Frontiers in Pharmacology
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2025
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IF 4.8
Tianyao Li,Jiaxin Chen,Zhouyuan Xie,Jiansong Fang,Qiqing Wu,Xinyue Cao,Ziying Chen,Yiyun Wang,Qiqi Fan,Qi Wang,Jinman Liu
Introduction Ginseng, known as the “king of herbs,” has long been used in traditional Chinese medicine due to its beneficial properties, including anti-aging, anti-inflammatory, and anti-apoptotic effects. Ginsenosides, the active compounds in ginseng, have shown promise in treating neurodegenerative diseases such as Alzheimer’s disease (AD). This study investigates the therapeutic potential of Ginsenoside Ro and its underlying mechanisms in AD treatment. Methods In this study, male APP/PS1 transgenic mice were divided into five groups and treated with Ginsenoside Ro or ginseng for one month. Cognitive function and anxiety were assessed through behavioral tests, including the open field test (OFT) and Morris water maze (MWM). To evaluate Aβ deposition, neuronal apoptosis, neuroinflammation, and the MAPK pathway, various techniques were employed: Thioflavin-T staining, Nissl staining, immunofluorescence, Western blot, and qRT-PCR analyses. Results Ginsenoside Ro significantly improved cognitive function and reduced anxiety in APP/PS1 mice. It also decreased Aβ deposition and ameliorated neuronal apoptosis in the cerebral cortex. The treatment regulated the expression of pro-apoptotic proteins (Bax and Caspase3) and increased the anti-apoptotic protein Bcl-2. Additionally, Ginsenoside Ro reduced neuroinflammation by decreasing IBA1-positive microglia and GFAP-positive astrocytes and lowering pro-inflammatory cytokines while enhancing anti-inflammatory cytokine IL-10. Furthermore, the phosphorylation levels of p38 and JNK in the MAPK pathway were significantly reduced, suggesting a key mechanism for its therapeutic effects. Discussion These findings provide strong evidence supporting Ginsenoside Ro as a potential therapeutic agent for Alzheimer’s disease. Its effects appear to be mediated through the modulation of the IBA1/GFAP-MAPK pathway, which may offer new insights into AD treatment strategies.
研究领域:
神经科学
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药理学
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中医药
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DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2022
·
IF 3.197
Lingjun Yang,Gang Zhou,Junming Chen,Sainan Zhang
Background Based on the previous findings on the relieving role of gelsemine in neuropathic pain, this research aims to further investigate the relevant regulatory mechanism. Methods Targets of gelsemine were predicted using SwissTargetPrediction. The peripheral neuropathic pain rat model was established by ligating spinal nerves, and then gelsemine (10 μg for one day) or dipeptidyl peptidase 4 (DPP4) oligonucleotides (5 μg/day, for 7 days) was injected into intrathecal bolus of rats. The mechanical threshold (0, 1, 2, 4 h after the last injection) was examined to evaluate the mechanical allodynia of rats. After the mechanical threshold measurement, the rats were anesthetized with isoflurane and then sacrificed by cervical dislocation. IBA1- and DPP4-positive cells in the spinal dorsal horn of rats were determined using immunohistochemistry and immunofluorescence assays. The expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats were measured by Western blot and quantitative real-time PCR. Results DPP4 was one of the targets of gelsemine. Gelsemine could elevate the down-regulated mechanical threshold, and lessen the up-regulated IBA1- and DPP4-positive cells and expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats with neuropathic pain. DPP4 overexpression reversed the role of gelsemine in neuropathic pain. Conclusion Gelsemine relieves neuropathic pain by down-regulating DPP4 level in rats, providing a novel drug candidate and biomarker for neuropathic pain treatment.
研究领域:
药理学
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神经科学
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疼痛管理
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2022
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IF 9.988
Ying Tu,Yongyong Yang,Yue Wang,Nana Wu,Junyan Tao,Guanghong Yang,Mingdan You
Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.
研究领域:
神经科学
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毒理学
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细胞生物学
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发育生物学
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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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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2022
·Vol. 48
·期 2
·625-640
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IF 4.414
Hui Yuzuo,Zhao Han,Shi Lei,Zhang Haitao
8-Methoxypsoralen (8-MOP) has anti-inflammatory, antioxidant and tissue-repairing abilities. Here, we probed the function and mechanism of 8-MOP in traumatic brain injury (TBI). The in - vivo TBI model was constructed in Sprague-Dawley (SD) rats using controlled cortical impact (CCI) surgery. In parallel, BV2 microglia and HT22 neurons were activated by lipopolysaccharide (LPS) to establish an in-vitro model. The modified neurological score (mNSS) and the Morris water maze experiment were employed to evaluate the rats’ neurological functions. The rats’ brain edema was assessed by the dry and wet method, and neuronal apoptosis in damaged brain tissues was monitored by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and Nissl’s staining. Immunohistochemistry (IHC) was applied to verify Iba1-microglial activation in brain lesions of rats. The expression of inflammatory cytokines in BV2 microglia and HT22 neurons in the injured lesion of TBI rats was examined by the enzyme-linked immunosorbent assay (ELISA). The levels of iNOS, COX2, TLR4, PPARγ, STAT3, and NF-κB in brain lesions, BV2 microglia and HT22 neurons were compared by Western blot. As a result, 8-MOP administration reduced inflammation and LPS-induced neuronal damage in BV2 microglia. In vivo, 8-MOP treatment relieved neurological deficits in TBI rats, improved cognitive, learning and motor functions and mitigated brain edema and neuroinflammation induced by TBI. Furthermore, LPS or TBI activated the NF-κB and STAT3 pathways and repressed the PPARγ expression. However, 8-MOP treatment attenuated NF-κB and STAT3 phosphorylation and elevated PPARγ levels. Hence, 8-MOP exerts neuroprotective and anti-inflammatory effects in TBI rats by modulating the PPARγ/NF-κB pathway.
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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神经保护
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2018
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IF 2.559
Fan Zhang,Chenhong Zhang
Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb)-incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112 −/− ) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112 −/− mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, was observed in perihematoma tissues of Rnf112 −/− mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKα, inhibitor of NF-κB (IκBα) and nuclear factor-kappa B (NF-κB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112 −/− mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS)-incubated glial cells . In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF-κB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development.
研究领域:
神经科学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
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