Journal of Integrative Neuroscience
·
2024
·Vol. 23
·期 11
·196
·
IF 2.5
Yan Shi,Yufeng Yang,Juntong Liu,Jinling Zheng
Background:
Avicularin (AL), an ingredient of Banxia, has anti-inflammatory properties in cerebral disease and regulates polarization of macrophages, but its effects on ischemic stroke (IS) damage have not been studied.
Methods:
In vivo, AL was administered by oral gavage to middle cerebral artery occlusion/reperfusion (MCAO/R) C57BL/6J mice in doses of 1.25, 2.5, and 5 mg/kg/day for seven days, and, in vitro, AL was added to treat oxygen-glucose deprivation (OGD)-BV2 cells. Modified neurological severity score, Triphenyltetrazolium chloride (TTC) staining, brain-water-content detection, TdT-mediated dUTP nick-end labeling (TUNEL) assay, flow cytometry, immunofluorescence assay, Enzyme linked immunosorbent assay (ELISA), and Western-blot analysis were used to investigate the functions and mechanism of the effect of AL treatment on IS. The exosomes of AL-treated microglia were studied by transmission electron microscope (TEM), nanoparticle tracking analyzer (NTA), and Western-blot analysis.
Results:
AL treatment reduced the neurological severity score, infarct volume, brain-water content, neuronal apoptosis, and the release of inflammatory factors, that were induced by MCAO/R. Notably, M2 microglia polarization was promoted but M1 microglia polarization was inhibited by AL in the ischemic penumbra of MCAO/R mice. Subsequently, anti-inflammatory and polarization-regulating effects of AL were verified in vitro. Suppressed NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation was found in the ischemic penumbra of animal and Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) cells treated with AL, as evidenced by decreasing NLRP3-inflammasome-related protein and downstream factors. After AL treatment, the anti-apoptosis effect of microglial exosomes on OGD/R primary cortical neurons was increased.
Conclusion:
AL reduce inflammatory responses and neuron death of IS-associated models by regulating microglia polarization by the NLRP3 pathway and by affecting microglial exosomes.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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炎症研究
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DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Yu Bi,Ziyi Xie,Xiang Cao,Huanyu Ni,Shengnan Xia,Xinyu Bao,Qinyue Huang,Yun Xu,Qingxiu Zhang
Microglia-associated neuroinflammation plays essential roles in pathology of acute stroke. Cedrol, a natural compound extracted from ginger, has been shown to confer inhibitory effects on inflammation in various diseases. However, whether Cedrol suppresses neuroinflammation and protects brains from acute ischemic injury still remains unclear. In this study, we found that Cedrol inhibited microglia activation and the production of inflammatory factors in LPS-challenged microglia and the penumbra region of middle cerebral artery occlusion (MCAO) mice. We also found that Cedrol reduced the infarct size and mNSS scores and improved acute cerebral ischemia-induced behavioral outcomes, suggesting remarked neuroprotection of Cedrol. Molecular docking analysis showed that Cedrol bound to estrogen receptor β (ERβ) with moderate-strong affinity. Intriguingly, treatment with fulvestrant, an ER blocker, abolished the anti-inflammatory effects of Cedrol. Cedrol significantly reversed the LPS- and MCAO-induced increases in phosphorylation levels of IκB and NF-κB P65 in primary microglia and MCAO mice, respectively. Additionally, Cedrol was observed to rescue LPS-induced shuttling of NF-κB P65 from cytoplasm to nuclei in primary microglia, indicating inhibitory effects of Cedrol on NF-κB signaling. These results suggest microglia associated neuroinflammation may be mediated by ERβ-NF-κB signaling pathway. Together, our study reveals that Cedrol protected brain function from acute cerebral ischemia through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways, and Cedrol may serve as an alternative option for treatment of acute stroke injury.
研究领域:
神经科学
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药理学
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分子生物学
·
炎症
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
·
2025
·
IF 4
Ling Zhu,Congyan Liu,Yang Wang,Xuanang Zhu,Lei Wu,Lvan Chen,Jing Zhou,Fan Wang
Background Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. Method Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N 6 -methyladenosine (m 6 A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. Results Stimulation with Aβ 1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m 6 A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. Conclusion Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
研究领域:
神经生物学
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医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Ying-Xin Zhao,Ke-Tian Zhu,Yu-Xuan Tong,Qi-Qian Wang,Jin-Long Li
Abstract Di-2-ethylhexyl phthalate (DEHP) accumulates in the food chain, threatening human and animal health. However, how DEHP induces neurotoxicity by interfering with microglia has not been fully revealed. Our research aims to explore the effects of DEHP on microglia and identify relevant targets that cause neurotoxicity. The results indicated that DEHP damaged neurons, leading to swelling, demyelination, and abnormal autophagy. Inhibition of autophagy resulted in α-Syn misfolding, characterized by an increase in dimers with increasing additive concentrations (P = 0.0096). Dimer formation was promoted by the addition of additives, which increased the electrostatic force, along with interactions between Glu106, Gly51, and Val66. Transmitted from neurons to microglia (Pearson r2 = 0.889), pathological aggregates under DEHP exposure induced microglial M1 subtype switching. This study elucidated a novel mechanism by which DEHP damages the nerves of birds and provided a therapeutic target for the neurotoxic disease risk caused by the transmission of plastic additives through the food chain.
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DOI
高影响因子
Journal of Functional Foods
·
2026
·
IF 3.9
Jiaqian Yang,Wenqi Wang,Kaiyuan Feng,Biying Ma,Liying Liu,Lanxi Xu,Lin Li,Xiangjiao Yi,Bo Yang,Yiqi Wang
Angelica keiskei (Miq.) Koidz. [Apiaceae] is a botanical drug with dual-purpose as food and medicine and its improvement in acute cerebral ischemic injury has not been studied. In the present study, we investigated the anti-neuroinflammatory and protective effects of the ethyl acetate extract of Angelica keiskei (EEAK) on acute cerebral ischemic injury. EEAK dose-dependently suppressed the production of inflammatory cytokines in lipopolysaccharide-activated BV2 microglia, with IC₅₀ values of 21.8 μg/mL for TNF-α and 7.9 μg/mL for IL-6, and also reduced NO and ROS levels at non-cytotoxic concentrations. In addition, EEAK inhibited the activation of the NF-κB and MAPK signaling pathways. In vivo, preventive oral administration of EEAK (50 and 100 mg/kg) significantly reduced infarct volume and improved neurological deficits in mice subjected to MCAO/R. EEAK also suppressed the mRNA expression of TNF-α, IL-6, IL-1β, and iNOS, as well as microglial activation, in ischemic brain tissues. These findings suggest that EEAK may protect against acute ischemic brain injury by inhibiting microglial activation and neuroinflammatory responses. Notably, as the treatment was administered preventively prior to acute ischemic brain injury, the therapeutic potential of EEAK in acute ischemic brain injury remains to be determined.
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DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Delong Meng,Qian Su,Kejuan Jia,Mengjie Jin,Wenting Liu,Shiqi Yang,Zhiqiang Su
Ischemic stroke is a kind of cerebrovascular disease with high mortality. The expression of ETS variant transcription factor 5 (ETV5) is down-regulated in ischemic stroke, but the specific role and mechanism remain unclear. In this study, the effects of ETV5 on ischemic stroke were investigated in vivo and in vitro by establishing the middle cerebral artery occlusion/reperfusion (MCAO/R) animal model and oxygen-glucose deprivation/reoxygenation (OGD/R) microglia model, respectively. We found that ETV5 reduced the infarct size, neurological deficit, microglia M1 polarization, and neuron pyroptosis level. Mechanistically, we further examined the expression of the HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) and nuclear factor erythroid 2-related factor 2 (Nrf2) based on animal and cellular models to assess whether ETV5 affects ischemic stroke through the HACE1/Nrf2 signaling pathway. We found that ETV5 promoted the expression of HACE1 and Nrf2 in microglia and that HACE1 was transcriptionally activated by ETV5, which in turn competed with the E3 ligase KEAP1 for binding of Nrf2 and enhances the protein stability and nuclear expression of Nrf2. Our results suggest that ETV5 can ameliorate brain injury caused by ischemic stroke and this is closely related to inducing the HACE1/Nrf2 pathway to inhibit microglia M1 polarization.
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Shuang Gao,Yaguang Wang,Huicong Feng,Zipeng Zhou,Yang Cui,Mingyu Bai,Biaobiao Wang,Yingqi Liu,Jidi Liu,Chao Wu,Xifan Mei,Yang Qiu,He Tian
Spinal cord injury (SCI) is a devastating condition from which there is limited recovery of motor function. Inhibiting oxidative stress and inflammation is an effective strategy for treating SCI. The polysaccharide component of Schisandra chinensis is receiving increasing attention due to its potential in neuroprotection. Based on our previous research, we synthesized an Schisandra chinensis polysaccharide-zinc complex (SPZn) for synergistic treatment of SCI. However, poor blood-spinal cord barrier permeability limited the efficacy of SPZn. Microglia are immune cells that are inherent to the spinal cord and possess intrinsic targeting ability combined with immune evasion capacity, making them an ideal drug delivery system for SCI. Therefore, in this study, we selected microglia membranes to encapsulate SPZn (M-SPZn) for the treatment of SCI. The nanovesicle (M-SPZn) designed by us can target the site of spinal cord trauma and has good biosafety. The results, both in vivo and in vitro, showed that M-SPZn is more effective at alleviating oxidative stress and inhibiting inflammation. Moreover, M-SPZn reduced cell death and promoted motor function recovery in mice after SCI. In summary, M-SPZn has multiple roles in treating SCI and has a good usage potential.
研究领域:
神经科学
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免疫学
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药剂学
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生物材料
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转化医学
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分子医学
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再生医学
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产品关联
DOI
PubMed
高影响因子
NEURON
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2025
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IF 15
Tao Qin,Tao Jiang,Zihan Zhou,Mengyuan Wu,Yuanzhen Zhang,Zhenqi Yang,Ziyang Zheng,Jiang Yi,Xiaowei Wang,Mingran Luo,Peng Gao,Jiayun Liu,Yifan Huang,Hao Liu,Qingqing Li,Wei Zhou,Shujun Zhang,Xiaodong Guo,Baorong He,Yongxiang Wang,Jin Fan,Shujie Zhao,Jian Chen,Guoyong Yin
The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.
研究领域:
免疫学
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神经科学
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分子生物学
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转化医学
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炎症与修复
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神经免疫学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2026
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IF 3.2
Tao Wang,Chao Chen,Ran Li,Li-Hong Su,Hao-Jie Tian,Hui-Jing Wang,Jia-Yi Xiong,Qing Dai,Di Wu,Gang Zheng
Elevated levels of lead and copper dyshomeostasis are significant risk factors for cognitive dysfunction in older adults. During brain aging, microglia transition to a senescence-associated secretory phenotype (SASP), thereby contributing to cognitive decline. However, whether lead affects cognitive function by promoting microglial SASP transition remains unclear. In this study, we exposed BV2 microglial cells to lead or co-exposure to lead and copper to simulate severe copper dyshomeostasis. Lead exposure promoted the transition of BV2 cells to a SASP, characterized by enlarged cell bodies, increased M1 activation, and enhanced release of inflammatory cytokines. This promotion was more enhanced in the presence of copper and was attributed to intracellular copper overload. Mechanistically, copper overload triggered reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) release, activating the cGAS–STING–NLRP3 axis, driving M1 microglial activation, and sustaining neuroinflammation. Copper chelation following lead or lead and copper co-exposure reduced ROS, mtDNA release, and neuroinflammatory cytokine production. Our findings suggest that cellular copper overload, responsible for activating mtDNA-cGAS–STING–NLRP3 axis, plays a significant role in microglial transition following lead exposure.
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DOI
PubMed
高影响因子
SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS
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2026
·
IF 6.6
Yaqi Liu,Biao Luo,Yun Xu,Dexiang Liu,Qiujing Wang
Ischemic stroke (IS) remains a leading cause of global disability and mortality, with limited effective anti-inflammatory interventions. Targeting histone deacetylase 3 (HDAC3) to reprogram microglial polarization holds great therapeutic promise, but the HDAC3-specific inhibitor RGFP966 suffers from poor blood-brain barrier (BBB) penetration and systemic toxicity. Herein, we developed a pH-responsive brain-targeted lipid nanoparticle (CD-TLNP@RGFP966) by integrating T7 peptide modification for BBB transcytosis and cinnamaldehyde-α-cyclodextrin (CA-αCD) encapsulation for acidic lesion-triggered drug release. CD-TLNP@RGFP966 exhibited favorable colloidal stability, biosafety, and pH-dependent release behavior. It efficiently crossed the BBB, accumulated in ischemic brain tissue, promoted microglial M2 polarization, attenuated neuroinflammation, reduced infarct volume, and improved neurological function in tMCAO mice. This study provides a novel targeted nanocarrier strategy for the anti-inflammatory treatment of IS.
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Hongyu Zhang,Guoshun Lin,Yifei Wang,Aihui Zheng,Hanlin Luo,Zhang Cao,Guige Hou,Yun Hou
Background Bisphenol S (BPS) is widely used in consumer products and food packaging, but its safety and potential risks have garnered increasing attention. Hydroxytyrosol (HT), a natural polyphenolic compound with potent antioxidant and anti-inflammatory activities, is yet to be investigated for its potential to reverse BPS-induced effects and the underlying mechanistic pathways. Methods The toxicological potential of BPS was assessed using the computational platform ProTox 3.0. Molecular experiments were performed to elucidate the effects of BPS on the nervous system. Protein-protein interaction networks were constructed to predict the targets of BPS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to explore the potential mechanisms of action, followed by molecular docking studies. We examined the therapeutic efficacy of HT against BPS-induced nerve damage using molecular assays and in vivo murine models. The key target identified by molecular docking was validated using RT-qPCR. Results Significant neurotoxic effects of BPS were identified using platform-based predictive analysis. The experimental results demonstrated that exposure to BPS not only reduced the viability of BV2 and HMC3 microglial and elevated intracellular reactive oxygen species (ROS) levels, but also induced a phenotypic shift in microglia toward a pro-inflammatory state, thereby may underscore its neurotoxic effects. Based on the results of the network toxicology analysis, BPS is potentially capable of exacerbating nerve damage via its modulatory effects, such as its modulation of cytochrome P450 Family 1 Subfamily A (CYP1A), like-CYP1A1, CYP1A2, and cytochrome P450 Family 2 Subfamily B6 (CYP2B6), etc. Finally, subsequent confirmation using network pharmacology and molecular docking analysis revealed that HT is capable of counteracting BPS-induced effects, and that CYP1A1 is highly likely to be a pivotal target implicated in both BPS-mediated toxicity in microglia and the therapeutic mechanisms of HT. This was further verified using RT-qPCR. Conclusion CYP1A1 is a critical mediator of BPS-induced toxicity and a potential therapeutic target of HT. These findings highlight the potential of natural compounds to mitigate environmental toxicant-induced neurological damage.
研究领域:
毒理学
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神经药理学
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环境健康
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Neuroscience
·
2024
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IF 3.2
Shuo Li,Alhamdu Adamu,Yucai Ye,Fankai Gao,Rulin Mi,Guofang Xue,Zhaojun Wang
Objective: To investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.Methods: Based on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia in vitro, we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia’s M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.Results: (+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.Conclusion: (+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.
研究领域:
神经科学
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药理学
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免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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