In different stages of schizophrenia (SZ), alterations in gray matter volume (GMV) of patients are normally regulated by various pathological mechanisms. Instead of analyzing stage-specific changes, this study employed a multivariate structural covariance model and sliding-window approach to investigate the illness duration-related developmental trajectory of GMV in SZ. The trajectory is defined as a sequence of brain regions activated by illness duration, represented as a sparsely directed matrix. By applying this approach to structural magnetic resonance imaging data from 145 patients with SZ, we observed a continuous developmental trajectory of GMV from cortical to subcortical regions, with an average change occurring every 0.208 years, covering a time window of 20.176 years. The starting points were widely distributed across all networks, except for the ventral attention network. These findings provide insights into the neuropathological mechanism of SZ with a neuroprogressive model and facilitate the development of process for aided diagnosis and intervention with the starting points.
Humans ; Schizophrenia/pathology* ; Gray Matter/pathology* ; Magnetic Resonance Imaging ; Disease Progression ; Male ; Female ; Brain/pathology* ; Cerebral Cortex/pathology* ; Adult

Objective To investigate the effects and molecular mechanism of Homer protein homolog 1a (Homer 1a) overexpression on nerve injury in mice with traumatic brain injury (TBI). Methods Sixty male C57BL/6 mice were randomly divided into five groups: sham group, TBI group, empty lentivirus (Lv-NC) group, Homer 1a overexpression lentivirus (Lv-Homer 1a) group and Lv-Homer 1a + 740 Y-P group, with 12 mice in each group. The lentivirus was orthotopic injected into the cerebral cortex of mice 5 d before modeling, while 740 Y-P was injected intraperitoneally 1 d before modeling. The TBI model was established using the free-fall impact method, and the modified neurological severity scores (mNSS) of the mice was assessed 72 h post-surgery. The water content of brain tissue was quantified, and the histopathological damage and neuronal loss in brain tissue were assessed using HE staining and Nissl staining respectively. The formation of autophagosomes in brain tissue was observed by transmission electron microscopy. The protein expression levels of Homer 1a, microtubule-associated protein 1 light chain 3B (LC3B), Beclin 1, phosphatidylinositol 3-kinase (PI3K), phosphorylation PI3K(p-PI3K), protein kinase B (AKT), p-AKT, mammalian target of rapamycin (mTOR), and p-mTOR in brain tissue were detected by Western blot analysis. Results Compared to the sham group, the mice in the TBI group exhibited a significant increase in mNSS and cerebral water content. Moreover, severe brain tissue pathological damage was observed, accompanied by a substantial loss of neurons and an increase in autophagosome formation. The protein expressions of Homer 1a and Beclin 1, as well as the protein ratio of LC3B-II/LC3B-I, in brain tissues were significantly elevated, while the protein ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR were significantly reduced. Compared to the TBI group, the Lv-Homer 1a group exhibited reduced mNSS and brain water content. Additionally, there was an improvement in pathological brain tissue damage and neuron loss. Furthermore, there was an increase in autophagosome formation and expression of autophagy-related proteins, while the protein ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR were decreased. Compared to the Lv-Homer 1a group, the nerve injury in the Lv-Homer 1a+740 Y-P group was exacerbated, accompanied by a reduction in autophagosome formation and expression of autophagy-related proteins, while the PI3K/AKT/mTOR signaling pathway was activated. Conclusion Overexpression of Homer 1a effectively mitigates neurological damage in TBI mice, potentially through modulation of autophagy mediated by the PI3K/AKT/mTOR signaling pathway.
Animals ; TOR Serine-Threonine Kinases/genetics* ; Autophagy ; Brain Injuries, Traumatic/pathology* ; Male ; Proto-Oncogene Proteins c-akt/genetics* ; Phosphatidylinositol 3-Kinases/genetics* ; Homer Scaffolding Proteins/metabolism* ; Mice, Inbred C57BL ; Signal Transduction ; Mice

Objective To investigate the expression and correlation of LY86-AS1 and KHDRBS2 in glioblastoma (GBM), and their impacts on the prognosis of patients and immune cell infiltration. Methods Based on the GSE50161 dataset from the Gene Expression Omnibus (GEO) database, LY86-AS1 and KHDRBS2, which are closely related to the development of GBM, were identified by WGCNA and differential expression analysis. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were used to analyze the relationship between the expression of LY86-AS1 and KHDRBS2 and the prognosis of GBM patients. Multiple datasets were employed to analyze the correlation between the expression levels of LY86-AS1 and KHDRBS2 and its relationship with immune cell infiltration. Real-time quantitative PCR was used to verify the expression of LY86-AS1 and KHDRBS2 in GBM and normal brain tissues. The Human Protein Atlas (HPA) database was accessed to obtain the protein expression of KHDRBS2, and immunohistochemical staining was conducted to verify the protein expression of KHDRBS2. Results LY86-AS1 and KHDRBS2 were lowly expressed in GBM tissues and were closely related to the development of GBM, showing a significant positive correlation. Patients with low expression levels of LY86-AS1 and KHDRBS2 had a lower overall survival rate than those with high expression levels. LY86-AS1 was positively correlated with naive B cells, plasma cells, activated NK cells, M1 macrophages, activated mast cells and monocytes. KHDRBS2 was positively correlated with naive B cells, plasma cells, helper T cells, activated NK cells and monocytes. Conclusion The low expression levels of LY86-AS1 and KHDRBS2 in GBM, which is associated with poor prognosis, affect the tumor immune microenvironment and may serve as potential new biomarkers for the diagnosis of GBM and the prognosis assessment of patients.
Humans ; Glioblastoma/metabolism* ; Prognosis ; Brain Neoplasms/pathology* ; Gene Expression Regulation, Neoplastic ; RNA-Binding Proteins/metabolism*

In hypoxic-ischemic brain damage (HIBD), the programmed cell death known as ferroptosis is significantly activated. Microglial cells demonstrate a high level of sensitivity to iron accumulation. Understanding how to regulate the dual role of microglia and transforming the microglial ferroptosis to a moderate and controllable process has considerable implications for the targeted treatment in HIBD. This paper serves as an overview of microglia-mediated ferroptosis in HIBD as a disease model. We discuss various aspects centered around microglia, including pathophysiological mechanisms, polarization and functions of microglia, molecular mechanisms of ferroptosis, signaling pathways, and therapeutic strategies. The review aims to provide a reference for studies of ferroptosis in microglia.
Microglia/physiology* ; Ferroptosis/physiology* ; Humans ; Animals ; Hypoxia-Ischemia, Brain/pathology* ; Signal Transduction

Objective To explore the effects of Shuanglu Tongnao Formula on neuroinflammation in ischemic stroke (IS) rats via the P2X purinoceptor 7 receptor (P2X7R)/NLR family pyrin domain-containing 3 (NLRP3) pathway. Methods The rats were divided into five groups: the IS group, control group, Shuanglu Tongnao Formula group, P2X7R inhibitor brilliant blue G (BBG) group, and Shuanglu Tongnao Formula combined with P2X7R activator adenosine triphosphate (ATP) group, with 18 rats in each group. Except for the control group, rats in all other groups were used to construct an IS model using the suture method. After successful modeling, the drug was given once a day for 2 weeks. Neurological function scores and cerebral infarction volume ratios were measured in rats. Pathological examination of the ischemic penumbra brain tissue was performed. Immunofluorescence staining was used to quantify the proportions of microglia co-expressing both inducible nitric oxide synthase (iNOS) and ionized calcium-binding adapter molecule 1 (Iba1), as well as arginase 1 (Arg1) and Iba1, in the ischemic penumbra brain tissue. ELISA was used to detect tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin 6 (IL-6) and IL-10 in the ischemic penumbra brain tissue. Western blotting was used to measure P2X7R, NLRP3, and IL-1β proteins in the ischemic penumbra brain tissue. Results Compared with the control group, the IS group showed disordered neuronal arrangement, nuclear condensation, and obvious infiltration of inflammatory cells in the ischemic penumbra; significantly elevated neurological function scores, cerebral infarction volume ratios, proportions of microglia co-expressing iNOS and Iba1, and levels of TNF-α, IL-6, and P2X7R, NLRP3, IL-1β proteins; along with reduced proportions of microglia co-expressing Arg1 and Iba1 and levels of TGF-β and IL-10. Compared with the IS group, the Zhuang medicine Shuanglu Tongnao Formula and BBG groups demonstrated alleviated brain tissue damage; reduced neurological function scores, cerebral infarction volume ratios, proportions of microglia co-expressing iNOS and Iba1, and levels of TNF-α, IL-6, and P2X7R, NLRP3, IL-1β proteins; along with increased proportions of microglia co-expressing Arg1 and Iba1 and levels of TGF-β and IL-10. ATP reversed the effects of Zhuang medicine Shuanglu Tongnao Formula on microglial polarization and neuroinflammation in IS rats. Conclusion Zhuang medicine Shuanglu Tongnao Formula may promote the transformation of microglia from M1 type to M2 type by inhibiting the P2X7R/NLRP3 pathway, thereby improving neuroinflammation in IS rats.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Receptors, Purinergic P2X7/metabolism* ; Male ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Ischemic Stroke/pathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Signal Transduction/drug effects* ; Neuroinflammatory Diseases/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Nitric Oxide Synthase Type II/metabolism* ; Interleukin-10/metabolism* ; Brain Ischemia/drug therapy* ; Microglia/metabolism*

OBJECTIVES: To evaluate preterm white matter injury (PWMI) in neonatal rats using multimodal magnetic resonance imaging (MRI) combined with histological assessments and to explore its underlying mechanisms. METHODS: Healthy 3-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group and a PWMI group (n=12 in each group). A PWMI model was established in neonatal rats through hypoxia-ischemia. Laser speckle imaging was used to observe changes in cerebral oxygen saturation and blood flow at different time points post-modeling. Multimodal MRI was employed to assess the condition of white matter injury, while hematoxylin-eosin staining was utilized to observe morphological changes in the striatal area on the injured side. Immunofluorescence staining was performed to detect the proliferation and differentiation of oligodendrocyte precursor cells. RESULTS: At 0, 6, 12, 24, and 72 hours post-modeling, the relative blood flow and relative oxygen saturation on the injured side in the PWMI group were significantly lower than those in the sham operation group (P<0.05). At 24 hours post-modeling, T2-weighted imaging showed high signals in the white matter of the injured side in the PWMI group, with relative apparent diffusion coefficient values and Lorenz differential values being lower than those in the sham operation group (P<0.001); additionally, the arrangement of nerve cells in the PWMI group was disordered, and the number of EdU⁺PDGFR-α⁺ cells was higher than that in the sham operation group (P<0.001). At 28 days post-modeling, the relative fractional anisotropy values, the number of EdU⁺Olig2⁺ cells, and the fluorescence intensity of myelin basic protein and neurofilament protein 200 in the white matter region of the PWMI group were all lower than those in the sham operation group (P<0.001). CONCLUSIONS Multimodal MRI can evaluate early and long-term changes in PWMI in neonatal rat models in vivo, providing both imaging and pathological evidence for the diagnosis and treatment of PWMI in neonates. Hypoxia-ischemia inhibits the proliferation and differentiation of oligodendrocyte precursor cells in neonatal rats, leading to PWMI.
Animals ; Rats, Sprague-Dawley ; Magnetic Resonance Imaging/methods* ; Rats ; White Matter/injuries* ; Animals, Newborn ; Female ; Multimodal Imaging ; Male ; Hypoxia-Ischemia, Brain/pathology*

OBJECTIVES: To investigate whether mesenchymal stem cell-derived exosomes (MSC-Exo) alleviate white matter damage (WMD) in neonatal rats by targeting the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). METHODS: Three-day-old Sprague-Dawley rats were randomly assigned to four groups: Sham, hypoxia-ischemia (HI), MSC-Exo, and MCC950 (NLRP3 inhibitor) (n=24 per group). The WMD model was established by unilateral common carotid artery ligation combined with hypoxia. Exosomes (1×10⁸ particles/μL) were transplanted into the lateral ventricle using stereotaxic guidance. Fourteen days after modeling, hematoxylin-eosin staining was used to observe pathological changes in brain tissue, and transmission electron microscopy was used to assess myelinated axons. Western blotting was performed to detect the expression of myelin basic protein (MBP), NLRP3, caspase-1, and interleukin-1β (IL-1β). Immunohistochemistry was used to measure NLRP3, caspase-1, and IL-1β expression. Twenty-eight days post-modeling, behavioral changes were evaluated using the Morris water maze. RESULTS: In the HI group, marked inflammatory cell infiltration, extensive vacuolation, and decreased numbers of myelinated axons were observed compared to the Sham group. The MSC-Exo group showed reduced inflammatory infiltration, fewer vacuoles, and increased myelinated axons compared to the HI group, while the MCC950 group showed nearly normal cell morphology. Compared to the Sham group, the HI group exhibited decreased MBP expression, fewer platform crossings, shorter time in the target quadrant, increased expression of NLRP3, caspase-1, and IL-1β, and longer escape latency (all P<0.05). Compared to the HI group, the MSC-Exo and MCC950 groups showed increased MBP expression, more platform crossings, longer target quadrant stay, and reduced NLRP3, caspase-1, and IL-1β expression, as well as shorter escape latency (all P<0.05). CONCLUSIONS MSC-Exo may attenuate white matter damage in neonatal rats by targeting the NLRP3 inflammasome and promoting oligodendrocyte maturation.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors* ; Rats, Sprague-Dawley ; White Matter/pathology* ; Inflammasomes/physiology* ; Rats ; Animals, Newborn ; Mesenchymal Stem Cells ; Interleukin-1beta/analysis* ; Male ; Caspase 1/analysis* ; Hypoxia-Ischemia, Brain/therapy* ; Myelin Basic Protein/analysis*

OBJECTIVES: To investigate whether human umbilical cord mesenchymal stem cells (HUC-MSCs) play protective effects against white matter injury (WMI) in neonatal rats via activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase-1 (HO-1) signaling pathway. METHODS: A neonatal WMI model was established in 3-day-old Sprague-Dawley rats by unilateral common carotid artery ligation combined with hypoxia. The study comprised two parts. (1) Rats were randomized into sham, hypoxia-ischemia (HI), and HUC-MSC groups (n=36 per group); brain tissues were collected at 7, 14, and 21 days after modeling. (2) Rats were randomized into sham, HI, HUC-MSC, and HUC-MSC+ML385 (Nrf2 inhibitor) groups (n=12 per group); tissues were collected 14 days after modeling. Hematoxylin-eosin staining assessed histopathology, and Luxol fast blue staining evaluated myelination. Immunohistochemistry examined the localization and expression of Nrf2, myelin basic protein (MBP), and proteolipid protein (PLP). Immunofluorescence assessed synaptophysin (SYP) and postsynaptic density-95 (PSD-95). Western blotting quantified Nrf2, Keap1, HO-1, SYP, PSD-95, MBP, and PLP. Spatial learning and memory were evaluated by the Morris water maze. RESULTS: At 7, 14, and 21 days after modeling, the sham group showed intact white matter, whereas the HI group exhibited white matter disruption, cellular vacuolation, and disorganized nerve fibers. These pathological changes were attenuated in the HUC-MSC group. Compared with the HI group, the HUC-MSC group showed increased Nrf2 immunopositivity and protein levels, increased HO-1 protein levels, and decreased Keap1 protein levels (P<0.05). Compared with the HI group, the HUC-MSC group had higher SYP and PSD-95 immunofluorescence intensities and protein levels, higher MBP and PLP positivity and protein levels, increased mean optical density of myelin, more platform crossings, and longer time in the target quadrant (all P<0.05). These improvements were reduced in the HUC-MSC+ML385 group compared with the HUC-MSC group (P<0.05). CONCLUSIONS HUC-MSCs may promote oligodendrocyte maturation and synaptogenesis after neonatal WMI by activating the Nrf2/Keap1/HO-1 pathway, thereby improving spatial cognitive function.
NF-E2-Related Factor 2/physiology* ; Animals ; Rats, Sprague-Dawley ; Signal Transduction/physiology* ; Humans ; Rats ; White Matter/pathology* ; Kelch-Like ECH-Associated Protein 1/physiology* ; Umbilical Cord/cytology* ; Heme Oxygenase-1/physiology* ; Animals, Newborn ; Male ; Mesenchymal Stem Cell Transplantation ; Heme Oxygenase (Decyclizing)/physiology* ; Mesenchymal Stem Cells/physiology* ; Female ; Hypoxia-Ischemia, Brain

Brain metastasis has emerged as a significant challenge in the comprehensive management of patients with non-small cell lung cancer (NSCLC), particularly in those harboring driver gene mutations. Traditional treatments such as radiotherapy and surgery offer limited clinical benefits and are often accompanied by cognitive dysfunction and a decline in quality of life. In recent years, novel small molecule tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and other pathways have been developed, effectively penetrating the blood-brain barrier while enhancing intracranial drug concentrations and improving patient outcomes. This advancement has transformed the treatment landscape for brain metastases in NSCLC. Consequently, the Lung Cancer Medical Education Committee of the Chinese Medical Education Association and the Brain Metastasis Collaboration Group of the Lung Cancer Youth Expert Committee of the Beijing Medical Reward Foundation have jointly initiated and formulated the Clinical Practice Guidelines for the Management of Brain Metastases from Non-small Cell Lung Cancer with Actionable Gene Alterations in China (2025 Edition). This guideline integrates the latest research findings with clinical experience, adhering to multidisciplinary treatment principles, and encompasses aspects such as diagnosis, timing of intervention, and systemic and local treatment options for driver gene positive NSCLC brain metastases. Additionally, it proposes individualized treatment strategies tailored to different driver gene types, aiming to provide clinicians with a reference to enhance the overall diagnostic and therapeutic standards for NSCLC brain metastases in China.
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Humans ; Brain Neoplasms/drug therapy* ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Lung Neoplasms/genetics*

Lung cancer is still one of the most common malignant tumors in the world. With the increase of its incidence and the development of medical technology, the overall survival of lung cancer patients has significantly extended compared to before. The incidence of brain and meningeal metastases from lung cancer has also been rising year by year, but patients with brain and meningeal metastases from lung cancer have a poor prognosis and a very high mortality rate, and the diagnosis is mainly based on computed tomography (CT), magnetic resonance imaging (MRI) and other imaging examinations. However, the imaging features are diverse and the specificity is low, which makes it easy to be misdiagnosed and missed. Therefore, accurately identifying brain and meningeal metastases and timely targeted treatment is crucial for improving patient prognosis. This paper analyzed the diagnosis and treatment of a case of lung cancer with no obvious recurrence and metastasis in nearly 7-year long-term follow-up after radical lung cancer surgery, but the patient with abnormal behavior, impaired consciousness and epilepsy in the past 5 months, and multiple punctate calcifications in the brain found by head CT and MRI. This paper consider that the patient's mental and behavioral symptoms were caused by brain and meningeal metastasis of lung cancer after excluding infectious disease and ineffective treatment of autoimmune encephalitis, and further pathological biopsy and genetic detection confirmed the diagnosis of metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) L858R gene mutation, and the patient's symptoms were significantly improved after targeted therapy by Osimertinib. This paper also searched the relevant literatures of brain calcifications in databases such as China National Knowledge Infrastructure (CNKI), Wanfang, UpToDate, PubMed, etc., and found that intracerebral calcifications exist in a variety of diseases, including infectious, genetic and neurodegenerative diseases, vascular diseases, metabolic diseases and tumors. However, brain calcification in brain and meningeal metastases are often underestimated, and the consequent risk is misdiagnosis and delayed treatment. Therefore, brain and meningeal metastases manifested as brain calcification should not be ignored in patients with a history of previous tumors.
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Humans ; Lung Neoplasms/pathology* ; Brain Neoplasms/diagnostic imaging* ; Meningeal Neoplasms/diagnostic imaging* ; Calcinosis/diagnostic imaging* ; Male ; Middle Aged ; Tomography, X-Ray Computed ; Magnetic Resonance Imaging