IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
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2021
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IF 2.73
Shengyu Sun,Yourui Zou,Shaocai Hao,Zhanfeng Niu,Liang Wu
Objective Polydatin has been used in the treatment of various inflammatory diseases. However, its role in the regulation of neuroinflammation has not been reported. In this study, we designed to investigate the anti-inflammatory effects of polydatin in LPS-stimulated BV2 microglia cells.Methods Inflammatory mediators TNF-α, IL-1β, NO, and PGE2 production were measured by ELISA. The protein of signaling pathways were detected by western blot analysis.Results The results showed that polydatin significantly ameliorated the production of TNF-α, IL-1β, NO, and PGE2 up-regulated by LPS. Polydatin also blocked LPS-induced NF-κB activation. In addition, PI3K and AKT, the up-stream molecules of NF-κB signaling pathway, were inhibited by the treatment of polydatin. Also, we found the formation of lipid rafts was inhibited by polydatin through attenuating the cholesterol content. Finally, polydatin was found to increase the expression of ABCA1 and ABCG1.Conclusion In conclusion, the results of the present study suggested that polydatin exhibited its anti-inflammatory effects in BV2 cells through disrupting lipid rafts, which subsequently inhibiting PI3K/AKT signaling pathway.
研究领域:
药理学
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神经科学
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免疫学
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DOI
PubMed
高影响因子
Journal of Stroke & Cerebrovascular Diseases
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2021
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IF 2.136
Zhiyu Xi,Canxin Xu,Xiao Chen,Baofeng Wang,Zhihong Zhong,Qingfang Sun,Yuhao Sun,Liuguan Bian
Objectives Microglia activation, a key process in secondary injury following intracerebral hemorrhage (ICH), is divided to M1 and M2 phenotype. Protocatechuic acid (PCA) is a phenolic acid been proved neuroprotection in ICH without understanding of details. Thus, this study aimed to observe the influence of PCA on microglia activation and explore underlying mechanisms. Materials and methods To assess PCA affected microglia activation in vivo, an experimental ICH mice model was established and then treated with PCA intraperitoneal injection . Immunofluorescence staining was performed in brain slices at day 3 post ICH. BV2 cells were stimulated with hemin for activation, then M1 and M2 biomarkers were analyzed using Western Blot and qPCR. At last, we detected the expression of mTOR and its downstream molecules to discuss possible mechanisms. Results At day 3 post ICH, less activated microglia gathering around hematoma after PCA treatment . Furtherly, in hemin treated BV2 cells, PCA downregulated M1 and promoted M2 biomarkers expression in both mRNA and protein level. PCA inhibited the phosphorylation of mTOR, S6K1 and 4E-BP1, while the inhibition was disappeared after supplemented with mTOR activator. Conclusions PCA impacted microglia activation by suppressing the mTOR signaling pathway , thereby improving M1/M2 switch and attenuated neuroinflammation .
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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DOI
PubMed
高影响因子
LIFE SCIENCES
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2021
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IF 5.037
Mengyuan Fang,Wencui Wan,Qiuming Li,Weiwei Wan,Yang Long,Hongzhuo Liu,Xin Yang
Aim This study aimed to evaluate the effects of Asiatic acid (AA), a naturally occurring compound of pentacyclic triterpenoid, on the pathological processes of diabetic retinopathy (DR). Methods SD rats were induced to develop early DR by intraperitoneal injection of STZ (60 mg/kg). Four weeks after injection, the diabetic rats were orally administrated with 37.5 mg/kg or 75 mg/kg AA every day for four weeks. The integrity of blood-retinal barrier (BRB) was measured by Evans blue staining. The polarization of microglia was determined by real-time PCR, western blot, and ELISA assays. The inner BRB (iBRB) or outer BRB (oBRB) breakdown was induced in human retinal endothelial cells or APRE19 cells through co-culture with high glucose and LPS-stimulated microglia BV2 cells. The damage to the iBRB and oBRB was measured using transendothelial/transepithelial electrical resistance (TEER/TER) and FITC-conjugated dextran cell permeability assays. Key findings Results demonstrated that AA alleviated BRB breakdown, as evidenced by decreased protein expression of occludin, claudin-5, and ZO-1. Furthermore, AA treatment suppressed inflammation and M1 polarization, while it increased M2 polarization in the retina of DR rats. In vitro , the iBRB or oBRB breakdown was alleviated by AA. LPS-induced M1-polarization of BV2 cells under high glucose condition was also repressed through AA administration. Finally, we demonstrated that AA weakened the TLR4/MyD88/NF-κB p65 signaling pathway both in vivo and in vitro . Significance AA ameliorated early DR by regulating microglia polarization via the TLR4/MyD88/NF-κB p65 pathway. These data indicate that AA is a potential candidate for DR treatment.
研究领域:
药理学
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眼科学
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免疫学
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细胞生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
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IF 3.263
Ying Liu,ShiJi Deng,Zhi Zhang,Yue Gu,ShengNan Xia,XinYu Bao,Xiang Cao,Yun Xu
Neuroinflammation is critical for the pathogenesis of ischemia brain damage . Over-activated microglia-mediated inflammation plays a very important role in ischemia cerebral injuries. 6-Gingerol, obtained from edible ginger (Zingiber Officinale) exhibits protective effects against inflammation. In this study, we found that 6-Gingerol could reduce the size of infarction (P = 0.0184) and improve neurological functions (P = 0.04) at the third day after ischemic brain injury in vivo. Since 6-Gingerol has the anti-inflammatory effects, we further investigated its impacts on neuroinflammation mediated by microglia both in vivo and in vitro. We found that the levels of pro-inflammatory cytokines Interleukin-1 beta (IL-1β, P = 0.0213), Interleukin-6 (IL-6, P = 0.0316), and inducible NO synthase (iNOS, P = 0.0229) in the infarct penumbra were lower in 6-Gingerol treated groups. Furthermore, microglia induced pro-inflammatory cytokines, such as IL-6, IL-1β, incremental intercellular nitric oxide (NO), as well as iNOS were blocked by the treatment of 6-Gingerol in lipopolysaccharide (LPS) stimulated microglia. In terms of mechanism, 6-Gingerol potently suppressed phosphorylation of serine-threonine protein kinase (Akt) - mammalian target of rapamycin (mTOR) - signal transducer and activator of transcription 3 (STAT3) in LPS-treated microglia. Taken together, the present study suggested that 6-Gingerol improved cerebral ischemia injury by suppressing microglia-mediated neuroinflammation by down-regulating Akt-mTOR-STAT3 pathway.
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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PubMed
高影响因子
FOLIA NEUROPATHOLOGICA
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2020
·Vol. 58
·期 1
·70-82
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IF 1.278
Yanxiang Zhang,Qi Chen,Yu Nai,Chunni Cao
IntroductionThe polarization state of microglia affects the progress of neuropathic pain. MiR-155 modulates polarization of microglia, while its role in neuropathic pain has not been well studied.Material and methodsWe separately used lipopolysaccharide (LPS) and interleukin 4 (IL-4) for constructing an M1/M2 polarization model in BV-2 cells. The levels of CD86, iNOS, CD206, Arg and miR-155 were measured by western blot or qRT-PCR, as needed. Subsequently, BV-2 cells were transfected with miR-155 mimics or inhibitor to explore the effects of miR-155 on polarization states. We also constructed a neuropathic pain model by applying spinal nerve ligation (SNL) in Wistar rats with miR-155 agomir or antagomir injection. The withdrawal threshold was measured by Von Frey fibre needle. The levels of interleukin 1b (IL-1b), tumour necrosis factor a (TNF-a) and the proportion of M1-polarized microglia in primary microglia from rats were measured by ELISA and flow cytometry.ResultsLPS induced M1 polarization in BV-2 cells with increasing of CD86, iNOS and miR-155, while IL-4 induced M2 polarization in BV-2 cells with increasing of CD206, Arg and decreasing of miR-155. MiR-155 mimics upregulated CD86 and downregulated CD206, whereas miR-155 inhibitor downregulated CD86 and upregulated CD206. MiR-155 antagomir increased the withdrawal threshold, decreased the production of IL-1b, TNF-a and the proportion of M1-polarized microglia in primary microglia.ConclusionsResults demonstrate that suppression of miR-155 attenuates neuropathic pain by inducing an M1 to M2 switch in microglia. Our findings provide a new perspective to understand the function of miR-155 in microglia.
研究领域:
神经科学
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疼痛研究
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Journal of Inflammation Research
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2021
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IF 6.922
Qianxue Mou,Ke Yao,Meng Ye,Bowen Zhao,Yuanyuan Hu,Xiaotong Lou,Huixia Li,Hong Zhang,Yin Zhao
Purpose Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI. Methods Cx3Cr1-Cre ERT2 / Raptor F/F and Cx3Cr1-Cre ERT2 / Sirt1 F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM). Results Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss. Conclusion Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.
研究领域:
神经科学
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眼科学
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分子生物学
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细胞生物学
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PubMed
高影响因子
PLoS One
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2013
·Vol. 8
·期 8
·e70565
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IF 3.73
Luyan Guo,Yanyan Xing,Rui Pan,Mingliang Jiang,Zheng Gong,Liqing Lin,Junbing Wang,Guoyin Xiong,Jun Dong
Curcumin is a molecule found in turmeric root that has anti-inflammatory, antioxidant, and anti-tumor properties and has been widely used as both an herbal drug and a food additive to treat or prevent neurodegenerative diseases. To explore whether curcumin is able to ameliorate HIV-1-associated neurotoxicity, we treated a murine microglial cell line (N9) and primary rat cortical neurons with curcumin in the presence or absence of neurotoxic HIV-1 gp120 (V3 loop) protein. We found that HIV-1 gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted a powerful inhibitory effect against HIV-1 gp120-induced neuronal damage, reducing the production of ROS, TNF-α and MCP-1 by N9 cells and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of the delayed rectification and transient outward potassium (K + ) current, as curcumin effectively reduced HIV-1 gp120-mediated elevation of the delayed rectification and transient outward K + channel current in neurons. We conclude that HIV-1 gp120 increases ROS, TNF-α and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the delayed rectification and transient outward K + channel current. Curcumin reduces production of ROS and inflammatory mediators in HIV-1-gp120-stimulated microglia, and protects cortical neurons against HIV-1-mediated apoptosis, most likely through inhibition of HIV-1 gp120-induced elevation of the delayed rectification and transient outward K + current.
研究领域:
神经科学
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免疫学
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药理学
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PubMed
高影响因子
RSC Advances
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2021
·Vol. 11
·期 52
·32549-32558
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IF 3.361
Hai Xiao,Shuqin Han,Huricha Baigude
The pro-inflammatory polarization of microglia after stroke is one of the major causes of secondary brain injury. Downregulation of the gene involved in canonical inflammatory pathways in glial cells can exert neuroprotective effects via inhibiting the release of pro-inflammatory factors. In this study, we functionalized DoGo lipids with mannose, the ligand of the mannose receptor (MR) that is expressed in microglia, and evaluated the MR-mediated cellular internalization of DoGo lipid nanoparticles (denote M3) carrying siRNA against TLR4 in BV2 cells in vitro. We confirmed that siTLR4/M3 complexes were specifically internalized by BV2 cells in a MR-dependent manner, and the treatment of oxygen glucose deprivation (OGD)-treated BV2 cells with siTLR4/M3 complexes resulted in remarkable silencing of TLR4, and induced downregulated M1 polarization and upregulated M2 polarization markers. Collectively, our data suggest that the M3 lipoplex is a promising microglia-targeting siRNA delivery agent.
研究领域:
神经科学
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药学
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分子生物学
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PubMed
高影响因子
MOLECULES
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2023
·Vol. 28
·期 8
·3482
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IF 4.6
Xingru Chen,Xiaolan Zhou,Xiaoqing Cheng,Liting Lin,Qi Wang,Ruoting Zhan,Qingguang Wu,Sijun Liu
In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1β (IL-1β). We further studied the mechanism of FA’s regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1β). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA’s inhibitory effects on TNF-α, IL-6 and IL-1β and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA’s inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.Keywords:BV2 microglia;ferulic acid;autophagy;AMPK/mTOR signaling pathway;NLRP3 inflammasome;neuroinflammation
研究领域:
神经科学
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药理学
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细胞生物学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Aihua Xu,Yang Yang,Yang Shao,Manyu Jiang,Yongxin Sun,Bo Feng
Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro , FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.
研究领域:
神经科学
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炎症
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Hongyu Zhang,Guoshun Lin,Yifei Wang,Aihui Zheng,Hanlin Luo,Zhang Cao,Guige Hou,Yun Hou
Background Bisphenol S (BPS) is widely used in consumer products and food packaging, but its safety and potential risks have garnered increasing attention. Hydroxytyrosol (HT), a natural polyphenolic compound with potent antioxidant and anti-inflammatory activities, is yet to be investigated for its potential to reverse BPS-induced effects and the underlying mechanistic pathways. Methods The toxicological potential of BPS was assessed using the computational platform ProTox 3.0. Molecular experiments were performed to elucidate the effects of BPS on the nervous system. Protein-protein interaction networks were constructed to predict the targets of BPS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to explore the potential mechanisms of action, followed by molecular docking studies. We examined the therapeutic efficacy of HT against BPS-induced nerve damage using molecular assays and in vivo murine models. The key target identified by molecular docking was validated using RT-qPCR. Results Significant neurotoxic effects of BPS were identified using platform-based predictive analysis. The experimental results demonstrated that exposure to BPS not only reduced the viability of BV2 and HMC3 microglial and elevated intracellular reactive oxygen species (ROS) levels, but also induced a phenotypic shift in microglia toward a pro-inflammatory state, thereby may underscore its neurotoxic effects. Based on the results of the network toxicology analysis, BPS is potentially capable of exacerbating nerve damage via its modulatory effects, such as its modulation of cytochrome P450 Family 1 Subfamily A (CYP1A), like-CYP1A1, CYP1A2, and cytochrome P450 Family 2 Subfamily B6 (CYP2B6), etc. Finally, subsequent confirmation using network pharmacology and molecular docking analysis revealed that HT is capable of counteracting BPS-induced effects, and that CYP1A1 is highly likely to be a pivotal target implicated in both BPS-mediated toxicity in microglia and the therapeutic mechanisms of HT. This was further verified using RT-qPCR. Conclusion CYP1A1 is a critical mediator of BPS-induced toxicity and a potential therapeutic target of HT. These findings highlight the potential of natural compounds to mitigate environmental toxicant-induced neurological damage.
研究领域:
毒理学
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神经药理学
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环境健康
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS
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2026
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IF 6.6
Yaqi Liu,Biao Luo,Yun Xu,Dexiang Liu,Qiujing Wang
Ischemic stroke (IS) remains a leading cause of global disability and mortality, with limited effective anti-inflammatory interventions. Targeting histone deacetylase 3 (HDAC3) to reprogram microglial polarization holds great therapeutic promise, but the HDAC3-specific inhibitor RGFP966 suffers from poor blood-brain barrier (BBB) penetration and systemic toxicity. Herein, we developed a pH-responsive brain-targeted lipid nanoparticle (CD-TLNP@RGFP966) by integrating T7 peptide modification for BBB transcytosis and cinnamaldehyde-α-cyclodextrin (CA-αCD) encapsulation for acidic lesion-triggered drug release. CD-TLNP@RGFP966 exhibited favorable colloidal stability, biosafety, and pH-dependent release behavior. It efficiently crossed the BBB, accumulated in ischemic brain tissue, promoted microglial M2 polarization, attenuated neuroinflammation, reduced infarct volume, and improved neurological function in tMCAO mice. This study provides a novel targeted nanocarrier strategy for the anti-inflammatory treatment of IS.
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PubMed
高影响因子
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