Food Bioscience
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2025
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IF 5.9
Yingwei Liu,Yunpeng Sun,Ting Zhou,Xiao Huang,Guokai Wang,Lijuan Sun
Swietenia macrophylla King, a medicine food homology, has garnered attention for the hypoglycemic and hypolipidemic activities of its fruit in the improvement of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the glucolipid regulating properties of its leaf remains unexplored. The study sought to examine the pharmacological mechanisms underlying the lipid-lowering effects of Swietenia macrophylla King leaf extract (SLE) and its active constituent senegalension B (one of 31 limonoids in SLE). Glucolipid regulation by SLE and active constituent was evaluated through cellular triglyceride content and peripheral glucose levels in primary mouse hepatocytes (PMHs), SLE dose-dependently reduced lipid accumulation in the range of 23.65±3.41% to 37.39±2.50%, validated by Oil Red O staining. Network pharmacology and RNA sequencing identified SREBP-1c/FASN axis as the key mechanism by which SLE improved lipid accumulation in PMHs, consistent with senegalension B. RT-qPCR and Western blot showed that SLE (40 μg/mL) decreased the lipid synthesis regulator SREBP-1c mRNA and protein levels by 60.69±1.69% and 48.07±11.83%, respectively, whereas senegalension B (40 μM) achieved 55.42 ±2.29% and 34.34±8.49% inhibition. Dual-luciferase reporter assays revealed that senegalension B suppressed SREBP-1c promoter activity in Hep G2 cells. Molecular docking suggested a potential interaction with SREBP1, consistent with molecular dynamics simulation comparing binding affinity and stability with LXRα, indicating that senegalension B may exert lipid-lowering activity by targeting key proteins involved in lipid synthesis, such as SREBP-1c. This study elucidated the mechanisms and potential of SLE and senegalension B in regulating MASLD through in vitro investigation, expanded the utilization of Swietenia macrophylla King resources, and provided a candidate plant-derived compound for dietary therapy.
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产品关联
DOI
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Pengfei Tang,Houli Jiang,Ze Zheng,Zhiqi Xiao,Lingyi Kong,Jun Luo
Background Septic acute kidney injury (S-AKI) is associated with high morbidity and mortality, and dysregulation of oxidative stress and remodeling of the inflammatory microenvironment are emerging as central pathogenic mechanisms. Alleviating inflammation and oxidative stress are the primary effects of limonoids found in nature, and our previously discovered walrobsin A (WA) from Walsura robusta has exhibited significant anti-inflammatory properties. Moreover, bioactive natural products with novel skeletons are ideal molecular probes for identifying potential novel molecular targets for diseases using chemical biology methods. Purpose To explore the therapeutic effect and mechanism of WA for treating S-AKI and to identify previously unrecognized targets in S-AKI. Methods The effect of WA was detected by establishing LPS-induced mouse S-AKI in vivo . Functional and pathological changes in murine kidneys were evaluated by measuring serum creatinine (CRE), cystatin C (Cys C), blood urea nitrogen (BUN), NGAL levels, and HE pathology. A RAW264.7/mTEC coculture system was established to elucidate the target and mechanism of WA by techniques such as RNA-seq, gene interference, DARTS, LC-MS/MS, molecular docking, BLI, and SPR. Results The screening results revealed that WA, a limonoid, significantly alleviated LPS-induced mouse S-AKI, and a RAW264.7/mTEC coculture experiment revealed that WA directly acted on macrophages. Transcriptomic analysis and further research revealed that WA promoted the expression of the antioxidant proteins HMOX1 and SOD2 and inhibited IL-1 β , IL-6, and TNF- α secretion. G protein-coupled receptor 75 (GPR75), which was highly expressed in the renal macrophages of S-AKI mice, was subsequently identified as the direct target of WA. In the RAW264.7/mTEC coculture system, siGPR75 inhibited macrophage oxidative stress and restrained IL-1 β , IL-6, and TNF- α secretion, thereby reducing mTEC injury, and overexpression of GPR75 resulted in the opposite effects. Moreover, siGPR75 reversed the WA-mediated remission of macrophage oxidative stress and the inflammatory microenvironment in vitro , and coadministration of WA failed to increase the therapeutic efficacy of 20-SOLA (a GPR75 inhibitor) in S-AKI in vivo . These results indicate that the WA-GPR75 axis mitigates S-AKI by regulating oxidative stress in macrophages and the inflammatory microenvironment. Conclusion In this study, we elucidated the novel role of GPR75 as a potential target for S-AKI using a bioactive limonoid-type natural product and identified a natural GPR75 inhibitor (WA) as a potential candidate for S-AKI treatment. This study firstly identifies GPR75 in pathological renal conditions and demonstrates its direct role in driving renal injury, thus establishing it as a novel therapeutic target for kidney diseases.
研究领域:
药理学
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免疫学
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天然产物化学
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分子生物学
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肾脏病学
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化学生物学
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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）