Frontiers in Pharmacology
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2026
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IF 5.4
Wentong Wu,Zhaoce Zheng,Danping Wang,Ming Shan,Jing Han,Dongqing Jing,Chunjng Liang,Xi Zhang,Jinxin Liu
Background and Aims Ferulic acid (FA) exerts anti-atherosclerotic effects, but the underlying mechanisms remain incompletely understood. The present study investigated whether smooth muscle cell (SMC)-derived insulin-like growth factor 1 (IGF1) mediate FA’s protective effects by regulating lysosome-associated membrane protein 2 (LAMP2), inflammatory cytokines, and matrix metalloproteinase 3 (MMP3). Methods Male ApoE −/− mice were fed a high-fat diet for 8 weeks to established atherosclerosis models and then treated with FA (40 mg/kg/d). SMC-specific Igf1 knockout (SMC- Igf1 -KO) mice were generated to determine cell-type-specific requirements. In vitro , SMC-derived foam cells were induced by oxidized low-density lipoprotein (ox-LDL) and treated with FA ± IGF1 receptor (IGF1R) inhibitor. Plaque area, lipid deposition, and expression of IGF1, LAMP2, interleukin (IL)-6, IL-4, and MMP3 were assessed by en face staining, histology, Western blot, quantitative real-time PCR (qRT-PCR), and immunofluorescence selected as needed. Results FA treatment significantly reduced atherosclerotic plaque area and lipid deposition in male ApoE −/− mice, accompanied by upregulated IGF1 and downregulated 45 kDa-LAMP2 expression in aortic lesions. FA also increased IL-4 expression and decreased IL-6 and MMP3 expression. SMC-IGF1-KO significantly weakened the protective effects of FA. In vitro , FA increased IGF1 expression and IGF1R phosphorylation, reduced 45 kDa-LAMP2, IL-6, and MMP3 expression, and increased IL-4 expression in ox-LDL-induced SMC-derived foam cells. These effects were reversed by IGF1R inhibition. Conclusion FA treatment significantly attenuates atherosclerosis. It partly resulted from that SMC-derived IGF1-mediated suppression of a 45 kDa-LAMP2 isoform, along with modulation of inflammatory balance (IL-6/IL-4) and MMP3 expression. The SMC-IGF1/45 kDa-LAMP2 axis may represent a potential therapeutic target for atherosclerosis.
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2021
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IF 3.575
Wenli Shi,Danyi Lu,Chunlei Wu,Meiqing Li,Zhihao Ding,Yanyan Li,Binghua Chen,Xian Lin,Wu Su,Ximing Shao,Zhihui Xia,Lijing Fang,Ke Liu,Hongchang Li
Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium , has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2 . As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.
研究领域:
癌症生物学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Qi Song,Lei Bi,Jiakang Jiao,Jinfeng Shang,Qiannan Li,Lizha Shabuerjiang,Meirong Bai,Xin Liu
Ethnopharmacological relevance Zhachong Shisanwei Pill (ZSP) is a commonly used Mongolian medicine in treating cerebrovascular diseases and plays a role in the clinical treatment of ischemic stroke (IS). Aim of the study Based on determining the protective effect of ZSP on cerebral ischemia, they adopted the proteomics method to explore the mechanism of ZSP against IS. Materials and methods Rats with middle cerebral artery occlusion (MCAO) model were prepared by wire embolization method, and divided into sham group, model group, ZSP high-dose group, medium-dose group, low-dose group and positive drug group. We collected the brain tissue of rats for 12 h after modeling. Neurological deficit score and cerebral infarction volume ratio evaluated pharmacodynamics , and we selected the optimal dose for subsequent experiments. Proteomics was used to screen out possible ZSP anti-IS mediated pathways and differentially expression proteins. Network pharmacology was used to verify the correlation between diseases and drugs. Hematoxylin-eosin (HE) staining and transmission electron microscope (TEM) were used to explore further the pharmacodynamic effect of ZSP against IS and its possible mechanism. Results The cerebral infarction rate and neurological function score in rats showed that the medium-dose ZSP group had the best efficacy. Proteomics results showed that the anti-IS action of ZSP was mainly through lysosome pathway. LAMP2 , AP3M1, and SCARB2 were the differentially changed proteins in this pathway. Network pharmacology verified this. HE staining and TEM results showed that ZSP could improve the pathological state of neurons in MCAO rats and reduce the number of lysosomes in MCAO rats. Western blot (WB) results showed that compared with the model group, the protein expression levels of LAMP2 and AP3M1 in the ZSP group were significantly down-regulated, and the protein expression levels of SCARB2 were significantly up-regulated. Conclusion This study confirms that ZSP regulates the lysosomal pathway, which may protect IS by down-regulating LAMP2 and AP3M1 and up-regulating SCARB2.
研究领域:
药理学
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神经科学
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蛋白质组学
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生物信息学
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DOI
PubMed
高影响因子
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