Reproductive and Developmental Medicine
·
2024
·Vol. 9
·期 1
·22
·
IF 0.7
Chen Xi,Zuo Wei-Wen,Zhang Guo-Dong,Xu Cong-Jian
Objective: Immune dysfunction plays an important role in the pathogenesis of endometriosis. C5a, a by-product of complement activation, binds to its receptor (C5a receptor 1, C5aR1) in various cells, including macrophages. The combination of C5a and C5aR1 in macrophages induces M2 polarization. There is no consistent conclusion regarding macrophage polarization status and its participation in the pathogenesis of endometriosis. Methods: We analyzed the expression of C5aR1 and the immunophenotype of macrophages in samples from patients with endometriosis using immunohistochemistry and flow cytometry. We tested the equivalent item in a mouse model and the THP-1 cell line in vivo and in vitro . Single-cell RNA sequencing (scRNA-seq) from the Gene Expression Omnibus (GEO, GSE213216) was used to investigate the phenotype and function of C5aR1 + macrophages. Results: The infiltration of C5aR1 + macrophages was associated with the severity of endometriosis. C5aR1 + macrophages polarized more toward the M2 phenotype and transformed into an immunosuppressive state. Inhibiting C5aR1 using PMX-53 decreased the expression of C5aR1 + macrophages and reduced their polarization to the M2 phenotype, consequently shrinking lesion size in a mouse model. Conclusion: Our study emphasizes the importance of C5aR1 and the macrophage phenotype in the pathogenesis of endometriosis. We propose PMX-53 as a potential therapeutic agent for endometriosis.
研究领域:
免疫学
·
生殖医学
·
分子生物学
✓ 已验证
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zong-hui Xu,Man Li,Lin Liu,Shu-jing Wu,Ruo-an Wei,Mpofu Uphakeme Inobubele Sitholumusa,Xiao-ping Zhao,Jun-qiu Liu,Guo-yin Kai
Astragaloside IV (AS-IV), derived from Astragalus membranaceus , exhibits significant anti-inflammatory properties in a variety of diseases. However, the specific anti-inflammatory mechanism of AS-IV depends on the different organs and doses. Its protective effect is still unknown in acute lung injury (ALI). This study aims to investigate the potential anti-inflammatory mechanism of AS-IV in ALI. Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were utilized to form pyroptosis models in MH-S and RAW264.7 cells. Mouse model of ALI was induced by intranasal LPS administration. In addition, the anti-pyroptosis effect of AS-IV was evaluated by using the C5aR1 agonists BM-213, the C5aR1 overexpression plasmids and C5aR1 siRNA. AS-IV significantly reduced pulmonary edema, improved histopathological injury, and decreased inflammatory factors. Meanwhile, AS-IV reduced ROS level and the amount of NLRP3 and GSDMD-N in vitro and in vivo . Inhibiting C5aR1 can effectively and significantly alleviate the pyroptosis of alveolar macrophages. Further studies found that BM-213 and C5aR1 overexpression plasmids partially reversed the anti-pyroptosis effect of AS-IV. The anti-pyroptosis effect of AS-IV was significantly inhibited when C5aR1 was knocked down. Our study demonstrate that AS-IV has anti-inflammatory protective effects on LPS-induced ALI, indicating that AS-IV may be a potential therapeutic agent for the treatment of ALI. This effect may be achieved by reducing the content of C5a, lowering the expression of C5aR1, and inhibiting cell pyroptosis.
研究领域:
药理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2025
·
IF 11.9
Miao Zhang,Shan Gao,Nannan Tan,Yu Yan,Rongxin Zhu,Jiajing Liu,Qin Mao,Keyan Wang,Wenhao Zhang,Gang Wang,Zhuo Wang,Tieshan Wang,Xueshi Huang,Rong Zhang,Baofeng Yang
The complement system activation-induced inflammation is a critical contributor to myocardial ischemia/reperfusion (I/R) injury. However, effective therapeutic targets and pharmacological interventions remain limited. In this study, we identified 13-methylpalmatine (13-Me-PLT), a natural isoquinoline alkaloid isolated from Coptidis chinensis , as a cardio-protective agent that improved cardiac function and reduced inflammation in a rat model of myocardial I/R injury. RNA sequencing (RNA-seq) analysis revealed significant up-regulation of neutrophil extracellular trap (NET) formation-related signaling pathway and C5ar1 gene in myocardial I/R, both of which were reversed by 13-Me-PLT treatment. Bioinformatics analysis, biophysical assays, and flow cytometry confirmed that 13-Me-PLT effectively inhibited C5a receptor 1 (C5aR1) on neutrophils. However, the role of the C5a-C5aR1 axis in NET formation during myocardial I/R injury has remained unclear. In this study, using a pharmacological inhibitor of C5aR1, we demonstrated that activation of the C5a-C5aR1 axis promoted myocardial I/R injury by inducing NET formation, and that 13-Me-PLT effectively inhibited both processes in a BM213 (C5aR1 agonist)-treated rat model. In vitro , 13-Me-PLT suppressed the expression of NET-associated proteins and alleviated fibrous NET structures in neutrophils, further supporting its cardio-protective effects. In conclusion, our findings revealed that C5a-C5aR1 axis activation exacerbated myocardial I/R injury in a NET-dependent manner. 13-Me-PLT exerted cardio-protective effects by potentially inhibiting C5a-C5aR1 axis-mediated NET formation, highlighting its potential as a therapeutic candidate for myocardial I/R injury.
研究领域:
药理学
·
心脏病学
·
免疫学
·
分子生物学
·
生物医学研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jing Guo,Qi-Yun Zhang,Lin Xu,Min Li,Qian-Yun Sun
Acute lung injury (ALI) is an acute respiratory-related progressive disorder, which lacks specific pharmacotherapy. Icariin (ICA) has been shown to be effective in treating ALI. However, the targets and pharmacological mechanisms underlying the effects of ICA in the treatment of ALI are relatively lacking. Based on network pharmacology and molecular docking analyses, the gene functions and potential target pathways of ICA in the treatment of ALI were determined. In addition, the underlying mechanisms of ICA were verified by immunohistochemistry, immunofluorescence, quantitative Real-time PCR, and Western blot in LPS-induced ALI mice. The biological processes targeted by ICA in the treatment of ALI included the pathological changes, inflammatory response, and cell signal transduction. Network pharmacology, molecular docking, and in vivo experimental results revealed that ICA inhibited the complement C5a-C5aR1 axis, TLR4 mediated NF-κB, MAPK, and JAK2-STAT3 signaling pathways related gene and protein expressions, and decreased inflammatory cytokine, chemokine, adhesion molecule expressions, and mitochondrial apoptosis in LPS-induced ALI.
研究领域:
药理学
·
免疫学
·
分子生物学
·
呼吸医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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