JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xiaolei Song,Chenchen Wang,Qin Ding,Peng Li,Shihao Sun,Wei Wei,Juan Zhang,Rongli Sun,Lihong Yin,Songqin Liu,Yuepu Pu
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD.
研究领域:
神经科学
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药学
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分子生物学
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DOI
PubMed
高影响因子
STAR Protocols
·
2021
·
IF 0
Zhen Xu,Bo Peng,Yanxia Rao
Summary Mutations in microglia may cause brain disorders. Replacement of dysfunctional microglia by allogeneic wild-type microglia from bone marrow transplantation (Mr BMT) or peripheral blood can correct the gene deficiency at the brain-wide scale but cannot achieve precise replacement at specific brain regions. Here, we introduce a strategy with potential clinical relevance—microglia replacement by microglia transplantation (Mr MT), combining tamoxifen-induced ablation of Mr BMT cells and intracranial injection of microglia to mouse brain, to achieve region-sepcific microglia replacement. The original abbreviation of this microglia replacement strategy is mrMT. We hereby change the name to Mr MT. For complete details on the use and execution of this protocol, please refer to Xu et al. (2020) .
研究领域:
神经科学
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细胞生物学
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移植学
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DOI
PubMed
Heliyon
·
2024
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IF 3.4
Fanzhuo Zeng,Anqi Chen,Wei Chen,Shuai Cheng,Sen Lin,Rongcheng Mei,Xifan Mei
Background Spinal cord injury (SCI) is a serious and difficult to treat traumatic disease of the central nervous system. Spinal cord injury causes a variety of detrimental effects, including neuroinflammation and ferroptosis, leading to chronic functional impairment and death. Recent studies have shown that microglia/macrophages (M/Ms) at the injury site remain primarily in the pro-inflammatory state, which is detrimental to recovery. However, information on the factors behind pro-inflammatory polarization skew in the injured spinal cord remains unclear. In this study, we found that Tumor Necrosis Factor-α(TNF-α) ablation protected after SCI by suppressing neuroinflammation and ferroptosis. Though using TNF-α knock out mice (TNF−/−), we induced downregulation of TNF-α in M/Ms and further investigated its effect on SCI outcome. In TNF−/− mice, significant behavioral improvements were observed as early as 7 days after injury. We showed that TNF-α inhibition promote injury-mediated M/Ms polarization from pro-inflammatory to anti-inflammatory phenotype in vivo. Furthermore, accumulated iron in M/Ms after SCI increased the expression of TNF-α and the population of M/Ms to pro-inflammatory phenotype. Moreover, zinc supplement reduced the secondary damage caused by iron overload. In conclusion, we found that knock out of TNF-α promotes recovery of motor function after spinal cord injury in mice by inhibiting ferroptosis and promoting the shift of macrophages to an anti-inflammatory phenotype, indicating that there is great potential for this therapy to SCI.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2026
·
IF 5.2
Feichi Chen,Xinhuang Lv,Kun Xiang,Xiaoou Lin,Conghui Dai,Chuhua Wei,Yang Zhang,Jiaming Liu,Jing Li
Microglia-mediated neuroinflammation is a key driver of Alzheimer’s disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β (Aβ) burden, Tau protein phosphorylation, microglial activation and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, Aβ deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for JAK2 at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/STAT3 phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.
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DOI
PubMed
高影响因子
Annals of Translational Medicine
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2022
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IF 3.616
Shi-Ji Deng,Jian-Wei Ge,Sheng-Nan Xia,Xin-Xin Zou,Xin-Yu Bao,Yue Gu,Yun Xu,Hai-Lan Meng
Background Neuroinflammation, which is mainly mediated by excessive microglia activation, plays a major role in ischemic stroke. Overactivated microglia secrete numerous inflammatory cytokines, causing excessive inflammatory responses and ultimately exacerbating ischemic brain injury. Hence, compounds that attenuate neuroinflammation could become promising drug candidates for ischemic stroke. Fraxetin has an anti-inflammatory effect in many inflammatory diseases. However, whether it possesses an anti-inflammatory capacity in microglia-mediated neuroinflammation after ischemic brain injury is unknown. Our study aimed to investigate the suppression effect of fraxetin on neuroinflammation in lipopolysaccharide (LPS)-activated microglia and establish whether fraxetin could alleviate ischemic brain injury in a rodent model of ischemic stroke. Methods For the in vitro experiment, primary microglia were obtained from 1-day-old C57/BL6J mice. The cells were activated with LPS and treated with fraxetin at a non-cytotoxic concentration. Real-time PCR, enzyme-linked immunosorbent assays, and immunofluorescence staining were used to evaluate the anti-inflammatory effects of fraxetin. The potential molecular mechanisms were explored and verified through RNA-sequencing analysis, western blotting and real-time PCR. For the in vivo experiment, focal ischemia was induced by middle cerebral artery occlusion (MCAO) in 8-week-old male C57/BL6J mice. Fraxetin (5 mg/kg) or an equal volume of saline was injected into mice intraperitoneally after MCAO, and 2% 2,3,5-triphenyltetrazolium chloride staining was applied to measure infarct volume. Behavioral tests were conducted to measure neurological deficits in the mice. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the expression of inflammatory cytokines and microglia activation in the ischemic penumbra. Results Fraxetin effectively inhibited the expression of proinflammatory cytokines including inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1 beta, and interleukin-6 in LPS-activated microglia. Fraxetin also suppressed the PI3K/Akt/NF-κB signaling pathway in activated microglia, which contributed to its anti-inflammatory effects. Furthermore, the administration of fraxetin attenuated ischemic brain injury and behavioral deficits after stroke. Finally, fraxetin was found to attenuate the activation of microglia both in vitro and in vivo . Conclusions Our results suggest that fraxetin has a suppression effect on microglia-mediated neuroinflammation, and this effect is associated with the PI3K/Akt/NF-κB signaling pathway. Fraxetin may therefore have potential neuroprotective properties for ischemic stroke.
研究领域:
神经科学
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药理学
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炎症
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中风
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DOI
PubMed
高影响因子
STAR Protocols
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2021
·
IF 0
Zhen Xu,Yanxia Rao,Bo Peng
Summary Microglia are important immune cells in the central nervous system. Replacement of mutated microglia by wild-type cells through microglia replacement by bone marrow transplantation can correct gene deficiencies. However, the limited availability of bone marrow cells may restrict its potential of becoming a widely used clinical treatment. Here, we introduce a potentially clinical-feasible strategy achieving efficient microglia replacement by peripheral blood cells in mice, boosting the donor cell availability. We named it microglia replacement by peripheral blood (Mr PB). For complete details on the use and execution of this protocol, please refer to Xu et al. (2020) . The original abbreviation of this microglia replacement strategy is mrPB. We hereby change the name to Mr PB.
研究领域:
神经科学
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免疫学
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再生医学
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DOI
PubMed
BRAIN BEHAVIOR AND IMMUNITY
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2026
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IF 7.5
Tingyi Zhou,Yi Yue,Juncai Leng,Yiming Jiang,Han Liu,Shiqi Zhang,Zhengchao Yang,Wei Zhao,Li Li
Lactobacillus plantarum enhances cognition in both normal and antibiotic-treated mice. • Microbial modulation elevates fecal acetate and reshapes brain immune homeostasis • Acetate supplementation alone improves cognition and restores microglial homeostasis. • Acetate enhances microglial homeostasis by reducing mitochondrial oxidative stress. • Acetate activates ACSS2-dependent acetyl-CoA production to reduce microglial inflammation. Gut microbiota profoundly influences cognition through immune and metabolic pathways, but how specific strains contribute to these processes remain unclear. Here, we show that supplementation with Lactobacillus plantarum C067 enhanced spatial and fear-associated memory, while restoring hippocampal cytokine expression and microglial morphology in both healthy and antibiotic-treated mice. L. plantarum also reshaped microbial composition and elevated short-chain fatty acids, particularly acetate. Acetate supplementation replicated the cognitive benefits and restored microglial homeostasis. Mechanistically, acetate exerted anti-inflammatory effects via acetyl-CoA synthetase 2 (ACSS2)–dependent acetyl-CoA production in microglia, reducing mitochondrial oxidative stress and cytokine release. Together, these findings identify an ACSS2-mediated microbe–metabolite–microglia axis that underlies the cognitive benefits of L. plantarum , providing a mechanistic framework for probiotic- and metabolite-based interventions against cognitive decline. Download: Download high-res image (148KB) Download: Download full-size image
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DOI
PubMed
高影响因子
Cell Reports
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2020
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IF 8.109
Zhen Xu,Yanxia Rao,Yubin Huang,Tian Zhou,Rui Feng,Shanshan Xiong,Ti-Fei Yuan,Shan Qin,Yijie Lu,Xin Zhou,Xiaoyu Li,Bo Qin,Ying Mao,Bo Peng
Summary Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB), and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.
研究领域:
神经科学
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免疫学
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细胞治疗
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DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
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2025
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IF 4.9
Lushan Xu,Chenggang Li,ChenChen Zhao,Zibu Wang,Zhi Zhang,Xin Shu,Xiang Cao,Shengnan Xia,Xinyu Bao,Pengfei Shao,Yun Xu
Microglia, the resident immune cells in the central nervous system (CNS), rapidly transition from a resting to an active state in the acute phase of ischemic brain injury. This active state mediates a pro-inflammatory response that can exacerbate the injury. Targeting the pro-inflammatory response of microglia in the semi-dark band during this acute phase may effectively reduce brain injury. Shionone (SH), an active ingredient extracted from the dried roots and rhizomes of the genus Aster (Asteraceae), has been reported to regulate the inflammatory response of macrophages in sepsis-induced acute lung injury. However, its function in post-stroke neuroinflammation, particularly microglia-mediated neuroinflammation, remains uninvestigated. This study found that SH significantly inhibited lipopolysaccharide (LPS)-induced elevation of inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), in microglia in vitro . Furthermore, the results demonstrated that SH alleviated infarct volume and improved behavioral performance in middle cerebral artery occlusion (MCAO) mice, which may be attributed to the inhibition of the microglial inflammatory response induced by SH treatment. Mechanistically, SH potently inhibited the phosphorylation of serine-threonine protein kinase B (AKT), mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 (STAT3). These findings suggest that SH may be a potential therapeutic agent for relieving ischemic stroke (IS) by alleviating microglia-associated neuroinflammation.
研究领域:
神经科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2024
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IF 3.5
Chenchen Zhao,Liang Sun,Yuxin Zhang,Xin Shu,Yujie Hu,Duo Chen,Zhi Zhang,Shengnan Xia,Haiyan Yang,Xinyu Bao,Jingwei Li,Yun Xu
Background Microglia-mediated inflammation is a critical factor in the progression of ischemic stroke. Consequently, mitigating excessive microglial activation represents a potential therapeutic strategy for ischemic injury. Thymol, a monophenol derived from plant essential oils, exhibits diverse beneficial biological activities, including anti-inflammatory and antioxidant properties, with demonstrated protective effects in various disease models. However, its specific effects on ischemic stroke and microglial inflammation remain unexplored. Methods Rodent transient middle cerebral artery occlusion (tMCAO) model was established to simulate ischemic stroke. TTC staining, modified neurological function score (mNSS), and behavioral tests were used to assess the severity of neurological damage. Then immunofluorescence staining and cytoskeleton analysis were used to determine activation of microglia. Lipopolysaccharide (LPS) was utilized to induce the inflammatory response of primary microglia in vitro . Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to exam the expression of inflammatory cytokines. And western blot was used to investigate the mechanism of the anti-inflammatory effect of thymol. Results In this study, we found that thymol treatment could ameliorate post-stroke neurological impairment and reduce infarct volume by mitigating microglial activation and pro-inflammatory response (IL-1β, IL-6, and TNF-α). Mechanically, thymol could inhibit the phosphorylation of phosphatidylinositol-3-kinase (PI3K), sink serine/threonine kinase (Akt), and mammalian target of rapamycin (mTOR), thereby suppressing the activation of nuclear factor-κB (NF-κB). Conclusions Our study demonstrated that thymol could reduce the microglial inflammation by targeting PI3K/Akt/mTOR/NF-κB signaling pathway, ultimately alleviating ischemic brain injury. These findings suggest that thymol is a promising candidate as a neuroprotective agent against ischemic stroke.
研究领域:
神经科学
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药理学
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炎症
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中风
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2024
·Vol. 19
·期 1
·e0297031
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IF 2.9
Qingting Yu,Yanzhuo Yang,Ting Xu,Yinsheng Cai,Zuisu Yang,Falei Yuan
Although palmitoleic acid (POA) is a lipokine with beneficial effects on obesity and is produced as a byproduct from the manufacture of prescription omega-3 fatty acids, its role in nervous system inflammation is still unknown. This study aims to examine the mechanisms and protective effects of POA against palmitic acid (PA)-induced microglial death. PA-induced microglial death was used as a model for POA intervention. Various inhibitors were employed to suppress potential routes of PA entry into the cell. Immunofluorescence staining and Western blotting were conducted to elucidate the protective pathways involved. The results suggest POA has the potential to eliminate PA-induced lactate dehydrogenase (LDH) release, which decreases the overall number of propidium iodide (PI)-positive cells compared with control. Moreover, POA has the potential to significantly increase lipid droplets (LDs) in the cytoplasm, without causing any lysosomal damage. POA inhibited both canonical and non-canonical gasdermin D (GSDMD)-mediated pyroptosis and gasdermin E (GSDME)-mediated pyroptosis, which PA typically induces. Additionally, POA inhibited the endoplasmic reticulum (ER) stress and apoptosis-related proteins induced by PA. Based on the findings, POA can exert a protective effect on microglial death induced by PA via pathways related to pyroptosis, apoptosis, ER stress, and LDs.
研究领域:
神经科学
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细胞生物学
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炎症
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脂质代谢
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产品关联
DOI
PubMed
高影响因子
NEUROTOXICOLOGY
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2026
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IF 3.8
Xianzheng Sang,Yichao Ye,Chengzi Yang,Xiaoxiang Hou,Yangu Guo,Hantong Shi,Chunhui Wang,Wen Chen,Danfeng Zhang,Lijun Hou
Background Hydroxymethylglutaryl-coenzyme A (HMGCR) inhibitors, known as statins, as first-line lipid-lowering therapies for cardiovascular diseases. Despite their widespread use, concerns persist regarding potential cognitive adverse effects, although a definitive causal relationship remains elusive. Methods To investigate the underlying mechanisms, this study integrated network toxicology, in vitro experiments, public RNA-sequencing data, computational simulations, and Mendelian randomization analysis. Rosuvastatin was chosen as a representative statin, with human as the focused species and the HMC3 human microglial cell line as the in vitro model. Results Network toxicology initially identified microglia as a critically involved cell type. A multi-method approach then demonstrated that rosuvastatin alters microglial functions—including cell viability, migration, phagocytosis, and inflammatory responses—potentially by the JAK-STAT signaling pathway. Conclusions These findings suggest that rosuvastatin-induced disruption of microglial function may contribute to cognitive impairment. Our study elucidates potential pathways for this adverse effect and provides novel insights for developing preventive and therapeutic strategies.
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DOI
PubMed
高影响因子
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