Shun Li

Ischemic stroke remains a leading cause of mortality and disability worldwide, yet current therapeutic strategies, such as thrombolysis and thrombectomy, are constrained by narrow treatment windows and incomplete microvascular repair. While angiogenesis is pivotal for long-term functional recovery, the epigenetic mechanisms governing post-stroke vascular remodeling remain poorly understood. Here, we demonstrate that the long non-coding RNA (lncRNA) Malat1 acts as a critical endothelial regulator of angiogenesis and neurological restoration. Using an endothelium-specific Malat1 overexpression mouse model (EC-Malat1 Tg), we demonstrate endothelial Malat1 upregulation enhances angiogenesis, restores cerebral blood flow, and improves sensorimotor and cognitive function following ischemic stroke. Mechanistically, fluorescence-activated cell sorting (FACS)-based RNA sequencing of brain endothelial cells identified novel downstream targets of Malat1, including Hapln2, Bcl6, Esr1, Sox17, Tfrc, Hsp90aa1, and Tek. Among these, Tek (Tie2) showed robust endothelial co-localization and direct interaction with Malat1. Notably, while Malat1 overexpression markedly increased Tek protein expression, adeno-associated virus (AAV)-mediated endothelial knockdown of Tek abrogated the pro-angiogenic and neurovascular reparative effects of Malat1. Collectively, our data establishes the Malat1-Tek axis as a novel signaling pathway essential for driving post-ischemic cerebrovascular remodeling and long-term functional recovery. Targeting Malat1 represents a novel restorative therapeutic approach for ischemic stroke.

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB) and compromises endothelial function, leading to persistent neurological dysfunction. Although miR‐15a/16‐1 deletion has recently been shown to be neuroprotective in brain injury, the endothelial pathways mediating long‐term structural and functional recovery after TBI remain unknown. Here, we demonstrate endothelial cell‐specific deletion of miR‐15a/16‐1 is sufficient to confer neurorestoration after TBI by reducing acute BBB leakage, preserving white and gray matter integrity, and accelerating sensorimotor and cognitive recovery. Mechanistically, transcriptomic profiling identified SYNE1 as a direct downstream target of miR‐15a/16‐1 , validated via in‐silico binding prediction and 3’‐UTR luciferase assays. Crucially, endothelial cell‐targeted AAV‐mediated knockdown of SYNE1 abrogated the neurorestorative effects of miR‐15a/16‐1 deletion, indicating SYNE1 is required for its function. Furthermore, single‐cell RNA‐seq analysis of human TBI tissue demonstrates significant downregulation of SYNE1 in endothelial cells within the contusion core relative to pericontusional endothelium. Together, these findings define a previously unrecognized miR‐15a/16‐1– SYNE1 axis that promotes endothelial repair after TBI, with significant translational potential.

Recently, with the rapid advancement of multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, new tools and approaches have been introduced for studying nerve injury and regeneration. This review highlights the application and progress of multi-omics in uncovering the mechanisms of nerve injury, guiding the development of regenerative strategies, and promoting clinical translation. By integrating multi-omics datasets, researchers can comprehensively track dynamic molecular changes following nerve injury, including abnormal gene expression, disrupted protein signaling, altered metabolic programs, and shifts in the immune microenvironment. Single-cell multi-omics technologies resolve cellular heterogeneity, revealing the distinct functions of neurons, glial cells, and immune cell subpopulations during the injury response. Spatially resolved transcriptomics maintain the spatial context of lesion and regeneration sites, enabling precise localization for targeted interventions. Multi-omics technologies not only identify key molecular players involved in nerve regeneration but also create opportunities for personalized medicine. Nonetheless, integrating multi-omics data poses technical challenges, including high dimensionality, batch effects, and algorithmic constraints, while ethical concerns related to stem cell therapy and gene editing require stringent oversight. To transition from structural reconstruction to functional remodeling, future research should emphasize artificial intelligence–driven data integration, organ-on-a-chip modeling, and cross-disciplinary collaboration to overcome existing technical barriers and accelerate the clinical application of neuroregenerative therapies.

Ischemic stroke is a complex cerebrovascular disorder characterized by highly unpredictable outcomes influenced by patient-specific variables, including age, stroke severity, and preventable stroke-related complications such as infections. Analyses of clinical data have indicated a cumulative post-stroke infection rate of approximately 30%, with reported rates ranging from 5% to 65%. Post-stroke infections pose a significant challenge, as they not only increase the financial burden of stroke care but are also associated with adverse clinical outcomes, prolonged hospital stays, and a higher risk of stroke recurrence. The inflammatory response plays a pivotal role in the pathophysiology of ischemic stroke, encompassing the activation of inflammatory cells, the release of inflammatory mediators, and the engagement of inflammatory signaling pathways. Recent advances in molecular biology have facilitated the identification and investigation of numerous inflammation-related biomarkers. This article reviews the roles and mechanisms of key inflammatory biomarkers, including cytokines, chemokines, adhesion molecules, inflammation-related enzymes and mediators, receptors, signaling pathway molecules, and acute-phase proteins in the context of ischemic stroke, highlighting their significance in stroke pathophysiology and prognostic assessment. Additionally, in conjunction with the latest research advances, the article discusses novel biomarkers such as microRNAs and galectin-3, which are emerging as important tools in multiple domains, including diagnosis and treatment. Drawing on clinical diagnostic and therapeutic practices, this review analyzes the diagnostic and therapeutic roles of both novel and traditional biomarkers in the progression of ischemic stroke, following the temporal sequence from disease onset to prognosis. Finally, the article addresses the limitations of current research and offers perspectives on future directions, providing insights that may contribute to the advancement of precision medicine in the management of ischemic stroke.

Nitro‐oleic acid (OA‐NO ₂ ) is an endogenous peroxisome proliferator‐activated receptor‐γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA‐NO ₂ in maintaining blood–brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of endothelial PPARγ signaling pathways. Endothelial cell‐selective PPARγ conditional knockout (EC‐PPARγ cKO) and wild‐type (WT) mice underwent 1 h middle cerebral artery occlusion (MCAO) with 1–7 days of reperfusion. Mice were treated with oleic acid (OA) or OA‐NO ₂ (5 mg/kg) via tail vein 2 h after MCAO. Neurobehavioral deficits were assessed on days 3, 5, and 7 after MCAO. Neuroinflammation and BBB function were assessed on days 1 or 2 after MCAO by immunohistochemistry, RT‐qPCR, or Western blot analysis. Compared to OA controls, intravenous administration of OA‐NO ₂ led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also almost abolished in the EC‐PPARγ cKO mice. Furthermore, OA‐NO ₂ treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC‐PPARγ cKO mice. Interestingly, OA‐NO ₂ treatment promoted a shift towards an anti‐inflammatory microglial phenotype (M2) in the peri‐infarct regions of WT mice, but not in EC‐PPARγ cKO mice. Mechanistically, OA‐NO ₂ increased levels of major endothelial tight junction proteins in WT mice but not in EC‐PPARγ cKO mice following ischemic stroke. These findings suggest that OA‐NO ₂ activation of endothelial PPARγ signaling cascade attenuates neurovascular injury after ischemic stroke.

Vascular dementia is a highly heterogeneous neurodegenerative disorder induced by a variety of factors. Currently, there are no definitive treatments for the cognitive dysfunction associated with vascular dementia. However, early detection and preventive measures have proven effective in reducing the risk of onset and improving patient prognosis. Nitric oxide plays an integral role in various physiological and pathological processes within the central nervous system. In recent years, nitric oxide has been implicated in the regulation of synaptic plasticity and has emerged as a crucial factor in the pathophysiology of vascular dementia. At different stages of vascular dementia, nitric oxide levels and bioavailability undergo dynamic alterations, with a marked reduction in the later stages, which significantly contributes to the cognitive deficits associated with the disease. This review provides a comprehensive review of the emerging role of nitric oxide in the physiological and pathological processes underlying vascular dementia, focusing on its effects on synaptic dysfunction, neuroinflammation, oxidative stress, and blood‒brain barrier integrity. Furthermore, we suggest that targeting the nitric oxide soluble guanylate cyclase-cyclic guanosine monophosphate pathway through specific therapeutic strategies may offer a novel approach for treating vascular dementia, potentially improving both cognitive function and patient prognosis. The review contributes to a better understanding of the multifaceted role of nitric oxide in vascular dementia and to offering insights into future therapeutic interventions.

Ischemic stroke is a serious medical event that cannot be predicted in advance and can have long-lasting effects on patients, families, and communities. A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue. In recent years, research into regulatory long non-coding (lnc)RNAs, a diverse group of RNA molecules with regulatory functions, has emerged as a promising direction in the study of cerebral infarction. This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction, as well as potential strategies for their application in clinical settings. LncRNAs have the potential to act as “sponges” that attract specific microRNAs, thereby regulating the expression of microRNA target genes. These interactions influence various aspects of ischemic stroke, including reperfusion-induced damage, cell death, immune responses, autophagy, angiogenesis, and the generation of reactive oxygen species. We highlight several regulatory lncRNAs that have been utilized in animal model treatments, including lncRNA NKILA, lncRNA Meg8, and lncRNA H19. Additionally, we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction, such as lncRNA FOXO3, lncRNA XIST, and lncRNA RMST. The lncRNAs hold potential for genetic-level treatments in patients. However, numerous challenges, including inefficiency, low targeting accuracy, and side effects observed in preliminary studies, indicate the need for thorough investigation. The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.

There is a significant global death and disability rate associated with ischemic stroke, making it one of the most prevalent disorders. With the increasing worldwide aging population, the prevalence of ischemic stroke has notably increased and has emerged as a pivotal issue in public health. The neurovascular unit primarily consists of neurons, astrocytes, microglia, and brain microvascular endothelial cells. These cells are structurally tightly connected; together, they maintain the balance of brain function and are crucial for brain function and cerebral ischemic damage. Emerging studies in recent years have demonstrated the development of associations between ischemic stroke and the vascular neural units. The neurovascular unit characterizes the whole-tissue response to stroke, encompassing the interrelationship and reciprocal impact of neurons, glial cells, and microvessels. The neurovascular unit results in compromised integrity of the microvasculature and blood–brain barrier, neuronal cell death, the glial response, the inflammatory response, and immune cell infiltration, all of which are strongly associated with the course of ischemic stroke. This narrative review explores the complex relationship between ischemic stroke and the neurovascular unit in the context of an aging population. With aging, the neurovascular unit undergoes structural and functional changes that predispose the elderly to higher risks of stroke and complicate recovery post-stroke. We explore the impact of aging on the neurovascular unit, focusing on how age-related alterations in the neurovascular unit contribute to the susceptibility to ischemic stroke and influence the repair mechanisms post-stroke. The review highlights the compromised integrity of the microvascular and blood-brain barriers, increased neuronal cell death, heightened glial response, inflammatory reactions, and immune cell infiltration associated with aging, all of which are critical in the progression of ischemic stroke. By examining the latest research, we aim to provide a comprehensive understanding of the neurovascular unit’s role in ischemic stroke within the aging population and discuss how regenerative medicine offers novel strategies for treatment, emphasizing neuroprotection, neuroregeneration, and neurorepair. These aspects are of paramount importance for clinical interventions tailored to the elderly, who often present with unique challenges in stroke management. The review underscores the importance of considering the aging factor in stroke research and treatment, as the cellular interactions within the neurovascular unit form a complex system that is significantly influenced by the aging process. These connections cannot be overlooked in the quest for effective stroke therapies. The development of regenerative medicine presents new perspectives on stroke treatment, particularly for the elderly, where traditional therapies may be less effective or carry higher risks. This narrative review aims to bridge the gap in knowledge regarding the neurovascular unit’s role in ischemic stroke within the context of aging, providing a foundation for the development of targeted therapies that can improve outcomes for this vulnerable population.

Traumatic brain injury (TBI) is a prevalent disease that poses a significant threat to global public health. Digestive dysfunction, as a common complication, is of particular importance to understand its pathogenesis, diagnostic criteria, and relevant treatment strategies. TBI can affect digestive function through inflammatory immune responses, the enteric nervous system, and hormonal levels. Furthermore, TBI can also impact neurologic recovery through bidirectional communication along the brain-gut axis. Therefore, this article aims to summarize the underlying mechanisms and further explore individualized feeding strategies, therapeutic approaches, long-term prognosis for TBI patients, as well as recent advancements in related technologies. Further understanding of the pathogenesis of digestive system dysfunction after TBI on the basis of the interaction of gut-brain axis is conducive to more future therapies to treat TBI and improve the long-term prognosis of patients through improving digestive function, and achieve good clinical efficacy.

In cerebrovascular illness, tissue hypoxia and nutrient deficiency or blood vessel obstruction cause angiogenesis. The brain forms new blood vessels to safeguard the organism during stress. However, it is impossible to ignore the possibility of ischemia‒reperfusion damage due to excessive angiogenesis. Therefore, how to better cope with stress in patients with cerebrovascular disorders by regulating angiogenesis is a challenge that we face and continue to focus on. Studies have shown that long non-coding RNAs can regulate angiogenesis in various cell types through different molecular mechanisms. After stroke, astrocytes secrete extracellular vesicles, including exosomes, to indirectly modulate brain angiogenesis, which involves long non-coding RNAs. These clinical studies on long non-coding RNAs provide new perspectives for the treatment of cerebrovascular disorders. As potential biomarkers, long non-coding RNAs contribute to the early diagnosis and monitoring of disease progression. In terms of regenerative medicine and regenerative therapies, research on long non-coding RNAs also opens new avenues. Understanding long non-coding RNA processes in angiogenesis will help create therapeutics that target specific long non-coding RNAs to promote neovascularization and brain tissue healing. This may include the use of long non-coding RNAs as drug carriers or the development of small-molecule drugs that target long non-coding RNAs to promote angiogenesis and neuroprotection. In conclusion, the application of long non-coding RNAs is promising in cerebrovascular disorders, especially in the fields of angiogenesis and regenerative medicine. Advanced technology and research are projected to make long non-coding RNAs key targets for the treatment of cerebrovascular disorders.