Neural Regeneration Research
·
2023
·Vol. 18
·期 10
·2291
·
IF 6.1
Zhang Zhong-Xia,Zhou Yong-Jie,Gu Ping,Zhao Wei,Chen Hong-Xu,Wu Ruo-Yu,Zhou Lu-Yang,Cui Qing-Zhuo,Sun Shao-Kang,Zhang Lin-Qi,Zhang Ke,Xu Hong-Jun,Chai Xi-Qing,An Sheng-Jun
Microglia -mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease . In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia -mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine -induced rat model of Parkinson’s disease . We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis -associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease , and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.
研究领域:
神经科学
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干细胞生物学
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炎症
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分子生物学
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神经退行性疾病
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DOI
PubMed
高影响因子
Brain Sciences
·
2023
·Vol. 13
·期 4
·541
·
IF 3.3
Min Zhou,Fang Pang,Dongmei Liao,Xinlu He,Yunhao Yang,Chenglin Tang
Background: Multiple studies have suggested that paralgesia (hyperalgesia and cutaneous allodynia) in migraine reflects the activation and sensitisation of the trigeminovascular system (TGVS). In particular, it reflects the second-order and higher nerve centre sensitisation, which is caused and maintained by neuroinflammation. Microglia activation leads to the release of proinflammatory cytokines involved in inflammatory responses. Accumulating evidence indicates that electroacupuncture (EA) is effective in ameliorating paralgesia, but the underlying mechanisms of EA in migraine attacks caused by microglia and microglia-mediated inflammatory responses are still unclear. The purpose of this study was to explore whether EA could ameliorate the dysregulation of pain sensation by suppressing microglial activation and the resulting neuroinflammatory response, and to evaluate whether this response was regulated by Toll-like receptor 4 (TLR4)/nuclear factor-kappa B(NF-κB) in the trigeminal nucleus caudalis (TNC) in a rat model of migraine. Methods: Repeated Inflammatory Soup (IS) was infused into the dura for seven sessions to establish a recurrent migraine-like rat model, and EA treatment was administered at Fengchi (GB20) and Yanglingquan (GB34) after daily IS infusion. Facial mechanical withdrawal thresholds were measured to evaluate the change in pain perception, and plasma samples and the TNC tissues of rats were collected to examine the changes in calcitonin gene-related peptide (CGRP), the Ibal-1-labelled microglial activation, and the resulting inflammatory response, including interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and their regulatory molecules TLR4/NF-κB, via enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and Western blot analysis. Results: Repeated IS injections into the dura induced facial mechanical paralgesia, which is the manifestation of migraine attacks, and increased the expression of CGRP, Ibal-1, microglial mediated inflammatory cytokines (IL-1β, TNF-α, IL-6), and regulatory molecules TLR4/NF-κB. EA at GB20/34 significantly attenuated repetitive IS-induced pain hypersensitivity. This effect was consistent with decreased levels of CGRP and inflammatory cytokines in the plasma and the TNC via the inhibition of microglia activation, and this response may be regulated by TLR4/NF-κB. Conclusions: EA ameliorated paralgesia in repetitive IS-induced migraine-like rats, which was mainly mediated by a reduction in microglial activation and microglial-mediated inflammatory responses that could be regulated by TLR4/NF-κB.Keywords:migraine;electroacupuncture;paralgesia;microglia;inflammatory response
研究领域:
神经科学
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疼痛管理
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针灸
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炎症
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DOI
PubMed
高影响因子
Small Structures
·
2025
·
IF 11.3
Xuan Wang,Zhiqi Hu,Youbo Zhao,Yang Fei,Menghuan Li,Min Su,Zhong Luo,Rong Hu
Traumatic brain injuries (TBIs) are often accompanied by severe neuroinflammation that markedly elevates the risk of neurodegeneration and cognitive impairment. Current insights reveal that the excessive accumulation of inflammatory microglial cells drives TBI-associated inflammatory responses. However, inhibiting neuroinflammation through reprograming microglial cells is challenging as the blood-brain barrier (BBB) severely impedes delivery of anti-inflammatory drugs. To address these challenges, a nanointegrative TBI treatment strategy is reported that can reprogram inflammatory microglial cells into a reparative phenotype for abolishing post-TBI neurodegeneration. Herein, methylprednisolone and Tempol are loaded into transactivator of transcription (TAT) peptide-modified PEGylated liposomes to afford a liposomal microglial reprogramming platform (LMRP). After intravenous administration, the liposomes efficiently cross the BBB and accumulate in TBI sites to release the therapeutic payload, which cooperatively activates multiple anti-inflammatory signaling pathways and scavenged reactive oxygen species for repolarizing inflammatory microglial cells to reparative phenotypes in situ, leading to effective amelioration of the neurodegeneration symptoms. In vivo analysis shows that LMRP treatment robustly recovers the neurological functions of TBI rat models with no obvious side effects, offering an approach for TBI treatment with clinical promise.
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高影响因子
MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·518
·
IF 5.5
Ma Ya-nan,Wang Zijie,Liang Yuchang,Tan Guoao,Hu Xiqi,Xia Ying
This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer’s disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ 1–42 . Immunofluorescence and biochemical assays were employed to assess the impact of OM-MSCs-Exo and its secreted protein FGFR1 on microglial polarization. Protein–protein interactions and immunoprecipitation were used to identify the target proteins of FGFR1 in microglial cells. Additionally, the effects of OM-MSCs-Exo-induced microglial polarization on neuronal inflammation and cognitive function in mice were evaluated. OM-MSCs-Exo were successfully isolated and purified. FGFR1 was significantly upregulated in OM-MSCs-Exo compared to OM-MSCs. Aβ 1–42 induced M1 polarization and suppressed M2 polarization of microglia, which was reversed by OM-MSCs-Exo. FGFR1 overexpression in OM-MSCs-Exo further enhanced M2 polarization in microglial cells. Phospholipase C gamma 1 (PLCγ1) was identified as the target of FGFR1, and knocking down PLCγ1 reversed the effects of FGFR1-overexpressing OM-MSCs-Exo. OM-MSCs-Exo alleviated cognitive decline and neuroinflammation in AD mice, with FGFR1 overexpression further enhancing these effects. OM-MSCs-Exo promote M2 polarization of microglia in AD mice through the FGFR1/PLCγ1 pathway, alleviating neuronal inflammation and cognitive dysfunction.
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
·
IF 2.5
Chunhui Shan,Qi Bing,Gang Qiu,Hui Zhang,Yingmin Chen
Galectin-3 disrupts microglial P2X7R/MerTK balance after stroke • ERK/ROS/BRD4 axis mediates Gal-3-induced P2X7R upregulation • Gal-3 promotes cGAS-STING inflammation and apoptosis via HIF1α/P2X7R • TD-139 restores P2X7R/MerTK balance and reduces cerebral infarction • Targeting Gal-3 improves motor, cognitive, and grip strength in MCAO rats This study demonstrates that Galectin-3 (Gal3) exacerbates cerebral infarction progression by modulating the P2X7R/MerTK equilibrium in microglia via the ERK/BRD4/HIF1α signaling axis, with reactive oxygen species (ROS) serving as a potential intermediate mediator linking ERK activation to BRD4 upregulation based on prior literature evidence. Single-cell transcriptomic analysis revealed that ischemia drives microglia from a homeostatic state to an activated disease phenotype, and virtual Gal3 knockout predicted corresponding downregulation of BRD4. Using a rat model of cerebral infarction, we found that the Gal3 inhibitor TD-139 significantly reduced infarct volume, promoted M2 polarization of microglia, and improved neurological function in behavioral assays. Mechanistic investigations in BV2 microglia revealed that Gal3 activates ERK1/2, leading to ROS accumulation, BRD4 upregulation, and subsequent HIF1α-mediated P2X7R transcription, while suppressing KLF4 and MerTK. This cascade increased P2X7R expression and suppressed MerTK/KLF4 expression, generating a pro-inflammatory and pro-apoptotic microenvironment. Notably, pharmacological inhibition of Gal3 enhanced efferocytosis and reduced apoptosis, whereas P2X7R blockade exerted similar neuroprotective effects. These findings identify Gal3 as a key regulator of microglial polarization via the experimentally validated ERK/BRD4/HIF1α-P2X7R signaling cascade, where P2X7R activation concurrently triggers cGAS-STING-mediated pro-inflammatory/pyroptotic responses and suppresses the KLF4/MerTK efferocytosis axis. Targeting this regulatory network could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Targeting this pathway could provide therapeutic benefits in cerebral infarction by shifting microglia toward the neuroprotective M2 phenotype and facilitating inflammation resolution. Data were analysed using one-way ANOVA followed by Tukey's post-hoc test for multiple comparisons; P < 0.05 was considered statistically significant.
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高影响因子
ACS Nano
·
2025
·
IF 16
Qing Zheng,Yifan Gao,Mengxiao Han,Yusong Wang,Hanghang Liu,Guozhi Cao,Tingting Wang,Hao Zhang,Zhen Li
Microglia usually phagocytose excessive α-synuclein (α-syn) aggregates and turn into diseased analogues in Parkinson’s disease (PD), which can present α-syn-associated antigens, secrete cytokines and chemokines to recruit peripheral immune cells, and form strong immune crosstalk to aggravate PD progression. Hence, targeting the diseased microglia and inhibiting their immune crosstalk emerge as promising strategies for PD therapy. Herein, we reprogram the diseased microglia to efficiently degrade α-syn aggregates and neutralize neuroinflammatory factors to reduce the detrimental immune crosstalk and enhance therapeutic efficacy using rationally designed core–shell IHM nanoparticles, which consist of a ligustilide-functionalized Cu2-xSe nanoparticle (CSL NP) core and a hybrid cell membrane shell. The CSL NPs can redress the diseased microglia to reduce over-presented antigens by dual roles of reducing microglial RAGE-mediated phagocytosis of α-syn aggregates and increasing the microglial mature cathepsin D (m-CTSD) to efficiently degrade α-syn aggregates. The hybrid cell membrane shell is formed by a MES23.5 cell membrane (MCM) and IFN-γ-treated RAW264.7 cell membrane (IRCM). It can not only target diseased microglia by the specific interactions between VCAM-1 on the MCM and α4β1 integrin on the microglial membrane but also absorb and reduce the secretion of neuroinflammatory factors by diseased microglia through upregulated neuroinflammatory cytokine receptors such as IL1R1, TNFR1, and CCR2 on the surface of IRCM. The biomimetic core–shell IHM nanoparticles can be effectively delivered into the brain via meningeal lymphatic vessels to modulate the diseased microglia for boosting PD therapy. Our study demonstrates the promise of targeting diseased microglia to reduce their immune crosstalk in the treatment of PD and other neurodegenerative diseases.
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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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Xu Yao,Liu Yongsheng,Wu Yan,Sun Jingshan,Lu Xiaocheng,Dai Kun,Zhang Yiting,Luo Chengliang,Zhang Jian
Early brain injury caused by subarachnoid hemorrhage (SAH) is associated with inflammatory response and ferroptosis. Curcumin alleviates neuroinflammation and oxidative stress by as yet unknown neuroprotective mechanisms. The objective of this study was to investigate the impact of curcumin on neuronal ferroptosis and microglia-induced neuroinflammation following SAH. By examining Nrf2/HO-1 expression levels and ferroptosis biomarkers expression both in vitro and in vivo, it was demonstrated that curcumin effectively suppressed ferroptosis in neurons after SAH through modulation of the Nrf2/HO-1 signaling pathway. Furthermore, by analyzing the expression levels of Nrf2, HO-1, p-p65, and inflammation-related genes, it was confirmed that curcumin could prevent the upregulation of pro-inflammatory factors following SAH by regulating the Nrf2/HO-1/NF-κB signaling pathway in microglia. The ability of curcumin to reduce neuronal damage and cerebral edemas after SAH in mice was validated using TUNEL staining, Nissl staining, and measurement of brain tissue water content. Additionally, through implementation of the modified Garcia test, open field test, and Y-maze test, it was established that curcumin ameliorated neurobehavioral impairments in mice post-SAH. Taken together, these data suggest that curcumin may offer a promising therapeutic approach for improving outcomes following SAH by concurrently attenuating neuronal ferroptosis and reducing neuroinflammation. Graphical Abstract
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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神经病学
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 5
·1-12
·
IF 3.8
Huang Manqian,Tang Meiling,Liu Lu
Epilepsy is a chronic neurological disorder featured by abnormal neural discharges that can lead to cognitive impairment. Salidroside (Sal), a biologically active component, protects neurons against various insults. The current study aims to explore the therapeutic potential of Sal in epilepsy and elucidate the mechanisms underlying its effects. We established a rat model of status epilepticus (SE) using pentylenetetrazol-kindling. SE rats were treated with Sal. Assessment of seizure latency and epileptic stage scores were performed. Cognitive function of rats was evaluated using a novel object recognition test and a Morris water maze test. Neuronal damage and hippocampal pathology were examined, alongside microglial and astrocyte activation, complement C3-C3a receptor (C3-C3aR) pathway involvement, and inflammatory factor levels. Sal prolonged seizure latency, decreased epilepsy stage scores, and improved cognitive performance compared to untreated SE rats. Furthermore, Sal suppressed the activation of C3-C3ar, microglia, and astrocytes, while decreasing the levels of inflammatory factors, which ameliorated hippocampal damage and neuronal loss. Sal may attenuate epilepsy and cognitive dysfunction by downregulating complement C3-C3aR pathway-mediated activation of microglia and astrocytes.
研究领域:
神经病学
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药理学
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神经药理学
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免疫学
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分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
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2025
·
IF 1.7
Sun Jingchi,Zheng Zhousong
Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0–1 mg/mL) and quercetin (0–0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H 2 O 2 -induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H 2 O 2 -induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H 2 O 2 -induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.
研究领域:
神经生物学
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药理学
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分子医学
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老年医学
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神经退行性疾病
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天然药物化学
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细胞信号转导
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PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Wei Shen,Xuzhong Zhang,Min Tang,Wei Chen,Ying Wang,Haoquan Zhou
Septic brain injury is a serious disease of the central nervous system that involves inflammation. Kelch repeat and BTB domain containing 7 (KBTBD7), an E3 ubiquitin ligase, is demonstrated to facilitate the pathological changes of various diseases, but its impact on septic brain injury is unclear. In this study, a rat model of septic brain injury was induced by cecal ligation and puncture (CLP). The neurobehavioral score and survival rate of CLP group were worse than those of sham group. In addition, CLP was found to evoke microglia activation, increase inflammation, induce the activation of NLRP3 inflammasome and NF-κB signaling pathway, and upregulate KBTBD7 expression. Immunofluorescence revealed strong positive KBTBD7 staining in CLP rat microglia. Furthermore, primary microglia were exposed to lipopolysaccharide (LPS) to explore the role and mechanism of KBTBD7. The results showed that KBTBD7 expression was increased in LPS-treated microglia. Knockdown of KBTBD7 markedly inhibited LPS-induced proinflammatory cytokine release, as well as the activation of NLRP3 inflammasome and NF-κB signaling pathway. The downstream molecular mechanism of KBTBD7 was then mined. Notably, co-immunoprecipitation (co-IP) results confirmed that KBTBD7 was a novel interacting protein of KLF transcription factor 15 (KLF15) and acted as an E3 ubiquitin ligase that catalyzed the ubiquitination degradation of KLF15 through the ubiquitin-proteasome system. Moreover, recovery experiment data suggested that KLF15 knockdown abolished the anti-inflammatory role of KBTBD7 knockdown in microglia, implying that KLF15 influenced the function of KBTBD7. Taken together, our results reveal a novel KBTBD7-KLF15 signal transduction pathway involved in septic brain injury and provide a potential therapeutic strategy for its treatment.
研究领域:
神经科学
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免疫学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2025
·
IF 12.9
Pengcheng Zhang,Yaxin Wang,Yigang Xu,Xueping Li,Xuya Yu,Yi Li,Dunwan Zhu,Fang Luo,Wen Li,Xu Jin
The dysregulation of the microglia-neuron axis plays a pivotal role in the pathogenesis of cognitive dysfunction following traumatic brain injury (TBI). The C–C chemokine receptor 5 (CCR5), markedly upregulated on both microglia and neurons post-injury, serves as a crucial mediator in the neuroinflammatory response and consequent neurological deficits. However, the therapeutic application of CCR5 antagonists in TBI is impeded by the delivery barriers presented by the blood-brain barrier (BBB) and their limited neuron-targeting efficacy. In this study, we introduce a novel nasal-to-brain delivery nanoplatform designed to facilitate the efficient brain delivery of DAPTA, a peptide antagonist of CCR5, aiming to inhibit CCR5 signaling and improving cognitive function following TBI. Biocompatible chitosan nanocarriers grafted with cell-penetrating peptide (TAT) and neuron-binding lactoferrin (Lf) were initially fabricated, demonstrating substantial DAPTA loading capacity, active mucosal and neural transportation, and enhanced neuron-targeting capabilities. The dual-engineered nanodrugs (DA@LT NPs) effectively penetrated the trigeminal and olfactory nerves, significantly enhancing the transport of DAPTA into the brain following intranasal delivery. In a TBI-induced mouse model, DA@LT NPs markedly alleviated the neuroinflammatory response, promoted M2 microglia polarization, protected neurons from pyroptosis, and improved both motor and cognitive functions of animals. The non-invasive intranasal delivery of the therapeutic CCR5 peptide antagonist using these mucus-penetrating and neuron-targeting nanoformulations presents a promising intervention for ameliorating neurological inflammation and cognitive impairments associated with TBI.
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PubMed
高影响因子
Bioactive Materials
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2022
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IF 16.874
Lulu Jin,Zhixin Zhu,Liangjie Hong,Zhefeng Qian,Fang Wang,Zhengwei Mao
Ischemic stroke is an acute and serious cerebral vascular disease, which greatly affects people's health and brings huge economic burden to society. Microglia, as important innate immune components in central nervous system (CNS), are double-edged swords in the battle of nerve injury, considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes. High mobility group box 1 (HMGB1) is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia. 18β-glycyrrhetinic acid (GA) is an effective intracellular inhibitor of HMGB1, but of poor water solubility and dose-dependent toxicity. To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy, herein, we designed reactive oxygen species (ROS) responsive polymer-drug conjugate nanoparticles (DGA) to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1. DGA presented excellent therapeutic efficacy in stroke mice, as evidenced by the reduction of infarct volume, recovery of motor function, suppressed of M1 microglia activation and enhanced M2 activation, and induction of neurogenesis. Altogether, our work demonstrates a close association between HMGB1 and microglia polarization, suggesting potential strategies for coping with inflammatory microglia-related diseases.
研究领域:
神经科学
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药学
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纳米技术
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炎症生物学
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DOI
PubMed
高影响因子
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