Author: Yang, Xu ; Xue, Hang ; Zhao, Ping ; Ding, Zixuan ; Jia, Yufei ; Fan, Shiyue ; Song, Yanhong ; Li, Xingyue ; Zhang, Yinong ; Wu, Ziyi ; Qiu, Yue

Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 minutes of 2.5% sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.

01 Jan 2025·Cellular Signalling

MFGE8 promotes gastric cancer progression by activating the IL-6/JAK/STAT3 signaling

Article

Author: Liu, Hui ; Ding, Long-long ; Liu, Peng-fei ; Ding, Long-Long ; Zhang, Tao ; Zhang, Meng ; Liu, Peng-Fei

OBJECTIVEGastric cancer is malignant cancer with high morbidity and mortality worldwide. Milk fat globule EGF and factor V/VIII domain containing (MFGE8) was involved in many cancers. Nevertheless, the role of MFGE8 in gastric cancer remained indistinct. To probe the role of MFGE8 in gastric cancer and further explore the regulating mechanism.METHODSGEPIA was employed for analysis of MFGE8 expression and survival of gastric cancer patients. MFGE8 expression in gastric cancer was determined by immunohistochemistry, PCR, and western blot. The effect of MFGE8 on gastric cancer cells were evaluated by a series of cell function experiments. The mechanism of MFGE8 on gastric cancer was analyzed by GSEA and verified by in vitro and in vivo experiments.RESULTSMFGE8 was over-expressed in gastric cancer. Silence of MFGE8 suppressed cell viability, proliferated ability, migrated and invasive ability, and EMT, but accelerated cell apoptosis. The opposite results were obtained in MFGE8-overexpressed gastric cancer cells. Zinc finger and BTB domain containing 7 A (ZBTB7A) was a transcription factor of MFGE8. ZBTB7A overexpression eliminated the effect of MFGE8 on gastric cancer cells. MFGE8 activated the IL-6/JAK/STAT3 signaling. Inhibition of IL-6/JAK/STAT3 signaling by Stattic (pathway inhibitor) could eliminate the promoting effect of MFGE8 on IL-6/JAK/STAT3 signaling. In addition, MFGE8 shRNA inhibited tumor growth.CONCLUSIONMFGE8 promoted cell proliferation, EMT progress, and tumor growth of gastric cancer by activating the IL-6/JAK/STAT3 signaling.

01 Dec 2024·International Immunopharmacology

P. Gingivalis induce macrophage polarization by regulating hepcidin expression in chronic apical periodontitis

Article

Author: Yang, Lei ; Huang, Dingming ; Dou, Jinge ; Lin, Jie ; Zhang, Jinglan ; Zhu, Wanling ; Tan, Xuelian ; Chen, Xuan

INTRODUCTIONHepcidin, a central regulatory molecule of iron metabolism, is upregulated through the IL-6/STAT3 signaling pathway in inflammatory and infectious states, contributing to the pathogenesis of various diseases. In chronic apical periodontitis (CAP), Porphyromonas gingivalis (P. gingivalis) and its lipopolysaccharides (LPS) activate various immune responses in vivo, contributing to disease progression. This study evaluated the role and mechanism of hepcidin in P. gingivalis-induced bone tissue damage in CAP, focusing on its promotion of macrophage M1 polarization via the IL-6/STAT3 signaling pathway.METHODSWe analyzed a GSE77459 dataset from the GEO database, containing data from inflammatory and normal dental pulp tissues. RT-qPCR and immunofluorescence staining were used to detect the expression of hepcidin in human CAP tissues and its relationship with macrophages. Mouse bone marrow derived macrophages (BMDMs) were cultured in vitro and stimulated with P. gingivalis LPS. The effects of Stattic on macrophage hepcidin expression, IL-6 expression, STAT3 phosphorylation, and macrophage polarization were detected by ELISA, western blotting, RT-qPCR, and flow cytometry, respectively.RESULTSHepcidin expression in human inflammatory dental pulp tissues was upregulated via the IL-6/STAT3 pathway and correlated with macrophage polarization. Hepcidin-encoding genes were found to be highly expressed and primarily associated with M1 macrophages in CAP tissues. In vitro experiments revealed that P. gingivalis LPS stimulation induced macrophages to express hepcidin through the IL-6/STAT3 pathway and polarize to M1. Additionally, the IL-6/STAT3 pathway inhibitor Stattic suppressed these changes.CONCLUSIONSOur study demonstrates that in CAP, macrophages highly express hepcidin, which subsequently alters macrophage metabolism, regulates M1 polarization, and leads to bone tissue destruction.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	DE	Max Planck Institute of Biochemistry	01 Nov 2006

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