Yuanyuan Ding,Tianyou Ma,Yonghui Zhang,Chenrui Zhao,Chao Wang,Zhao Wang
Background Allergic contact dermatitis (ACD) is one of the most common dermatoses, which has high disease burden and quality of life impairment. Anti-histamine is not effective in a part of the ACD patients. Thus, the discovery of novel antipruritic therapy is of highly demand. Objective In this study, we investigated the anti-pruritic effects of rosmarinic acid (RA) and explored the underlying mechanism. Method SPF Balb/c mice were randomly divided into control group, ACD model group, RA group (1.0 mg/kg) and loratadine (LORA) group (1.5 mg/kg). Back epidermal thickness was recorded. H&E staining was used for pathological observation. Mast cell degranulation was assessed by toluidine blue staining. ELISA assay was employed to detect cytokines levels. Cortistatin-14 (CST-14) and Mas-related G protein-coupled receptor X2 (MRGPRX2) expression was detetcted by RT-PCR and western blot. Molecular docking assay was used to predict the affinity of RA and MRGPRX2. Surface plasmon resonance (SPR) assay was used to verify structure affinity of RA and MRGPRX2. Results RA treatment significantly decreased epidermal keratinization and inflammatory cell infiltration in ACD mouse model. Administration of RA significantly reduced secretion of histamine, IL-13, and mRNA expression of CST-14. Furthermore, RA treatment increased mRNA expression of MRGPRX2. In addition, Molecular docking results predict that RA has a good affinity with MRGPRX2. RA displayed a structure affinity ( K D = 8.89 × 10 -4 ) with MRGPRX2 by SPR. RA inhibited CST-14 and Compound 48/80 (C48/80)-induced mast cell activation via MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. Conclusion RA exhibits anti-pruritic and anti-inflammatory effects in ACD mice by inhibiting MRGPRX2-PLCγ1-PKC-NF-κB signaling pathway. RA might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD.
Ma Ya-nan,Wang Zijie,Liang Yuchang,Tan Guoao,Hu Xiqi,Xia Ying
This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer’s disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ 1–42 . Immunofluorescence and biochemical assays were employed to assess the impact of OM-MSCs-Exo and its secreted protein FGFR1 on microglial polarization. Protein–protein interactions and immunoprecipitation were used to identify the target proteins of FGFR1 in microglial cells. Additionally, the effects of OM-MSCs-Exo-induced microglial polarization on neuronal inflammation and cognitive function in mice were evaluated. OM-MSCs-Exo were successfully isolated and purified. FGFR1 was significantly upregulated in OM-MSCs-Exo compared to OM-MSCs. Aβ 1–42 induced M1 polarization and suppressed M2 polarization of microglia, which was reversed by OM-MSCs-Exo. FGFR1 overexpression in OM-MSCs-Exo further enhanced M2 polarization in microglial cells. Phospholipase C gamma 1 (PLCγ1) was identified as the target of FGFR1, and knocking down PLCγ1 reversed the effects of FGFR1-overexpressing OM-MSCs-Exo. OM-MSCs-Exo alleviated cognitive decline and neuroinflammation in AD mice, with FGFR1 overexpression further enhancing these effects. OM-MSCs-Exo promote M2 polarization of microglia in AD mice through the FGFR1/PLCγ1 pathway, alleviating neuronal inflammation and cognitive dysfunction.
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