Communications Biology
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2025
·Vol. 8
·期 1
·1-16
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IF 5.1
Bie Pengfei,Su Dongpo,Gao Yang,Wu Liang,Niu Zhanfeng,Zhao Yanbin,He He,Jiang Zhanfeng,Zeng Zhong,Zhang Yaolin,Fan Heng,Xia Hechun
Microglia play significant roles in spinal cord injury (SCI) progression. Previous studies have suggested that ferroptosis plays a crucial role in exacerbating neuronal death following SCI; however, the role of microglial ferroptosis in SCI and the underlying mechanisms remain elusive. Here, we elucidate that lipid droplets accumulate in microglia to facilitate microglial ferroptosis after SCI. Notably, microglial ferroptosis peaks at 3 days post-injury, after which it decreases. Microglial Period 2 (Per2) expression is elevated after SCI in vivo; this change is highly synchronized with the changes in microglial ferroptosis. Microglia-specific Per2 knockout promoted neurological function recovery by suppressing microglial ferroptosis. In vitro, Per2 overexpression and deficiency amplified and mitigated microglial ferroptosis, respectively. RNA-seq indicated that Gpx4 was downregulated by Per2. Coimmunoprecipitation demonstrated that Per2 directly interacted with PPARα. Overall, our results indicate that Per2 determines the susceptibility of microglial ferroptosis via the PPARα-Gpx4 axis after SCI.
研究领域:
神经科学
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细胞生物学
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分子生物学
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免疫学
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CNS Neuroscience & Therapeutics
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2025
·Vol. 31
·期 7
·e70502
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IF 5
Xin Shu,Xinxin Zou,Jingxuan Zhang,Xu Fang,Xinyu Wang,Hui Wu,Xuan He,Dujuan Sha
Background Neuroinflammation is an important factor in ischemic stroke. Dehydrocostus lactone (DHC) plays an anti-inflammatory role in certain diseases. However, the role of DHC in neuroinflammation after ischemic stroke remains unclear. Methods DHC was administered to lipopolysaccharide (LPS)-treated BV2 cells and a middle cerebral artery occlusion (MCAO) model to detect the levels of inflammatory factors using quantitative real-time PCR, western blotting, and behavioral tests. Morphological changes in microglia were observed using immunofluorescence. The Swiss Target Prediction database was used to predict the target of DHC. Finally, a specific inhibitor of the target protein was used to investigate its potential synergistic role in neuroinflammation, both with and without being combined with DHC. Results The expression of inflammation-related factors both in vivo and in vitro was improved by DHC, and the neurological deficits in mice after MCAO were improved in the DHC administration group. In addition, the Swiss Target Prediction showed that CYP2A6 was a target of DHC. Specifically, the combination of DHC with the CYP2A6 inhibitor showed that DHC exerts anti-inflammatory effects in a CYP2A6-dependent manner. Conclusion Mechanistically, DHC inhibited neuroinflammation by binding to the target CYP2A6. Our study suggests that DHC is a promising new strategy for treating ischemic stroke.
研究领域:
神经生物学
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药理学
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免疫学
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生物化学
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高影响因子
ADVANCED MATERIALS
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2025
·
IF 26.8
Zhixin Zhu,Lulu Jin,Qiaoxuan Wang,Haifei Shi,Ke Cheng,Zhengwei Mao
There is a desperate need for precise nanomedications to treat ischemic cerebral injury. Yet, the drawbacks of poor delivery efficiency and off-target toxicity in pathologic parenchyma for traditional antioxidants against ischemic stroke result in inadequate brain accumulation. M13 bacteriophages are highly phagocytosed by M1-polarized microglia and can be carried toward the neuroinflammatory sites. Here, a bio-active, inhalable, Ce 0.9 Zr 0.1 O 2 -backpacked-M13 phage (abbreviated as CZM) is developed and demonstrates how M13 bacteriophages are taken up by different phenotypes’ microglia. With the M1 microglia's proliferating and migrating, CZM can be extensively and specifically delivered to the site of the ischemic core and penumbra, where the surviving nerve cells need to be shielded from secondary oxidative stress and inflammatory cascade initiated by reactive oxygen species (ROS). With non-invasive administration, CZM effectively alleviates oxidative damage and apoptosis of neurons by eliminating ROS generated by hyperactive M1-polarized microglia. Here, a secure and effective strategy for the targeted therapy of neuroinflammatory maladies is offered by this research.
研究领域:
神经科学
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纳米医学
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药理学
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PubMed
高影响因子
Bioactive Materials
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2025
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IF 20.3
Yinhe Han,Lina Guo,Mingqi Wang,Zhen Cao,Xu Zheng,Xinyu Wang,Lingling Jin,Xiaoqing Wei,Xiuli Wang,Jie Zhao
Interactions among neurons, microglia, and endothelial cells (ECs) —the principal components of the neurovascular unit (NVU)—are vital for maintaining central nervous system (CNS) homeostasis and are implicated in numerous neurological disorders. However, mechanistic insights into their crosstalk remain limited due to the lack of physiologically relevant in vitro models. In this study, we present an improved 3D vascularized tri-culture model that integrates human-induced neural stem cells (hiNSCs), human vascular organoids (hVOs), and microglia within a geometrically engineered silk fibroin scaffold. This platform effectively recapitulates critical features of the native CNS microenvironment, including spatial neurovascular patterning and cell-type-specific interactions. Within this model, hVOs significantly promoted neuronal differentiation of hiNSCs, resulting in extended axonal networks and improved neurovascular alignment. Microglial effects were found to be phenotype-dependent: both resting (M0) and pro-inflammatory (M1) microglia inhibited hiNSCs differentiation and vascular development, with M1 cells exerting the strongest suppressive influence. In contrast, anti-inflammatory (M2) microglia displayed the least inhibitory effect and even modestly supported neurovascular maturation. Mechanistic studies revealed that M2 microglia cooperate with hVOs via the stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis to promote neuronal differentiation. To our knowledge, this represents the first demonstration of SDF-1/CXCR4-mediated immune-neurovascular interaction within a human tri-culture system. Thereafter, this 3D vascularized co-culture model provides a physiologically relevant in vitro platform to investigate neuroimmune and neurovascular interactions. It holds broad potential for mechanistic studies in neurodevelopment and neurodegeneration, drug evaluation, and the development of regenerative therapies.
研究领域:
神经科学
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生物工程
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细胞生物学
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免疫学
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发育生物学
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再生医学
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药理学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
·
IF 6.2
Jia-Gen Cui,Hao Zhang,Ming-Shan Chen,Jia-Xin Wang,Xue-Nan Li,Jin-Long Li
Lycopene (LYC), a natural antioxidant compound abundant in tomatoes, has established neuroprotective roles due to its antioxidant and anti-inflammatory properties. Di (2-ethylhexyl) phthalate (DEHP), a common plasticizer, is known to exert neurotoxic effects. However, the mechanisms of DEHP-induced neurotoxicity remain unclear. Furthermore, effective preventive strategies against this neurotoxicity are still lacking. This study, employing in vitro (BV2 cells) and in vivo (ICR mouse) models, demonstrates that LYC prevents DEHP-induced cerebellar damage by suppressing the triggering of dose-dependent microglial ferroptosis and neuroinflammation. Mechanistically, LYC inhibited the phosphatidylethanolamine-binding protein 1 (PEBP1)/arachidonate 15-lipoxygenase (ALOX15) axis (supported by immunofluorescence and Western blot assays), leading to reduced reactive oxygen species by approximately 48% in the cerebellum, which ultimately prevented neuroinflammation. Our findings reveal that LYC prevents DEHP-induced neurotoxicity by inhibiting microglial ferroptosis via the PEBP1/ALOX15 axis. Furthermore, our findings highlight the clinical promise of LYC as a novel neuroprotective treatment against environmental toxicant-induced damage.
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MOLECULAR NEUROBIOLOGY
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2025
·Vol. 63
·期 1
·44
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IF 4.3
Xie Min,Cheng Yu,Yang Lizhen,Lin Zijin,Shen Hao,Zhou Xinhua,Liu Zheng,Xing Jieyu,Zhou Sigui,Chen Haiyun
Parkinson’s disease (PD) is the second most prevalent neurological disorder without a clear etiology and specific cure. Microglia-mediated neuroinflammation plays a pivotal role in the pathogenesis and progression of PD, which is influenced by various factors and involves multiple signaling pathways. CT-011, synthesized by combining nitrone-tetramethyl pyrazine (TMP) and caffeic acid through an ester bond, has shown neuroprotection against ischemic stroke and glutamate-induced neuronal damage in animal models. The purpose of this study is to explore the impact of CT-011 on PD-related neuroinflammation and its potential in treating PD. Results showed that CT-011 significantly inhibited lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines and mediators in BV2 microglial cells. CT-011 also effectively mitigated LPS-induced mitochondrial membrane potential (MMP) reduction, mitochondrial and intracellular reactive oxygen species (ROS) production. Meanwhile, CT-011's anti-inflammatory effect was related to its inhibition of the TLR4-mediated MyD88/NF-B and PI3K-mediated AKT/GSK3β pathways. More significantly, CT-011 repressed the NLRP3 inflammasome activation. Additionally, CT-011 protected primary neurons against microglial-mediated neurotoxicity in vitro , and ameliorated dopaminergic neuronal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice with a consistent anti-neuroinflammatory effect in vivo. These results demonstrate that CT-011 effectively inhibits microglia-mediated neuroinflammation and exerts neuroprotective effects on dopamine neurons, thus making it a promising therapeutic candidate for PD.
研究领域:
神经药理学
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神经退行性疾病
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分子神经科学
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炎症研究
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-14
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IF 10.2
Li Shiyi,Zhang Ru,Wang Anni,Li Yang,Zhang Miaomiao,Kim Jisu,Zhu Ying,Wang Qizheng,Zhang Yue,Wei Ying,Wang Jianxin
Cerebral ischemia/reperfusion (CI/R) injury is a clinical conundrum during the treatment of ischemic stroke. Cell-derived exosomes (CDE) were proved to be therapeutically effective for CI/R injury. However, production of CDE is time and effort consuming. Increasing studies reported that plants can also generate exosome-like nanoparticles (ELN) which are therapeutically effective and have higher yield compared with CDE. In this study, a commonly used Chinese herb Panax notoginseng (PN), whose active ingredients were well-documented in the treatment of CI/R injury, was chosen as a source of ELNs. It was found that Panax notoginseng derived exosome like nanoparticles (PDN) could enter the brain without modification and ameliorate cerebral infarct volume, improve behavior outcome and maintained the integrity of BBB. PDNs attenuated CI/R injury by altering the phenotype of microglia from “pro-inflammation” M1 type to “anti-inflammation” M2 type. Also, we found that lipids from PDNs were the major therapeutic effective component. As a mechanism of action, PDN was proved to exert therapeutic effect via activating pI3k/Akt pathway. Graphical Abstract
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Immunity & Ageing
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2023
·Vol. 20
·期 1
·1-17
·
IF 7.9
Han Hao,Zhao Yawei,Du Junda,Wang Sushan,Yang Xuehan,Li Weijie,Song Jiayi,Zhang Siwei,Zhang Ziyi,Tan Yongfei,Hatch Grant M.,Zhang Ming,Chen Li
Background Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory.Results Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype.Conclusion The elevated lactate acted as an “accelerator” of the endogenous “lactate timer” in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.
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Frontiers in Cellular Neuroscience
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2025
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IF 4
Hongxia Zhao,Lingge Huang,Jian Liu,Min Feng,Yeqian Liu,Hong Li,Shan Gong,Chunming Chen,Shuiqing Zeng,Weiqiong Ren
Hypertension-related Depression (HD) is a complex mental disorder that exerts a significant negative impact on patients’ quality of life. Previous studies have demonstrated that damages to vascular endothelial and hippocampus are the primary pathological features in HD rats. Under hypertensive conditions, inflammatory cytokines in peripheral blood vessels can induce central nervous system inflammation through penetration of a damaged blood-brain barrier, peripheral immune cells, and neural pathways, damaging the brain and triggering HD. Therefore, interactions between vascular endothelial cells, neurons, and glial cells are critical for the understanding of HD. However, in vivo animal models are often limited by the complexity of intrinsic systems, high inter-individual variability, and stringent ethical regulations. A reliable model that could be easily manipulated is needed for investigating the mechanisms involved in communication between vascular endothelial cells, neurons, and glial cells in HD. We therefore aimed to create a composite tri-culture model consisting of rat aortic endothelial cells (RAECs), neurons, and microglia to study HD. First, RAECs were stimulated with lipopolysaccharide to mimic endothelial injury under hypertensive conditions. Vascular endothelial function and inflammatory levels were assessed using fluorescent probes and enzyme-linked immunosorbent assays. RAECs treated with 1 μg/ml LPS for 24 h had reduced levels of nitric oxide, increased levels of endothelin-1 and inflammatory mediators. These findings are consistent with the endothelial dysfunction and inflammatory responses observed in spontaneously hypertensive rats, which suggests that the lipopolysaccharide-induced RAECs model effectively mimics key pathological features of hypertension-related endothelial injury. Subsequently, the supernatants from lipopolysaccharide-induced RAECs were combined with 200 μM corticosterone and transferred to neuron-microglia co-cultures to simulate damages to hippocampal neuron under HD conditions. To evaluate the features of cells, neuronal viability was measured by CCK-8 and live-dead assays. Nissl staining was used to assess neuronal Nissl bodies, while the levels of inflammatory factors and monoamine neurotransmitters in the culture supernatants were evaluated by enzyme-linked immunosorbent assays. Reactive oxygen species in neurons were visualized by a fluorescent probe, apoptosis was detected using TUNEL assays, and immunofluorescence was used to assess microglial phenotypes and the levels of TLR4 and NF-κB. It was found that neurons in the tri-culture model had reduced viability, higher levels of apoptosis, fewer Nissl bodies, increased inflammation, and reduced levels of monoamine neurotransmitters. Additionally, the number of M1 microglia was increased, along with elevated levels of TLR4 and NF-κB proteins. These findings were similar to damages of hippocampal neuron, abnormal levels of monoamine neurotransmitters, microglia polarization, and hippocampal inflammatory response observed in the HD rat model. In conclusion, our findings indicate that the tri-culture model can effectively simulate the pathological characteristics of HD, especially in vascular endothelial damage, neuroinflammation, monoamine neurotransmitters disorders. Therefore, the tri-culture model would provides a reliable and invaluable experimental tool for further research on the pathogenesis and treatment of HD.
研究领域:
神经科学
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病理学
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药理学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2019
·
IF 3.414
Qiburi Qiburi,Tsogzolmaa Ganbold,Qingming Bao,Man Da,Aoqier Aoqier,Temuqile Temuqile,Huricha Baigude
Ethnopharmacological relevance The traditional Mongolian medicine Eerdun Wurile (EW) has remarkable neural recovery effect, and has been playing a key role in the clinical treatment of neurological disorders including ischemic stroke in Inner Mongolia Autonomous Region of China. The preliminary pharmacological studies in animal suggested that EW regulates the expression of trophic factors in brain lesion and may also balance the polarization of activated microglia (Gaowa et al., 2018). Aim of the study : The pool of leading bioactive chemicals underlying the therapeutic effects of EW has not been identified. Therefore, the mechanism of action of EW is poorly understood. This study was aimed to identify the major group of compounds that contribute to the inhibition of neuroinflammation during stroke recovery through regulation of microglia polarization. Materials and methods The extracts of EW in different solvents were evaluated for their inhibitory ability of cytokine (IP-10) expression in LPS stimulated BV2 cells. The most effective extract (of petroleum ether extract) was further separated to 18 fractionations on a semi-preparative HPLC column, which were assess for the IP-10 down-regulation efficiency by RT-qPCR. The potent isolate was further fractionated in 12 fractions, which showed fewer peaks. The fraction 6 from this isolates, which remarkably down-regulates cytokines expression including IP-10, TNFα and IL-1β, was analyzed on UPLC-qTOF MS . The key chemicals were measured for their cytokine inhibition in BV2 cells and mouse primary microglia. Results After two consecutive fractionating by preparative HPLC, petroleum ether extraction of EW gave 12 fractions with relatively distinctive chromatograms. A particular fraction (fraction 6) preserved the inhibitory effects on expression of pro-inflammatory cytokines including IP-10, TNFα, IL-1β and iNOS. The result of UPLC-qTOF MS analysis showed that the fraction contains 21 chemicals including costunolide , alantolactone , myristicin and linolenic acid , which significantly down-regulate the expression of key pro-inflammatory cytokines in LPS stimulated BV2 cells as well as mouse primary microglia. Conclusion Collectively our data suggest that the bioactive chemical pool which is responsible for the therapeutic effects of EW can be extracted in petroleum ether, and fractionated to a relatively small multiple components. Such components include known anti-inflammatory chemicals, which may contribute to the possible microglia polarization in brain lesion during the recovery of ischemic stroke.
研究领域:
民族药理学
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神经科学
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药理学
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炎症研究
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PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 11
·2828
·
IF 3.098
Linna Wang,Xiaoli Wang,Tingting Li,Yihua Zhang,Hui Ji
The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury.8esignificantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that8eregulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that8eis a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.Keywords:hydrogen sulfide;cerebral ischemia/reperfusion;microglial activation;NOX2;PI3Kγ
研究领域:
神经科学
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药理学
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炎症反应
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
·
IF 11.5
Sufen Li,Jingyan Zhang,Tong Yu,Guangtao Song,Jia Ke,Kai Wang,Yichong Xu,Yiling Hong,Tingting Meng,Yun Hong,Hong Yuan,Fuqiang Hu
Glioblastoma-associated macrophages & microglia (GAMs) are critical immune cells within the glioblastoma (GBM) microenvironment. Their phagocytosis of GBM cells is crucial for initiating both innate and adaptive immune responses. GBM cells evade this immune attack by upregulating the anti-phagocytic molecule CD47 on their surface. Although CD47 knockdown has shown promise in reducing tumor volume and increasing survival in GBM models, the efficacy of anti-CD47 antibodies remains limited clinically, partly due to the blood-brain tumor barrier (BBTB) and the insufficient pro-phagocytosis efficacy of CD47 blockade alone. Here, we introduce CSSOssMIT@MM-PEP 20 , a PEP 20 -linked microglia membrane (MM) camouflaged CSSOssMIT prodrug micelle. The MM targets vascular cell adhesion molecule-1 on the BBTB and enhances the penetration of CSSOssMIT@MM-PEP 20 into the GBM tissue. CSSOssMIT@MM-PEP 20 disassembles into MM-PEP 20 and CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEP 20 blocks the CD47-SIRPα axis, disabling the ‘don't eat me’ signal, while CSSOssMIT releases MIT within tumor cells to promote immunogenic cell death and amplify the ‘eat me’ signal. In an orthotopic GBM mouse model, CSSOssMIT@MM-PEP 20 increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8 + T cell infiltration by 8.63-fold, demonstrating significant GBM inhibition. Overall, this study presents a noninvasive strategy to traverse the BBTB and modulate GAMs phagocytosis, thereby facilitating effective anti-GBM chemo-immunotherapy.
研究领域:
肿瘤学
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神经科学
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药理学
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免疫学
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高影响因子
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