TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Qiaozhu Tan,Ming Zhang,Lujing Geng,Zhenghua Xia,Cen Li,Muhammad Usman,Yuzhi Du,Lixin Wei,Hongtao Bi
Methylmercury (MeHg + ) is an extremely toxic organomercury cation that can induce severe neurological damage. Once it enters the body, methylmercury binds to amino acids or proteins containing free sulfhydryl groups. In particular, methylmercury is known to bind with human serum albumin (HSA) in human plasma; however, the effects of methylmercury-HSA conjugate (MeHg-HSA) on the central nervous system (CNS) are not fully understood. In the present study, we used the microglial cell line N9 as the target cells to evaluate the effect of MeHg-HSA on physiological function of the CNS preliminarily. The various factors in the cell culture were monitored by MTT assay, total lactate dehydrogenase assay, ELISA , qPCR, Western blot and flow cytometry techniques. The results showed that low-dose treatment with MeHg-HSA activated N9 cells, promoting cell proliferation and total cell number, enhancing NO and intracellular Ca 2+ levels, and suppressing the release of TNFα and IL1β without cytotoxic effects; while high-dose MeHg-HSA exhibited cytotoxic effects on N9 cells, including promoting cell death and increasing the secretion of TNFα and IL1β. These results indicate that MeHg-HSA causes hormesis in microglia N9 cells. Furthermore, ERK/MAPKs and STAT3 signaling pathways related to the hormesis of MeHg-HSA on N9 cells. In addition, low dose of MeHg-HSA might be viewed as something very close to a lowest observed adverse effect level (LOAEL) for N9 cells. These findings will be useful for investigating the hormesis mechanism of MeHg + and exploring the specific functions of MeHg-sulfhydryl conjugates on the central nervous system.
研究领域:
神经毒理学
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细胞生物学
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药理学
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毒理学
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PubMed
高影响因子
Frontiers in Immunology
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2022
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IF 8.786
Gu Lingui,Sun Mingjiang,Li Ruihao,Zhang Xingyu,Tao Yihao,Yuan Ye,Luo Xu,Xie Zongyi
Neuroinflammation has been proven to exert an important effect on brain injury after intracerebral hemorrhage (ICH). Previous studies reported that Didymin possessed anti-inflammatory properties after acute hepatic injury, hyperglycemia-induced endothelial dysfunction, and death. However, the role of Didymin in microglial pyroptosis and neuroinflammation after ICH is unclear. The current study aimed to investigate the effect of Didymin on neuroinflammation mediated by microglial pyroptosis in mouse models of ICH and shed some light on the underlying mechanisms. In this study, we observed that Didymin treatment remarkably improved neurobehavioral performance and decreased BBB disruption and brain water content. Microglial activation and neutrophil infiltration in the peri-hematoma tissue after ICH were strikingly mitigated by Didymin as well. At the molecular level, administration of Didymin significantly unregulated the expression of Rkip and downregulated the expression of pyroptotic molecules and inflammatory cytokines such as Nlrp3 inflammasome, GSDMD, caspase-1, and mature IL-1β, TNF-α, and MPO after ICH. Besides, Didymin treatment decreased the number of Caspase-1-positive microglia and GSDMD-positive microglia after ICH. Inversely, Locostatin, an Rkip-specific inhibitor, significantly abolished the anti-pyroptosis and anti-neuroinflammation effects of Didymin. Moreover, Rkip binding with Asc could interrupt the activation and assembly of the inflammasome. Mechanistically, inhibition of Caspase-1 by VX-765 attenuated brain injury and suppressed microglial pyroptosis and neuroinflammation by downregulation of GSDMD, mature IL-1β, TNF-α, and MPO based on Locostatin-treated ICH. Taken together, Didymin alleviated microglial pyroptosis and neuroinflammation, at least in part through the Asc/Caspase-1/GSDMD pathway via upregulating Rkip expression after ICH. Therefore, Didymin may be a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.
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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神经病学
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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 47
·期 10
·3178-3191
·
IF 4.414
Wang Lei,Li Min,Zhu Cuiping,Qin Aiping,Wang Jinchun,Wei Xianni
The purpose of the present study was to evaluate the protective effect of Palmatine on LPS-induced depressive like behavior and explore its potential mechanism. The mice were intragastrically treated with Fluoxetine or Palmatine once daily for 1 week. After the last drug administration, the mice were intraperitoneally challenged with LPS and suffered for Sucrose preference test, Tail suspension test, Forced swimming test and Open field test. The pro-inflammatory biomarkers were measured by ELISA, qPCR, WB and immunofluorescence. As a result, the administration of Palmatine effectively lessened depressive-like behavior. Palmatine could decrease the levels of pro-inflammatory cytokines TNF-α, IL-6, the expressions of CD68, iNOS mRNA, as well as increase the levels of anti-inflammatory cytokines IL-4, IL-10, the expressions of CD206, Arg1 mRNA, Ym1 mRNA both in LPS-induced mice and in LPS-induced BV2 cells. The beneficial effect of Palmatine might be attributed to the suppression of M1 microglia polarization and the promotion of M2 microglia polarization via PDE4B/KLF4 signaling. The similar results were observed in CUMS-induced depressive mice. The transfection with PDE4B SiRNA or KLF4 SiRNA indicated that PDE4B and KLF4 were both involved in the Palmatine-mediated microglia polarization. Molecular docking indicated that Palmatine could interact with PDE4B. In conclusion, this research demonstrated that Palmatine attenuated depressive like behavior by modulating microglia polarization via PDE4B/KLF4 signaling.
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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行为科学
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PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2021
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IF 4.079
Hongzhi Chen,Haichao Chu,Qian Jiang,Cong Wang,Yue Tian
Perioperative neurocognitive disorder (PND) frequently occurs in elderly patients following anesthesia, and is associated with pro-inflammatory activation of microglia in hippocampus. In this study, sevoflurane , a commonly used inhaled anesthetic in clinic, was used to induce PND-like symptoms in aged SD rats (18–20 months). Data from novel object recognition and Y-maze tests first confirmed that aged SD rats exposed to 2% sevoflurane for 5 h developed cognitive impairment . Microglia preferred to polarizing towards pro-inflammatory M1 subtype (iNOS+Iba-1 +) in rat hippocampus post sevoflurane exposure, but not anti-inflammatory M2 subtype (Arg-1 +Iba-1 +). Microarray data identified interferon regulatory factor 6 (Irf6) as one (Fold change = −2.52, p = 0.006) of the 15 downregulated genes in hippocampus of the rats exposed to sevoflurane. Co-immunofluorescence data further illustrated that sevoflurane decreased Irf6 expression in hippocampal microglia. In vitro, sevoflurane enhanced lipopolysaccharide-induced M1 polarization of BV-2 cells and inhibited interleukin-4 induced M2 polarization. Interestingly, manipulation of Irf6 expression hardly affected M1 polarization. However, Irf6 overexpression further augmented the inhibitory effects on M2 polarization, and its silencing showed opposite effects. In addition, such M2 polarization-promoting effects of Irf6 knockdown may be associated with induction of peroxisome proliferator activated receptor gamma expression. Collectively, these findings suggest that Irf6 downregulation in hippocampal microglia may be a compensatory mechanism against sevoflurane-induced PND in the elderly.
研究领域:
神经科学
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麻醉学
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免疫学
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分子生物学
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PubMed
高影响因子
Theranostics
·
2021
·
IF 11.556
Yiliang Wang,Weisheng Luo,Lianzhou Huang,Ji Xiao,Xiaowei Song,Feng Li,Yuying Ma,Xiaohui Wang,Fujun Jin,Ping Liu,Yexuan Zhu,Kaio Kitazato,Yifei Wang,Zhe Ren
Microglia are the primary cellular source of type I interferons (I-IFNs) in the brain upon neurotropic virus infection. Although the I-IFN-based antiviral innate immune response is crucial for eliminating viruses, overproduction led to immune disorders. Therefore, the relatively long-lasting I-IFNs must be precisely controlled, but the regulatory mechanism for the innate antiviral response in microglia remains largely unknown. Long non-coding RNAs (lncRNAs) are being recognized as crucial factors in numerous diseases, but their regulatory roles in the innate antiviral response in microglia are undefined. Methods: The high-throughput RNA sequencing was performed to obtain differentially expressed lncRNAs (DELs) in primary microglia infected with or without the neurotropic herpes simplex virus type 1 (HSV-1). We selected four DELs ranked in the top 15 in basic level and their fold change induced by HSV-1, i.e., FPKM HSV-1 /FPKM Cells .We subsequently found a key lncRNA affecting the innate antiviral response of microglia significantly. We next used dual-luciferase reporter assays, bioinformatical tools, and truncation mutants of both lncRNA and targeted proteins to elucidate the downstream and upstream mechanism of action of lncRNA. Further, we established microglia-specific knock-in (KI) mice to investigate the role of lncRNA in vivo . Results: We identified a long intergenic non-coding RNA, linc-AhRA, involved in regulating the innate antiviral response in murine microglia. linc-AhRA is activated by aryl hydrocarbon receptor (AhR) and restricts I-IFN production in microglia upon neurotropic herpesvirus infection and innate immune stimulation. Mechanistically, linc-AhRA binds to both tripartite motif-containing 27 (TRIM27) and TANK-binding kinase 1 (TBK1) through its conserved 117nt fragment as a molecular scaffold to enhance TRIM27-TBK1 interaction. This interaction facilitates the TRIM27-mediated ubiquitination of TBK1 and results in ubiquitin-proteasome-dependent degradation of TBK1. Consequently, linc-AhRA suppresses I-IFN production through facilitating TBK1 degradation and limits the microglial innate immune response against neurotropic herpesvirus infection. Microglia-specific KI of linc-AhRA mice shows a weakened antiviral immune response upon neurotropic herpesvirus challenge due to a reduction of TBK1 in microglia. Conclusion: Our findings indicate that linc-AhRA is a negative regulator of I-IFN production in microglia to avoid excessive autoimmune responses. These findings uncover a previously unappreciated role for lncRNA conserved fragments in the innate antiviral response, providing a strong foundation for developing nucleotide drugs based on conserved functional fragments within lncRNAs.
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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病毒学
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DOI
PubMed
高影响因子
Cells
·
2022
·Vol. 11
·期 22
·3588
·
IF 7.666
Tuo Li,Lei Li,Ruilong Peng,Hongying Hao,Hejun Zhang,Yalong Gao,Cong Wang,Fanjian Li,Xilei Liu,Fanglian Chen,Shu Zhang,Jianning Zhang
Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib’s effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.Keywords:TBI;abrocitinib;neuroinflammation;JAK1/STAT1/NF-κB
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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创伤
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PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2023
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IF 3.6
Deng Shanshan,Gao Yuan,Lv Mengting,Li Xinyu,Ma Yulin,Guo Yuchen,Li Tiejun,Zhang Yuefan
Chronic cerebral hypoperfusion (CCH) is the leading cause of chronic cerebral dysfunction syndrome with its complex pathological mechanisms involving cortical and hippocampal neuronal loss, white matter lesions, and neuroinflammation. I-C-F-6 is a septapeptide, which has anti-inflammatory and anti-fibrotic effects. This study aimed to evaluate the neuroprotective effect of I-C-F-6 in chronic cerebral hypoperfusion (CCH)-induced neurological injury. C57BL/6 J mice were subjected to bilateral common carotid artery stenosis (BCAS), and BV2 microglia cells were induced with oxygen-glucose deprivation (OGD). In vivo, mice were divided randomly into four groups: Sham, BCAS, GBE (30 mg/kg), and I-C-F-6 (0.5 mg/kg). In vitro, microglia were divided randomly into four groups: control, OGD, I-C-F-6 (25 μg/mL), and Shikonin (800 nmol/L). Through LFB, TUNEL, and NeuN staining, we found that I-C-F-6 was able to mitigate myelin pathology and reduce the number of apoptotic neurons. Furthermore, immunofluorescence staining revealed that I-C-F-6 was able to reduce microglia clustering and downregulate NF-κB p65. We also observed a significant downregulation of M1 phenotype microglia signature genes, such as TNF-α, iNOS, and upregulation of anti-inflammatory cytokines, such as Arg-1 and IL-10, indicating that I-C-F-6 may mainly reduce polarization towards the M1 phenotype in microglia. Notably, I-C-F-6 downregulated the expression of NF-κB signaling pathway-related proteins IKK-β and NF-κB p65, as well as pro-inflammatory cytokines IL-1β and iNOS. In conclusion, I-C-F-6 can improve neurological damage, alleviate neuroinflammation, and inhibit microglia polarization to the M1 phenotype via the NF-κB signaling pathway.
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Zheyu Fang,Kun Xiang,Xinhuang Lv,Qiyao Li,Conghui Dai,Yao Yang,Yan Lin,Jiaming Liu,Jing Sun
Post-stroke cognitive impairment (PSCI) is characterized by progressive cognitive decline following ischemic stroke, and recent studies have suggested that natural compounds may offer therapeutic benefits; however, the effects and mechanisms of Betulin in PSCI remain unclear. Male C57BL/6 mice were subjected to ischemic stroke surgery to induce PSCI and treated with Betulin (50 mg/kg/day) for 3 weeks, followed by assessments of cognitive impairment, pathological changes, and the production of pro-inflammatory cytokines. Network pharmacology and RNA sequencing were performed to explore potential mechanisms. In vitro, BV2 microglia were stimulated with lipopolysaccharide to examine the anti-inflammatory effects of Betulin. Betulin improved cognitive performance, reduced microglial activation, and attenuated neuroinflammation, as evidenced by decreased levels of TNF-α, IL-1β, and IL-6. Mechanistically, the epidermal growth factor receptor (EGFR)/JAK2/STAT3 pathway was identified as a key pathway potentially involved in these effects. Further experiments with EGFR point-mutation constructs indicated that disrupting the Betulin-EGFR interaction attenuated the inhibitory effect of Betulin on the EGFR/JAK2/STAT3 pathway. Collectively, these findings suggest that Betulin mitigates microglia-driven neuroinflammation by targeting EGFR and may represent a potential therapeutic candidate for PSCI.
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高影响因子
NEUROCHEMICAL RESEARCH
·
2026
·Vol. 51
·期 4
·207
·
IF 4.5
Fu Jie,Zhang Shaotao,Chu Yifei,Li Jinglun,Chen Xiu
Microglia-mediated neuroinflammation is closely associated with the pathogenesis of epilepsy. Mammalian sterile-20-like kinase 4 (MST4) has been suggested a regulator of inflammation. However, the effect of MST4 on microglia neuroinflammation in epilepsy remains unclear. A pilocarpine-induced rat epilepsy model was constructed and a lipopolysaccharide (LPS)-stimulated microglia cell model was applied in the current research. Knockdown or overexpression of MST4 was established using lentivirus transfection. Electroencephalograph (EEG) was employed to measure brain activities of rats. The protein and mRNA expressions were detected using western blot and qRT-PCR, respectively. Immunofluorescent staining was conducted to detect the distribution of the proteins. TUNEL staining was performed to evaluate cell apoptosis. The protein interaction was evaluated with Co-IP assay. Our results showed that MST4 and nuclear PKM2 expressions were increased in epileptic rats compared to control and colocalized with microglia. MST4 overexpression inhibited microglia activation, the release of TNF-α and IL-1β, and improved neuronal apoptosis in epileptic rats. Furthermore, MST4 interacted with PKM2 and regulated PKM2 nuclear translocation. Inhibiting PKM2 nuclear translocation by TEPP-46 reversed the promoting effect of MST4 knockdown on microglia neuroinflammation. In summary, our study demonstrated that MST4 alleviated microglia-mediated neuroinflammation in epilepsy, and the mechanism of MST4-mediated anti-neuroinflammatory effects may be associated with the inhibition of PKM2 nuclear translocation.
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高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Qian Feng,Cai-Zhi Li,Yi-Hua Zou,Xue-Yu Wang,Xia Yang,Rong Zhang*,Zhong-Qiu Liu*,Rong-Rong Zhang
Introduction: Brain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.Methods: An intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.Results: The BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK–STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.Conclusion: Our work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.
研究领域:
肿瘤学
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免疫学
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药理学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-26
·
IF 12.6
Mu Zhenlong,Chen Yang,Hu Yunfeng,Wang Hui,Li Jin
Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer’s disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co‐loaded with manganese dioxide nanoenzyme (BMn) and autophagy‐activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs‐associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H 2 O 2 triggers the structural disintegration of LAbs‐camouflaged liposomes and their reassembly into ultra‐small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi‐target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β‐amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs‐based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment. Graphical abstract
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高影响因子
PeerJ
·
2024
·
IF 2.3
Junli Du,Chao Chen,Jie Chen
Background Cirsilineol is a trimethoxy and dihydroxy flavonoid isolated from plant species such as Artemisia vestita and has a variety of pharmacological properties. This study analyzed whether cirsilineol could prevent postoperative cognitive dysfunction (POCD). Methods A POCD mouse model induced by anesthesia/surgery induction and a cell model established with hydrogen peroxide (H 2 O 2 )-induced microglia BV-2 were employed to explore the efficacy of cirsilineol on POCD. The cognition function of the mice were assessed by carrying out behavioral tests (Morris water maze test and Y-maze test). We assessed the activation and polarization status of microglia using immunofluorescence analysis and detected the expression levels of CD86 and CD206 using the quantitative PCR (qPCR). Subsequently, cell viability was determined by CCK-8 assay and apoptosis was assessed using Calcein-AM/PI staining. Meanwhile, superoxide dismutase (SOD) and malondialdehyde (MDA) levels in plasma and cell culture medium were detected using chemiluminescence. Finally, the phosphorylation levels of JAK/STAT signaling pathway-related proteins were analyzed by Western blot. Results Cirsilineol reduced the escape latency and times of crossing island and increased spontaneous alternation (SA) rate, restoring the cognitive dysfunctions of POCD-modeled mice. Meanwhile, POCD elevated CD86 expression and malondialdehyde content and lowered the level of SOD; however, cirsilineol promoted CD206 expression and generation of SOD and inhibited malondialdehyde production. In H 2 O 2 -induced microglia BV-2, cirsilineol treatment increased SOD content and suppressed the generation of reactive oxygen species (ROS) and malondialdehyde, modulating microglia M1/M2 polarization and JAK/STAT pathway. Conclusion Cirsilineol prevented against POCD by attenuating oxidative stress and modulating microglia M1/M2 polarization, providing novel insights for the management of POCD.
研究领域:
药理学
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神经科学
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外科手术
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分子生物学
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PubMed
高影响因子
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