JOURNAL OF PROTEOME RESEARCH
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2023
·
IF 4.4
Mengmeng Zheng,Yanmei Zhang,Yao Xu,Ying Han,Yingli Wu,Jingwu Kang
Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Bunge (Danshen), displays strong antiproliferative activity against cancer cells. However, their protein targets remain unknown. Here, we deconvoluted the protein targets of SAA using chemoproteomics and phosphoproteomics. By using alkynylated SAA as a probe, we discovered that SAA is a covalent ligand that can modify cellular proteins via its electrophilic α,β-unsaturated ester moiety. The subsequent chemoproteomics profiling revealed that 46 proteins were covalently modified by SAA, including Raptor, a subunit of mTORC1 for recruiting substrates for mTORC1. Although gene ontology enrichment analysis of these proteins suggested that SAA displays a promiscuous protein interaction, phosphoproteomics profiling revealed that the SAA modulated phosphoproteins were mainly enriched in the signaling pathways of PI3K-Akt-mTOR, which is closely related to cell growth and proliferation. This was confirmed by the biochemical assay with purified mTORC1, a Western blot assay with phospho-specific antibodies, and a cellular thermal shift assay. Our work discovered that SAA is a covalent ligand for protein modification and mTORC1 is one of its targets. Moreover, our work demonstrated that the integrative profiling of chemoproteomics and phosphoproteomics can be a powerful tool for target deconvolution for bioactive natural products.
研究领域:
药理学
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蛋白质组学
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癌症研究
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2025
·
IF 6
Jiayu Chen,Qing Liu,Jiayang Wan,Qihua Cao,Zili Guo,Kaijia Tang,Xin Chen,Qilei Lou,Xiaodong Xu,Yong Fu,Xiaoqiang Jin,Songying Zhang,Xiaohua Yu,Chang Li
Natural products, especially phenolic components isolated from Traditional Chinese Medicine (TCM), were reported to exhibit significant osteogenic potential in treating bone defects. However, low bioavailability, short half-life, and high clearance rate in the body hindered their practical applications in many cases. To develop delivery technologies for a bioactive phenolic acid from Salvia miltiorrhiza ( Danshen ), salvianolic acid A (SAA), a sustained release system based on biocompatible extracellular matrix (ECM) meticulously modified with a Hydroxyapatite (HAP) mineralized coating was established. The SAA construction of such delivery system not only addressed the low bioavailability of TCM formulation for SAA by local sustained release of this molecule, but also remarkably promoted its bone healing outcomes by synergizing with calcium and phosphate ion release during SAA release period. This approach collectively had a synergistic effect of osteogenesis with SAA, thereby significantly enhanced the efficacy of SAA in promoting bone formation. The in vitro experimental results indicated that the SAA@MECM exhibited good biocompatibility and significantly enhances angiogenesis and osteogenic differentiation. By day 14, compared to the MECM group, the gene expression levels of Col I, ALP, Runx-2, and OCN in the SAA-H group increased by 1.8, 1.5, 1.5, and 2.0 times, respectively. This demonstrates the potential role of SAA in promoting the activity and differentiation of osteoblasts, highlighting its potential applications in bone tissue engineering. Leveraging such favorable feature of this system, SAA-loaded MECM demonstrated extraordinary bone healing capability in a rat calvarial defect model by showing successful bridging of the defects and large amount of new bone formation. Histological analysis further confirmed its outstanding osteogenic potential, while the dense distribution of micro vessels in the newly formed bone revealed the scaffold's remarkable potential in enhancing vascularization. This study might offer an innovative delivery strategy for enhancing the efficacy of natural phenolic acids through biomaterials.
研究领域:
组织工程学
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药理学
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生物材料科学
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2022
·Vol. 7
·期 1
·1-17
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IF 38.104
Zeng Hao,Pan Ting,Zhan Meiling,Hailiwu Renaguli,Liu Baolin,Yang Hua,Li Ping
Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza , attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.
研究领域:
心脏病学
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细胞代谢
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Nuo Cheng,Qianqian Zhou,Zongfang Jia,Yang Mu,Sheng Zhang,Lei Wang,Yunna Chen
The therapeutic effect of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC) is unsatisfactory. The immune "cold" microenvironment caused by tumor-associated fibroblasts (TAFs) has an adverse effect on the antitumor response. Therefore, in this study, mixed cell membrane-coated porous magnetic nanoparticles (PMNPs) were constructed to deliver salvianolic acid B (SAB) to induce an antitumor immune response, facilitating the transition from a "cold" to a "hot" tumor and ultimately enhancing the therapeutic efficacy of immune checkpoint inhibitors. PMNP-SAB, which is based on a mixed coating of red blood cell membrane and TAF membrane (named PMNP-SAB@RTM), can simultaneously achieve the dual effects of "immune escape" and "homologous targeting". Under the influence of an external magnetic field (MF), SAB can be targeted and concentrated at the tumor site. The SAB released in tumors can effectively inhibit the production of extracellular matrix (ECM) by TAFs, promote T-cell infiltration, and induce antitumor immune responses. Ultimately, the combination of PMNP-SAB@RTM and BMS-1 (PD-1/PD-L1 inhibitor 1) effectively inhibited tumor growth. Finally, this study presents a precise and effective new strategy for TNBC immunotherapy on the basis of the differentiation of "cold" and "hot" microenvironments.
研究领域:
肿瘤学
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免疫学
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纳米医学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
SEPARATION AND PURIFICATION TECHNOLOGY
·
2023
·
IF 8.6
Jiajia Su,Jun Qian,Weihuan Zeng,Yue Wang,Guoyin Kai
It is important to separate salvianolic acids from Danshen owing to their significant therapy-related activities of cardiovascular and cerebrovascular diseases. In this study, phenylboronic acid functionalized polyethyleneimine-intercalated montmorillonite (PAPIM) was successfully synthesized via intercalation and amidation to capture salvianolic acid A (SAA), salvianolic acid B (SAB) and rosmarinic acid (RA) effectively. Adsorption of three salvianolic acids kinetically follows a pseudo-second-order model. The maximum adsorption capacities can be determined to be 1.285, 0.692 and 1.154 mmol/g for SAA, SAB and RA by Langmuir adsorption model, respectively. Comprehensive factors of function groups of adsorbents and structure of phenolic acids result in the affinity order of adsorbent for phenolic acids: SAA > SAB > RA > other phenolic acids with simple structure. Different dominant processes lead to different adsorption thermodynamics of three salvianolic acids. It is found that the adsorption mechanism includes covalent bond, electrostatic interaction, hydrogen bond and π-π stacking interaction. Remarkably, boronic acid affinity and electrostatic interaction play the important role in the selective adsorption process, which is verified by density functional theory (DFT) calculations. This work highlights that PAPIM is a promising adsorbent to realize effective separation of salvianolic acids and provides an alternative potential strategy to selective separate certain compound with multiple synergetic interactions.
研究领域:
化学
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药学
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材料科学
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产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Jian-Li Chen,Xiao-Hui Jia,Xuan Wu,Ming-Heng Yuan,Xinyue Xia,Dan Yin,Xu Chen,Ze-Yun Gu,Jia-Zheng Liu,Li-Ping Bai,Kathy Qian Luo,Jianfang Wang,Xiao-Ming Zhu
Acute kidney injury (AKI) is highly correlated with oxidative stress, and the application of antioxidants is one of the promising treatments. Salvianolic acid B (SAB) is a natural polyphenol with powerful antioxidant effects. Due to its inherent characteristic of inferior bioavailability, its clinical application is impeded. In this study, small SAB-incorporated nanoparticles (SFA) were synthesized via the self-assembly of SAB, ferric ions, and bovine serum albumin (BSA). Apart from antioxidant activity, the SFA nanoparticles were found to efficiently restore lysosome dysfunction induced by reactive oxygen species (ROS) in human kidney proximal tubular epithelial HK-2 cells. The small size and BSA incorporation make the SFA nanoparticles to be promising AKI-targeting nanoparticles. They are rapidly accumulated and long-term retained in injured kidneys of glycerol-induced AKI mice, especially in the proximal tubules which are the key lesion location during AKI. In vivo studies indicate that SFA nanoparticles show a superior protective effect compared with the free drug by suppressing oxidative stress and maintaining lysosome homeostasis indicated by enhanced heme oxygenase-1 (HO-1) expression and restored cathepsin B (CTSB) activity, respectively. In summary, this study develops a delivery system for the antioxidant SAB enhancing local delivery and offering an additional lysosome restoring mechanism for AKI therapy.
研究领域:
药理学
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纳米技术
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肾脏生理学
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生物医学工程
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产品关联
DOI
高影响因子
Separation Science Plus
·
2022
·Vol. 5
·期 8
·368-377
·
IF 0
Jian Gao,Lin Zhou,Lele Zhang,Xi Luo,Zhifei Fu,Guixiang Pan,Qiang Xu,Lifeng Han
In this work, an effective method for simultaneous isolation of eight compounds from Salvianolic Acids for Injection was developed by preparative high-performance liquid chromatography based on improved dry load injection. Firstly, the chemical structures of the obtained compounds were identified by mass spectrometry and nuclear magnetic resonance spectra. Subsequently, a sensitive liquid chromatography-tandem mass spectrometry method was established to precisely quantify the eight isolated target analytes. The quantitative results show salvianolic acid B as the most abundant component (460.06–514.68‰) and protocatechualdehyde (0.03–0.08‰) as the least. Finally, the antioxidant activities of the isolated compounds were further investigated. The 2,2-diphenyl-1-picrylhydrazyl-scavenging assay indicated that (7′ R , 8′ S , 8″ R , 8′′′ R )-epi-salvianolic acid B had the lowest half-maximal inhibitory concentration (5.05 μg/ml). This study reports on the development of an effective and rapid method for simultaneous isolation of multiple compounds from traditional Chinese medicine preparation, which could be used as reference compounds for further quality control and activities screening.
研究领域:
药学
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分析化学
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中药学
✓ 已验证
产品关联
DOI
危险品化学品经营许可证（带存储）