Dataset Information

Synergistic Effects of Cryptotanshinone and Senkyunolide I in Guanxinning Tablet Against Endogenous Thrombus Formation in Zebrafish.

ABSTRACT: Thrombosis is a key pathological event in cardiovascular diseases, and is also the most important targeting process for their clinical management. New drug development in thrombosis treatment is still in great demand. According to the traditional Chinese medicine (TCM) theory, thrombosis belongs to the syndrome of blood stasis. Salvia miltiorrhiza Bunge and Ligusticum striatum DC. are two common TCM herbs with long-term documented function in promoting blood circulation and inhibiting thrombosis, especially when used together. Guanxinning Tablet, a modern Chinese drug which contains extracts of the two herbs, also showed strong therapeutic effects in coronary heart disease. However, the pharmacological mechanism is still lacking for the compatibility of the two herbs. Here, through zebrafish-based in vivo fluorescence screening, we demonstrated the synergistic effects between S. miltiorrhiza Bunge and L. striatum DC. in regulating endogenous thrombosis. Moreover, combined with high-resolution mass spectrometry, the main compounds of the botanical drugs were analyzed and screened in our model system. Interestingly, cryptotanshinone and senkyunolide I, two representative compounds, respectively derived from the two herbs, also showed synergistic antithrombotic effects. Further analysis suggested that they may regulate thrombi formation at different levels via multiple signaling pathways, including oxidative stress, platelet activation and coagulation cascade. Taken together, our findings provided solid biological supports toward the drug compatibility theory of TCM, and suggested cryptotanshinone and senkyunolide I as promising drug candidates in thrombosis management.

SUBMITTER: Li J

PROVIDER: S-EPMC7841298 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Synergistic Effects of Cryptotanshinone and Senkyunolide I in Guanxinning Tablet Against Endogenous Thrombus Formation in Zebrafish.

Li Jun J Liu Hao H Yang Zhenzhong Z Yu Qingqing Q Zhao Lu L Wang Yi Y

Frontiers in pharmacology 20210114

Thrombosis is a key pathological event in cardiovascular diseases, and is also the most important targeting process for their clinical management. New drug development in thrombosis treatment is still in great demand. According to the traditional Chinese medicine (TCM) theory, thrombosis belongs to the syndrome of blood stasis. Salvia miltiorrhiza Bunge and Ligusticum striatum DC. are two common TCM herbs with long-term documented function in promoting blood circulation and ...[more]

PMID: 33519488

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Project description:Background:GuanXinNing tablet (GXNT), a traditional Chinese patent medicine, has been found to have remarkable antithrombotic effects and can effectively inhibit pro-thrombotic factors in previous studies. However, the mechanism of its antithrombotic effects remains little known. Methods:In this study, we first determined and identified the sources of each main compound in GXNT using liquid chromatography-mass spectrometry (LC-MS). Through the approach of network pharmacology, we predicted the action targets of the active components, mapped the target genes related to thrombus, and obtained potential antithrombotic targets for active ingredients. We then performed gene ontology (GO) enrichment analyses and KEGG signaling pathway analyses for the action targets, and constructed networks of active component-target and active component-target-pathway for GXNT. Additionally, we evaluated the pharmacodynamic effects of GXNT on thrombus using the rat thrombus model induced by FeCl3, observed the effects of antiplatelet aggregation via platelet assay, and further verified the results predicted by network pharmacology via Western blot. Results:In total, 14 active ingredients were identified in GXNT, and 83 action targets were predicted, 17 of which are antithrombotic targets that potentially participate in processes including response to oxidative stress and positive regulation of blood vessel endothelial cell migration. KEGG pathway analyses revealed that the predicted action targets were involved in multiple signal pathways, such as MAPK, IL-17, and platelet activation. Pharmacodynamics study found that GXNT could significantly reduce the thrombus length and weight, lower platelet aggregation function, and decrease the levels of Fbg and PAI-1. In addition, GXNT could significantly increase 6-keto-PGF1? content and regulate the ratio of TXB2/6-keto-PGF1?, while not having dramatic effects on TXB2. GXNT was also observed to visibly inhibit maximum platelet aggregation. Herein, we further studied the thrombus-related MAPKs signaling pathway and found that GXNT could significantly reduce the phosphorylation levels of p38MAPK, ERK, and JNK proteins in platelet. Conclusions:This study revealed the pharmacodynamic material basis of GXNT and its potential multicomponent-multitarget-multipath pharmacological effects, confirmed the antithrombotic effects of GXNT, and showed that its mechanism may be related to inhibiting phosphorylation of p38, ERK, and JNK proteins in MAPKs signaling pathway, partially verifying the results from network pharmacology. The results from this study could provide a theoretical basis for the development and clinical application of GXNT.

Project description:BackgroundDiabetic encephalopathy (DE) is a complication of diabetes that leads to cognitive and behavioral decline. Utilizing safe and effective complementary and alternative medications for its management is a wise choice. Previous studies have shown that GuanXinNing Tablet (GXNT), an oral preparation primarily derived from two Chinese herbs, Salvia miltiorrhiza Bge. and Ligusticum chuanxiong Hort., exerts a beneficial neuroprotective effect. In this study, we explored the protective effects of GXNT on DE in male Zucker diabetic fatty (ZDF) rats induced by a high-fat diet, aiming to ascertain its significance and potential mechanisms.MethodsZDF rats were induced to develop type 2 diabetes (T2DM) with DE by a high-fat diet and treated with GXNT for 8 weeks until they were 20 weeks old. Throughout the experiment, the animals' vital parameters, such as body weight, were continuously monitored. Cognitive function was evaluated using the Y maze test. Biochemical kits were employed to analyze blood glucose, lipids, and vascular endothelial-related factors. Cerebrovascular lesions were assessed using magnetic resonance angiography (MRA) imaging. Brain lesions were evaluated using hematoxylin and eosin (H&E) staining and ultrastructure observation. IgG and albumin (ALB) leakage were detected using immunofluorescence.ResultsGXNT demonstrated an enhancement in the overall well-being of the animals. It notably improved cognitive and behavioral abilities, as demonstrated by extended retention time in the novel heterogeneous arm during the Y-maze test. GXNT effectively regulated glucose and lipid metabolism, reducing fasting and postprandial blood glucose, glycated hemoglobin (HbA1c), and total cholesterol (TC) levels. Additionally, it exhibited a protective effect on the vascular endothelium by reducing the serum TXB2/PGI2 ratio while elevating NO and PGI2 levels. Moreover, GXNT ameliorated stenosis and occlusion in cerebral vessel branches, increased the number of microvessels and neurons around the hippocampus, and improved microvascular occlusion in the cerebral cortex, along with addressing perivascular cell abnormalities. Immunofluorescence staining showed a decrease in the fluorescence intensity of IgG and ALB in the cerebral cortex.ConclusionsGXNT demonstrated a highly satisfactory protective effect on DE in ZDF rats. Its mechanism of action could be based on the regulation of glucolipid metabolism and its protective effect on the vascular endothelium.

Project description:Coronary atherosclerosis (CA) is a chronic and evolving inflammatory disease characterized by the build-up of atherosclerotic plaque in the wall of coronary arteries. Guanxinning tablet (GXNT) is a novel Chinese medicine formula, which has been clinically used to treat coronary heart disease for many years. However, the potential mechanism for treating CA remains unclear. Thus, the study was aimed at investigating the therapeutic effect of GXNT on CA and further explore the underlying mechanisms from the perspective of gut microbiota. Following the establishment of a CA model in Tibetan minipigs, GXNT was orally administrated. We simultaneously detected blood lipid levels, observed ventricular function using ultrasound examination, measured platelet aggregation, and checked changes in inflammatory factors, oxidative stress factors, and vascular endothelial injury-related indexes applying ELISA assays. Histopathological changes of coronary artery tissue were subsequently evaluated using Sudan IV staining, HE staining, Oil red “O” staining, and immunohistochemistry assays. Finally, alterations of the gut microbiota and microbial metabolites were detected using metagenomic sequencing and targeted metabolomics, respectively. The results have suggested that GXNT could regulate dyslipidemia, improve heart function, and inhibit the levels of ox-LDL, CRP, TNF-α, IL-1β, SOD, MDA, vWF, and ET-1, as well as platelet aggregation. Additionally, histopathological findings revealed that GXNT could reduce lipid deposition, alleviate AS lesions, and restrain the expressions of NF-κB, TNF-α, and MMP-9. Furthermore, the composition of the gut microbiota was altered. Specifically, GXNT could upregulate the relative abundance of Prevotellaceae and Prevotella and downregulate the abundance of Proteobacteria, Enterobacteriaceae, and Escherichia. As for microbial metabolites, GXNT could increase fecal propionic acid, butyric acid, and LCA-3S and decrease fecal TMA-related metabolites, CDCA, and serum TMAO. In sum, the results showed that GXNT had a satisfactory anti-CA effect, and the mechanism was closely associated with modulating gut microbiota and related metabolites.

Dataset Information

Synergistic Effects of Cryptotanshinone and Senkyunolide I in Guanxinning Tablet Against Endogenous Thrombus Formation in Zebrafish.

Publications

Synergistic Effects of Cryptotanshinone and Senkyunolide I in Guanxinning Tablet Against Endogenous Thrombus Formation in Zebrafish.

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