PHYTOMEDICINE
·
2025
·
IF 8.3
Jun Wang,Yongzheng Liu,Chongxiang Sun,Long Chen,Sikai Chen,Xingyu Huang,Zhijia Lu,Chunliu Dong,Yadan Zheng,Zhiyun Zhang,Yanyan Liu,Qianwei Qu,Yanhua Li
Background : Streptococcus suis is a zoonotic pathogen that causes meningitis, septicaemia, endocarditis, arthritis, and pneumonia in human beings. With the increasing prevalence of S. suis infections and a general decline in the effectiveness of antibiotics, the development of novel drugs that have effect on S. suis is extremely urgent. Emodin, a natural anthraquinone derivative of Rheum palmatum L., Reynoutria japonica Houtt., Polygonum multiflorum Thunb. and Cassia obtusifolia L., has been reported to exert anti- S. suis effect; however, the specific mechanism of the anti- S. suis action by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ (FabF) in the fatty acid synthesis pathway remains unexplored. Purpose: We sought to reveal the potential role of emodin to prevent S. suis infection, investigate its mechanism of anti- S. suis action, and provide further evidence of emodin as an alternative to traditional antibiotic agents. Methods : The in vitro anti- S. suis properties of emodin were assessed through minimum inhibitory concentration (MIC) assays, and time-kill assays. Subsequently, the mechanisms underlying emodin’s mode of action at the molecular level by targeting FabF were elucidated using molecular docking, site-directed mutagenesis, bio-layer interferometry assays, and cellular thermal shift assays. Finally, metabolomics, cell membrane phospholipid content assay and biochemical parameters assays were used to detect emodin disrupting cell membrane integrity and function by affecting fatty acid biosynthesis. Results : In this study, we have identified that emodin inhibits S. suis by suppressing free fatty acids (FFAs) synthesis and disrupting phospholipid production by targeting FabF, a key enzyme in the fatty acid biosynthesis pathway. This interference compromises the integrity and functionality of the cell membranes of S. suis . Emodin also triggers the dissipation of the proton motive force, accelerates the tricarboxylic acid cycle, and enhances cellular respiration, ultimately leading to S. suis cell death. Conclusion : This study suggested that emodin inhibits the growth of S. suis via targeting FabF and the inhibition of fatty acid biosynthesis through enzyme-targeted drug design. This represents a novel strategy for developing antimicrobial agents against S. suis and addressing the challenge of antibiotic resistance.
研究领域:
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2020
·
IF 3.184
Yulian Chen,Tao Zhang,Lili Wu,Yilin Huang,Zhihao Mao,Zhikun Zhan,Weizhong Chen,Fahong Dai,Wenyu Cao,Yong Cao,Shuwen Liu,Zheng Cai,Lan Tang
Emodin is the main toxic component in Chinese medicinal herbs such as rhubarb. Our previous studies demonstrated that genetic polymorphisms of UDP-glucuronosyltransferase 2B7 (UGT2B7) had an effect on the glucuronidation and detoxification of emodin. This study aimed to reveal the transcriptional regulation mechanism of UGT2B7 on emodin glucuronidation and its effect on toxicity. Emodin glucuronic activity and genome and transcriptome data were obtained from 36 clinical human kidney tissues. The genome-wide association studies (GWAS) identified that four single nucleotide polymorphisms (SNPs) (rs6093966, rs2868094, rs2071197, and rs6073433), which were located on the hepatocyte nuclear factor 4α (HNF4A) gene, were significantly associated with the emodin glucuronidation (p < 0.05). Notably, rs2071197 was significantly associated with the gene expression of HNF4A and UGT2B7 and the glucuronidation of emodin. The gene expression of HNF4A showed a high correlation with UGT2B7 (R2 = 0.721, p = 5.83 × 10–11). The luciferase activity was increased 7.68-fold in 293T cells and 2.03-fold in HepG2 cells, confirming a significant transcriptional activation of UGT2B7 promoter by HNF4A. The knockdown of HNF4A in HepG2 cells (36.6%) led to a significant decrease of UGT2B7 (19.8%) and higher cytotoxicity (p < 0.05). The overexpression of HNF4A in HepG2 cells (31.2%) led to a significant increase of UGT2B7 (24.4%) and improved cell viability (p < 0.05). Besides, HNF4A and UGT2B7 were both decreased in HepG2 cells and rats after treatment with emodin. In conclusion, emodin used long term or in high doses could inhibit the expression of HNF4A, thereby reducing the expression of UGT2B7 and causing hepatotoxicity.
研究领域:
药理学
·
遗传学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Yang Xu,Shujing Lv,Xiang Li,Chuanjia Zhai,Yulian Shi,Xuejiao Li,Zhiyang Feng,Gan Luo,Ying Wang,Xiaoyan Gao
Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling. From lysates of an active strain, Bifidobacterium pseudocatenulatum ( B . pseudocatenulatum ), 397 proteins were enriched and subsequently identified using mass spectrometry. Among these proteins, chromate reductase/nicotinamide adenine dinucleotide phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and Uniprot database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.
研究领域:
微生物学
·
药理学
·
蛋白质组学
✓ 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）