ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhao Tong,Zhou Zhi-ruo,Wan Hui-qi,Feng Tian,Hu Xu-hui,Li Xiao-qian,Zhao Shi-mei,Li Hong-lin,Hou Ji-wei,Li Wei,Lu Da-yun,Qian Min-yi,Shen Xu
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC 50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg −1 ·d −1 , i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
研究领域:
药理学
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肺病学
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分子生物学
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2026
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IF 11.5
Xiaojing Liu,Meng Zhang,Yue Zhang,Yining Hao,Dayun Lu,Wenjun Li,Xu Shen
Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a severe side effect lacking effective treatment, largely due to its complex and poorly understood pathogenesis. Here, we observed the pathological inhibition of phosphatase PPM1A activity in the dorsal root ganglia (DRG) tissues of PIPN mice. We also found that otilonium bromide (OB), as a PPM1A activator, ameliorated the PIPN-like pathology in mice, as evidenced by the alleviation of sensory dysfunction, myelin sheath injury, intraepidermal nerve fiber loss and vascular lesions. Using PPM1A-specific knockdown mice, we demonstrated that OB suppresses pro-inflammatory M1 macrophage polarization in the DRG through the PPM1A/NF-κB/NLRP3/IL-1β pathway, thereby alleviating axonal degeneration and neuronal apoptosis. In vitro experiments revealed that PTX-damaged DRG neurons release high-mobility group box 1 (HMGB1) to promote pro-inflammatory macrophage polarization, while OB disrupts this neuron-macrophage interaction by limiting HMGB1 release and subsequent macrophage activation. Together, our findings highlight PPM1A activation as a promising therapeutic strategy for PIPN and identify OB as a potential agent for treating this clinical side effect.
✓ 已验证
DOI
PubMed
高影响因子
LIFE SCIENCES
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2020
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IF 3.647
Li Li,Sufang Zhang,Lei Wei,Zhongfu Wang,Wei Ma,Fangying Liu,Yanhua Shen,Shanfang Zhang,Xiulian Zhang,Yu Hang,Yechang Qian
Aims To investigate the effect and underlying mechanism of melittin and tripartite motif (TRIM) family in human embryonic lung fibroblast (HELF). Materials and methods Lentiviral RNA interference vector and lentiviral overexpression vector were constructed and packaged by transfecting 293T cells; the proliferation of HELF was examined using Cell Counting Kit 8; Western blot and qRT-PCR were performed to examine protein and mRNA expression; the interaction with protein phosphatase magnesium-dependent 1A (PPM1A) was examined by Co-immunoprecipitation. Key findings Compared with the control group, the mRNA expression of the TRIM6, TRIM8 and TRIM47 in the IPF group significantly increased. Melittin inhibited the mRNA expression and protein expression levels of TRIM47, the HELF proliferation, the hydroxyproline levels, and the phosphorylation of Smad2/3; the interference of TRIM47 inhibited the protein expression of Vimentin, α-SMA, CTGF, the phosphorylation of Smad2/3 and the synthesis of hydroxyproline; TRIM47 overexpression elevated the phosphorylation of Smad2/3, induced ubiquitination of PPM1A and decreased the expression level of PPM1A, while TRIM47 RNA interference reversed this result. Significance Melittin has anti-fibrotic effect in HELF by directly reducing the phosphorylation of Smad2/3 or indirectly reducing the phosphorylation of Smad2/3 by decreasing the expression levels of TRIM47 whose overexpression induces ubiquitination of PPM1A.
研究领域:
药理学
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分子生物学
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细胞生物学
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肺纤维化
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）