disease, Parkinson’s disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.

The pathophysiology of intracerebral hemorrhage (ICH) is complex and can cause variable degrees of cell death. Recently, ferroptosis, an emerging cell death mechanism, has garnered significant attention in cerebral hemorrhage disorder. This study aimed to examine iron mortality after cerebral hemorrhage and current targets for potential therapeutic interventions. We specifically focused on iron metabolism abnormalities, lipid peroxidation, and related neuroinflammation and introduced molecular mechanisms, including transcription factors, to gain a better understanding of the underlying mechanisms of ferroptosis and investigate possible therapeutic options for ICH.

Hesperidin is a kind of flavonoids, which has the biological activities of antioxidation, anti-inflammation, antibacterial, anti-virus, anti-allergy, anti-cancer, heart protection and neuroprotection. More and more studies have begun to pay attention to the therapeutic prospect of hesperidin in central nervous system (CNS) diseases. This paper describes its current role in the treatment of central nervous system diseases, especially stroke, and discusses its bioavailability, so as to provide a theoretical basis for the clinical application of hesperidin.

To explore the targets and pathways of

Background: Obesity is recognized as a primary risk factor for cerebral ischemia, which has shown a significant increase in its incidence among obese patients. The exact mechanism by which obesity exacerbates cerebral ischemic injury is not fully understood though. The present study validated the hypothesis that obesity mediates pyroptosis by the AGEs/RAGE signaling pathway to exacerbate cerebral ischemic injury. Methods: Leptin receptor knockout ( Lepr (-/-) ) rats were used in this study to construct an obesity model, and the middle cerebral artery occlusion (MCAO) models of ischemic stroke were established in Lepr(-/- ) obese rats and their wild-type (WT) littermates respectively. Zea-Longa score, TTC and H&E staining were utilized to evaluate the neurological impairment. Western Blot, immunohistochemistry, and immunofluorescence were used to detect protein expressions. Transmission electron microscopy was used to observe the pores in the neuronal cell membrane in the ischemic penumbra cortex. Results: Compared with WT littermates, Lepr(-/-) obese rats exhibited exacerbated neuronal injury after MCAO, with higher expressions of NLRP3 inflammasome and pyroptosis-related proteins in the cortical tissue of the penumbra. Moreover, more GSDMD pores were observed on the neuronal cell membranes of Lepr(-/-)obese rats according to the electron microscopy. Inhibition of NLRP3 inflammasome expression with MCC950 inhibited neuronal pyroptosis after cerebral ischemia in Lepr(-/-) rats, thus reducing neuronal injury. We also found that compared with WT littermates, the levels of AGEs and RAGE in the cortex of Lepr-/-obese -/- obese rats are significantly higher, with further increase after cerebral ischemia. Inhibition of AGEs/RAGE signaling pathway with FPS-ZM1 reduced the NLRP3 inflammasome-mediated neuronal pyroptosis in Lepr-/-obese -/- obese rats, thereby mitigating the neuronal damage after cerebral ischemia. Conclusion: The AGEs/RAGE signaling pathway is involved in the exacerbation of cerebral ischemic injury in Lepr-/-obese -/- obese rats via regulating NLRP3-mediated neuronal pyroptosis.

Ginseng is frequently used in traditional Chinese medicine to treat neurological disorders. The primary active component of ginseng is ginsenoside, which has been classified into more than 110 types based on their chemical structures. Ginsenoside Rb1 (GsRb1)—a protopanaxadiol saponin and a typical ginseng component—exhibits anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-autophagy properties in the nervous system. Neurological disorders remain a leading cause of death and disability globally. GsRb1 effectively treats neurological disorders. To contribute novel insights to the understanding and treatment of neurological disorders, we present a comprehensive review of the pharmacokinetics, actions, mechanisms, and research development of GsRb1 in neurological disorders.

Background:Dementia is a neuropsychiatric disorder with cognitive decline due to multiple factors. With the arrival of the aging population, the incidence of dementia has gradually increased. There is still no effective treatment for dementia, and therefore, the prevention of dementia has become crucial. Oxidative stress is considered to be one of the pathogenesis of dementia; therefore, antioxidant therapy and prevention of dementia have been gradually proposed. Objective:Our meta-analysis aimed to investigate the association of antioxidants with risk of dementia. Methods:We searched PubMed, Embase, and Web of Science databases for articles on antioxidants associated with dementia risk, and those containing cohort studies with high-dose versus low-dose controls were included in our meta-analysis. The resulting risk ratios (RR) and hazard ratios (HR) and 95% confidence intervals were statistically analyzed using Stata12.0 free software. Results:A total of 17 articles were included in this meta-analysis. Of 98,264 participants, 7,425 had dementia after 3-23 years of follow-up. The results of the meta-analysis showed a trend towards a lower incidence of dementia with high intake of antioxidants (RR = 0.84, 95% CI 0.77-1.19 I2 = 54.6%), but this was not statistically significant. High antioxidant intake significantly reduced the incidence of Alzheimer 's disease (RR = 0.85, 95% CI 0.79-0.92 I2 = 45.5%), and we additionally carried out subgroup analyses by nutrient type, diet or supplement, region, and study quality score. Conclusion:Dietary intake of antioxidants or supplements reduces both the risk of dementia and the risk of Alzheimer's disease.

Medical anthropology plays a crucial role in understanding health, disease, and treatment within contemporary anthropology. As the incidence of tumors rises, with cancer posing a significant threat to human health, particularly malignant brain tumors, such as glioma, the need for accurate preoperative diagnosis and effective treatment strategies is paramount.

In the realm of this study, obtaining a comprehensive understanding of ischemic brain injury and its molecular foundations is of paramount importance. Our study delved into single-cell data analysis, with a specific focus on sub-celltypes and differentially expressed genes in the aftermath of ischemic injury. Notably, we observed a significant enrichment of the "ATP METABOLIC PROCESS" and "ATP HYDROLYSIS ACTIVITY" pathways, featuring pivotal genes such as Pbx3, Dguok, and Kif21b. A remarkable finding was the consistent upregulation of genes like Fabp7 and Bcl11a within the MCAO group, highlighting their crucial roles in regulating the pathway of mitochondrial ATP synthesis coupled proton transport. Furthermore, our network analysis unveiled pathways like "Neuron differentiation" and "T cell differentiation" as central in the regulatory processes of sub-celltypes. These findings provide valuable insights into the intricate molecular responses and regulatory mechanisms that govern brain injury. The shared differentially expressed genes among sub-celltypes emphasize their significance in orchestrating responses post-ischemic injury. Our research, viewed from the perspective of a medical researcher, contributes to the evolving understanding of the molecular landscape underlying ischemic brain injury, potentially paving the way for targeted therapeutic strategies and improved patient outcomes.

Cerebral ischemic preconditioning (CIP) has been shown to improve brain ischemic tolerance against subsequent lethal ischemia. Reactive astrocytes play important roles in cerebral ischemia–reperfusion. Recent studies have shown that reactive astrocytes can be polarized into neurotoxic A1 phenotype (C3d) and neuroprotective A2 phenotype (S100A10). However, their role in CIP remains unclear. Here, we focused on the role of N-myc downstream-regulated gene 2 (NDRG2) in regulating the transformation of A1/A2 astrocytes and promoting to brain ischemic tolerance induced by CIP. A Sprague Dawley rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) was used. Rats were divided into the following six groups: (1) sham group; (2) CIP group: left middle cerebral artery was blocked for 10 min; (3) MCAO/R group: left middle cerebral artery was blocked for 90 min; (4) CIP + MCAO/R group: CIP was performed 72 h before MCAO/R; (5) AAV-NDRG2 + CIP + MCAO/R group: adeno-associated virus (AAV) carrying NDRG2 was administered 14 days before CIP + MCAO/R; (6) AAV-Ctrl + CIP + MCAO/R group: empty control group. The rats were subjected to neurological evaluation 24 h after the above treatments, and then were sacrificed for 2, 3, 5-triphenyltetraolium chloride staining, thionin staining, immunofluorescence and western blot analysis. In CIP + MCAO/R group, the neurological deficit scores decreased, infarct volume reduced, and neuronal density increased compared with MCAO/R group. Notably, CIP significantly increased S100A10 expression and the number of S100A10 + /GFAP + cells, and also increased NDRG2 expression. MCAO/R significantly decreased S100A10 expression and the number of S100A10 + /GFAP + cells yet increased C3d expression and the number of C3d + /GFAP + cells and NDRG2 expression, and these trends were reversed by CIP + MCAO/R. Furthermore, over-expression of NDRG2 before CIP + MCAO/R, the C3d expression and the number of C3d + /GFAP + cells increased, while S100A10 expression and the number of S100A10 + /GFAP + cells decreased. Meanwhile, over-expression of NDRG2 blocked the CIP-induced brain ischemic tolerance. Taken together, these results suggest that CIP exerts neuroprotective effects against ischemic injury by suppressing A1 astrocyte polarization and promoting A2 astrocyte polarization via inhibiting NDRG2 expression.

Hypoxic-ischemic brain damage (HIBD) is a leading cause of neonatal death and neurological dysfunction for which no particularly effective treatment is available. Stem cells possess multi-directional differentiation potential and can secrete a variety of cytokines. They not only have the ability to replace tissue and repair lesions but also improve neurological damage caused by HIBD through paracrine mechanisms, including anti-apoptosis, reduction of inflammation, and promotion of endogenous repair. Recently, as research on stem cells, particularly mesenchymal stem cells, has deepened, the application of stem cells in treating HIBD has become a prominent research topic, yielding fruitful results, particularly regarding the neuroprotective effects and mechanisms of the stem cell paracrine pathway. With advances in stem cell injection, distribution, and biomaterial incorporation, applications of stem cells have become more widespread and comprehensive. This review summarizes and discusses the research progress on stem cells in HIBD treatment to provide theoretical support for HIBD treatment and enhance the feasibility of clinical translation.