Heliyon
·
2023
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IF 4
Yuanyuan Gou,Zichen Wang,Liping Zhou,Jinpan Du,Jiaxin Huang,Jing Li,Xuyu Zhang,Su Guan
Inflammatory bowel disease is a relapsing inflammatory disease seriously endanger human health. Wedelolactone (WED) is a major active ingredient from Eclipta prostrata (L.) L. and has shown anti-inflammatory effects. However, the mechanism of WED in treating inflammatory colitis remains unknown. We aimed to investigate the mechanisms of WED in treating ulcerative colitis through lipidomic study. Sixty male C57BL/6 mice were exposed to DSS to induce acute colitis. Disease progression was judged by the disease activity index (DAI) and pathological changes of colon tissue. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method was performed for colon and plasma lipidomics analyses. Differential metabolites in the three groups were distinguished by univariate and multivariate analysis. WED exerted anti-inflammatory effects representing by body weight and DAI score. Three metabolites were identified in plasma and 20 in colon. According to pathway analysis, the effects of WED on colitis were associated with seven pathways. The glycerophospholipid metabolism and ether lipid metabolism were the primary pathways. The findings provide important insight of the mechanism of WED in treating DSS induced colitis through lipidomic perspective.
研究领域:
药理学
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炎症性肠病研究
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代谢组学
✓ 已验证
DOI
PubMed
高影响因子
TISSUE & CELL
·
2025
·
IF 2.5
Xiaoxue Zhao,Bingyu Zhang,Sining Duan,Tengfei Wu,Xiaojiao Yang,Yuxiang Liu
Growing evidence demonstrated the involvement of ferroptosis in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). The nature compound Wedelolactone (Wed) exhibits anti-ferroptosis effects. The current study aims to explore the impact of Wed on MIRI and reveal whether Wed could protect cardiomyocytes from ferroptosis. Rats underwent cardiac IR operation, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Rats or cell in Wed-treated group were subdivided into 2 different dose regimens: low and high. Wed intervention alleviated myocardial infarction and left ventricle dysfunction, and diminished the levels of biochemical markers for cardiac injury caused by cardiac IR. The content of Fe 2+ and MDA, 4-HNE expression, and ROS production were increased in infarct zone, as well as GSH content, GSH-Px activity, and the levels of ferroptosis-related proteins were reduced. Treatment with Wed reversed the aforementioned changes. Similar results were observed in vitro experiments. Molecular docking analysis showed good binding affinity between Wed and the target protein METTL3. In OGD/R-induced H9c2 cells, Wed downregulated METTL3 protein expression and further blocked METTL3-mediated m 6 A modification of BRD4 mRNA. Overexpression of METTL3 reversed the antagonistic effect of Wed on cardiomyocyte ferroptosis. Collectively, our findings uncovered that Wed showed anti-ferroptosis effects in cardiomyocytes through downregulating the METTL3/BRD4 axis, thereby ameliorating MIRI.
研究领域:
药理学
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心脏病学
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分子生物学
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生物化学
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生物医学研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Rong Fan,Jidong Sui,Xuepeng Dong,Biao Jing,Zhenming Gao
Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure . Pyroptosis and ferroptosis are two newly recognized cell death , and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities , the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes , and proinflammatory cytokines . The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/caspase11 activation, reduced mature interleukin-1β (IL-1β) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.
研究领域:
药理学
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炎症
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细胞死亡机制
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氧化应激
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胰腺病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Zimei Wu,Yan Xu,Lang Qin,Zemin Ling,Yingjie Mai,Xiong Tian Guo,Jiajia Chen,Leping Yan,Lin Wang,Liming Bian,Fuxin Wei
Intervertebral disc degeneration (IVDD) is driven by persistent inflammation–oxidative stress that disrupts annulus fibrosus (AF) homeostasis. Guided by network pharmacology and docking, we prioritized the NF-κB–LCN2 axis as a druggable target of wedelolactone (WDL). To achieve targeted modulation, we engineered a dual-network ROS-responsive hydrogel (WPG) in which a phenylboronic-ester/PVA redox-cleavable network interpenetrates a covalently crosslinked GelMA–elastin matrix, enabling mechanically robust yet stimulus-triggered WDL release. WDL suppressed NF-κB activation and downregulated LCN2 in both macrophages and AF cells. Conditioned-medium co-culture demonstrated that WDL disrupts macrophage-derived LCN2-mediated paracrine amplification, breaking the self-sustaining inflammatory loop. Bulk RNA-seq across both cell types revealed coordinated downregulation of NF-κB – driven chemokine cascades and restoration of adhesion and ECM gene programs following WPG treatment. In a rat AF-defect model, intradiscal WPG administration preserved disc height and T 2 -weighted MRI signal, reduced MMP13 while increasing Collagen I and Aggrecan expression, suppressed nuclear P-p65 and LCN2, and improved segment biomechanics—without eliciting adverse hematological or organ responses. Collectively, these findings establish that aligning molecular targeting (NF-κB–LCN2 modulation) with the pathophysiological context via ROS-gated delivery provides a synergistic strategy for AF repair and attenuation of IVDD progression.
✓ 已验证
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Panpan Chen,Zihan Zhu,Haoyuan Geng,Xiaoqing Cui,Yuhao Han,Lei Wang,Yaqi Zhang,Heng Lu,Xiao Wang,Yun Zhang,Chenglong Sun
Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in Eclipta prostrata L.. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a ''multi-omics'' platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Mei-Qi Wang,Kai-Hui Zhang,Fang-Le Liu,Rui Zhou,Yun Zeng,A-Li Chen,Yang Yu,Quan Xia,Chen-Chen Zhu,Chao-Zhan Lin
Background : Cholestatic liver diseases (CLD) comprise a variety of disorders of bile formation, which causes chronic exposure to bile acid (BA) in the liver generally and results in hepatotoxicity and progressive hepatobiliary injury. Wedelolactone (7-methoxy-5, 11, 12-trihydroxy-coumestan, WED), the natural active compound derived from Ecliptae Herba, has been reported with valuable bioactivity for liver protection. Nevertheless, the effect of WED on cholestatic liver injury (CLI) remains unexplored. Purpose : The present study aims to elucidate the protective effect of WED on Alpha-naphthylisothiocyanate (ANIT)-induced CLI mice, and to investigate its potential pharmacological mechanism. Methods : The anti-cholestasis and hepatoprotective effects of WED were evaluated in ANIT-induced CLI mice. Non-targeted metabolomics study combined with ingenuity pathway analysis (IPA) was used to explore the key mechanism of WED. The BA metabolic profile in enterohepatic circulation was analyzed to evaluate the effect of WED in regulating BA metabolism. Further, molecular dynamics (MD) simulation and cellular thermal shift assay (CETSA) were used to simulate and verify the targeting activation of WED on the Farnesoid X receptor (FXR). The core role of FXR in WED promoting BA transportation, and alleviating BA accumulation-induced hepatotoxicity was further evaluated in WT and FXR knockout mice or hepatocytes. Results : WED dose-dependently alleviated ANIT-induced cholestasis and liver injury in mice, and simultaneously suppressed the nuclear signaling pathway of factor-kappa B/nuclear factor-erythroid 2-related factor 2 (NF-κB/NRF2) to relieve inflammation and oxidative stress. At the metabolite level, WED improved the metabolic disorder in CLI mice focusing on the metabolism of BA, arachidonic acid, and glycerophospholipid, closely related to the process of BA regulation, inflammation, and oxidative damage. WED targeting activated FXR, which then transcribed its target genes, including the bile salt export pump (BSEP) and the BA transporter, which subsequently increased BA transportation to restore the damaged enterohepatic circulation of BA. Meanwhile, WED alleviated hepatic BA accumulation and protected the liver from BA-induced damage via NF-κB/NRF2 signaling pathway. Furthermore, FXR deficiency suppressed the protective effect of WED in vitro and in vivo . Conclusion : WED regulated BA metabolism and alleviated hepatic damage in cholestasis. It protected the liver according to adjusted BA transportation and relieved BA accumulation-related hepatotoxicity via FXR-bile acid-NF-κB/NRF2 axis. Our study provides novel insights that WED might be a promising strategy for cholestatic liver disease.
研究领域:
药理学
·
肝病学
·
代谢组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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