INTERNATIONAL IMMUNOPHARMACOLOGY
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2018
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IF 3.118
Lang Yi,Yan-jun Lyn,Chong Peng,Rui-li Zhu,Sha-sha Bai,Liang Liu,Pei-xun Wang,Hua Zhou,Yan Dong
Fibroblast like synoviocyte (FLS) is a crucial in the pathogenesis of rheumatoid arthritis (RA), and involved in inflammation and joint destruction. Sinomenine (SIN), an alkaloid derived from the plant Sinomenium acutum , has anti-inflammatory and analgesic effect and been used for RA treatment in China. Alpha 7 nicotinic acetylcholine receptors (α7nAChR), as the key receptor in cholinergic anti-inflammatory pathway (CAP) to inhibit inflammation, has been detected in RA patients synovium , but its role is still unclear. Here we investigated the association between the aggressive proliferation of FLS and α7nAChR expression and the effect of sinomenine. FLS was isolated from synovial tissues of adjuvant-induced-arthritis (AIA) rat. Tumor necrosis factor(TNF)-α was used to induce the aggressive proliferation of FLS. MTT assay was applied to evaluate the proliferation of FLS. The messenger RNA (mRNA) and protein levels of α7nAChR and early growth response gene-1 (Egr-1) were measured. The results showed that TNF-α induced FLS proliferation in vitro (P < .01) and increased the phosphorylation of ERK1/2 and the expression of Egr-1 and α7nAChR (P < .05 or P < .01). U0126 , the inhibitor of ERK1/2 inhibited α7nAChR expression and FLS proliferation significantly (P < .05 or P < .01). Specific short interference RNA(siRNA) of α7nAChR decreased α7nAChR expression and inhibited FLS proliferation as well. SIN inhibited the proliferation of FLS and decreased the phosphorylation of ERK1/2, and the expression of Egr-1 and α7nAChR induced by TNF-α (P < .05). In conclusion, the expression of α7nAChR involved in the aggressive proliferation of FLS induced by TNF-α and was regulated by ERK/Egr-1 signal pathway . SIN inhibited FLS proliferation and α7nAChR expression through inhibiting ERK/Egr-1 signal pathway, this may contribute to the anti-inflammatory and anti-arthritic effect of SIN.
研究领域:
免疫学
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药理学
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风湿病学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
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IF 6.656
Ying-kun Zhi,Jing Li,Lang Yi,Rui-li Zhu,Jin-fang Luo,Qing-ping Shi,Sha-sha Bai,Yan-wu Li,Qun Du,Jia-zhong Cai,Liang Liu,Pei-xun Wang,Hua Zhou,Yan Dong
Background Sinomenine (SIN) is an anti-inflammatory drug that has been used for decades in China to treat arthritis . In a previous study, SIN acted on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit inflammatory responses in macrophages, which indicates a new anti-inflammatory mechanism of SIN. However, the level of α7nAChR was increased in the inflammatory responses and was downregulated by SIN in vitro, so the underlying mechanisms of SIN acting on α7nAChR remain unclear. Purpose To analyze the role of α7nAChR in inflammation and the effect and mechanism of SIN regulation of α7nAChR. Methods The effects of SIN on α7nAChR in endotoxemic mice and LPS-stimulated macrophages were observed. Nicotine (Nic) was used as a positive control, and berberine (Ber) was used as a negative control targeting α7nAChR. The antagonists of α7nAChR, α-bungarotoxin (BTX) and mecamylamine (Me), were used to block α7nAChR. In RAW264.7 macrophage cells in vitro , α7nAChR short hairpin RNA (shRNA) was used to knock down α7nAChR. Macrophage polarization was analyzed by the detection of TNF-α, IL-6, iNOS, IL-10, Arg-1, and Fizz1. U0126 was used to block ERK phosphorylation. The cytokines α7nAChR, ERK1/2, p-ERK1/2 and Egr-1 were detected. Results SIN decreased the levels of TNF-α, IL-6 and the expression of α7nAChR increased by LPS in endotoxemic mice. The above effects of SIN were attenuated by BTX. In the α7nAChR shRNA transfected RAW264.7 cells, compared with the control, α7nAChR was knocked down, and M1 phenotype markers (including TNF-α, IL-6, and iNOS) were significantly downregulated, whereas M2 phenotype markers (including IL-10, Arg-1, and Fizz1) were significantly upregulated when stimulated by LPS. SIN inhibited the expression of p-ERK1/2 and the transcription factor Egr-1 induced by LPS in RAW264.7 cells, and the above effects of SIN were attenuated by BTX. The expression of α7nAChR was suppressed by U0126, which lessened the expression of p-ERK1/2 and Egr-1. Conclusions SIN acts on α7nAChR to inhibit inflammatory responses and downregulates high expression of α7nAChR in vivo and in vitro . The increase of α7nAChR expression is correlated with inflammatory responses and participates in macrophage M1 polarization. SIN downregulates α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1, which contributes to inhibiting macrophage M1 polarization and inflammatory responses.
研究领域:
免疫学
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药理学
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细胞生物学
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炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2022
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IF 6.633
Huiwen Wang,Jian Zhang,Xiaoxun Zhang,Nan Zhao,Zongtao Zhou,Lijian Tao,Lei Fu,Shifang Peng,Jin Chai
Cholestasis is characterized by intrahepatic accumulation of bile acids (BAs), resulting in liver injury, fibrosis, and liver failure. To date, only ursodeoxycholic acid and obeticholic acid have been approved for the treatment of cholestasis. As fluorofenidone (AKF-PD) was previously reported to play significant anti-fibrotic and anti-inflammatory roles in various diseases, we investigated whether AKF-PD ameliorates cholestasis. A mouse model of cholestasis was constructed by administering a 0.1 % 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) diet for 14 days. Male C57BL/6 J mice were treated with either AKF-PD or pirfenidone (PD) orally in addition to the DDC diet. Serum and liver tissues were subsequently collected and analyzed. We found that AKF-PD significantly reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile salts (TBA), as well as hepatic bile acids (BAs) levels. Hepatic histological analyses demonstrated that AKF-PD markedly attenuated hepatic inflammation and fibrosis. Further mechanistic analyses revealed that AKF-PD markedly inhibited expression of Cyp7a1, an enzyme key to BAs synthesis, by increasing Fxr nuclear translocation, and decreased hepatic inflammation by attenuating Erk/-Egr-1-mediated expression of inflammatory cytokines and chemokines Tnfα, Il-1β, Il-6, Ccl2, Ccl5 and Cxcl10. Moreover, AKF-PD was found to substantially reduce liver fibrosis via inhibition of Tgfβ1/Smad pathway in our mouse model. Here, we found that AKF-PD effectively attenuates cholestasis and hepatic fibrosis in the mouse model of DDC-induced cholestasis. As such, AKF-PD warrants further investigation as a candidate drug for treatment of cholestasis.
研究领域:
肝病学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2026
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IF 4
Zhang Xiaojuan,Song Yingying,Han Xinyan,Wang Mengxue,Chen Yufeng,Weng Yue,Li Yaxin,Huang Fei,Shi Hailian,Wu Hui,Wu Xiaojun
White peony root ( Paeonia lactiflora Pall.) is the dried root of peony. White peony root has a long history in Traditional Chinese Medicine (TCM) and is primarily used to treat various conditions, including pain, inflammation, and immune system disorders. Paeoniflorin (PF) is one of the main active components of white peony root, and it has multiple functions such as anti-inflammation, immune regulation, and neuroprotection. However, the impact of PF on multiple sclerosis (MS) remains to be fully elucidated. In this study, we observed that PF treatment markedly attenuated neurological symptoms in experimental autoimmune encephalomyelitis (EAE) mice, reduced disease severity, and alleviated spinal cord inflammation and demyelination, indicating a significant neuroprotective effect. PF administration was accompanied by reduced CD4 + T cell infiltration, decreased Th17 cell proportions, and increased Treg cell frequency in vivo. It also balanced Th17/Treg-associated cytokine secretion by suppressing IL-17 and promoting IL-10 expression. In addition, PF modulated the expression of differentiation-related proteins in lymphoid tissues and inhibited inflammatory gene and protein levels. In primary murine CD4 + T cells, PF enhanced Treg differentiation under Treg-polarizing conditions. In Jurkat cells, PF induced phosphorylation of Raf, MEK 1/2 , and ERK 1/2 , together with increased expression of Egr-1 and Foxp3. These findings indicate that PF treatment is associated with modulation of the Treg/Th17 balance in EAE mice and with changes in Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling in Jurkat cells. In summary, PF treatment ameliorated EAE manifestations, together with restoration of Treg/Th17 homeostasis and activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 pathway. However, whether the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis directly contributes to PF-induced Treg differentiation in primary T cells or to the therapeutic effects of PF in vivo remains to be determined. Graphical abstract PF treatment ameliorated EAE manifestations and was associated with reduced CD4 + T-cell infiltration, restoration of the Th17/Treg balance, and attenuation of CNS inflammation and demyelination in EAE mice. PF also enhanced Treg differentiation in primary murine CD4 + T cells and was associated with the activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis in Jurkat cells. The causal contribution of this signaling axis to Treg differentiation and the therapeutic effects of PF remains to be determined.
✓ 已验证
DOI
高影响因子
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