JOURNAL OF ETHNOPHARMACOLOGY
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2023
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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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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2024
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IF 4.2
Haocong Zhang,Liangbi Xiang,Hong Yuan,Hailong Yu
Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1β and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo . Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro . ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.
研究领域:
神经科学
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炎症
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2026
·Vol. 23
·期 1
·155
·
IF 11.5
Hu Yu,Tang Kaici,Hu Hongli,Mi Hongbo,Li Xue,Wang Hao,Liu Jiali,Xia Yiqing,Huang Wenhui,Kirchhoff Frank,Xiao Guo-dong,Jia Jia,Cheng Jian
White matter repair relies on microglial clearance of cholesterol-rich myelin debris. Microglia have been reported to predominantly depend on de novo sterol synthesis to support this repair process. Lysosomal acid lipase (LAL) is the only known lysosomal enzyme capable of hydrolyzing cholesterol esters. In stark contrast to previous studies, we demonstrate here that LAL-mediated lysosomal lipolysis—not de novo sterol synthesis—serves as a central determinant of the microglial capacity to drive white matter repair. Using single-cell RNA sequencing, we identified a novel reparative microglial state characterized by simultaneously high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) and LAL. Following white matter injury, GPNMB + microglia expanded and constituted the major microglial subset responsible for myelin debris engulfment. However, GPNMB + microglia displayed context-dependent capacity to digest internalized myelin debris and mediate remyelination, with marked differences between reparable white matter injury and nonregenerative injury induced by white matter stroke (WMS). Transcriptomic profiling identified LAL as a key regulator of the reparative phenotype in GPNMB + microglia. Independent of cytosolic lipases—widely regarded as synergistic mediators of LAL in cholesteryl ester hydrolysis, microglial LAL was both indispensable for myelin debris clearance and spontaneous remyelination in the reparable injury model, and sufficient to restore these processes following WMS-induced irreparable white matter injury. Mechanistically, LAL-mediated lysosomal lipolysis constituted the primary pathway for cholesteryl ester hydrolysis in microglia after white matter injury. This pathway converted cholesteryl esters into free cholesterol and activates liver X receptors (LXRs), both of which were required to reprogram microglial into the reparative state. Consistently, LXR activation alone was insufficient to rescue defective white matter repair caused by LAL deficiency. Hydroxypropyl-β-cyclodextrin (HβCD), an FDA-approved drug carrier, effectively lowers intracellular cholesterol levels through incompletely defined mechanisms. HβCD specifically upregulated LAL expression within white matter lesions and promoted remyelination via a LAL-dependent manner following WMS, supporting its potential as a therapeutic agent for WMS. Collectively, this study identifies lysosomal cholesterol ester hydrolysis as a novel therapeutic target for the treatment of irreversible white matter injury.
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DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·458
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IF 15
Ma Yuxiao,Chen Guojie,Xu Pengcheng,Wang Baofeng,Teng Teng,Zheng Yongtao,Liu Yikui,Zhang Qixiang,Lai Tianqi,Wang Zhuohang,Sun Qingfang,Zhang Yongkang,Sun Yuhao,Bian Liuguan
Neuroinflammation mediated by microglia and excessive oxidative stress are key pathological processes driving the progression of brain injuries such as intracerebral hemorrhage (ICH) and traumatic brain injury (TBI). Modulating lactate transport has emerged as a promising approach to mitigate M1 microglia polarization and alleviate neuroinflammation. Liposomal nanoparticles provide a safe and efficient platform for drug delivery. Here, we developed reactive oxygen species (ROS) responsive MiRCM nanoparticles that co-deliver monocarboxylate transporter 1 (MCT1) inhibitor AR-C155858 and a ROS-scavenging PPS core, modified with CAQK and MG1 peptides for brain injury site and microglia targeting. MiRCM nanoparticles demonstrated ROS-induced degradation and controlled drug release, effectively protecting AR-C155858 from enzymatic degradation. In vitro and in vivo experiments exhibited that MiRCM nanoparticles selectively accumulated at injured brain regions and in M1-type microglia, where they scavenged ROS, inhibited lactate efflux, suppressed M1 microglia polarization and reduced inflammatory cytokine production in ICH and TBI models. Consequently, MiRCM treatment protected neurons, reduced astrocyte activation, preserved blood-brain barrier integrity, enhanced endogenous antioxidant enzyme activities, and alleviated neurological deficits in both ICH and TBI models. RNA sequencing further confirmed downregulation of inflammatory pathways. Moreover, biosafety evaluations revealed no significant histopathological or biochemical abnormalities in major organs, indicating good biocompatibility. In summary, this study offers a new MiRCM nanoparticle that effectively modulates lactate transport and eliminates ROS to suppress microglia M1 polarization and neuroinflammation, ultimately enhancing neural protection and functional recovery after ICH and TBI. Graphical The alternative text for this image may have been generated using AI. Schematic of MiRCM nanoparticles for ICH and TBI treatment
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DOI
高影响因子
MATERIALS & DESIGN
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2025
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IF 7.9
Jingmei Huang,Ning Wang,Xiaoxiao Huang,Shihong Huang,Guoliang Xie,Jianfeng Zhang,Zhengzhao Li
Traumatic brain injury (TBI) is characterized by oxidative stress, neuroinflammation, and microglial dysregulation, leading to secondary neuronal damage. Here, we constructed coordination polymer nanoenzymes (Fe-FN CPs) with multiple enzyme-like activities and favorable biocompatibility. In vitro, Fe-FN CPs suppressed ROS accumulation, reduced pro-inflammatory cytokine release, and promoted microglial polarization toward the M2 phenotype. In vivo, Fe-FN CPs enhanced antioxidant defense, alleviated mitochondrial damage and cerebral edema, restored blood–brain barrier integrity, and improved cognitive performance. Mechanistically, Fe-FN CPs achieved dual regulation by inhibiting pro-inflammatory M1 polarization while promoting anti-inflammatory M2 polarization. These findings demonstrate that Fe-FN CPs exert potent neuroprotective effects and provide a promising nanomedicine strategy for TBI therapy based on natural active compounds.
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DOI
高影响因子
Toxicology Research
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2025
·Vol. 14
·期 2
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IF 2.1
Fu Dan,Li Ziyou,Feng Huafeng,Fan Fangling,Zhang Wang,He Liang
Spinal cord injury (SCI)-induced ischemic delayed paralysis is one of the most serious side effects of aneurysms surgeries. Recent studies prove that the activation of autophagy, including macroautophagy and micro-autophagy pathways, occur during SCI-induced brain neuron damage. However, the role of chaperone mediated autophagy (CMA) during SCI remains to be unveiled. In the present work, rat model of delayed paralysis after aneurysms operation and adenovrius induced LAMP2A knockdown in microglia cells were applied in the present work to investigate the involvement of LAMP2A-mediated CMA in the aneurysm operation related SCI and delayed paralysis. The results showed that LAMP2A was upregulated in the SCI procedure, and contributed to neuron death and pro-inflammation perturbation via inducing iNOS+ polarization in microgila. We additionally observed that knockdown of LAMP2A resulted in the shift of microglia from iNOS+ to ARG1+ phenotype, as well as alleviated neuron damage during SCI. Furthermore, the analysis of BBB score, the result of immunohistological staining, and protein detection confirmed the activation of LAMP2A-mediated CMA activation and its interaction with NF-κB signaling, which leads to neuron death and motor function loss. These results prove that LAMP2A-mediated CMA contributes to the upregulation of pro-inflammatory cytokines and results in cell death in neurons during ischemic delayed paralysis via activating NF-κB signaling. Inhibition of LAMP2A promotes neurons survival during ischemic delayed paralysis.
研究领域:
神经科学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
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2025
·Vol. 39
·期 9
·e70561
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IF 4.2
Haocong Zhang,Xianyun Qin,Hong Yuan,Liangbi Xiang,Hailong Yu
Neuronal inflammation and apoptosis aggravate the secondary injury after spinal cord injury (SCI). Cathepsin L (CTSL) is a lysosomal cysteine protease with effects on the regulation of inflammation, but its role in SCI remains unclear. The in vivo T10 mouse spinal cord contusion model was established. The results showed that CTSL expression was increased following SCI and then gradually decreased. Moreover, CTSL was mainly expressed in microglia. To detect the function of CTSL, after contusive injury, the mice were immediately injected with lentiviruses carrying CTSL shRNA. The results showed that CTSL depletion promoted functional recovery, accompanied by increased locomotor ability. CTSL deficiency reduced lesion cavity areas by inhibiting neuronal apoptosis and neuroinflammation. Indeed, CTSL deficiency decreased the secretion of TNF-α, IL-6, and MCP-1 and M1 microglia polarization in the spinal cord. CTSL depletion inhibited the expression and assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In vitro, CTSL expression was increased in LPS-treated BV2 cells. CTSL silencing repressed LPS-induced M1 polarization, as evidenced by the reduction in TNF-α, IL-6, and MCP-1 expression in the supernatant of BV2 cells. CTSL knockdown induced the downregulation of NLRP3 expression and activation. The inhibition role of CTSL knockdown in microglial inflammation and M1 polarization was reversed by NLRP3 agonist. Collectively, the study suggests that CTSL induces the microglia M1 polarization-mediated inflammation via promoting NLRP3 activation and thereby inhibits functional recovery after SCI. Graphical The inhibition of CTSL improves functional recovery and alleviates neuroinflammation through microglial polarization after spinal cord injury. Mechanically, CTSL knockdown inhibited NLRP3 expression and activation, which repressed the production of pro-inflammatory cytokines in M1 microglia, thereby inhibiting spinal cord injury-induced neuroinflammation.
研究领域:
神经科学
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免疫学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Ruyi Zhu,Yaling Zhang,Weitai He,Yanan Sun,Xin Zhao,Yaping Yan,Qian Zhang
Wogonoside (WG) is a natural flavonoid extracted from Scutellariae Radix, recognized for its established anti-inflammatory properties. However, the role of WG in the context of neuroinflammation after spinal cord injury (SCI) remains inadequately elucidated. This study employed in silico , in vitro , and in vivo methodologies to investigate the impact of WG on microglia-mediated neuroinflammation after SCI. In the in silico experiment, we identified 15 potential target genes of WG associated with SCI. These genes were linked to the regulation of inflammatory response and immune defense. Molecular docking maps revealed toll-like receptor 4 as a molecular target for WG, demonstrating binding through a hydrogen bond (Lys263, Ser120). In lipopolysaccharide-stimulated BV2 cells and SCI mice, WG significantly attenuated microglial activation and facilitated a phenotype shift from M1 to M2. This was evidenced by the reversal of the increased expressions of Iba1, GFAP, and iNOS, as well as the decreased expression of Arg1. WG also suppressed the production of pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1α, IL-1β, C1q). WG exerted these effects by suppressing the TLR4/MyD88/NF-κB signaling axis in microglia. Furthermore, by reducing levels of TNF-α, IL-1α, and C1q in supernatant of LPS-induced microglia, WG indirectly induced astrocytes change to A2 phenotype, evidenced by transcriptome sequencing result of primary mouse astrocytes. All these events above collectively created a favorable microenvironment, contributing to a significant alleviation of weight loss and neuronal damage at the lesion site of SCI mice. Our findings substantiate the efficacy of WG in mitigating neuroinflammation after SCI, thereby warranting further exploration.
研究领域:
药理学
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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
MOLECULAR NEUROBIOLOGY
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2025
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IF 4.3
Xu Wenting,Zhou Mengjia,Li Linlin,Zhang Yuqing,Zhang Tianya,Zhang Xiangjian
Activated and polarized microglia regulate neuroinflammatory responses and programmed cell death processes in ischemic stroke. Although the inactivation of muscleblind-like 1 (Mbnl1) is known to cause structural defects in the brain, its role in microglial apoptosis and polarization remains unclear. This study aims to explore the mechanism of Mbnl1 in ischemic stroke, particularly its role in the regulation of microglial apoptosis and polarization, as well as its impact on neuroinflammatory responses and cognitive dysfunction. The expression level of Mbnl1 in the serum of stroke patients was determined. Furthermore, Mbnl1 was overexpressed in a C57BL/6N stroke model and an oxygen-glucose deprivation model in BV-2 cells. Changes in relevant marker proteins were detected using histological assays, cognitive function tests, enzyme-linked immunosorbent assay for inflammatory factor detection, flow cytometry for apoptosis assessment, immunofluorescence, and Western blot analysis. The expression level of Mbnl1 in the serum of stroke patients was determined. Furthermore, Mbnl1 was overexpressed in a C57BL/6N stroke model and an oxygen-glucose deprivation model in BV-2 cells. Changes in relevant marker proteins were detected using histological assays, cognitive function tests, enzyme-linked immunosorbent assay for inflammatory factor detection, flow cytometry for apoptosis assessment, immunofluorescence, and Western blot analysis. Mbnl1 overexpression exerts a protective effect against ischemic stroke by regulating microglia-mediated neuroinflammation through inhibition of the NF-κB signaling pathway. This modulation promotes cognitive recovery in C57BL/6N mice with stroke, highlighting Mbnl1 as a potential therapeutic target for stroke treatment.
研究领域:
神经生物学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Translational Neurodegeneration
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2025
·Vol. 14
·期 1
·1-27
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IF 15.2
Wang Jie,Ni Hong,Wang Yu,Wei Luyao,Ding Hanqing,Guo Zhongzhao,Pan Hao,Yu Ying,Luo Jia,Pan Weidong,Wang Deheng,Ke Zun-Ji
Background Alzheimer's disease (AD) is a neurodegenerative disease with major symptoms including memory and learning deficits. Neuroinflammation associated with reactive microglia promotes AD progression. These reactive microglia secrete prostaglandins, which are synthesized through the enzymatic activity of cyclooxygenase (COX)-1 and COX-2. Here, we aimed to elucidate the specific mechanisms of COX1 in AD pathogenesis and its interactions with neuroinflammatory processes.Methods We conducted backcrossing between COX-1 knockout (KO) and 5 × FAD mice to evaluate the effect of COX-1 deficiency on neuroinflammation. In addition, single-cell sequencing and microarray datasets from public databases and ingenuity pathway analysis in vitro were employed to explore gene expression profiles in the brains of AD mice.Results We identified a significant upregulation of COX-1 in 5 × FAD mice, with expression specifically localized to microglia in an age-dependent manner. Additionally, COX-1 KO alleviated neuroinflammation and accumulation of Aβ plaques, subsequently improving cognitive behavior in 5 × FAD mice. Moreover, microglia exhibited an amoeboid morphology in 5 × FAD mice, whereas in age-matched 5 × FAD/COX-1 KO mice, microglia had a ramified appearance. Additionally, our study demonstrated a pharmacological approach that inhibits the prostaglandin E2 (PGE2)/EP2 receptors via inhibition of the cAMP-PKA-NFκB-p65 pathway and NLRP3 inflammasome activation, producing similar beneficial effects as observed in COX-1 KO mice.Conclusion Our findings indicate that targeting the COX-1/PGE2/EP2 signaling pathway may alleviate neuroinflammation and impede AD progression. Moreover, the EP2 receptor presents a promising pharmacological target for mitigating the pathological effects associated with COX-1 activity in AD patients.
研究领域:
神经科学
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分子生物学
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药理学
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免疫学
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遗传学
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神经退行性疾病
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DOI
PubMed
高影响因子
Nutrients
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2026
·Vol. 18
·期 13
·2071
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IF 5.8
Jian-Qiang Wang,Bing-Bing Hu,Yi-Yue Wang,Ya-Wei Lu,Xiao-Jie Gong,Shan Tang,Ling-Jie Song,Yin-Shi Sun,Jing-Tian Zhang,Zi Wang,Wei Li
Objectives:Neuroinflammation is recognized as a significant characteristic of Alzheimer’s disease (AD). Currently, there is a notable absence of effective pharmacological agents to prevent or treat neuroinflammatory processes associated with AD. Heat shock protein 70 (HSP70) is pivotal in the progression of neuroinflammation. In this study, we explored the potential of maltol, a Maillard reaction product derived from red ginseng, as a therapeutic agent for neuroinflammation.Methods:In vitro, HMC3 microglial cell models were developed to examine the regulatory effects of gradient concentrations of maltol (12.5, 25, 50 μM) on the TLR4/MyD88/NF-κB p65 signaling pathway, neuroinflammation, and pyroptosis. Analyses of the GEO database and Gene Set Enrichment Analysis (GSEA) were performed to identify the core targets of maltol, followed by HSP70 gene silencing experiments to validate the targeted regulatory mechanism.Results:Maltol significantly mitigated LPS-induced neuronal damage and cognitive deficits in mice. It effectively suppressed microglia-mediated neuroinflammation and pyroptosis, reversed oxidative stress-induced neuronal ferroptosis, and inhibited neuronal apoptosis. In vitro experiments demonstrated that maltol obstructed TLR4/MyD88 binding, thereby inhibiting NF-κB p65-mediated neuroinflammation and pyroptosis, while also alleviating excessive ROS accumulation to enhance oxidative stress and ferroptosis. Bioinformatics analysis identified HSP70 as a crucial target for the anti-inflammatory and antioxidant effects of maltol. Subsequent gene silencing experiments confirmed that maltol exerted its inhibitory effects on LPS-induced neuroinflammation and pyroptosis in an HSP70-dependent manner.Conclusions:Maltol exhibits significant protective effects against Alzheimer’s disease-related neuroinflammation, oxidative stress, pyroptosis, and ferroptosis through the targeting of HSP70. This study elucidates the molecular mechanisms by which maltol improves neuroinflammatory injury and provides a novel theoretical foundation and therapeutic strategy for the intervention of Alzheimer’s disease neuroinflammation using traditional Chinese medicine.
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Ping Wang,Cong-Ying Song,Xuan Lu,Jia-Ning Zhou,Li-Ying Lin,Ting Li,Qin Zhang,Yuan-Qiang Lu
Diquat (DQ) is a widely utilized nonselective herbicide that is primarily used to control a wide range of weeds and crop residues. It also has significant environmental implications. DQ exposure can cause severe damage to the central nervous system (CNS), a critical symptom of acute poisoning that endangers patients. Despite its severity, the underlying mechanisms of DQ-induced toxic encephalopathy remain unclear, hindering the development of precise treatments. Our research demonstrated that acute DQ exposure in mice significantly increases oxidative stress and triggers neuroinflammation in the hippocampus. Furthermore, in vitro findings indicate that the detrimental effects of DQ are mediated by its disruption of autophagic processes, leading to exacerbated neural damage. DQ initially promotes autophagy in BV2 microglia for self-protection against oxidative stress and inflammation. However, this process is subsequently blocked, intensifying neural damage. Crucially, our results show that the activation of autophagy can reverse these adverse effects. This study not only sheds light on the intricate mechanisms of DQ neurotoxicity but also provides potential therapeutic targets for mitigating DQ-induced toxic encephalopathy.
研究领域:
神经科学
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毒理学
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药理学
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DOI
高影响因子
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