Medicina-Lithuania
·
2022
·Vol. 58
·期 12
·1749
·
IF 2.948
Aoqi Song,Zhenghua Wu,Wenjuan Zhao,Wenqing Shi,Ru Cheng,Jingjing Jiang,Zhuojun Ni,Han Qu,Xijier Qiaolongbatu,Guorong Fan,Yuefen Lou
Background and Objectives:Hypericum perforatum(HP) is widely used for depressive therapy. Nevertheless, the antidepressant effect and potential mechanism of hyperoside (Hyp), the main active component of HP, have not been determined. Materials and Methods: We performed ultra-performance liquid chromatography–quadrupole-time-of-flight–tandem mass spectrometry (UPLC-Q-TOF-MS/MS) technology to analyze the components in HP. Using data mining and network pharmacology methods, combined with Cytoscape v3.7.1 and other software, the active components, drug-disease targets, and key pathways of HP in the treatment of depression were evaluated. Finally, the antidepressant effects of Hyp and the mechanism involved were verified in chronic-stress-induced mice. Results: We identified 12 compounds from HP. Hyp, isoquercetin, and quercetin are the main active components of HP. The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), the Analysis Platform, DrugBank, and other databases were analyzed using data mining, and the results show that the active components of HP and depression are linked to targets such as TNF-, IL-2, TLR4, and so on. A potential signaling pathway that was most relevant to the antidepressant effects of Hyp is the C-type lectin receptor signaling pathway. Furthermore, the antidepressant effects of Hyp were examined, and it is verified for the first time that Hyp significantly alleviated depressive-like behaviors in chronic-stress-induced mice, which may be mediated by inhibiting the NLRP1 inflammasome through the CXCL1/CXCR2/BDNF signaling pathway. Conclusion: Hyp is one of the main active components of HP, and Hyp has antidepressant effects through the NLRP1 inflammasome, which may be connected with the CXCL1/CXCR2/BDNF signaling pathway.Keywords:depression;NLRP1 inflammasome;Hypericum perforatum;hyperoside;CXCL1/CXCR2;BDNF
研究领域:
药理学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Kai Yu,Lidan Fu,Yu Chao,Xiaodong Zeng,Yonggang Zhang,Yuanyuan Chen,Jialu Gao,Binchun Lu,Hua Zhu,Lijuan Gu,Xiaoxing Xiong,Zhenhua Hu,Xuechuan Hong,Yuling Xiao
Small interfering RNA (siRNA) targeting the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a promising therapeutic strategy to mitigate infarct volume and brain injury following ischemic stroke. However, the clinical translation of siRNA-based therapies is significantly hampered by the formidable blood-brain barrier (BBB), which restricts drug penetration into the central nervous system. To address this challenge, we have developed an innovative long-circulating near-infrared II (NIR-II) nanoparticle platform YWFC NPs, which is meticulously engineered to enhance BBB transcytosis and enable efficient delivery of siRNA targeting NLRP3 (siNLRP3@YWFC NPs) in preclinical models of ischemic stroke. Furthermore, we integrated advanced deep learning neural network algorithms to optimize in vivo NIR-II imaging of the cerebral infarct penumbra, achieving an improved signal-to-background ratio at 72 h poststroke. In vivo studies employing middle cerebral artery occlusion (MCAO) mouse models demonstrated that image-guided therapy with siNLRP3@YWFC NPs, guided by prolonged NIR-II imaging, resulted in significant therapeutic benefits.
研究领域:
神经科学
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药理学
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医学影像学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Zhihong Zhuo,Yao Wang,Huimin Kong,Tianjiao Fu
Neuroinflammation is a major component of epilepsy. Gut-enriched Kruppel-like factor (GKLF), a transcription factor of Kruppel-like factor family, has been reported to promote microglia activation and mediate neuroinflammation. However, the role of GKLF in epilepsy remains poorly characterized. This study focused on the function of GKLF in neuron loss and neuroinflammation in epilepsy and the molecular mechanism underlying microglia activation induced by GKLF upon lipopolysaccharides (LPS) treatment. An experimental epileptic model was induced by an intraperitoneal injection of 25 mg/kg kainic acid (KA). Lentivirus vectors (Lv) carrying Gklf CDS or short hairpin RNA targeting Gklf (shGKLF) was injected into the hippocampus, resulting in Gklf overexpression or knockdown in the hippocampus. BV-2 cells were co-infected with Lv-shGKLF or/and Lv carrying thioredoxin interacting protein ( Txnip ) CDS for 48 h and treated with 1 μg/mL LPS for 24 h. Results showed that GKLF enhanced KA-induced neuronal loss, pro-inflammatory cytokine secretion, activation of NOD-like receptor protein-3 (NLRP3) inflammasomes and microglia, and TXNIP expression in the hippocampus. GKLF inhibition showed negative effects on LPS-induced microglia activation, as evidenced by reduced pro-inflammatory cytokine secretion and activation of NLRP3 inflammasomes. GKLF bound to Txnip promoter and increased TXNIP expression in LPS-activated microglia. Interestingly, Txnip overexpression reversed the inhibitory effect of Gklf knockdown on microglia activation. These findings indicated that GKLF was involved in microglia activation via TXNIP. This study demonstrates the underlying mechanism of GKLF in the pathogenesis of epilepsy and uncovers that GKLF inhibition may be a therapeutic strategy for epilepsy treatment.
研究领域:
神经科学
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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
INTERNATIONAL JOURNAL OF NEUROSCIENCE
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2020
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IF 2.107
Xinguo Li,Jing Tong,Jihui Liu,Yibao Wang
Objective Alcohol abuse can cause severe injury to human brain. Astrocytes are the most abundant nonneuronal cells that function to maintain the brain homeostasis. In present study, we aimed to investigate the role of ROCK2 in astrocytes exposed to alcohol.Methods Astrocytes were transfected with lentivirus (LV)-anti-ROCK2 vector to downregulate the expression of ROCK2. The ROCK2 expression in mRNA and protein level was analyzed by real-time PCR and Western blotting, respectively. Cytokines or indicators involved in inflammation and oxidative stress were determined by assay kits. Proteins involved in nuclear factor kappa B (NF-κB) signaling pathway and NOD-like receptor protein 3 (NLRP3) inflammasome were analyzed by Western blotting.Results Alcohol exposure dramatically upregulated ROCK2 expression and lactate dehydrogenase (LDH) activity in astrocytes. On the contrary, transfecting with LV-anti-ROCK2 vector downregulated ROCK2 expression and LDH activity in astrocytes, demonstrating that downregulation of ROCK2 alleviated alcohol-induced astrocytic injury. Furthermore, downregulation of ROCK2 attenuated alcohol-induced inflammation by reducing the levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) and enhanced the level of anti-inflammatory IL-10. Downregulation of ROCK2 also attenuated alcohol-induced oxidative stress by reducing the reactive oxygen species (ROS) production, as well as enhancing the activity of anti-oxidative superoxide dismutase (SOD) and glutathione (GSH). More importantly, downregulation of ROCK2 inhibited the activation of NF-κB signaling pathway and NLRP3 inflammasome.Conclusion Therefore, ROCK2 could be a potential target to treat alcohol-induced astrocytic injury and the downregulation of ROCK2 might be a promising approach to protect against alcohol-induced astrocytic injury.
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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DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2019
·
IF 3.277
Yan Jiang,Hongjiao Du,Xue Liu,Xi Fu,Xiaodong Li,Qian Cao
There is increasing evidence that atherosclerosis is the significant risk factor for cardiovascular diseases, which are the leading causes of morbidity and mortality worldwide. Artemisinin is a natural endoperoxides quiterpene lactone compound in Artemisia annua L with vasculoprotective effects. The primary aim of this study was to investigate whether artemisinin could be conferred an anti-atherosclerotic effect in high-fat diet (HFD)-fed ApoE–/– mice and explore the possible mechanism. We found that treatment with artemisinin (50 and 100 mg/kg) effectively ameliorated atherosclerotic lesions, such as foam cell formation, hyperplasia and fibrosis in the aortic intima. Atherosclerotic mice treated with artemisinin showed reduced inflammation by up-regulating adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK) activation and by down-regulating nuclear factor-κB (NF-κB) phosphorylation and nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression in the aortas. In addition, artemisinin was found to promote AMPK activity in macrophages and its anti-inflammatory effect was neutralised by AMPK silence using specific siRNA. In conclusion, we demonstrate that artemisinin may protect the aortas from atherosclerotic lesions by suppression of inflammatory reaction via AMPK/NF-κB/NLRP3 inflammasomes signalling in macrophages.
研究领域:
心血管疾病
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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
EXPERIMENTAL ANIMALS
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2021
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IF 2.319
Jianhua Wu,Lizhen Wu,Li Zhang,Huanhuan Xu,Min Wang,Lin Wang,Jie Chen,Kaiyue Sun
Inflammatory allergic reaction is the main cause of allergic rhinitis (AR). Previous studies indicated that miR-224-5p was downregulated in the nasal mucosa of patients with AR, while the function of miR-224-5p in AR remains unclear. To explore this issue, AR mouse model was established using ovalbumin (OVA). For treatment group, lentivirus (LV)-miR-224-5p or its control was intranasally administrated to AR mice. miR-224-5p expression was detected by reverse transcription-quantitative PCR, followed by assessing the immunoglobulin E (IgE) level. Pathological alterations in nasal mucosa were detected using Hematoxylin-Eosin staining and Sirius red staining, followed by assessing the levels of inflammatory cells and factors. The NLRP3 inflammasome and TLR4/MyD88/NF-κB pathway were measured by Western blot, and then the relationship between miR-224-5p and toll-like receptor 4 (TLR4) was verified. The results showed that miR-224-5p was significantly decreased in nasal mucosa of AR mice. AR mice exhibited increased sneezing and nasal rubbing events, IgE level in serum, and pathological alterations in nasal mucosa, while overexpression of miR-224-5p markedly attenuated these changes. The levels of inflammatory cells in nasal lavage fluid and pro-inflammatory factors in serum and nasal mucosa were significantly increased in AR mice, which were reduced by miR-224-5p overexpression. Of note, LV-miR-224-5p treatment remarkably suppressed the activations of NLRP3 inflammasome and the TLR4/MyD88/NF-κB pathway in AR mice. Furthermore, miR-224-5p could bind to 3’-untranslated region (3’-UTR) of TLR4 and negatively regulate TLR4 level. Overall, we conclude that miR-224-5p may relieve AR by negatively regulating TLR4/MyD88/NF-κB pathway, indicating that miR-224-5p may be a promising target for AR treatment.
研究领域:
免疫学
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分子生物学
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过敏
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药理学
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产品关联
DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2023
·
IF 2.8
Yanli Song,Dongjie He,Shaoqi Shi,Tianwei Cui,Hui Zhang,Xianmin Zhao,Tingting Ni,Huidongzi Xiao,Aiwu Wei
BackgroundWomen with antiphospholipid syndrome (APS) or antiphospholipid antibodies (aPLs) are at high risk for obstetric complications, including recurrent pregnancy loss (RPL). However, effective treatments for RPL are lacking.ObjectiveThis study aimed to reveal the function and underlying mechanism of hyperoside (Hyp) in RPL associated with antiphospholipid antibodies (aCLs).MethodsThe pregnant rats (N = 24) were divided randomly into four groups: normal human-IgG (NH-IgG); aCL-pregnancy loss (aCL-PL); aCL-PL + Hyp (40 mg/kg/day); aCL-PL + low molecular weight heparin (LMWH, 525 μg/kg/day). HTR‐8 cells were treated with 80 μg/mL aCL to establish the cell models of miscarriage.ResultsIn pregnant rats, aCL-IgG injection raised the abortion rate of embryos, while Hyp treatment inhibited the effects. Additionally, Hyp inhibited the platelet activation and uteroplacental insufficiency caused by aCL. In vivo and in vitro experiments further suggested that Hyp suppressed aCL-induced inflammation and apoptosis by downregulating NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-related factors and decreasing apoptotic rates. After aCL administration, Hyp therapy downregulated the expression of purinergic ligand-gated ion channel 7 (P2X7), which is reported to induce cytokine release and apoptosis. Furthermore, we found that the treatment of 3′-O-(4-Benzoyl) benzoyl-ATP (BzATP, an agonist of the P2X7 receptor) reversed the inhibitory effects of Hyp on cell function.ConclusionsHyp exerts protective effects on aCL-induced pregnancy loss by preventing platelet activation-mediated P2X7/NLRP3 pathway. Therefore, Hyp may provide a feasible pharmaceutical strategy for the treatment of RPL.
研究领域:
妇产科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 8
·3482
·
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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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
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2023
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IF 6.1
Jing Qiu,Jun Guo,Liang Liu,Xin Liu,Xianhui Sun,Huisheng Chen
Microglia, which are the resident macrophages of the central nervous system, are an important part of the inflammatory response that occurs after cerebral ischemia. Vav guanine nucleotide exchange factor 1 ( Vav1 ) is a guanine nucleotide exchange factor that is related to microglial activation. However, how Vav1 participates in the inflammatory response after cerebral ischemia/reperfusion injury remains unclear. In this study, we subjected rats to occlusion and reperfusion of the middle cerebral artery and subjected the BV-2 microglia cell line to oxygen-glucose deprivation/reoxygenation to mimic cerebral ischemia/reperfusion in vivo and in vitro , respectively. We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral artery and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation. Silencing Vav1 reduced the cerebral infarct volume and brain water content, inhibited neuronal loss and apoptosis in the ischemic penumbra, and improved neurological function in rats subjected to occlusion and reperfusion of the middle cerebral artery. Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3 (NLRP3) inflammasome in the ischemic penumbra, as well as the expression of inflammatory factors. In addition, Vav1 knockdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxygenation. Taken together, these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/reperfusion through inhibiting the activation of microglia and NLRP3 inflammasome.
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
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 16
·8878
·
IF 4.9
Lanfei Wang,Nianfeng Qiu,Suyuan Tong,Yan Yu,Shuhua Xi,Fei Wang
Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO2exposure rat model and a long-term NaAsO2exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.
研究领域:
毒理学
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癌症研究
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2024
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IF 13.7
Cai Jiangxue,Li Chenxuan,Liu Suyuan,Tan Meiling,Sun Yiran,Sun Xiaoxiao,Yang Miaoxin,He Bin
The cellular stress response system in immune cells plays a crucial role in regulating the development of inflammatory diseases. In response to cellular damage or microbial infection, the assembly of the NLRP3 inflammasome induces pyroptosis and the release of inflammatory cytokines. Meanwhile, Angiogenin (Ang)-mediated transfer RNA-derived small RNAs (tsRNAs) promote cell survival under stressful conditions. While both tsRNAs and inflammasomes are induced under stress conditions, the interplay between these two systems and their implications in regulating inflammatory diseases remains poorly understood. In this study, it was demonstrated that Ang deficiency exacerbated sodium arsenite-induced activation of NLRP3 inflammasome and pyroptosis. Moreover, Ang-induced 5′-tsRNAs inhibited NLRP3 inflammasome activation and pyroptosis. Mechanistically, 5′-tsRNAs recruit DDX3X protein into stress granules (SGs), consequently inhibiting the interaction between DDX3X and NLRP3, thus leading to the suppression of NLRP3 inflammasome activation. Furthermore, in vivo results showed that Ang deficiency led to the downregulation of tsRNAs, ultimately leading to an exacerbation of NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and type-2 diabetes-related inflammation. Altogether, our study sheds a new light on the role of Ang-induced 5′-tsRNAs in regulating NLRP3 inflammasome activation via SGs, and highlights tsRNAs as a promising target for the treatment of NLRP3 inflammasome-related diseases.
研究领域:
免疫学
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分子生物学
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炎症
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代谢紊乱
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DOI
PubMed
高影响因子
International Journal of Ophthalmology
·
2021
·
IF 1.779
Rong Li,Lin Chen,Guo-Min Yao,Hong-Lin Yan,Li Wang
AIM To investigate the effects of quercetin on diabetic retinopathy (DR) and its association with nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome and autophagy using retinal endothelial cell as an experimental model. METHODS Human retinal microvascular endothelial cells (HRMECs) were cultured in vitro and assigned into the control group, high-glucose (HG) group, and HG+different concentrations of quercetin groups. Cellular viability, migration, and tube formation in these groups was detected by MTT, transwell and matrigel assay, respectively. Expressions of NLRP3, apoptosis-associated speck-like protein (ASC), cysteiny aspartate-specific protease-1 (Caspase-1) as well as microtubule-related protein 1 light chain 3 (LC3) and Beclin-1 were detected by Western blotting. Expressions of IL-1β and IL-18 were detected by ELISA and cellular autophagy was detected by Cyto-ID ® autophagy detection kit. RESULTS Under an HG condition, the viability, migration, tube formation of HRMECs, and the protein expressions of NLRP3, ASC, Caspase-1, IL-1β, IL-18, LC3, and Beclin-1 as well as autophagy were all increased. Quercetin inhibited angiogenesis of HRMECs as well as the expressions of NLRP3, ASC, Caspase-1, IL-1β, IL-18, LC3, Beclin-1, and autophagy of HRMECs under a HG condition. The inhibitory effects of quercetin on angiogenesis, NLRP3 inflammasome and autophagy increased with the increase of its concentration. CONCLUSION The therapeutic potential of quercetin in retinal neovascularization of DR, and inhibition of NLRP3 inflammasome and autophagy signaling pathway may be involved.
研究领域:
眼科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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