BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2025
·Vol. 136
·期 5
·e70027
·
IF 3.3
Mengjie Guo,Han Meng,Yi Sun,Lianxin Zhou,Tingting Hu,Tianyi Yu,Haowen Bai,Yuanjiao Zhang,Chunyan Gu,Ye Yang
Multiple myeloma (MM) is an incurable hematologic malignancy, driving significant interest in the discovery of novel therapeutic strategies. Bruceine A (BA), a tetracyclic triterpene quassinoid derived from Brucea javanica , has shown anticancer properties by modulating multiple intracellular signalling pathways and exhibiting various biological effects. However, the specific pharmacological mechanisms by which it combats MM remain unclear. In this study, we identified USP13 as a potential target of BA. We observed a significant increase in USP13 expression in patients with MM, which was strongly associated with a poorer prognosis. Furthermore, enhanced USP13 expression can stimulate MM cell proliferation both in vitro and in vivo. Mass spectrometry analysis, combined with co-immunoprecipitation and in vitro ubiquitination experiments, revealed PARP1 as a critical downstream target of USP13. USP13 can stabilize PARP1 protein through deubiquitination, promoting PARP1-mediated DNA damage repair (DDR) and facilitating MM progression. Notably, we utilized MM cell lines, an MM Patient-Derived Tumour Xenograft model, and a 5TMM3VT mouse model to determine the anticancer effects of BA on MM progression, revealing its potential to target USP13/PARP1 signalling and disrupt DDR in MM cells. In conclusion, these findings suggest that BA inhibiting USP13/PARP1-mediated DDR might be a promising therapeutic strategy for MM.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Hao Yan,Xiangliang Huang,Jiangxin Xu,Ying Zhang,Jiajia Chen,Zhifei Xu,Hui Li,Zeng Wang,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
研究领域:
药理学
·
肿瘤学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
2025
·
IF 2.5
Xiaoli Liu,Shan Wang,Chuangfu Kuang,Yuwen Deng,Shuaicai Yuan,Juying Zou
We aim to explore the key metabolic components and underlying mechanisms of the Bushen Huoxue Formula (BH) in treating Osteoarthritis (OA). The mouse knee OA model was constructed using the destabilization of the medial meniscus method. OA mice were orally administered the BH. Mouse cartilage damage was assessed. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS), network pharmacology analysis and molecular docking were employed to analyze the serum metabolite components and target protein of BH. After lipopolysaccharide (LPS) treatment, different concentrations of β-Estradiol 3-acetate were added to primary chondrocytes. Flow cytometry was utilized for detecting cell apoptosis. The Ubiquitin-Specific Protease 13 (USP13)/Toll-like Receptor 4 (TLR4)/Myeloid Differentiation Primary Response Protein 88 (MYD88)/NF-κB pathway and the TLR4 ubiquitination levels were assessed using immunological quantification and biochemical methods. Relative to normal mice, OA mice exhibited decreased knee joint cartilage thickness and increased inflammatory damage. BH treatment reversed these effects. Furthermore, BH enhanced TLR4 ubiquitination. Estradiol acetate was identified as the metabolic component of BH that alleviates OA. Estradiol acetate and its subtype molecule β-Estradiol 3-acetate could bind to the USP13 protein. The β-Estradiol 3-acetate concentration-dependently decreased the elevated levels of USP13, TLR4, MYD88, p-p65/p65 in chondrocytes induced by LPS, while increasing the TLR4 ubiquitination. β-Estradiol 3-acetate reversed LPS-induced chondrocyte apoptosis and elevation of inflammatory factors. Moreover, USP13 overexpression abolished the protective effects of BH and β-Estradiol 3-acetate against LPS-induced chondrocytes. In Conclusion, the BH metabolite β-Estradiol 3-acetate promotes TLR4 ubiquitination to relieve inflammation and apoptosis in OA chondrocytes by inhibiting USP13.
研究领域:
药理学
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中医中药
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分子生物学
·
风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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