NEUROCHEMICAL RESEARCH
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2026
·Vol. 51
·期 4
·232
·
IF 4.5
Zhang Xinfeng,Lian Zhuo,Lei Sijie,Yi Tanhui,Zhao Shuyin,Liu Mingxiang,Gui Yiling,Zhu Chengyi,Xie Qian,Ma Rong
The selection of appropriate in vitro inflammatory models is critical for mechanistic studies of neuroinflammation and the screening of anti-inflammatory therapeutics. Lipopolysaccharide (LPS) combined with interferon-γ (IFN-γ) and LPS combined with adenosine triphosphate (ATP) are widely used to induce microglial inflammation; however, their distinct phenotypic characteristics and optimal applications have not been systematically compared. In this study, we combined transcriptomic profiling with functional assays to compare these two inflammatory paradigms in BV2 microglia. Our results showed that both models activated the chemokine–cytokine inflammatory network and induced the production of inflammatory mediators and chemokines, but exhibited distinct molecular and functional biases. LPS/IFN-γ stimulation preferentially upregulated genes such as Lcn2 , Ccl2 , Upp1 , and Pim2 , which are associated with innate immune activation, chemokine-mediated inflammatory responses, and cell survival signaling, and was accompanied by marked increases in NO and TNF-α production. In contrast, the LPS/ATP model preferentially upregulated genes associated with ECM/cell adhesion, inflammatory and cellular homeostatic regulation, oxidative stress, and calcium-dependent secretion, including Thbs1 , Thbd , Srxn1 , Syt7 , and Procr . Functionally, this model exhibited more pronounced IL-1β maturation and release, relatively lower NO production, and greater mitochondrial dysfunction and cell injury. Pharmacological inhibition of NLRP3 with MCC950 significantly attenuated ATP-induced IL-1β maturation, supporting the involvement of the NLRP3 inflammasome in the LPS/ATP model. Overall, the LPS/IFN-γ model is more suitable for investigating the NO/iNOS–TNF-α axis, IFN-γ-mediated synergistic pro-inflammatory responses, and classical pro-inflammatory activation, as well as for screening anti-inflammatory agents. In contrast, the LPS/ATP model is more appropriate for studying IL-1β maturation and release, NLRP3 inflammasome activation, mitochondrial damage, and inflammation-related cell death, as well as for screening inflammasome inhibitors. Our findings provide an empirical framework for rational model selection in microglial inflammation research.
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高影响因子
IMMUNITY
·
2026
·
IF 30.6
Jingyan Zhang,Yufei Huang,Yanbing Chen,Yusi Zhang,Jianmin Chen,Yihong Huang,Haizhi Zhong,Haobing He,Xiaoman Dai,Xiaoxin Yan,Wanjin Chen,Qinyong Ye,Xiaochun Chen,Jing Zhang
Glial crosstalk surrounding amyloid-β (Aβ) plaques establishes a self-propagating inflammatory niche fueling Alzheimer’s disease (AD), yet the molecular triggers remain incompletely defined. We found that the calcium-dependent enzyme peptidyl-arginine deiminase 2 (PAD2) was selectively upregulated in plaque-associated astrocytes in human AD cortex and multiple APP AD transgenic mouse models. Astrocyte-specific deletion of Padi2 in 5×FAD mice rescued learning and memory, lowered Aβ load, restrained pro-inflammatory microglial activation, and restored microglial phagocytosis. Multi-omics profiling tied these benefits to rewiring of the astrocytic proteome and the microglial transcriptome toward homeostasis. PAD2 converted astrocytic vimentin to citrullinated Cit-Vim175/184. The released Cit-vimentin drove a proinflammatory phenotype while dampening Aβ clearance in microglia—a process dependent on TLR4 signaling. Pharmacological PAD2 inhibition mimicked the genetic rescue, normalizing glial signatures and cognition. These findings identify PAD2-dependent vimentin citrullination as a key inter-glial signaling hub that worsens AD pathology and highlight PAD2 as a promising therapeutic target.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-25
·
IF 12.6
Han Yuhan,Gu Jiacheng,Xu Miaomiao,Ma Yufei,Weng Weiji,Feng Qiyuan,He Zhenghui,Qi Wenlan,Mao Qing,Jiang Jiyao,Feng Junfeng
Microglia play a critical role in neuroinflammation, a key secondary injury mechanism following traumatic brain injury (TBI). The colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 has shown promise in suppressing neuroinflammation by depleting microglia, but it lacks specificity in targeting microglia at the injury site. To overcome this limitation, we developed PLX5622 nanoparticles functionalized with the CAQK peptide for lesion-specific targeting and combined them with a hydrogel (GelMA-PPS) that possesses potent reactive oxygen species (ROS) scavenging capabilities. This nanoparticle-hydrogel drug delivery system (GelMA-PPS/P) significantly enhanced the delivery efficiency and therapeutic efficacy of PLX5622 in TBI treatment. Localized administration of this system effectively depleted microglia at the injury site, suppressed neuroinflammation, and reduced the release of inflammatory cytokines. Its ROS scavenging ability was also validated in vitro and in vivo. Together, these effects synergistically improved neurological function recovery in TBI mouse models. This innovative strategy offers a comprehensive and targeted approach to managing neuroinflammation after TBI, providing a promising avenue for advancing TBI therapies.
研究领域:
神经科学
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生物医学工程
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药剂学
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炎症研究
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纳米技术
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PubMed
高影响因子
Frontiers in Cellular Neuroscience
·
2025
·
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 CONTROLLED RELEASE
·
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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PubMed
高影响因子
IMMUNITY
·
2024
·
IF 25.5
Bo Wei,Guo Cheng,Qianqian Bi,Cheng Lu,Qihang Sun,Li Li,Ningting Chen,Miner Hu,Haoran Lu,Xuancheng Xu,Genxiang Mao,Shu Wan,Zhechun Hu,Yan Gu,Jiaxin Zheng,Li Zhao,Xiao Z. Shen,Xiaoli Liu,Peng Shi
Hypertension is usually accompanied by elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not clear. Recent advances revealed that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels and found that microglia in the hypothalamic paraventricular nucleus (PVN), a sympathetic center, were early responders to hypertensive challenges. Vasculature analyses revealed that the PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology relative to other brain regions. As such, the PVN was susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. Mechanistically, ATP ligation to microglial P2Y12 receptor was responsible for microglial inflammatory activation and the eventual sympathetic overflow. Together, these findings identified a distinct vasculature pattern rendering vulnerability of PVN pre-sympathetic neurons to hypertension-associated microglia-mediated inflammatory insults.
研究领域:
神经科学
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心血管研究
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免疫学
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-17
·
IF 10.6
Guan Pengfei,Fan Lei,Zhu Zhaobo,Yang Qinfeng,Kang Xinchang,Li Junji,Zhang Zuyu,Liu Shencai,Liu Can,Wang Xuelian,Xu Jing,Wang Kun,Sun Yongjian
Electroconductive hydrogels offer a promising avenue for enhancing the repair efficacy of spinal cord injuries (SCI) by restoring disrupted electrical signals along the spinal cord’s conduction pathway. Nonetheless, the application of hydrogels composed of diverse electroconductive materials has demonstrated limited capacity to mitigate the post-SCI inflammatory response. Recent research has indicated that the transplantation of M2 microglia effectively fosters SCI recovery by attenuating the excessive inflammatory response. Exosomes (Exos), small vesicles discharged by cells carrying similar biological functions to their originating cells, present a compelling alternative to cellular transplantation. This investigation endeavors to exploit M2 microglia-derived exosomes (M2-Exos) successfully isolated and reversibly bonded to electroconductive hydrogels through hydrogen bonding for synergistic promotion of SCI repair to synergistically enhance SCI repair. In vitro experiments substantiated the significant capacity of M2-Exos-laden electroconductive hydrogels to stimulate the growth of neural stem cells and axons in the dorsal root ganglion and modulate microglial M2 polarization. Furthermore, M2-Exos demonstrated a remarkable ability to mitigate the initial inflammatory reaction within the injury site. When combined with the electroconductive hydrogel, M2-Exos worked synergistically to expedite neuronal and axonal regeneration, substantially enhancing the functional recovery of rats afflicted with SCI. These findings underscore the potential of M2-Exos as a valuable reparative factor, amplifying the efficacy of electroconductive hydrogels in their capacity to foster SCI rehabilitation.
研究领域:
神经科学
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再生医学
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生物材料学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
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
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
He-Tao Bian,Gao-Hua Wang,Jun-Jie Huang,Liang Liang,Ling Xiao,Hui-Ling Wang
Depression is a complex and heterogeneous mental disorder. Yet, the mechanisms behind depression remain elusive. Increasing evidence suggests that inflammatory reaction and microglia activation are involved in the pathogenesis of depression. Scutellarin has been found to have anti-inflammatory and antioxidant effects in various diseases. The aim of the present study was to investigate the anti-depressant effects and potential mechanism of scutellarin in the lipopolysaccharide (LPS)-induced depression animal model. The behavioral tests showed that scutellarin administration ameliorated LPS-induced depressive-like behaviors. Additionally, the scutellarin treatment inhibited reactive oxygen species (ROS) generation. Western blot analysis results showed that scutellarin pretreatment suppressed LPS-induced the protein levels of NLRP3 , caspase-1, and IL-1β. Furthermore, immunostaining results showed that scutellarin pretreatment inhibited LPS-induced microglia activation in the hippocampus of rats. These findings suggest that scutellarin effectively improves LPS-induced inflammation-related depressive-like behaviors by inhibiting LPS-induced neuroinflammation and microglia activation, possibly via regulation of the ROS/NLRP3 signaling pathway and microglia activation. Thus, scutellarin may serve as a potential therapeutic strategy for depression.
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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PubMed
高影响因子
JOURNAL OF CHEMICAL NEUROANATOMY
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2022
·
IF 3.097
Liaoxi Tan,Yixin Hu,Xinyi Zhang,Chunlei Zhang,Chuchu Xi,Zhao Yang,Zhengyu Cao,Fang Zhao
Background and purpose Microglial activation plays an important role in the onset and progression of neuropathic pain by producing a variety of pro-inflammatory cytokines that interact with neurons to enhance neuronal hyperexcitability. Corydalis decumbens (Thunb.) pers., a traditional Chinese medicine has been used to treat mild cancer pain, dementia and to remit cerebral ischemia in clinics. Phenylphthalide isoquinolines are the major type of metabolites of C. decumbens and one of the derivatives, Corydecumine G (Cor G) has been shown to inhibit neuronal excitability . The present study aims to investigate the analgesic efficacy of Cor G in neuropathic pain rat model, the effects of Cor G on microglia activation and the possible mechanisms. Experimental approach Neuropathic pain was modeled using chronic constriction sciatic nerve injury (CCI) in rats. Western blot , immunofluorescence, and qRT-PCR were used to evaluate the levels of protein and mRNA. Key results Intraperitoneal administration of Cor G concentration-dependently ameliorates mechanical and thermo allodynia , suppresses CCI-induced p38/ERK phosphorylation and spinal cord microglia activation, and attenuates the expression levels of NO, inos , Tnf-α , Pge 2 in dorsal horn of L4-L6 spinal cord on the ligation side in CCI rats. Pretreatment with 30 μM Cor G decreased LPS-induced BV2 microglia activation, which occurred via the inos , Tnf-α , Il-1β , Il-6 and phospho-p38/ERK pathways. Conclusions and implications Taken together, we suggest that Cor G, the specific phthalide isoquinoline from traditional Chinese medicine Corydalis Decumbentis Rhizoma, may be promising for treatment of neuropathic pain.
研究领域:
药理学
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神经科学
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传统中药
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PubMed
高影响因子
JOURNAL OF MATERIALS SCIENCE
·
2022
·Vol. 57
·期 3
·2073-2088
·
IF 4.682
Lin Jingjing,Song Xingying,Yin Hang,Song Nijia,Wang Yanchao,Li Zhen,Luo Feng,Tan Hong,He Xueling,Li Jiehua
Regulating the immune microenvironment around the central neurons is a difficult problem. To address this critical matter, drug-loading scaffolds are promising ways of releasing drugs directly to the surrounding cells and ignoring the influence of blood–brain barrier and blood–medullary barrier. Microglia are fundamental innate immune sentinels in the central nervous system, usually activated during neuroinflammation. Citicoline (CDPC), a neuroprotective agent on secondary injuries, is used in clinical treatment of central nervous system diseases. To overcome low efficiency of CDPC uptake and improve immune microenvironment of CDPC in central nervous system (CNS), in this work, double local drug delivery systems, hybrid CDPC–liposome and CDPC blending directly waterborne polyurethane scaffolds, were prepared. It shows that CDPC–liposome composite scaffolds are more conducive to inhibit the inflammatory response of microglia and promote axon elongation, which presents a certain prospect in the field of nerve repair. Graphical abstract
研究领域:
神经科学
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生物材料
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药学
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组织工程
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Xinmei Wang,Shanshan Li,Jiayu Yu,Wenlin Wang,Zhuoqi Du,Shuchun Gao,Yin Ma,Ruixin Tang,Ting Liu,Shiping Ma,Qiang Fu,Xueyang Deng
s Ethnopharmacological relevance Saikosaponins B2 (SSB2) is one of the main active components isolated from Radix Bupleuri (Bupleurum chinense DC.), a herb widely used of traditional Chinese medicine. It has been used for the treatment of depression for more than two thousand years. However, the molecular mechanisms remain to be determined. Aim of the study In this study, we evaluated the anti-inflammatory effect and elucidated underlying molecular mechanisms of SSB2 in LPS-induced primary microglia and CUMS-induced mice model of depression. Method The effects of SSB2 treatment were investigated both in vitro and in vivo. The chronic unpredictable mild stimulation (CUMS) procedure was applied to establish the animal model of depression. Behavioural tests were used to evaluate the depressive-like behaviors in CUMS-exposed mice, including sucrose preference test, open field test, tail suspension test, and forced swimming test. The GPX4 gene of microglia was silenced using shRNA, and inflammatory cytokines were determined by Western Blot and immunofluorescence analysis. Endoplasmic reticulum stress and ferroptosis-related markers were detected by qPCR, flow cytometry and confocal microscopy. Result SSB2 reversed depressive-like behaviours in CUMS-exposed mice and relieved central neuroinflammation and ameliorated hippocampal neural damage. SSB2 alleviated LPS-induced activation of microglia through the TLR4/NF-κB pathway. LPS-induced ferroptosis, with increased levels of ROS, intracellular Fe 2+ , mitochondrial membrane potential, lipid peroxidation, GSH, SLC7A11, FTH, GPX4 and Nrf2, and decreased transcription levels of ACSL4 and TFR1, was attenuated with SSB2 treatment in primary microglia cells. GPX4 knockdown activated ferroptosis, induced endoplasmic reticulum (ER) stress, and abrogated the protective effects of SSB2. Further, SSB2 attenuated ER stress, balanced calcium homeostasis, reduced lipid peroxidation and intracellular Fe 2+ content by regulating the level of intracellular Ca 2+ . Conclusions Our study suggested that SSB2 treatment can inhibit ferroptosis, maintain calcium homeostasis, relieve endoplasmic reticulum stress and attenuate central neuroinflammation. SSB2 exhibited anti-ferroptosis and anti-neuroinflammatory effects through the TLR4/NF-κB pathway in a GPX4-dependent manner.
研究领域:
药理学
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神经科学
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民族药理学
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分子生物学
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PubMed
高影响因子
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