Pub Date : 2026-02-01Epub Date: 2025-12-20DOI: 10.1016/j.brainresbull.2025.111693
Shuangkai Li , Xiang Li Jr , Lu Peng , Haojie Ding , Xuan Shi , Jiale Liu , Haiying Li , Jianguo Xu , Qing Sun
Neuroinflammation mediated by microglial hyperactivation represents a pivotal pathological mechanism exacerbating neuronal damage following cerebral ischemia. Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays a crucial regulatory role in metabolic and inflammatory processes. However, its specific function in post-ischemic neuroinflammation remains incompletely understood. This study found that SCD1 was highly expressed in the penumbra region following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Then, we systematically evaluated the role of SCD1 in regulating neuroinflammation after cerebral ischemia–reperfusion and explored its underlying mechanisms through administrating SCD1-specific inhibitor CAY10566. Results showed that CAY10566 significantly reduced level of pro-inflammatory cytokines and infarct volume after cerebral ischemia–reperfusion. Furthermore,suppression of SCD1 also alleviated neuronal apoptosis and improved cognitive and motor functions after ischemic stroke Mechanistically, the modulation of the NF-κB signaling pathway by SCD1 may involve the participation of TNFR1. Collectively, these findings suggested that the SCD1 may serve as a critical checkpoint regulating NF-κB signaling in cerebral ischemia–reperfusion injury. Targeting SCD1 may represent a promising therapeutic strategy for ischemic stroke.
{"title":"Inhibition of SCD1 attenuates neuroinflammation and brain injury after cerebral ischemia-reperfusion","authors":"Shuangkai Li , Xiang Li Jr , Lu Peng , Haojie Ding , Xuan Shi , Jiale Liu , Haiying Li , Jianguo Xu , Qing Sun","doi":"10.1016/j.brainresbull.2025.111693","DOIUrl":"10.1016/j.brainresbull.2025.111693","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglial hyperactivation represents a pivotal pathological mechanism exacerbating neuronal damage following cerebral ischemia. Stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis, plays a crucial regulatory role in metabolic and inflammatory processes. However, its specific function in post-ischemic neuroinflammation remains incompletely understood. This study found that SCD1 was highly expressed in the penumbra region following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Then, we systematically evaluated the role of SCD1 in regulating neuroinflammation after cerebral ischemia–reperfusion and explored its underlying mechanisms through administrating SCD1-specific inhibitor CAY10566. Results showed that CAY10566 significantly reduced level of pro-inflammatory cytokines and infarct volume after cerebral ischemia–reperfusion. Furthermore,suppression of SCD1 also alleviated neuronal apoptosis and improved cognitive and motor functions after ischemic stroke Mechanistically, the modulation of the NF-κB signaling pathway by SCD1 may involve the participation of TNFR1. Collectively, these findings suggested that the SCD1 may serve as a critical checkpoint regulating NF-κB signaling in cerebral ischemia–reperfusion injury. Targeting SCD1 may represent a promising therapeutic strategy for ischemic stroke.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111693"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-30DOI: 10.1016/j.brainresbull.2026.111755
Renke He , Yuhan Liu , Wenxuan Li , Shengqiang Xie , Jiayu Liu , Gang Cheng , Jianning Zhang
Purpose
This study compared the time-dependent changes in brain metabolites and gut microbiota at early and late post-irradiation stages in mice receiving conventional radiotherapy (CONV-RT) or ultra-high dose-rate FLASH radiotherapy (FLASH-RT).
Methods
Male C57BL/6 J mice received whole-brain irradiation using CONV-RT (2 Gy/min) or X-ray-based FLASH-RT (200 Gy/s). Brain tissue and gut contents were collected on days 1, 3, 7, and 21 post-irradiation. Targeted LC–MS metabolomics profiled dynamic brain metabolite changes, and 16S rRNA sequencing characterized gut microbiota trajectories. Neuroinflammation and brain injury were assessed by immunofluorescence (microglia/astrocyte markers) and laser speckle cerebral blood flow imaging, while behavioral assays evaluated cognition and anxiety-like behaviors.
Results
Compared with CONV-RT, FLASH-RT was associated with less pronounced hippocampal microglial and astrocytic reactivity, a smaller reduction in cerebral blood flow perfusion, and attenuated radiation-associated cognitive deficits. Metabolomics revealed distinct temporal trajectories: CONV-RT showed sustained late-phase suppression of metabolic programs, whereas FLASH-RT exhibited a coordinated late-stage rebound in pathways related to amino acid/carbohydrate metabolism and synaptic neurotransmission. Mechanistically relevant metabolites linked to antioxidation, energy metabolism, and neural repair were increased under FLASH-RT, consistent with reduced neuroinflammation. Gut microbiota profiling demonstrated that FLASH-RT induced a milder and more transient dysbiosis, with faster restoration toward a Sham-like structure and enrichment of putative beneficial taxa (including Lachnospiraceae, Peptostreptococcaceae, and Dubosiella), while CONV-RT was associated with more persistent Proteobacteria/Enterobacteriaceae-related disruptions and opportunistic signatures.
Conclusion
In summary, we have innovatively explored the changes in brain metabolites and gut microbiota induced by FLASH-RT whole-brain irradiation, providing a theoretical foundation for further investigation into the mechanisms underlying FLASH-RT’s effects.
{"title":"Time-dependent alterations in brain metabolites and gut microbiota following whole-brain FLASH versus conventional radiotherapy in mice","authors":"Renke He , Yuhan Liu , Wenxuan Li , Shengqiang Xie , Jiayu Liu , Gang Cheng , Jianning Zhang","doi":"10.1016/j.brainresbull.2026.111755","DOIUrl":"10.1016/j.brainresbull.2026.111755","url":null,"abstract":"<div><h3>Purpose</h3><div>This study compared the time-dependent changes in brain metabolites and gut microbiota at early and late post-irradiation stages in mice receiving conventional radiotherapy (CONV-RT) or ultra-high dose-rate FLASH radiotherapy (FLASH-RT).</div></div><div><h3>Methods</h3><div>Male C57BL/6 J mice received whole-brain irradiation using CONV-RT (2 Gy/min) or X-ray-based FLASH-RT (200 Gy/s). Brain tissue and gut contents were collected on days 1, 3, 7, and 21 post-irradiation. Targeted LC–MS metabolomics profiled dynamic brain metabolite changes, and 16S rRNA sequencing characterized gut microbiota trajectories. Neuroinflammation and brain injury were assessed by immunofluorescence (microglia/astrocyte markers) and laser speckle cerebral blood flow imaging, while behavioral assays evaluated cognition and anxiety-like behaviors.</div></div><div><h3>Results</h3><div>Compared with CONV-RT, FLASH-RT was associated with less pronounced hippocampal microglial and astrocytic reactivity, a smaller reduction in cerebral blood flow perfusion, and attenuated radiation-associated cognitive deficits. Metabolomics revealed distinct temporal trajectories: CONV-RT showed sustained late-phase suppression of metabolic programs, whereas FLASH-RT exhibited a coordinated late-stage rebound in pathways related to amino acid/carbohydrate metabolism and synaptic neurotransmission. Mechanistically relevant metabolites linked to antioxidation, energy metabolism, and neural repair were increased under FLASH-RT, consistent with reduced neuroinflammation. Gut microbiota profiling demonstrated that FLASH-RT induced a milder and more transient dysbiosis, with faster restoration toward a Sham-like structure and enrichment of putative beneficial taxa (including <em>Lachnospiraceae</em>, <em>Peptostreptococcaceae</em>, and <em>Dubosiella</em>), while CONV-RT was associated with more persistent <em>Proteobacteria/Enterobacteriaceae</em>-related disruptions and opportunistic signatures.</div></div><div><h3>Conclusion</h3><div>In summary, we have innovatively explored the changes in brain metabolites and gut microbiota induced by FLASH-RT whole-brain irradiation, providing a theoretical foundation for further investigation into the mechanisms underlying FLASH-RT’s effects.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111755"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-15DOI: 10.1016/j.brainresbull.2026.111733
Miao Zhao , Shichu Sun , Shiqi Jing , Zifei Ma , Zihan Zhang , Yonghua Ji , Chenchen Xia , You Zhou
Neuronal hyperexcitability resulting from an inhibitory-excitatory imbalance in the primary auditory cortex (A1) is a key pathological feature of tinnitus. Voltage-gated sodium channels (VGSCs) are crucial in regulating neuronal excitability by facilitating action potential generation and propagation. However, the specific involvement of VGSC subtypes in tinnitus-related hyperexcitability within the A1 cortex remains poorly understood. Previous studies have shown that acute and chronic salicylate administration can induce stable tinnitus in rats. In this study, we investigated the distribution and expression profiles of four VGSC subtypes (Nav1.1, Nav1.2, Nav1.3, and Nav1.6) in the A1 cortex of rats following systemic salicylate administration. Immunohistochemical staining and quantitative PCR analyses revealed dynamic and subtype-specific changes in VGSC expression. Notably, while the expression of Nav1.1 and Nav1.2 was significantly reduced in GAD67-immunoreactive GABAergic neurons, both Nav1.3 and Nav1.6 showed substantial upregulation, particularly in VGLUT2-immunoreactive glutamatergic neurons in the A1 cortex. Among these, Nav1.6 exhibited the most pronounced changes, suggesting it could be a key player in the altered excitatory-inhibitory balance observed in tinnitus. Furthermore, Nav1.6 knockout mice displayed reduced central gain enhancement following salicylate administration, further implicating Nav1.6 in tinnitus pathology. Treatment with NBI-921352, a selective Nav1.6 inhibitor, alleviated tinnitus-like behaviors induced by both acute and chronic salicylate treatments, concomitant with a suppression of salicylate-induced central gain enhancement. These findings suggest that the bidirectional regulation of VGSC subtypes contributes to tinnitus-associated excitatory-inhibitory imbalances in the A1 cortex, with Nav1.6 representing a promising therapeutic target for tinnitus.
{"title":"Cell-type-specific reorganization of VGSCs in auditory cortex and therapeutic potential of Nav1.6 blockade for tinnitus","authors":"Miao Zhao , Shichu Sun , Shiqi Jing , Zifei Ma , Zihan Zhang , Yonghua Ji , Chenchen Xia , You Zhou","doi":"10.1016/j.brainresbull.2026.111733","DOIUrl":"10.1016/j.brainresbull.2026.111733","url":null,"abstract":"<div><div>Neuronal hyperexcitability resulting from an inhibitory-excitatory imbalance in the primary auditory cortex (A1) is a key pathological feature of tinnitus. Voltage-gated sodium channels (VGSCs) are crucial in regulating neuronal excitability by facilitating action potential generation and propagation. However, the specific involvement of VGSC subtypes in tinnitus-related hyperexcitability within the A1 cortex remains poorly understood. Previous studies have shown that acute and chronic salicylate administration can induce stable tinnitus in rats. In this study, we investigated the distribution and expression profiles of four VGSC subtypes (Nav1.1, Nav1.2, Nav1.3, and Nav1.6) in the A1 cortex of rats following systemic salicylate administration. Immunohistochemical staining and quantitative PCR analyses revealed dynamic and subtype-specific changes in VGSC expression. Notably, while the expression of Nav1.1 and Nav1.2 was significantly reduced in GAD67-immunoreactive GABAergic neurons, both Nav1.3 and Nav1.6 showed substantial upregulation, particularly in VGLUT2-immunoreactive glutamatergic neurons in the A1 cortex. Among these, Nav1.6 exhibited the most pronounced changes, suggesting it could be a key player in the altered excitatory-inhibitory balance observed in tinnitus. Furthermore, Nav1.6 knockout mice displayed reduced central gain enhancement following salicylate administration, further implicating Nav1.6 in tinnitus pathology. Treatment with NBI-921352, a selective Nav1.6 inhibitor, alleviated tinnitus-like behaviors induced by both acute and chronic salicylate treatments, concomitant with a suppression of salicylate-induced central gain enhancement. These findings suggest that the bidirectional regulation of VGSC subtypes contributes to tinnitus-associated excitatory-inhibitory imbalances in the A1 cortex, with Nav1.6 representing a promising therapeutic target for tinnitus.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111733"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-29DOI: 10.1016/j.brainresbull.2026.111753
Jing Yang , Qian-qian Niu , Na Liu , Bo Wang , Ya-jun Shen , De-sheng Liu , Xiao-wen Li , Mo-li Zhu , Qian-qian Wang , Ya-qi Guo
Vascular dementia (VaD) is a neurodegenerative disease caused by chronic cerebral hypoperfusion and is mainly characterized by cognitive dysfunction. This study established a VaD rat model using permanent bilateral common carotid artery occlusion (2-VO), administered different doses of nerol for 8 weeks, and evaluated cognitive function using the Morris water maze and Y-maze tests, while systematically analyzing hippocampal neuronal structure, senescence, mitochondrial function, oxidative stress, and apoptosis-related changes. The results showed that nerol improved spatial learning, memory ability, and exploratory behavior in VaD rats, and alleviated hippocampal neuronal structural damage and dendritic degeneration. At the same time, nerol reduced the number of senescence-associated β-galactosidase–positive and TUNEL-positive cells and downregulated the expression of p53 and p21. Mechanistically, nerol inhibited NOX2/NOX4-mediated reactive oxygen species production, enhanced antioxidant capacity, stabilized mitochondrial membrane potential, and suppressed DRP1/FIS1-mediated abnormal mitochondrial fission, thereby potentially attenuating oxidative stress–related neuronal senescence and apoptosis and improving cognitive function. These findings provide experimental evidence supporting the potential therapeutic value of nerol in vascular dementia.
{"title":"Nerol ameliorates cognitive dysfunction in vascular dementia rats by inhibiting mitochondrial oxidative stress and reducing hippocampal senescence","authors":"Jing Yang , Qian-qian Niu , Na Liu , Bo Wang , Ya-jun Shen , De-sheng Liu , Xiao-wen Li , Mo-li Zhu , Qian-qian Wang , Ya-qi Guo","doi":"10.1016/j.brainresbull.2026.111753","DOIUrl":"10.1016/j.brainresbull.2026.111753","url":null,"abstract":"<div><div>Vascular dementia (VaD) is a neurodegenerative disease caused by chronic cerebral hypoperfusion and is mainly characterized by cognitive dysfunction. This study established a VaD rat model using permanent bilateral common carotid artery occlusion (2-VO), administered different doses of nerol for 8 weeks, and evaluated cognitive function using the Morris water maze and Y-maze tests, while systematically analyzing hippocampal neuronal structure, senescence, mitochondrial function, oxidative stress, and apoptosis-related changes. The results showed that nerol improved spatial learning, memory ability, and exploratory behavior in VaD rats, and alleviated hippocampal neuronal structural damage and dendritic degeneration. At the same time, nerol reduced the number of senescence-associated β-galactosidase–positive and TUNEL-positive cells and downregulated the expression of p53 and p21. Mechanistically, nerol inhibited NOX2/NOX4-mediated reactive oxygen species production, enhanced antioxidant capacity, stabilized mitochondrial membrane potential, and suppressed DRP1/FIS1-mediated abnormal mitochondrial fission, thereby potentially attenuating oxidative stress–related neuronal senescence and apoptosis and improving cognitive function. These findings provide experimental evidence supporting the potential therapeutic value of nerol in vascular dementia.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111753"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-22DOI: 10.1016/j.brainresbull.2026.111743
Shengjie Hu , Yimei Lin , Jingyi Wu , Yuejiao Song , Junmei Wu , Minmin Yao , Yan Yang , Juan Guo , Changhong Miao , XiaoDan Han , Chao Liang
Propofol, a widely utilized general anesthetic, can result in developmental neurotoxicity. Previous studies suggest that astrocytes-derived exosomes (ADEs) carrying microRNAs (miRNAs), facilitating neuronal protection. Nevertheless, the underlying mechanism by which miRNAs in ADEs promoting protective effect for propofol-induced neuronal damage remains unknown. Thus, this investigation aims to explore the mechanisms that astrocytes resist propofol-induced neuron injury. Primary neurons and astrocytes were extracted from the hippocampus of mouse embryonic brain. The influence of propofol on neuronal apoptosis were evaluated utilizing a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. To analyze synaptic growth in neurons, immunofluorescence staining for the evaluation of neurite length was conducted. Differentially expressed miRNAs in primary mouse astrocytes were identified through miRNA sequencing, followed by validation using quantitative polymerase chain reaction (qPCR). Luciferase reporter assays, qPCR and western blotting were conducted to explore the effects of miR-381–3p on cyclin-dependent kinase 1 (CDK1) expression. We demonstrated that ADEs mitigated the neuronal damage caused by propofol. MiRNA sequencing revealed a significant upregulation of miR-381–3p within ADEs. Moreover, CDK1 was recognized as the downstream target gene of miR-381–3p. By targeting CDK1, miR-381–3p can counteract propofol-induced neuronal damage. Notably, knockdown of miR-381–3p in astrocytes distinctly diminished the neuroprotective effects of ADEs. Exosomal miR-381–3p derived from astrocytes targets neuronal CDK1 to mitigate propofol-induced neuronal damage.
{"title":"Exosomal miR-381–3p derived from astrocytes targets neuronal CDK1 to resist propofol-induced neuronal damage in vitro","authors":"Shengjie Hu , Yimei Lin , Jingyi Wu , Yuejiao Song , Junmei Wu , Minmin Yao , Yan Yang , Juan Guo , Changhong Miao , XiaoDan Han , Chao Liang","doi":"10.1016/j.brainresbull.2026.111743","DOIUrl":"10.1016/j.brainresbull.2026.111743","url":null,"abstract":"<div><div>Propofol, a widely utilized general anesthetic, can result in developmental neurotoxicity. Previous studies suggest that astrocytes-derived exosomes (ADEs) carrying microRNAs (miRNAs), facilitating neuronal protection. Nevertheless, the underlying mechanism by which miRNAs in ADEs promoting protective effect for propofol-induced neuronal damage remains unknown. Thus, this investigation aims to explore the mechanisms that astrocytes resist propofol-induced neuron injury. Primary neurons and astrocytes were extracted from the hippocampus of mouse embryonic brain. The influence of propofol on neuronal apoptosis were evaluated utilizing a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. To analyze synaptic growth in neurons, immunofluorescence staining for the evaluation of neurite length was conducted. Differentially expressed miRNAs in primary mouse astrocytes were identified through miRNA sequencing, followed by validation using quantitative polymerase chain reaction (qPCR). Luciferase reporter assays, qPCR and western blotting were conducted to explore the effects of miR-381–3p on cyclin-dependent kinase 1 (CDK1) expression. We demonstrated that ADEs mitigated the neuronal damage caused by propofol. MiRNA sequencing revealed a significant upregulation of miR-381–3p within ADEs. Moreover, CDK1 was recognized as the downstream target gene of miR-381–3p. By targeting CDK1, miR-381–3p can counteract propofol-induced neuronal damage. Notably, knockdown of miR-381–3p in astrocytes distinctly diminished the neuroprotective effects of ADEs. Exosomal miR-381–3p derived from astrocytes targets neuronal CDK1 to mitigate propofol-induced neuronal damage.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111743"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-14DOI: 10.1016/j.brainresbull.2026.111734
Ao Li , Shujuan Qu , Shengfeng Wang , Qiong Guo , Sinian Tan , Mao Peng , Lin Liu
Background
Microglial pyroptosis-mediated neuroinflammation is a key pathogenic mechanism in Sepsis-Associated Encephalopathy (SAE). However, the role of prodynorphin (PDYN) in SAE and the relationship between PDYN and microglial pyroptosis remain unknown.
Methods
Mice were subjected to cecal ligation and puncture (CLP) or sham surgery. Microglial cells were treated with lipopolysaccharide (LPS) in vitro. Cognitive function was assessed using the Morris water maze, novel object recognition, and open field tests. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining was used to observe glial apoptosis; Nissl staining was used to observe microglial infiltration; H&E staining was used to detect histopathological changes. Pyroptosis and the expression levels of relevant signaling molecules were assessed by Western blot analysis.
Results
PDYN protected against neuronal damage and cognitive impairment in septic mice. PDYN inhibits microglial pyroptosis and secretion of inflammatory cytokines in vivo and in vitro. Further examination revealed that PDYN inhibits microglial pyroptosis by inhibiting the PI3K/AKT/mTORC pathway. Moreover, the PI3K activator 740Y-P promoted microglial pyroptosis by activating the PI3K/AKT/mTORC pathway.
Conclusion
This study reveals, for the first time, that PDYN exerts neuroprotective effects in SAE by suppressing microglial pyroptosis through inhibition of the PI3K/AKT/mTOR signaling pathway. These findings identify PDYN and the PI3K/AKT/mTOR-pyroptosis axis as novel therapeutic targets for SAE, providing a mechanistic foundation for developing adjunctive neuroprotective strategies alongside standard sepsis care.
{"title":"Suppression of the PI3K/AKT/mTOR signaling pathway by PDYN alleviates sepsis-associated encephalopathy in mice","authors":"Ao Li , Shujuan Qu , Shengfeng Wang , Qiong Guo , Sinian Tan , Mao Peng , Lin Liu","doi":"10.1016/j.brainresbull.2026.111734","DOIUrl":"10.1016/j.brainresbull.2026.111734","url":null,"abstract":"<div><h3>Background</h3><div>Microglial pyroptosis-mediated neuroinflammation is a key pathogenic mechanism in Sepsis-Associated Encephalopathy (SAE). However, the role of prodynorphin (PDYN) in SAE and the relationship between PDYN and microglial pyroptosis remain unknown.</div></div><div><h3>Methods</h3><div>Mice were subjected to cecal ligation and puncture (CLP) or sham surgery. Microglial cells were treated with lipopolysaccharide (LPS) <em>in vitro</em>. Cognitive function was assessed using the Morris water maze, novel object recognition, and open field tests. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining was used to observe glial apoptosis; Nissl staining was used to observe microglial infiltration; H&E staining was used to detect histopathological changes. Pyroptosis and the expression levels of relevant signaling molecules were assessed by Western blot analysis.</div></div><div><h3>Results</h3><div>PDYN protected against neuronal damage and cognitive impairment in septic mice. PDYN inhibits microglial pyroptosis and secretion of inflammatory cytokines <em>in vivo</em> and <em>in vitro</em>. Further examination revealed that PDYN inhibits microglial pyroptosis by inhibiting the PI3K/AKT/mTORC pathway. Moreover, the PI3K activator 740Y-P promoted microglial pyroptosis by activating the PI3K/AKT/mTORC pathway.</div></div><div><h3>Conclusion</h3><div>This study reveals, for the first time, that PDYN exerts neuroprotective effects in SAE by suppressing microglial pyroptosis through inhibition of the PI3K/AKT/mTOR signaling pathway. These findings identify PDYN and the PI3K/AKT/mTOR-pyroptosis axis as novel therapeutic targets for SAE, providing a mechanistic foundation for developing adjunctive neuroprotective strategies alongside standard sepsis care.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111734"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-19DOI: 10.1016/j.brainresbull.2026.111740
Yuan Wang , Jing Zhao , Kaijie Wang , Shuwei Wang , Jie Li , Chaopeng Xu , Haoyu Wang , Jianzhong Cui
Objective
Although the pathological mechanisms underlying intracerebral hemorrhage (ICH) have been widely explored, the contribution of kininogen-1 (Kng1) to inflammation-associated neuronal damage has not been fully elucidated. This study was designed to investigate the functional involvement of Kng1 and the cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling cascade in inflammation-driven neuronal injury following cerebral hemorrhage.
Methods
Bioinformatics analyses based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were employed to identify Kng1 and the cGMP-PKG pathway as key candidates. An in vivo ICH model was generated by intracerebral injection of autologous blood, while an in vitro hemorrhagic injury model was established by treating neuronal cells with hemoglobin chloride. Levels of inflammatory mediators and gene expression were determined using enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and reverse transcription-quantitative polymerase chain reaction. Neurological impairment and cerebral edema were evaluated through behavioral deficit scoring and brain water content analysis, respectively.
Results
Kng1 protein levels were markedly increased in the serum of patients with ICH as well as in experimental hemorrhage models, and this elevation was closely associated with enhanced neuroinflammatory responses. Suppression of Kng1 expression significantly alleviated neurological dysfunction, reduced cerebral edema, mitigated inflammatory activation, and limited neuronal apoptosis in ICH rats. Further mechanistic investigations demonstrated that Kng1 modulates the cGMP-PKG signaling axis, as pharmacological stimulation of cGMP or PKG reversed the protective effects induced by Kng1 silencing. Consistent findings from both animal and cellular rescue experiments indicated that Kng1 aggravates neuronal injury after ICH by activating cGMP-PKG-dependent inflammatory signaling pathways.
Conclusion
Kng1 regulates the cGMP-PKG signaling pathway, influencing neuronal cell injury induced by the inflammatory response in ICH conditions. These findings suggest Kng1 as a potential therapeutic target for mitigating ICH-induced neuronal damage.
{"title":"Kininogen-1 modulates cGMP-PKG signaling to alleviate inflammatory neuronal injury in intracerebral hemorrhage","authors":"Yuan Wang , Jing Zhao , Kaijie Wang , Shuwei Wang , Jie Li , Chaopeng Xu , Haoyu Wang , Jianzhong Cui","doi":"10.1016/j.brainresbull.2026.111740","DOIUrl":"10.1016/j.brainresbull.2026.111740","url":null,"abstract":"<div><h3>Objective</h3><div>Although the pathological mechanisms underlying intracerebral hemorrhage (ICH) have been widely explored, the contribution of kininogen-1 (Kng1) to inflammation-associated neuronal damage has not been fully elucidated. This study was designed to investigate the functional involvement of Kng1 and the cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling cascade in inflammation-driven neuronal injury following cerebral hemorrhage.</div></div><div><h3>Methods</h3><div>Bioinformatics analyses based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were employed to identify Kng1 and the cGMP-PKG pathway as key candidates. An in vivo ICH model was generated by intracerebral injection of autologous blood, while an in vitro hemorrhagic injury model was established by treating neuronal cells with hemoglobin chloride. Levels of inflammatory mediators and gene expression were determined using enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and reverse transcription-quantitative polymerase chain reaction. Neurological impairment and cerebral edema were evaluated through behavioral deficit scoring and brain water content analysis, respectively.</div></div><div><h3>Results</h3><div>Kng1 protein levels were markedly increased in the serum of patients with ICH as well as in experimental hemorrhage models, and this elevation was closely associated with enhanced neuroinflammatory responses. Suppression of Kng1 expression significantly alleviated neurological dysfunction, reduced cerebral edema, mitigated inflammatory activation, and limited neuronal apoptosis in ICH rats. Further mechanistic investigations demonstrated that Kng1 modulates the cGMP-PKG signaling axis, as pharmacological stimulation of cGMP or PKG reversed the protective effects induced by Kng1 silencing. Consistent findings from both animal and cellular rescue experiments indicated that Kng1 aggravates neuronal injury after ICH by activating cGMP-PKG-dependent inflammatory signaling pathways.</div></div><div><h3>Conclusion</h3><div>Kng1 regulates the cGMP-PKG signaling pathway, influencing neuronal cell injury induced by the inflammatory response in ICH conditions. These findings suggest Kng1 as a potential therapeutic target for mitigating ICH-induced neuronal damage.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111740"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-29DOI: 10.1016/j.brainresbull.2026.111752
Liekui Hu , Zhaozhi Qiu , Zhifu Ai , Rui Liu , Bike Zhang , Huizhen Li
The association between central adaptive immunity and depression remains highly debated. In this study, we systematically assessed the role of adaptive immune mechanisms in depression using a mouse model of chronic unpredictable mild stress (CUMS) and the peripheral blood of patients with depression. The behavioral results demonstrated that the CUMS mice exhibited typical depression-like behaviors. Subsequent transcriptomic analysis of the hippocampus identified 203 differentially expressed genes (DEGs), of which CD4 expression was significantly downregulated. Furthermore, DEGs were enriched in the tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways. Validation experiments further corroborated the hypothesis that the CD4 gene in the hippocampal region of CUMS mice was reduced in parallel with the protein levels. Immunocorrelation assays revealed a decrease in intercellular cell adhesion molecule-1 expression in the hippocampus, along with an increase in vascular cell adhesion molecule-1 expression. These changes were accompanied by cytokine level disruption in CUMS mice. A total of 391 DEGs were identified in the transcriptome sequencing of peripheral blood CD4+T cells from patients with depression using the Gene Expression Omnibus database. These DEGs were significantly associated with the PI3K-AKT, IL-17, and TNF signaling pathways. Immune checkpoint analysis revealed elevated PDCD1 and decreased TIGIT expression in CD4+T cells of the patients. The integration of animal models and clinical data revealed a convergent pattern of findings, indicating CD4+ T-cell dysfunction and the activation of pro-inflammatory pathways as immune features shared across species in depression. This provides a novel rationale for targeted immunomodulatory treatment of depression.
{"title":"Adaptive immune dysregulation in depression: Cross-species evidence of CD4+ T cell dysfunction and pro-inflammatory pathway activation","authors":"Liekui Hu , Zhaozhi Qiu , Zhifu Ai , Rui Liu , Bike Zhang , Huizhen Li","doi":"10.1016/j.brainresbull.2026.111752","DOIUrl":"10.1016/j.brainresbull.2026.111752","url":null,"abstract":"<div><div>The association between central adaptive immunity and depression remains highly debated. In this study, we systematically assessed the role of adaptive immune mechanisms in depression using a mouse model of chronic unpredictable mild stress (CUMS) and the peripheral blood of patients with depression. The behavioral results demonstrated that the CUMS mice exhibited typical depression-like behaviors. Subsequent transcriptomic analysis of the hippocampus identified 203 differentially expressed genes (DEGs), of which CD4 expression was significantly downregulated. Furthermore, DEGs were enriched in the tumor necrosis factor (TNF) and interleukin (IL)-17 signaling pathways. Validation experiments further corroborated the hypothesis that the CD4 gene in the hippocampal region of CUMS mice was reduced in parallel with the protein levels. Immunocorrelation assays revealed a decrease in intercellular cell adhesion molecule-1 expression in the hippocampus, along with an increase in vascular cell adhesion molecule-1 expression. These changes were accompanied by cytokine level disruption in CUMS mice. A total of 391 DEGs were identified in the transcriptome sequencing of peripheral blood CD4<sup>+</sup>T cells from patients with depression using the Gene Expression Omnibus database. These DEGs were significantly associated with the PI3K-AKT, IL-17, and TNF signaling pathways. Immune checkpoint analysis revealed elevated PDCD1 and decreased TIGIT expression in CD4<sup>+</sup>T cells of the patients. The integration of animal models and clinical data revealed a convergent pattern of findings, indicating CD4<sup>+</sup> T-cell dysfunction and the activation of pro-inflammatory pathways as immune features shared across species in depression. This provides a novel rationale for targeted immunomodulatory treatment of depression.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111752"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-29DOI: 10.1016/j.brainresbull.2026.111746
Dong Ji , Qingyu Sun , Chengcheng Zhang , Mingyi Zang , Wei Xiao , Jie Liu , Xiaohua Fan , Hongbing Wang
Background
Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity.
Methods
POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5–3335), and overexpression in BV2 cells.
Results
Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine’s anti-inflammatory effects, whereas RUNX1 overexpression abolished them.
Conclusion
Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection.
{"title":"Dendrobine attenuates postoperative cognitive dysfunction by inhibiting Runx1-mediated NF-κB signaling pathway","authors":"Dong Ji , Qingyu Sun , Chengcheng Zhang , Mingyi Zang , Wei Xiao , Jie Liu , Xiaohua Fan , Hongbing Wang","doi":"10.1016/j.brainresbull.2026.111746","DOIUrl":"10.1016/j.brainresbull.2026.111746","url":null,"abstract":"<div><h3>Background</h3><div>Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity.</div></div><div><h3>Methods</h3><div>POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5–3335), and overexpression in BV2 cells.</div></div><div><h3>Results</h3><div>Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine’s anti-inflammatory effects, whereas RUNX1 overexpression abolished them.</div></div><div><h3>Conclusion</h3><div>Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111746"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-16DOI: 10.1016/j.brainresbull.2026.111737
Yongsheng Wu , Hao Zhang , Junyu Qu , Rui Zhu , Guihua Xu , Wenwen Xu , Guizhen Yan , Jianhong Yang , Jiaxiang Xin , Yi Li , Dawei Wang , for Alzheimer’s Disease Neuroimaging Initiative
Background
Alzheimer’s disease (AD) is increasingly conceptualized as a disconnection syndrome involving widespread alterations in large-scale brain networks. Previous studies using morphometric similarity networks (MSNs) have revealed broad structural and transcriptomic changes, yet vertex-level structural disconnection and its molecular basis remain poorly understood. We applied morphometric inverse divergence (MIND), an innovative approach for fine-grained mapping of structural disconnection and its transcriptomic correlates in AD.
Methods
Utilizing two independent datasets: [ADNI (219 AD, 219 cognitively normal, CN) and the Qilu dataset (100 AD, 137 CN)], we mapped robust MIND network alterations in AD patients and examined their associations with cognitive performance and biomarker quantifications. Additionally, we linked MIND connectome to spatial gene expression using partial least squares regression, followed by gene enrichment analysis to identify relevant biological pathways. Finally, to validate the clinical utility of MIND, a residual deep neural network (ResDNN) was developed to compare its diagnostic performance against MSNs in distinguishing AD from CN.
Results
Significantly decreased MIND degree was identified in the bilateral frontal, lateral occipital, and posterior temporal lobes (P FDR < 0.05), positively correlating with MMSE score and FDG-PET SUVR (all P < 0.001). Conversely, increased MIND degree was observed in the bilateral cuneus, entorhinal, lingual, and parahippocampal regions (P FDR < 0.05), negatively correlating with cognition assessment, CSF Aβ-42 levels and FDG-PET SUVR (all P < 0.001). These AD-related MIND alterations were spatially correlated with gene expression profiles crucial for synaptic function, neurotransmission, and metabolic regulation. Importantly, MIND achieved superior diagnostic efficacy (AUC=0.90/0.88 in ADNI/Qilu) over MSNs.
Conclusions
We mapped a robust pattern of structural disconnection in Alzheimer's disease with MIND approach and associate it with particular transcriptomic signatures. These findings not only improve our mechanistic understanding of AD as a disconnection syndrome but also demonstrate MIND as a sensitive tool for identifying disease-specific alterations, holding promise for future mechanistic and clinical investigations into AD pathology.
{"title":"Mapping structural disconnection and transcriptomic signatures in Alzheimer’s disease with MIND networks","authors":"Yongsheng Wu , Hao Zhang , Junyu Qu , Rui Zhu , Guihua Xu , Wenwen Xu , Guizhen Yan , Jianhong Yang , Jiaxiang Xin , Yi Li , Dawei Wang , for Alzheimer’s Disease Neuroimaging Initiative","doi":"10.1016/j.brainresbull.2026.111737","DOIUrl":"10.1016/j.brainresbull.2026.111737","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer’s disease (AD) is increasingly conceptualized as a disconnection syndrome involving widespread alterations in large-scale brain networks. Previous studies using morphometric similarity networks (MSNs) have revealed broad structural and transcriptomic changes, yet vertex-level structural disconnection and its molecular basis remain poorly understood. We applied morphometric inverse divergence (MIND), an innovative approach for fine-grained mapping of structural disconnection and its transcriptomic correlates in AD.</div></div><div><h3>Methods</h3><div>Utilizing two independent datasets: [ADNI (219 AD, 219 cognitively normal, CN) and the Qilu dataset (100 AD, 137 CN)], we mapped robust MIND network alterations in AD patients and examined their associations with cognitive performance and biomarker quantifications. Additionally, we linked MIND connectome to spatial gene expression using partial least squares regression, followed by gene enrichment analysis to identify relevant biological pathways. Finally, to validate the clinical utility of MIND, a residual deep neural network (ResDNN) was developed to compare its diagnostic performance against MSNs in distinguishing AD from CN.</div></div><div><h3>Results</h3><div>Significantly decreased MIND degree was identified in the bilateral frontal, lateral occipital, and posterior temporal lobes (P <sub>FDR</sub> < 0.05), positively correlating with MMSE score and FDG-PET SUVR (all P < 0.001). Conversely, increased MIND degree was observed in the bilateral cuneus, entorhinal, lingual, and parahippocampal regions (P <sub>FDR</sub> < 0.05), negatively correlating with cognition assessment, CSF Aβ-42 levels and FDG-PET SUVR (all P < 0.001). These AD-related MIND alterations were spatially correlated with gene expression profiles crucial for synaptic function, neurotransmission, and metabolic regulation. Importantly, MIND achieved superior diagnostic efficacy (AUC=0.90/0.88 in ADNI/Qilu) over MSNs.</div></div><div><h3>Conclusions</h3><div>We mapped a robust pattern of structural disconnection in Alzheimer's disease with MIND approach and associate it with particular transcriptomic signatures. These findings not only improve our mechanistic understanding of AD as a disconnection syndrome but also demonstrate MIND as a sensitive tool for identifying disease-specific alterations, holding promise for future mechanistic and clinical investigations into AD pathology.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"235 ","pages":"Article 111737"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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