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Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity. When a diseased artery within the brain bursts, expansion and absorption of the resulting hematoma trigger a series of reactions that cause primary and secondary brain injury. Microglia are extremely important for removing the hematoma and clearing debris, but they are also a source of ongoing inflammation. This article discusses the role of microglial activation/polarization and related inflammatory mediators, such as Toll-like receptor 4, matrix metalloproteinases, high-mobility group protein box-1, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron, in secondary injury after ICH and highlights the potential targets for ICH treatment.

With over 2 million new cases annually, stroke is associated with the highest disability-adjusted life-years lost of any disease in China. The burden is expected to increase further as a result of population ageing, an ongoing high prevalence of risk factors (eg, hypertension), and inadequate management. Despite improved access to overall health services, the availability of specialist stroke care is variable across the country, and especially uneven in rural areas. In-hospital outcomes have improved because of a greater availability of reperfusion therapies and supportive care, but adherence to secondary prevention strategies and long-term care are inadequate. Thrombolysis and stroke units are accepted as standards of care across the world, including in China, but bleeding-risk concerns and organisational challenges hamper widespread adoption of this care in China. Despite little supporting evidence, Chinese herbal products and neuroprotective drugs are widely used, and the increased availability of neuroimaging techniques also results in overdiagnosis and overtreatment of so-called silent stroke. Future efforts should focus on providing more balanced availability of specialised stroke services across the country, enhancing evidence-based practice, and encouraging greater translational research to improve outcome of patients with stroke.

Rodents are the most commonly used laboratory animals in medical research. However, significant evolutionary divergences between humans and rodents, particularly in the complexity of white matter connectome, which are fundamentally shaped by myelin as their major structural component, pose critical challenges in modeling the human neurological diseases. Given the divergences and central roles of myelin in pathology, a thorough reevaluation of the rodent models used in contemporary research is critical, alongside the careful selection, optimization, or de novo development of models that faithfully recapitulate human white matter disorders. In this review, we summarize the strengths and limitations of existing rodent models, emphasizing their contributions to understanding demyelinating pathologies across autoimmune, neurodegenerative, vascular, perinatal, traumatic, infectious and genetic diseases. We also overview white mater disease models using other species and human stem cells. Subsequently we discuss critical interspecies differences in white matter biology that may limit translational relevance, while highlighting how rodent models enhance our comprehension of various pathological conditions. Lastly, we outline strategies to refine rodent models through advanced genetic engineering, humanized microenvironments, and multimodal phenotyping, with the goal of progressively improving existing them to increase their preclinical translational potentials.

Stroke is a major cause of morbidity and mortality worldwide. In the early stages of stroke, irreversible damage to neurons leads to high mortality and disability rates in patients. However, there are still no effective prevention and treatment measures for the resulting massive neuronal death in clinical practice. Astrocyte reprogramming has recently attracted much attention as an avenue for increasing neurons in mice after cerebral ischemia. However, the field of astrocyte reprogramming has recently been mired in controversy due to reports questioning whether newborn neurons are derived from astrocyte transformation. To better understand the process and controversies of astrocyte reprogramming, this review introduces the method of astrocyte reprogramming and its application in stroke. By targeting key transcription factors or microRNAs, astrocytes in the mouse brain could be reprogrammed into functional neurons. Additionally, we summarize some of the current controversies over the lack of cell lineage tracing and single-cell sequencing experiments to provide evidence of gene expression profile changes throughout the process of astrocyte reprogramming. Finally, we present recent advances in cell lineage tracing and single-cell sequencing, suggesting that it is possible to characterize the entire process of astrocyte reprogramming by combining these techniques.

Despite extensive research on the relationship between choline and cardiovascular disease (CVD), conflicting findings have been reported. We aim to investigate the relationship between choline and CVD. Our analysis screened a retrospective cohort study of 14,663 participants from the National Health and Nutrition Examination Survey conducted between 2013 and 2018. Propensity score matching and restricted cubic splines was used to access the association between choline intake and the risk of CVD. A two-sample Mendelian randomization (MR) analysis was conducted to examine the potential causality. Additionally, sets of single cell RNA-sequencing data were extracted and analyzed, in order to explore the role of choline metabolism pathway in the progression and severity of the CVD and the underlying potential mechanisms involved. The adjusted odds ratios and 95% confidence intervals for stroke were 0.72 (0.53–0.98; p = 0.035) for quartile 3 and 0.54 (0.39–0.75; p < 0.001) for quartile 4. A stratified analysis revealed that the relationship between choline intake and stroke varied among different body mass index and waist circumference groups. The results of MR analysis showed that choline and phosphatidylcholine had a predominantly negative causal effect on fat percentage, fat mass, and fat-free mass, while glycine had opposite effects. Results from bioinformatics analysis revealed that alterations in the choline metabolism pathway following stroke may be associated with the prognosis. Our study indicated that the consumption of an appropriate quantity of choline in the diet may help to protect against CVD and the effect may be choline-mediated, resulting in a healthier body composition. Furthermore, the regulation of the choline metabolism pathway following stroke may be a promising therapeutic target.

Stroke is a major cause of morbidity and mortality worldwide. There is an urgent need for effective neuroprotective agents to reduce brain injury. SARM1 (sterile alpha and TIR motif-containing 1) has been identified as a key mediator of axonal degeneration. However, its role in stroke and the underlying mechanisms remain insufficiently understood. In the present study, a mouse model of stroke with focal infarction in the cortex was used to investigate the potential relation between SARM1 and post-stroke brain injury. We found that SARM1 expression increased in neurons of the peri-infarct cortex at an early stage after photothrombotic stroke induction (PTI) and was evenly distributed between excitatory and inhibitory neurons. Deficiency of SARM1 improved neurological performance, reduced the infarct volume and the inflammatory response including reactive gliosis and TNF-α level after PTI. Meanwhile, SARM1 deficiency promoted neuronal preservation in the peri-infarct cortex and mitigated axonal degeneration, possibly because of reduced NAD + consumption of neurons in the peri-infarct cortex. Additionally, we found that SARM1 deficiency inhibited glial scar formation and decreased activated microglia. FK866 and DSRM-3716, two recently reported pharmacological inhibitors of SARM1, failed to alleviate brain injury in mice with stroke. Our findings demonstrate that SARM1 deficiency attenuates ischemic neuronal injury and improves neurological performance post PTI, suggesting that the SARM1 signaling pathway could serve as a potential therapeutic target for stroke in the future.

Background At low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. However, the effect of CO-releasing molecule (CORM)-3, a water-soluble CORM, on ischemic stroke and its mechanism of action are still unclear. Methods We investigated the role of CORM-3 in the mouse model of transient middle cerebral artery occlusion (tMCAO). CORM-3 or saline was administered to mice by retro-orbital injection at the time of reperfusion after 1-h tMCAO or at 1 h after sham surgery. We assessed infarct volume and brain water content at 24 and 72 h after ischemia, blood-brain barrier permeability at 6 and 72 h after ischemia, and neurologic deficits on days 1, 3, 7, and 14. Results Among mice that underwent tMCAO, those that received CORM-3 had significantly smaller infarct volume and greater expression of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 than did saline-treated mice. CORM-3-treated mice had significantly fewer activated microglia in the peri-infarction zone than did control mice and exhibited downregulated expression of ionized calcium-binding adapter molecule (Iba)-1, tumor necrosis factor-α, and interleukin 1β. CORM-3-treated mice had significantly lower brain water content and enhanced neurologic outcomes on days 3, 7, and 14 post-tMCAO. Lastly, CORM-3 treatment reduced Evans blue leakage; increased expression of platelet-derived growth factor receptor-β, tight junction protein ZO-1, and matrix protein laminin; and decreased protein level of matrix metalloproteinase-9. Conclusion CORM-3 treatment at the time of reperfusion reduces ischemia-reperfusion-induced brain injury by suppressing neuroinflammation and alleviating blood-brain barrier disruption. Our data suggest that CORM-3 may provide an effective therapy for ischemic stroke.

Autism spectrum disorders (ASD) are neurodevelopmental disorders associated with synaptic deficits. Oligodendrocyte precursor cells (OPCs) are the only type of glial cells that establish direct synaptic connections with neurons within the central nervous system (CNS). However, the mechanism that results in the delicate construction of OPC-neuron synaptic connections remain poorly understood. Here we show in a mouse model that BAF155, a chromatin remodeling factor, is highly expressed in committed OPCs. BAF155 influences the OPC differentiation and myelination by coordinating the expression of multiple synapse-related genes that mediate OPC-neuron synaptic communication. The varying chromatin regulatory roles of BAF155 across brain regions give rise to local myelin deficits, contributing to the diverse clinical manifestations observed in individuals with ASD. Collectively, these results deepen our insight into OPC-neuron interactions under pathophysiological conditions and uncover a mechanism that integrates synaptic and ASD susceptibility genes, implying that abnormal OPC-neuron synaptogenesis could be an early instigator of ASD. The mechanisms underlying oligodendrocyte precursor cells (OPCs) and neuron interactions remain unclear. Here, the authors show that chromatin remodeler BAF155 regulates OPC differentiation and myelination by coordinating synaptic genes for OPC neuron communication, contributing to autism-like behavioral deficits in mice

Ischemic stroke, an intractable neurovascular disease with high lethality, disability and recurrence rates, poses a serious challenge to human health. The only effective treatment for acute stroke is reperfusion therapy. However, the inflammatory response caused by reperfusion therapy often aggravates secondary brain tissue damage, which greatly affects the treatment effect. Currently, therapeutic options for reperfusion injury remain unsatisfactory, and neuroprotective options are lacking. The inhibition of microglia polarization and promotion of neovascular maturation are essential for reestablishing the integrity of the BBB. Specifically, McM/RNPs effectively inhibited the secretion of pro-inflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and promoted the release of anti-inflammatory and neuroprotective factors such as interleukin-10 (IL-10), vascular endothelial growth factor-A (VEGF-A), and brain-derived neurotrophic factor (BDNF). This effect not only alleviated the inflammatory response but also promoted the expression of endothelial tight junction proteins (such as ZO-1 and Claudin 5), thereby enhancing the integrity of the BBB. Furthermore, McM/RNPs exerted multiple effects, such as promoting neuronal survival, regulating pericyte function, and accelerating the maturation of the neovasculature, which are essential for repairing the damaged BBB. Through the multi-functional effects of anti-inflammation, anti-apoptosis and pericyte regulation, the McM/RNPs nanosystem successfully maintained the stability of the intracerebral environment, providing novel ideas and strategies for the clinical treatment of reperfusion injury in ischemic stroke. Graphical Abstract

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α  (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases. Podocyte‐specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease. Mechanically, Dock5 deficiency enhanced CD36‐mediated fatty acid uptake of podocytes via upregulating LXRα in an m6A‐dependent way. Moreover, rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Current study suggests that Dock5 may serve as a promising therapeutic target in proteinuric kidney diseases.