MOLECULAR PHARMACEUTICS
·
2017
·
IF 4.44
Guo Ma,Ying Zhang,Wenyan Chen,Zhifang Tang,Xiaoming Xin,Ping Yang,Xiaoqin Liu,Weimin Cai,Ming Hu
Bilirubin-related adverse reactions (ADR, e.g., jaundice and hyperbilirubinemia) induced by herbs rich in certain polyphenolic acids are widely reported. However, the causes and the mechanisms underlying these ADR are not well understood. The purpose of this article is to determine the mechanism by which certain polyphenolic acids inhibit UGT1A1-mediated bilirubin glucuronidation, leading to jaundice or hyperbilirubinemia. We investigated in vitro inhibitory effects on bilirubin glucuronidation of salvianolic acid A (SAA), salvianolic acid B (SAB), danshensu (DSS), protocatechuic aldehyde (PA), and rosmarinic acid (RA), as well as two Salvia miltiorrhiza injections (DSI and CDI) rich in polyphenolic acids. The results showed that average formation rates of three bilirubin glucuronides displayed a significant difference (p < 0.05) and the formation of monoglucuronide was favored regardless if an inhibitor was present or not. SAA, SAB, DSI, and CDI, but not DSS, PA, and RA, significantly inhibited human UGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibitory mechanism. Average IC50 values of SAA, SAB, DSI, and CDI-mediated inhibition of bilirubin glucuronidation were bilirubin concentration-dependent, and their values (against total bilirubin glucuronidation) were in the range 0.44 ± 0.02 to 0.86 ± 0.04 μg/mL (for SAA), 4.22 ± 0.30 to 12.50 ± 0.93 μg/mL (for SAB), 9.29 ± 0.76 to 18.82 ± 0.63 μg/mL (for DSI), and 9.18 ± 2.00 to 22.36 ± 1.39 μg/mL (for CDI), respectively. In conclusion, SAA and its analog SAB are the main ingredients responsible for inhibition of bilirubin glucuronidation by DSI and CDI, whose use is associated with many high bilirubin-related ADR.
研究领域:
药理学
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中药学
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临床医学
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高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-11
·
IF 3.8
Qiao Xilin,Cao Shuyu,Chen Shuaiyu,Guo Yan,Chen Nipi,Zheng Ying,Jin Bo
Oxidative stress induced endothelial dysfunction plays a particularly important role in promoting the development of cardiovascular diseases (CVDs). Salvianolic acid A (SalA) is a water-soluble component of traditional Chinese medicine Salvia miltiorrhiza Bunge with anti-oxidant potency. This study aims to explore the regulatory effect of SalA on oxidative injury using an in vitro model of H 2 O 2 -induced injury in human umbilical vein endothelial cells (HUVECs). In the study, we determined cell viability, the activities of Lactate dehydrogenase (LDH) and Superoxide dismutase (SOD), cell proliferation rate and intracellular reactive oxygen species (ROS). Flow cytometry was used to detect cell apoptosis. Western-blotting was used to evaluate the expression of cell senescence, apoptosis, autophagy and pyroptosis protein factors. The expression level of miRNA was determined by qRT-PCR. Compared with H 2 O 2 -induced HUVECs, SalA promoted cell viability and cell proliferation rate; decreased LDH and ROS levels; and increased SOD activity. SalA also significantly attenuated endothelial senescence, inhibited cell apoptosis, reversed the increase of LC3 II/I ratio and NLRP3 accumulation. Furthermore, miR-204-5p was regulated by SalA. Importantly, miR-204-5p inhibitor had similar effect to that of SalA on H 2 O 2 -induced HUVECs. Our results indicated that SalA could alleviate H 2 O 2 -induced oxidative injury by downregulating miR-204-5p in HUVECs.
研究领域:
药理学
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心血管科学
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分子生物学
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细胞生物学
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高影响因子
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.
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高影响因子
PHARMACOLOGICAL RESEARCH
·
2021
·
IF 7.658
Yujiao Yang,Junke Song,NanNan Liu,Guangyi Wei,Shan Liu,Sen Zhang,Nan Jiang,Haiguang Yang,Guanhua Du
Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment . The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.
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高影响因子
MATERIALS & DESIGN
·
2026
·
IF 8.2
Yuanchao Li,Shengyu Wang,Lei He,Heyan Wang,Zhaoxiang Zhang,Yongze Liu,Jun Zhang,Xiaofeng Ma,Xia Gao
The Fe 2 B 2 nanoshets-mediated antibacterial system did not induce drug resistance and demonstrates excellent efficacy. • The self-assembled nanomaterial composed of Salvianolic acid A (a traditional Chinese medicine) with Fe 2 B 2 nanoshets exhibited anti-inflammatory and antioxidant functions, provided superior therapeutic effects for acute sinusitis. • The composite nanomaterials with natural hydrogel helped reduce the dissipation of nasal nanomedicines. The treatment of acute sinusitis faces dual challenges of drug delivery and antibiotic resistance. Traditional Chinese medicine composite nanomaterials show tremendous potential for therapy. We combined the traditional Chinese medicine Salvianolic acid A (SAA) with Fe 2 B 2 nanosheets, then encapsulated the modified Fe 2 B 2 nanosheets within a hydrogel matrix containing alginate oligosaccharides (AOS) and chitosan (CS), resulting in an injectable AOS/CS@Fe 2 B 2 @SAA hydrogel. Characterization demonstrated excellent gelling properties and sustained-release characteristics. Cellular studies confirmed high biocompatibility. Bacterial culture, Live/Dead cell staining experiments, CT scans, and histological staining collectively demonstrated the anti-inflammatory and antibacterial effects of this hydrogel at the cellular, individual, and tissue levels. This hydrogel demonstrated remarkable synergistic effects in photothermal therapy and photodynamic therapy: the dual action effectively inhibited pathogen growth (with a photothermal conversion efficiency of 37.9%). Furthermore, the hydrogel can regulate macrophage polarization and associated cytokine secretion, exerting dual antioxidant and anti-inflammatory effects: post-treatment ROS levels in macrophages significantly decreased, while the proportion of M1 macrophages significantly dropped. Additionally, the secretion of key proinflammatory factors, IL-6 and TNF-α, was markedly decreased. These results fully confirm the efficacy of the hydrogel in mitigating cellular oxidative damage and suppressing inflammatory responses. Download: Download high-res image (150KB) Download: Download full-size image
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MATERIALS & DESIGN
·
2025
·
IF 7.9
Lifang Xie,Tianxiang Yuan,Su Hu,Chenmin Zhao,WenLi Huang,Wei Ding,Ye Zhang,Xianwen Hu
Chronic diabetic wounds exhibit impaired healing due to a complex interplay of pathological mechanisms, including persistent hyperglycemia, excessive matrix metalloproteinase-9 (MMP9) activity, and chronic inflammation, which disrupt tissue repair and regeneration. A central driver of this dysregulated healing is macrophage polarization imbalance, with excessive pro-inflammatory M1 and insufficient reparative M2 macrophages, prolonging inflammation and delaying tissue remodeling. To address these challenges, we developed a dual-responsive hydrogel composed of phenylboronic acid-functionalized polyethyleneimine (PEI-PBA), polyvinyl alcohol (PVA), and Benzaldehyde-PEG-Benzaldehyde (DF-PEG-DF) for controlled co-delivery of interleukin-4 (IL-4) and salvianolic acid A (SalA). This dynamically crosslinked hydrogel responds to the diabetic wound microenvironment, enabling pH- and glucose-triggered release. IL-4 promotes M2 macrophage repolarization, resolving inflammation and enhancing tissue repair, while SalA scavenges reactive oxygen species (ROS) and inhibits MMP9 activity, preserving extracellular matrix (ECM) integrity and supporting regeneration. In vivo, the hydrogel significantly accelerated wound closure in diabetic mice by promoting M2 polarization and reducing MMP9-mediated matrix degradation. This coordinated modulation of the inflammatory and proteolytic microenvironment attenuated inflammation, enhanced angiogenesis, and increased collagen deposition, collectively facilitating tissue regeneration. These findings suggest this intelligent hydrogel is a promising therapeutic strategy for chronic diabetic wound healing with translational potential.
研究领域:
生物材料
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药物递送
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糖尿病创面修复
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免疫调控
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再生医学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
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IF 3.571
Fuqiong Zhou,Linxin Teng,Yu Liu,Yanxia Ma,Weiping Chen,Lei Bi
Salvianolic acid A (Sal A) has a wide range of pharmacological activities. To date, there have been no systematic and detailed metabolite research data of Sal A after oral administration in vitro and in vivo. In this study, a rapid and systematic method based on ultrafast liquid chromatography-quadrupole-time-of-flight mass spectrometry was developed to detect metabolites of Sal A in vitro (human liver microsome, human intestinal microbiota, artificial gastric, and intestinal juice) and in vivo (urine, plasma, feces, and various organs collected after oral administration of Sal A to normal rats and pseudo-germ-free rats). A total of 26 metabolites of Sal A were characterized. These metabolites were formed through extensive metabolic reactions, such as hydroxylation, hydrogenation, and glucuronidation reactions. This study provides novel possibility for exploring the potential biological mechanism of Sal A, and aids the promotion of clinical application.
研究领域:
药理学
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分析化学
·
代谢组学
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PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Yao-lei Ma,Xiao-wei Huo,Colin Wong,Feng-jie Zhou,Shan-ze Li,Han Zhang,Wei Lei
Background Although doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, it greatly increases the risk of heart damage. Salvianolic acid A (SAA), a water-soluble active component from traditional Chinese medicine Salvia miltiorrhiza Bunge, is shown to exert various cardioprotective effects. However, the potential of SAA in protecting DOX-induced cardiotoxicity (DIC) and its underlying mechanisms have yet to be elucidated. Purpose In the current study, we aimed to identify the targets and investigate the cardioprotective mechanism of SAA improving DIC. Methods we established DIC mice to evaluate the cardioprotective effects of SAA by pharmacodynamics, myocardial metabolomic and protomics analysis. Multipe protein-small molecule interaction strategies including surface plasmon resonance, microscale thermophoresis and cellular thermal shift assay, combined with target-depleted cell and animal models were applied for identifying potential targets of SAA. For clinical translation, we also investigated cardioprotective activities of SAA in DOX-treated lewis lung carcinoma-bearing mice. Results SAA significantly alleviated cardiomyocyte apoptosis and oxidative damage, and improved echocardiographic parameters in DIC mice. In addition, myocardium metabolomic and proteomics analysis revealed that SAA preserved hearts by modulating L-Glutamic acid, L-Aspartic acid, citrate and isocitrate and restoring glutamic-oxaloacetic transaminase 2 (GOT2) expression. With the help of multipe protein-small molecule interaction strategies, GOT2 was identified as one of the targets of SAA, and a strong affinity was characterized with a dissociation constant of 1.712 μM. SAA ameliorated DOX-induced oxidative damage, mitochondrial respiration suppression, mitochondrial membrane potential loss and NADH levels, which were validated in GOT2 knockdown H9C2 cells. In GOT2 depleted zebrafish, SAA did not display a protective effect against DIC, while in lewis lung carcinoma-bearing mice, SAA not only improved DIC, but also exerted combined anti-tumor effects with DOX. Conclusion SAA targets GOT2 to alleviate myocardial oxidative stress by regulating malate-aspartate NADH shuttle, thereby protecting against DIC. Our findings highlighted the therapeutic potential of activating GOT2 in mitigating DIC and the possibility of SAA and DOX-based combination therapy.
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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
·
生物材料科学
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PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Xiuya Guan,Mengkai Lu,Xinhai Cui,Dawei Zhang,Lei Zhang,Lin Lin,Yuan Li,Yuanlong Hu,Chao Li
Atherosclerosis is a chronic inflammatory disease driven by senescent vascular smooth muscle cells (VSMCs). Salvianolic acid A (SAA) exhibits cardiovascular protective effects; however, its role in atherosclerosis remains unclear. This study aimed to investigate the effects and targets of SAA in atherosclerosis. In vitro studies were performed in senescent VSMCs with heat shock protein 90 alpha (HSP90α) overexpression or knockdown, with or without SAA treatment. In vivo, ApoE −/− mice fed a high‐fat diet were treated with SAA and adeno‐associated virus‐mediated VSMC‐specific HSP90α overexpression or knockdown. SAA promoted apoptosis in senescent VSMCs by inhibiting HSP90α. This inhibition promoted ubiquitin‐proteasome‐dependent degradation of protein kinase B (AKT) and activation of PRKR‐Like Endoplasmic Reticulum Kinase (PERK) signaling. SAA increased endoplasmic reticulum‐mitochondrial contacts and mitochondrial calcium uptake. These effects were reversed by HSP90α overexpression. In ApoE −/− mice, SAA reduced the burden of senescent VSMCs, decreased the size of plaque, and increased the stability of the fibrous cap. VSMC‐specific HSP90α knockdown mimicked the protective effects of SAA, whereas HSP90α overexpression reversed SAA‐mediated effects on disease. SAA reduces the burden of senescent VSMCs in atherosclerosis by inhibiting the scaffold function of HSP90α which maintains the AKT‐PERK interaction, to reactivate PERK signaling, thereby alleviating disease progression. Salvianolic acid A (SAA) selectively induces senescent vascular smooth muscle cell apoptosis, alleviating atherosclerosis. Mechanistically, SAA targets heat shock protein 90 alpha (HSP90α) to disrupt the protein inase B (AKT)‐PRKR‐Like Endoplasmic Reticulum Kinase (PERK) scaffold, driving ubiquitin‐proteasome‐dependent AKT degradation. This pathway reactivates PERK signaling, enhances endoplasmic reticulum‐mitochondria contact area, and increases mitochondrial calcium uptake, offering a promising senolytic approach for cardiovascular protection.
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PubMed
高影响因子
Polymers
·
2025
·Vol. 17
·期 14
·1900
·
IF 4.9
Guoying Zhou,Yujia Yan,Linh Nguyen,Jiangkai Fan,Xiao Zhang,Li Gan,Tingzi Yan,Haitong Wan
Traumatic brain injury (TBI) leads to severe neurological dysfunction, disability, and even death. Surgical intervention and neurorehabilitation represent the current clinical management methods, yet there remains no effective treatment for recovery after TBI. Post-traumatic hyperinflammation and vascular injury are the key therapeutic challenges. Therefore, a novel-designed multifunctional HT/SAA/HSYA hydrogel based on hyaluronic acid (HA) co-loaded with salvianolic acid A (SAA) and hydroxysafflor yellow A (HSYA) was developed in order to simultaneously target inflammation and vascular injury, addressing key pathological processes in TBI. The HT hydrogel was formed through covalent cross-linking of tyramine-modified HA catalyzed by horseradish peroxidase (HRP). Results demonstrated that the HT hydrogel possesses a porous structure, sustained release capabilities of loaded drugs, suitable biodegradability, and excellent biocompatibility both in vitro and in vivo. WB, immunofluorescence staining, and PCR results revealed that SAA and HSYA significantly reduced the expression level of pro-inflammatory cytokines (IL-1β and TNF-α) and inhibited M1 macrophage polarization through the suppression of the TLR4/NF-κB inflammatory pathway. In vivo experiments confirmed that the HT/SAA/HSYA hydrogel exhibited remarkable pro-angiogenic effects, as evidenced by increased expression of CD31 and α-SMA. Finally, H&E staining showed that the HT/SAA/HSYA hydrogel effectively reduced the lesion volume in a mouse TBI model, and demonstrated more pronounced effects in promoting brain repair at the injury site, compared to the control and single-drug-loaded hydrogel groups. In conclusion, the HT hydrogel co-loaded with SAA and HSYA demonstrates excellent anti-inflammatory and pro-angiogenic effects, offering a promising therapeutic approach for brain repair following TBI.
研究领域:
神经外科学
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生物材料学
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免疫学
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药理学
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再生医学
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PubMed
高影响因子
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