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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DOI
PubMed
高影响因子
Cell Communication and Signaling
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2023
·Vol. 21
·期 1
·1-18
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IF 8.4
Liao Zhaohong,Lan Haiqiang,Jian Xiaoting,Huang Jingwen,Wang Han,Hu Jijie,Liao Hua
Background To explore the role of skeletal muscle specific TGF-β signaling on macrophages efferocytosis in inflamed muscle caused by Cardiotoxin (CTX) injection. Methods CTX myoinjury was manipulated in TGF-βr2 flox/flox (control) mice or transgenic mice with TGF-β receptor 2 (TGF-βr2) being specifically deleted in skeletal muscle (SM TGF-βr2 −/− ). Gene levels of TGF-β signal molecules, special inflammatory mediators in damaged muscle or in cultured and differentiated myogenic precursor cells (MPC-myotubes) were monitored by transcriptome microarray or qRT-PCR. TGF-β pathway molecules, myokines and embryonic myosin heavy chain in regenerating myofibers, the phenotype and efferocytosis of macrophages were evaluated by immunofluorescence, immunoblotting, Luminex, or FACS analysis. In vitro apoptotic cells were prepared by UV-irradiation. Results In control mice, TGF-β-Smad2/3 signaling were significantly up-regulated in regenerating centronuclear myofibers after CTX-myoinjury. More severe muscle inflammation was caused by the deficiency of muscle TGF-β signaling, with the increased number of M1, but the decreased number of M2 macrophages. Notably, the deficiency of TGF-β signaling in myofibers dramatically affected on the ability of macrophages to conduct efferocytosis, marked by the decreased number of Annexin-V − F4/80 + Tunel + macrophages in inflamed muscle, and the impaired uptake of macrophages to PKH67 + apoptotic cells transferred into damaged muscle. Further, our study suggested that, the intrinsic TGF-β signaling directed IL-10-Vav1-Rac1 efferocytosis signaling in muscle macrophages. Conclusions Our data demonstrate that muscle inflammation can be suppressed potentially by activating the intrinsic TGF-β signaling in myofibers to promote IL-10 dependent-macrophages efferocytosis.
Video Abstract
研究领域:
免疫学
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肌肉生物学
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细胞信号传导
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炎症
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Huimin Kong,Yao Wang,Dandan Song,Haohui Zhao,Zhihong Zhuo
Epilepsy is a chronic brain disorder characterized by recurrent epileptic seizures, which are caused by abnormal discharges of neurons in the brain. The Vav guanine nucleotide exchange factor (Vav1) has been reported to modulate inflammation and neuronal apoptosis; however, its role in epilepsy remains elusive. This study aimed to investigate the specific function of Vav1 in epileptogenesis and its underlying molecular mechanisms. Rats were challenged with lithium chloride-pilocarpine (LiCl-Pilo) treatment to induce epilepsy model. It was found a high expression of Vav1 in hippocampal tissue of epileptic rats. Vav1 knockdown reduced seizure frequency and mortality in epileptic rats. Besides, LiCl-Pilo treatment-induced spontaneous recurrent seizures was inhibited by Vav1 downregulation, as well as epileptic activity and abnormal sprouting of mossy fibers. We also showed that interfering with the expression of Vav1 alleviates seizure-induced cognitive impairment. Vav1 knockdown restrained neuronal damage and degeneration. Moreover, Sirtuin 1 (Sirt1) was found to regulate the histone acetylation of Vav1 promotor. Sirt1 activation increased the neuronal activity and decreased the neuronal apoptosis, while Vav1 overexpression reversed it. Additionally, the results of mRNA-seq indicated that Vav1 is related to neuronal function and apoptosis regulation. Our study demonstrated that Vav1 accelerates the development of epilepsy, and neuronal damage might be the critical event. These findings could provide a novel direction for epilepsy therapy.
研究领域:
神经科学
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分子生物学
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癫痫研究
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细胞信号传导
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Weilai Yu,Boyang Li,Luxi Chen,Qiu Chen,QingQing Song,Xiaosheng Jin,Yandan Yin,Haibin Tong,Liwei Xue
Ethnopharmacological relevance Dendrobium, recognized as “Shihu” in traditional Chinese medicine, holds a rich history of medicinal utilization documented in the Chinese Pharmacopoeia. Ancient texts like “Shen Nong Ben Cao Jing” extol Dendrobium 's virtues as a superior herbal medicine fortifying “Yin” and invigorating the five viscera. Dendrobium is extensively employed for the treatment of gastrointestinal inflammatory disorders, showcasing significant therapeutic efficacy, particularly against ulcerative colitis (UC), within the realm of Chinese ethnopharmacology. Dendrobium plays crucial pharmacological roles due to its rich content of polysaccharides, alkaloids, phenanthrenes, and bibenzyls. Gigantol, a prominent bibenzyl compound, stands out as one of the most vital active constituents within Dendrobium , the gigantol content of Dendrobium leaves can reach approximately 4.79 μg/g. Its significance lies in being recognized as a noteworthy anti-inflammatory compound derived from Dendrobium . Aim of the study Given the pivotal role of gigantol as a primary active substance in Dendrobium , the therapeutic potential of gigantol for gastrointestinal diseases remains enigmatic. Our present investigation aimed to evaluate the therapeutic effects of gigantol on dextran sulfate sodium (DSS)-induced colitis and reveal its potential mechanism in countering UC activity. Materials and methods The protective efficacy of gigantol against colitis was assessed by examining the histopathological changes and conducting biochemical analyses of colon from DSS-challenged mice. Assessments focused on gigantol's impact on improving the intestinal epithelial barrier and its anti-inflammatory effects in colonic tissues of colitis mice. Investigative techniques included the exploration of the macrophage inflammatory signaling pathway via q PCR and Western blot analyses. In vitro studies scrutinized macrophage adhesion, migration, and chemotaxis utilizing transwell and Zigmond chambers. Furthermore, F-actin and Rac1 activation assays detailed cellular cytoskeletal remodeling. The potential therapeutic target of gigantol was identified and validated through protein binding analysis, competitive enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. The binding sites between gigantol and its target were predicted via molecular docking. Results Gigantol ameliorated symptoms of DSS-induced colitis, rectified damage to the intestinal barrier, and suppressed the production of pro-inflammatory cytokines in colonic tissues. Intriguingly, gigantol significantly curtailed NF-κB signaling activation in the colons of DSS-induced colitis mice. Notably, gigantol impaired the β2 integrin-dependent adhesion and migratory capacity of RAW264.7 cells. Moreover, gigantol notably influenced the cytoskeleton remodeling of RAW264.7 cells by suppressing Vav1 phosphorylation and Rac1 activation. Mechanistically, gigantol interacted with β2 integrin, subsequently diminishing binding affinity with intercellular adhesion molecule-1 (ICAM-1). Conclusions In conclusion, these findings elucidate that gigantol ameliorates DSS-induced colitis by antagonizing β2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thus it may impede macrophage recruitment and infiltration into colonic tissues. This study suggests that gigantol shows promise as a viable candidate for clinical colitis therapy.
研究领域:
药理学
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免疫学
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炎症性肠病
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传统中药
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分子生物学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Jiangwei Ni,Ge Li,Ningfeng Dai,Zijiao Quan,Haibin Tong,Yu Liu
Objectives Acute lung injury (ALI) poses a serious threat to human health globally, particularly with the Coronavirus 2019 (COVID-19) pandemic. Excessive recruitment and infiltration of neutrophils is the major etiopathogenesis of ALI. Esculin, also known as 6,7-dihydroxycoumarin, is a remarkable compound derived from traditional Chinese medicine Cortex fraxini . Accumulated evidence indicates that esculin has potent anti-inflammatory effects, but its pharmaceutical effect against ALI and potential mechanisms are still unclear. Methods This study evaluated the protective effect of esculin against ALI by histopathological observation and biochemical analysis of lung tissues and bronchoalveolar lavage fluid (BALF) in lipopolysaccharide (LPS)-challenged ALI mice in vivo . The effects of esculin on N-formyl-met-leu-phe (fMLP)-induced neutrophil migration and chemotaxis were quantitatively assessed using a Transwell assay and an automated cell imaging system equipped with a Zigmond chamber, respectively. The drug affinity responsive target stability (DARTS) assay, in vitro protein binding assay and molecular docking were performed to identify the potential therapeutic target of esculin and the potential binding sites and pattern. Results Esculin significantly attenuated LPS-induced lung pathological injury, reduced the levels of pro-inflammatory cytokines in both BALF and lung, and suppressed the activation of NF-κB signaling. Esculin also significantly reduced the number of total cells and neutrophils as well as myeloperoxidase (MPO) activity in the BALF. Esculin impaired neutrophil migration and chemotaxis as evidenced by the reduced migration distance and velocity. Furthermore, esculin remarkably inhibited Vav1 phosphorylation, suppressed Rac1 activation and the PAK1/LIMK1/cofilin signaling axis. Mechanistically, esculin could interact with β 2 integrin and then diminish its ligand affinity with intercellular adhesion molecule-1 (ICAM-1). Conclusions Esculin inhibits β 2 integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.
研究领域:
药理学
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免疫学
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病理生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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