BACKGROUND:Stroke is a leading cause of disability and mortality worldwide, with ischemic stroke accounting for approximately 87% of all cases. Despite advances in reperfusion therapy, effective treatments targeting secondary neuroinflammation remain limited. Accumulating evidence indicates that γδ T cells, particularly through the production of interleukin (IL)-17, contribute to ischemic brain injury. As the intestine represents a major reservoir of γδ T cells, brain-gut communication may connect intestinal immune alterations with post-stroke neuroinflammation. This review examines the role of γδ T cells in ischemic stroke from the perspective of the brain-gut axis. METHODS:We synthesized current mechanistic evidence from experimental, translational, and clinical studies concerning γδ T-cell activation and recruitment after ischemic stroke. Particular attention was given to IL-17-mediated neuroinflammation, intestinal barrier dysfunction, gut microbiota dysbiosis, and bidirectional immune communication between the ischemic brain and the intestine. RESULTS:Following ischemic stroke, γδ T cells are activated and recruited to the injured brain, where their production of IL-17 promotes neuroinflammation, blood-brain barrier disruption, and secondary tissue injury. Concurrently, cerebral ischemia induces autonomic, immune, and metabolic disturbances that alter the gut microbiota and compromise intestinal barrier integrity. These changes may facilitate microbial product translocation and systemic inflammation, thereby amplifying cerebral inflammatory responses. Gut-resident γδ T cells may participate in this process by regulating mucosal immunity and IL-17-associated inflammatory signaling. Together, these mechanisms may establish a self-reinforcing brain-gut injury cycle. However, direct evidence defining the contributions, trafficking patterns, and functional heterogeneity of specific intestinal γδ T-cell subsets in ischemic brain injury remains limited. CONCLUSIONS:γδ T cells may serve as important immunological mediators linking intestinal dysfunction to neuroinflammation after ischemic stroke. Therapeutic strategies targeting γδ T-cell activation, IL-17 signaling, intestinal barrier disruption, or gut microbiota dysbiosis may help interrupt the brain-gut injury cycle. Future studies integrating lineage tracing, single-cell and spatial profiling, and tissue-specific interventions are required to distinguish the roles of brain-infiltrating and gut-resident γδ T-cell subsets and facilitate the clinical translation of brain-gut axis-based therapies.

BACKGROUND/AIM:Endoplasmic reticulum resident protein 44 (ERP44), a protein disulfide isomerase family member, has been implicated in tumor biology, but its role in lower-grade glioma (LGG) remains unclear. This study investigated the prognostic significance and biological function of ERP44 in LGG, focusing on proliferation and temozolomide (TMZ) resistance. MATERIALS AND METHODS:ERP44 expression, clinicopathological associations, and prognostic value were analyzed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets. Time-dependent receiver operating characteristic (ROC) curves, Cox regression, and a prognostic nomogram were constructed. Differential expression, Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) enrichment, immune infiltration, and drug sensitivity analyses were performed. Functional validation was conducted in SW1088 and SW1783 cells using shRNA-mediated ERP44 knockdown, followed by RT-qPCR, western blotting, CCK-8, colony formation, and TMZ IC50 assays. Subcutaneous xenograft models with or without TMZ treatment were used for in vivo validation. RESULTS:ERP44 was markedly upregulated in LGG and associated with higher WHO grade, IDH wildtype status, 1p/19q non-codeletion, and poor survival in TCGA and CGGA cohorts. ERP44 showed strong prognostic performance and improved risk stratification in a multivariable nomogram. Enrichment analyses linked high ERP44 expression to immune/inflammatory pathways and reduced neuronal functional signatures. ERP44 positively correlated with immune infiltration, proliferation/stemness markers, and predicted TMZ resistance, while its knockdown inhibited proliferation and colony formation, reduced TMZ IC50, suppressed xenograft growth, enhanced TMZ efficacy, and decreased Ki67 positivity. CONCLUSION:ERP44 is a prognostic biomarker that promotes LGG proliferation and TMZ resistance, suggesting its potential as a therapeutic target.

The central nervous system (CNS) has long been regarded as relatively immune-privileged, but the discovery of glymphatic transport and meningeal lymphatic vessels has reshaped our understanding of neuroimmune communication. In ischemic stroke, emerging evidence suggests that post-injury inflammation is regulated not only by systemic leukocyte recruitment and blood-brain barrier disruption but also by a spatially organized skull bone marrow-meninges-brain axis. Anatomical studies have identified vascular channels connecting calvarial bone marrow with the dura mater, providing a potential route for rapid communication between skull marrow immune niches and CNS border compartments. After ischemic injury, brain-derived inflammatory signals may activate adjacent skull marrow niches, while skull marrow-derived myeloid cells may migrate toward the meninges and contribute to early neuroinflammatory responses. In parallel, meningeal lymphatic vessels support the clearance of cerebrospinal fluid (CSF)-derived solutes, inflammatory mediators, antigens, and cellular debris toward deep cervical lymph nodes. This review integrates current evidence into a stage-dependent influx-efflux framework. In this model, skull-dura vascular channels may support local cellular influx and immune sensing, whereas meningeal lymphatic vessels provide a molecular and antigenic efflux pathway. The balance between these processes may influence edema formation, inflammatory amplification, immune resolution, and tissue repair after stroke. However, this axis remains an emerging concept rather than a fully established therapeutic target. Human evidence mainly supports anatomical plausibility and imaging accessibility, while direct demonstration of skull marrow-derived immune-cell trafficking in human stroke is still lacking. Further mechanistic, imaging, and translational studies are needed to determine whether this axis can guide precision monitoring and modulation of post-stroke neuroinflammation.

Background Despite advances in reperfusion therapy, effective neuroprotective interventions for ischemic stroke that can be reliably translated into clinical benefit are lacking. A persistent obstacle is the frequent disconnect between mechanistic validity and effective drug exposure within the injured brain, a limitation that is particularly evident for natural products with pleiotropic but weakly defined modes of action. Nootkatone (NKT), a naturally occurring sesquiterpenoid, has antioxidant and neuroprotective activity, yet its direct molecular target and translational limitations in ischemic stroke remain unresolved. This study aimed to define a target-anchored mechanism for NKT and to determine whether improving brain exposure is required to translate this mechanism into effective neuroprotection.Results Through an integrative disease-informed target discovery strategy combining network-based prediction, structure-informed docking, and cross-species biochemical validation, monoamine oxidase B was identified as the primary molecular target engaged by NKT. Pharmacological inhibition or genetic suppression of monoamine oxidase B (MAOB) activated an Nrf2-dependent antioxidant program, reinforced glutathione homeostasis, suppressed lipid peroxidation and ferroptotic injury, preserved mitochondrial integrity, and conferred robust neuroprotection in neuronal oxygen-glucose deprivation models and in mice subjected to transient cerebral ischemia. NKT was encapsulated within a hyaluronic acid modified polyethylene glycol nanocarrier engineered to increase circulation stability and lesion-associated accumulation and to improve brain exposure. This nanodelivery strategy markedly strengthened the neuroprotective efficacy and functional recovery in vivo while preserving the same intracellular signaling mechanisms observed with the free compound, indicating improved pharmacological activity rather than altered bioactivity.Conclusions These findings establish MAOB as a druggable mitochondrial redox regulator underlying NKT-mediated neuroprotection. In parallel, the results demonstrated that insufficient brain exposure represents a critical barrier to converting this mechanism into a consistent therapeutic benefit after stroke. By resolving both target definitions and exposure limitations within a single experimental framework, this study explains a major source of inconsistency in natural product-based neuroprotection and provides a practical strategy for achieving reproducible neuroprotective efficacy in ischemic stroke.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the IRF family, playing a pivotal role in modulating immune responses, particularly within the innate immune system. IRF5 regulates the expression of type I interferons (IFNs), proinflammatory cytokines, and other immune-related genes, essential for effective host defense against infections and immune surveillance. Its functions, however, are diverse and highly context-dependent, adapting to different immune challenges and tissue environments. Studies have demonstrated that dysregulated IRF5 activation contributes to the pathogenesis of numerous diseases, including cancer, autoimmune disorders, and chronic inflammatory conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This dysregulation underscores the dual role of IRF5, both in immune protection and in driving pathological inflammation. Given its significant involvement in both physiological and pathological processes, IRF5 presents a promising therapeutic target for managing diseases characterized by excessive inflammation and immune dysregulation. However, developing effective molecules to specifically modulate the IRF5 pathway remains challenging, with limited therapeutic agents available for clinical application. In this review, we examine the diverse roles of IRF5 in various disease contexts, the mechanisms by which IRF5 contributes to disease progression, and the potential therapeutic strategies targeting IRF5. Additionally, we discuss potential complications and risks associated with IRF5-targeted therapies, including the balance between dampening pathological inflammation and preserving essential immune functions. This exploration highlights both the therapeutic potential and the complexity of modulating IRF5 activity in clinical settings.

Stroke remains a leading cause of long-term disability and mortality worldwide, necessitating novel therapeutic strategies to enhance recovery. Traditional rehabilitation approaches, including physical therapy and pharmacological interventions, often provide limited functional improvement. Neuromodulation has emerged as a promising strategy to promote post-stroke recovery by enhancing neuroplasticity and functional reorganization. Among various neuromodulatory techniques, chemogenetics, particularly Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers precise, cell-type-specific, and temporally controlled modulation of neuronal and glial activity. This review explores the mechanisms and therapeutic potential of chemogenetic modulation in stroke recovery. Preclinical studies have demonstrated that activation of excitatory DREADDs (hM3Dq) in neurons located within the peri-infarct area or contralateral M1 has been shown to enhance neuroplasticity, facilitate axonal sprouting, and lead to improved behavioral recovery following stroke. Conversely, stimulation of inhibitory DREADDs (hM4Di) suppresses stroke-induced excitotoxicity, mitigates peri-infarct spreading depolarizations (PIDs), and modulates neuroinflammatory responses. By targeting specific neuronal and glial populations, chemogenetics enables phase-specific interventions-early inhibition to minimize damage during the acute phase and late excitation to promote plasticity during the recovery phase. Despite its advantages over traditional neuromodulation techniques, such as optogenetics and deep brain stimulation, several challenges remain before chemogenetics can be translated into clinical applications. These include optimizing viral vector delivery, improving ligand specificity, minimizing off-target effects, and ensuring long-term receptor stability. Furthermore, integrating chemogenetics with existing stroke rehabilitation strategies, including brain-computer interfaces and physical therapy, may enhance functional recovery by facilitating adaptive neuroplasticity. Future research should focus on refining chemogenetic tools to enable clinical application. By offering a highly selective, reversible, and minimally invasive approach, chemogenetics holds great potential for revolutionizing post-stroke therapy and advancing personalized neuromodulation strategies.

Stroke is the fifth leading cause of death worldwide, and the functional status of the gut plays a key role in patients’ prognosis. Recent publications have explored the gut association with stroke, but few articles have been published that specifically address a comprehensive bibliometric analysis of the gut microbiota and its association with stroke. To address this gap, we used bibliometric methods to examine the landscape of research concerning the gut and stroke over approximately two decades, utilizing the Web of Science Core Collection (WoSCC). On November 1, 2022, a search was conducted for English-language articles published between 2002 and 2022, with only including original articles. Visual and statistical analyses were performed using CiteSpace, VOSviewer, and Bibliometrix 4.1.0 Package. After screening relevant articles, the results revealed that the number of articles published in this field has progressively increased during the last two decades. In particular, the total number of publications rapidly increased year by year from 2014. Among them, China ranked first in the world with a total of 227 publications. Authorship analysis highlighted Wang Z as the most prolific author, with 18 publications and an H-index of 14, highlighting significant contributions to this field. Meanwhile, the Southern Medical University of China was identified as the most productive institution. Moreover, analysis of keywords revealed that ‘cerebral ischemia’, ‘intestinal microbiota’, ‘gut microbiota’, and ‘trimethylamine N-oxide’ were popular topics searched, and research on the relationship between stroke and the gut continues to be a research hotspot. In summary, this study presents an overview of the progress and emerging trends in research on the relationship between stroke and gut health over the past two decades, providing a valuable resource for researchers aiming to understand the current state of the field and identify potential directions for future studies.

Ischemic stroke, the second leading cause of death and fourth leading cause of disability worldwide, occurs when the blood supply to the brain is blocked. It initiates a programmed cell death through apoptosis, autophagy, and ferroptosis, which results in neuronal damage and brain injury. Ferroptosis—cell death characterized by the accumulation of iron due to lipid peroxidation and excessive generation of reactive oxygen species (ROS)—was recently identified as a major cause of nerve damage and is believed to be a vital pathological process after ischemic stroke. However, existing methods for in situ detection of ferroptosis are currently insufficient. Therefore, we constructed a series of hydrogen peroxide (H2O2—one of the major ROS) probes (QH2O2, MQH2O2, and BQH2O2) with quinoline derivatives as two-photon fluorophores and boronate as the recognition domain. Experimental results indicated that the linear response range of the probe MQH2O2 to H2O2 increased from < 10 to 300μM as compared with the probe QH2O2. Moreover, the linear correlation coefficient also increased from 0.9012 to 0.999, indicating that the ratiometric fluorescent probe has built-in corrections for environmental interference, which allows a more accurate fluorescence analysis. Modification of the probe by connecting triethylene glycol monomethyl ether (BQH2O2) increased the lipophilic index of the probe to 2.01, which enhanced its ability to cross the blood–brain barrier. Therefore, the developed probe is useful for analyzing the H2O2 production during an ischemic stroke and its fluctuatation with ferroptosis.

Ischemic stroke, which accounts for the majority of stroke cases, triggers a complex series of pathophysiological events, prominently characterized by acute oxidative stress due to excessive production of reactive oxygen species (ROS). Oxidative stress plays a crucial role in driving cell death and inflammation in ischemic stroke, making it a significant target for therapeutic intervention. Nanomedicine presents an innovative approach to directly mitigate oxidative damage. This review consolidates existing knowledge on the role of oxidative stress in ischemic stroke and assesses the potential of various ROS-scavenging nanoparticles (NPs) as therapeutic agents. We explore the properties and mechanisms of metal, metal-oxide, and carbon-based NPs, emphasizing their catalytic activity and biocompatibility in scavenging free radicals and facilitating the delivery of therapeutic agents across the blood-brain barrier. Additionally, we address the challenges such as cytotoxicity, immunogenicity, and biodistribution that need to be overcome to translate these nanotechnologies from bench to bedside. The future of NP-based therapies for ischemic stroke holds promise, with the potential to enhance outcomes through targeted modulation of oxidative stress.

Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.

BackgroundResearch in the areas of inflammation and mitochondrial stress in ischemic stroke is rapidly expanding, but a comprehensive overview that integrates bibliometric trends with an in-depth review of molecular mechanisms is lacking.ObjectiveTo map the evolving landscape of research using bibliometric analysis and to detail the molecular mechanisms that underpin these trends, emphasizing their implications in ischemic stroke.MethodsWe conducted a bibliometric analysis to identify key trends, top contributors, and focal research themes. In addition, we review recent research advances in mitochondrial stress and inflammation in ischemic stroke to gain a detailed understanding of the pathophysiological processes involved.ConclusionOur integrative approach not only highlights the growing research interest and collaborations but also provides a detailed exploration of the molecular mechanisms that are central to the pathology of ischemic stroke. This synthesis offers valuable insights for researchers and paves the way for targeted therapeutic interventions.

AIMS:Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB-PTPIP51 in experimental cerebral ischemia.METHODS:We simulated cerebral ischemia-reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model.RESULTS:We observed a decrease in VAPB-PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria-ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator.CONCLUSIONS:Our findings suggest that the downregulation of VAPB-PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS.

Background: Cardiovascular diseases (CVDs) are a major public health concern. The impact of dietary components on CVD risk has been recognized, but their interactions require further investigation. This study aimed to examine the associations between major nutrient intake and CVD risk and to assess potential causal relationships via Mendelian randomization. Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020, with a sample size of 5464 adult participants. Nutrient intake was derived from two 24 h dietary recalls. Associations between four principal nutrients and CVD risk were evaluated via Mendelian randomization analysis. Additionally, weighted multivariable logistic regression analyses were performed to adjust for potential confounders, including age, sex, BMI, and other lifestyle factors. Results: An observational analysis revealed that increased log-transformed dietary fat intake was associated with reduced heart failure risk (OR = 0.722, 95% CI: 0.549-0.954). Log-transformed protein intake was protective against heart failure (OR = 0.645, 95% CI: 0.471-0.889), coronary artery disease (OR = 0.684, 95% CI: 0.504-0.931), and stroke (OR = 0.747, 95% CI: 0.568-0.988). IVW-MR analyses confirmed causal relationships between relative fat intake and heart failure risk (OR = 0.766, 95% CI: 0.598-0.982, p = 0.035) and between protein intake and stroke risk (OR = 0.993, 95% CI: 0.988-0.998, p = 0.010). MR analysis also revealed causal relationships between relative fat intake and coronary artery disease risk and between relative protein intake and hypertension risk. Conclusions: Both the observational and Mendelian randomization studies indicated that dietary fat is inversely associated with heart failure risk and that protein intake is correlated with reduced stroke risk. Future studies should investigate the optimal balance of macronutrients for CVD prevention, explore potential mechanisms underlying these associations, and consider long-term dietary interventions to validate these findings.

Glioma, the most prevalent primary brain tumor in adults, is characterized by significant invasiveness and resistance. Current glioma treatments include surgery, radiation, chemotherapy, and targeted therapy, but these methods often fail to eliminate the tumor completely, leading to recurrence and poor prognosis. Immune checkpoint inhibitors, a class of commonly used immunotherapeutic drugs, have demonstrated excellent efficacy in treating various solid malignancies. Recent research has indicated that unconventional levels of expression of the MAP2K3 gene closely correlates with glioma malignancy, hinting it could be a potential immunotherapy target. Our study unveiled substantial involvement of MAP2K3 in gliomas, indicating the potential of the enzyme to serve as a prognostic biomarker related to immunity. Through the regulation of the infiltration of immune cells, MAP2K3 can affect the prognosis of patients with glioma. These discoveries establish a theoretical foundation for exploring the biological mechanisms underlying MAP2K3 and its potential applications in glioma treatment.

BACKGROUND:Ischemic stroke is a leading cause of permanent disability and death globally. The nucleotide-biding oligomaerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that plays a role in ischemic stroke. Recently, research on the role of NLRP3 in ischemic stroke has developed rapidly worldwide. However, there is no bibliometric analysis of NLRP3 in ischemic stroke to date.AIM:Through bibliometric analysis, the aim of this study was to assess the current state of research on NLRP3 in the field of ischemic stroke research worldwide over the past 12 years and to identify important results, major research areas, and emerging trends.METHODS:Publications related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022 were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSviewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. The Total Global Citation Score (TGCS) was employed to assess the impact of publications.RESULTS:We found that research of NLRP3 in ischemic stroke developed rapidly starting in 2011. 601 relevant studies have been published in 245 journals over the past 12 years. Journal of Neuroinflammation and International Immunopharmacology were the most productive journals and Journal of Neuroinflammation was the most cited journal. Additionally, Stroke and Journal of Cerebral Blood Flow & Metabolism were the most co-cited journal. The most productive country was China (records = 430) and the most productive university was the Zhejiang University (records = 24). Arumugam TV (TGCS = 949) was the most cited author in this field. NLRP3 inflammasome activation, nf-κb, oxidative stress, and inflammation were the knowledge bases for the research in this field.CONCLUSION:This study is a scientometric study utilizing quantitative and qualitative methods to comprehensively review the publications on NLRP3 in ischemic stroke. This information provides a reference for scholars to further study NLRP3 in ischemic stroke.

AIMS:Cell death, except for cuproptosis, in gliomas has been extensively studied, providing novel targets for immunotherapy by reshaping the tumor immune microenvironment through multiple mechanisms. This study aimed to explore the effect of cuproptosis on the immune microenvironment and its predictive power in prognosis and immunotherapy response.METHODS:Eight glioma cohorts were included in this study. We employed the unsupervised clustering algorithm to identify novel cuproptosis clusters and described their immune microenvironmental characteristics, mutation landscape, and altered signaling pathways. We verified the correlation among FDX1, SLC31A1, and macrophage infiltration in 56 glioma tissues. Next, based on multicenter cohorts and 10 machine learning algorithms, we constructed an artificial intelligence-driven cuproptosis-related signature named CuproScore.RESULTS:Our findings suggested that glioma patients with high levels of cuproptosis had a worse prognosis owing to immunosuppression caused by unique immune escape mechanisms. Meanwhile, we experimentally validated the positive association between cuproptosis and macrophages and its tumor-promoting mechanism in vitro. Furthermore, our CuproScore exhibited powerful and robust prognostic predictive ability. It was also capable of predicting response to immunotherapy and chemotherapy drug sensitivity.CONCLUSIONS:Cuproptosis facilitates immune activation but promotes immune escape. The CuproScore could predict prognosis and immunotherapy response in gliomas.

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood-brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

目的:明确缺血性脑卒中(IS)后不同区域脑组织中干扰素调节因子4(IRF4)表达水平的变化趋势并探讨其在IS后神经功能损伤中的保护作用与可能机制.方法:首先通过短暂性大脑中动脉闭塞(tMCAO)构建小鼠IS模型(包括野生型和IRF4基因敲除组),随后分别利用RT-PCR与Western Blot检测核心梗死区域、缺血半暗带与对侧正常脑组织内IRF4mRNA与蛋白表达水平.同时利用ELISA检测缺血半暗带区域促炎细胞因子IL-1β、IL-6与TNF-α的表达水平.分别利用RT-PCR与Western Blot检测M1型巨噬细胞标志物iNOS与M2型巨噬细胞标志物Arg-1的mRNA与蛋白表达水平;随后进行神经功能评分与水迷宫试验检测逃逸潜伏期(EL),利用2,3,5-氯化三苯基四氮唑(TTC)染色检测小鼠脑梗死体积,同时利用免疫荧光染色检测细胞凋亡.结果:缺血半暗带IRF4表达水平较核心梗死区域与对侧正常脑组织均明显增加.此外,缺血半暗带促炎细胞因子IL-1β、IL-6与TNF-α表达均明显增加,且与IRF4表达水平呈明显负相关;iNOS表达明显上调且Arg-1表达显著减少.而IRF4基因敲除导致IS小鼠脑梗死体积增加且神经功能明显恶化.IRF4基因敲除致使1S小鼠脑组织促炎细胞因子表达显著上调,巨噬细胞标志物检测表明IRF4基因敲除致使巨噬细胞向M1型极化.此外,IRF4基因敲除导致神经元凋亡明显增加.结论:IS显著诱导缺血半暗带IRF4表达,IRF4敲减可导致IS小鼠炎症反应加重,巨噬细胞向M1型极化且神经功能损伤明显恶化.因此,IRF4表达可能通过调节巨噬细胞极化,抑制促炎细胞因子表达,继而在IS中发挥抗炎和脑保护作用.

PURPOSE:Myocardial injury induced by sepsis can increase the patient's mortality, which is an important complication of sepsis. Myocardial apoptosis plays a key role in septic myocardial injury. Here we explored the potential mechanism of astaxanthin (ATX) inhibiting myocardial apoptosis induced by lipopolysaccharide (LPS) in vitro. METHODS:The H9C2 cell experiment was conducted in three parts. In the first part, we set up three groups: control group, LPS group (10 µg/ml), a model of septic myocardial injury, and LPS + ATX (5, 10, 30 µM); In the second part, we set up four groups: control group, LPS group, LPS + PTP1B-IN-1, a protein tyrosine phosphatase 1B (PTP1B) inhibitor, and LPS + PTP1B-IN-1 + ATX; In the third part, we set up four groups: control group, LPS group, LPS + Anisomycin, a c-Jun N-terminal kinase (JNK) activator, and LPS + Anisomycin + ATX. We assessed H9C2 cell viability using the Cell Counting Kit-8 (CCK-8) assay. We observed cell apoptosis using flow cytometry analysis. We tested the mitochondrial membrane potential (ΔΨm) using JC-1 staining. To identify the molecular targets of ATX, Astaxanthin targets were predicted through the SwissTargetPrediction database. We verified the binding affinity of ATX and its targets using microscale thermophoresis (MST). We investigated the p-JNK expression using immunofluorescence staining. Finally, Western blot was used to evaluate PTP1B, JNK, p-JNK and the mitochondrial apoptosis-associated protein expression. RESULTS:LPS inhibited H9C2 cell viability in a time-dependent manner and ATX treatment enhances H9C2 cell viability in a concentration dependent manner after LPS administration. ATX inhibited the LPS-induced apoptosis and loss of mitochondrial membrane potential in H9C2 cells. As predicted by the SwissTargetPrediction database, PTP1B was a potential target of ATX, and the interaction between ATX and PTP1B was further verified by MST. ATX attenuated the LPS-induced protein expression of PTP1B and p-JNK, regardless of PTP1B inhibition. Both immunofluorescence staining and Western blotting showed that ATX suppressed the LPS-induced p-JNK expression in H9C2 cells, regardless of Anisomycin administration. In addition, by adding Anisomycin to overexpress JNK, ATX inhibited the LPS-induced apoptosis, loss of mitochondrial membrane potential and upregulation of mitochondrial apoptosis-associated proteins in H9C2 cells via JNK signaling. CONCLUSION:ATX inhibited LPS-induced mitochondrial apoptosis of H9C2 cells by PTP1B/JNK pathway and PTP1B was the target of ATX.