A novel Danshensu/tetramethylpyrazine derivative induces vasorelaxation on rat aorta and exerts cardioprotection in dogs

Xu, Benhong; Deng, Hong‐Wei; Zhang, Xiaojing; Luo, Jingxiong; Zhang, Gaoxiao; Zhang, Zaijun; Wang, Yuqiang; Shan, Luchen

doi:10.1016/j.ejphar.2017.10.034

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Previous studies have reported that ADTM is associated with the progression of myocardial infarction [18][19][20]. ADTM induces vasodilation on rat aorta and exerts cardio-protection in dogs of myocardial infarction [18]. After experimental myocardial infarction in mice, ADTM promotes angiogenesis and cardiac healing [19].…”

Section: Discussionmentioning

confidence: 99%

“…Platelet-activating factor (PAF) is a potent inflammatory mediator that exerts its actions via the single PAFR and PAFR-deficiency alleviates MIR injury in mice [27,28]. Additionally, ADTM displayed cardio-protective effects in animal myocardial infarction and promoted angiogenesis served as a Ca 2+ current blocker [18,19] and PAF treatment increased intracellular Ca 2+ level in isolated myocytes of guinea pig and rat ventricle, or H9c2 cells via its receptor [29][30][31]. Therefore, we speculate that ADTM may prevent MIR possibly through PAF/PAFR regulation.…”

Section: Adtm Regulates Paf/pafr In Mir In Vivo and In Vitromentioning

confidence: 99%

“…1A), in which Danshensu and Tetramethylpyrazine are coupled via an ester bond [16,17]. ADTM has protective effects on acute myocardial infarction in animals and oxidative stress-induced cardiomyocytes injury in H9c2 cells [18][19][20]. However, the role of ADTM in the regulating MIR and its underlying molecular mechanism remains to be studied.…”

Section: Introductionmentioning

confidence: 99%

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A novel Danshensu/tetramethylpyrazine protects against Myocardial Ischemia Reperfusion Injury in rats

Wang

Fan

et al. 2021

Int. J. Med. Sci.

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A new Danshensu/tetramethylpyrazine derivative (ADTM) with cardio-protection effects such as antioxidant, arterial relaxation, pro-angiogenesis and antiplatelet activities. Platelet activating factor receptor (PAFR) plays a key role in myocardial ischemia reperfusion (MIR) injury. This study aims to investigate the protective role of ADTM in MIR injury and clarify the potential role of PAFR. We measured the effects of ADTM on MIR injury in rats in vivo and hypoxia re-oxygenation (HR) injury in neonatal rat ventricular myocytes (NRVMs) in vitro. The results show that ADTM can significantly improve the IR-induced decline in heart function as increasing EF and FS, and restore the decreased cardiac hemodynamic parameters (LVSP, ± dp/dt max) and increased the level of LVEDP, decrease the infarct size of damaged myocardium and lactate dehydrogenase (LDH) activity in serum. Additionally, ADTM inhibits cardiomyocytes apoptosis, caspase-3 activity, and inflammatory response as well as down-regulates the MIR-induced IL-1β and TNFα production. Next, PAFR expression was significantly down-regulated in cardiomyocytes of MIR model in vivo and in vitro after treated with ADTM compare to IR group. At the same time, ADTM and PAFR small interfering RNA (siRNA) could inhibit cardiomyocytes apoptosis and inflammation during HR, while PAF presents the opposite effect. Furthermore, the above effects of PAF in HR induced cardiomyocytes were reversed by co-treatment of ADTM. Our findings demonstrate for the first time that ADTM protects against MIR injury through inhibition of PAFR signaling, which provides a new treatment for MIR.

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Section: Discussionmentioning

confidence: 99%

Section: Adtm Regulates Paf/pafr In Mir In Vivo and In Vitromentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel Danshensu/tetramethylpyrazine protects against Myocardial Ischemia Reperfusion Injury in rats

Wang

Fan

et al. 2021

Int. J. Med. Sci.

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“…SalAs are important water‐soluble ingredients in S. miltiorrhiza , which contribute to curing cerebrovascular and cardiovascular diseases (Cui et al ., 2016; Zhou et al ., 2016). In our study, among the 12 increased salvianolic acids, salvianolic acid B, salvianolic acid A, rosmarinic acid, and danshensu have been reported to be active in the treatment of cerebrovascular diseases (Zhang et al ., 2017; Fan et al ., 2018; Xu et al ., 2018; Feng et al ., 2019). Recently, increasing research has been conducted with the aim to increase SalA content in S. miltiorrhiza (Xiao et al ., 2009; Zhang et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

Integrative omic and transgenic analyses reveal the positive effect of ultraviolet‐B irradiation on salvianolic acid biosynthesis through upregulation of SmNAC1

Fan

Chen

et al. 2020

The Plant Journal

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Salvianolic acids (SalAs), a group of secondary metabolites in Salvia miltiorrhiza, are widely used for treating cerebrovascular diseases. Their biosynthesis is modulated by a variety of abiotic factors, including ultraviolet-B (UV-B) irradiation; however, the underlying mechanisms remain largely unknown. Here, an integrated metabolomic, proteomic, and transcriptomic approach coupled with transgenic analyses was employed to dissect the mechanisms underlying UV-B irradiation-induced SalA biosynthesis. Results of metabolomics showed that 28 metabolites, including 12 SalAs, were elevated in leaves of UV-B-treated S. miltiorrhiza. Meanwhile, the contents of several phytohormones, including jasmonic acid and salicylic acid, which positively modulate the biosynthesis of SalAs, also increased in UV-B-treated S. miltiorrhiza. Consistently, 20 core biosynthetic enzymes and numerous transcription factors that are involved in SalA biosynthesis were elevated in treated samples as indicated by a comprehensive proteomic analysis. Correlation and gene expression analyses demonstrated that the NAC1 gene, encoding a NAC transcriptional factor, was positively involved in UV-B-induced SalA biosynthesis. Accordingly, overexpression and RNA interference of NAC1 increased and decreased SalA contents, respectively, through regulation of key biosynthetic enzymes. Furthermore, ChIP-qPCR and Dual-LUC assays showed that NAC1 could directly bind to the CATGTG and CATGTC motifs present in the promoters of the SalA biosynthesis-related genes PAL3 and TAT3, respectively, and activate their expression. Our results collectively demonstrate that NAC1 plays a crucial role in UV-B irradiation-induced SalA biosynthesis. Taken together, our findings provide mechanistic insights into the UV-B-induced SalA biosynthesis in S. miltiorrhiza, and shed light on a great potential for the development of SalA-abundant varieties through genetic engineering.

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“…These two compounds were coupled through an ester bond to form ADTM (Figure 1) [14]. In previous studies, ADTM demonstrated a wide range of pharmacological activities such as strong cardio-protective [15], anti-thrombolytic [16], and vasorelaxation effects [17,18]. However, despite its strong activity, ADTM was rapidly metabolized into DSS and (3,5,6-Trimethylpyrazin-2-yl) methanol (TMP-OH), resulting in short half-life and low blood levels, as shown in previous pharmacokinetic studies [19].…”

Section: Introductionmentioning

confidence: 99%

Concurrent Determination of Danshensu and Hydroxyl Ligustrazine in Rat Plasma Using High-Performance Liquid Chromatography and its Application to the Pharmacokinetic Study of ADTM, DSS and TMP-OH Following Intravenous Administration

Li¹,

Sheng

Zhang³

et al. 2019

BJSTR

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R)- (3,5,6-trimethylpyrazinyl) methyl-2-acetoxy-3- (3,4-diacetoxyphenyl) propanoate (named as ADTM), a novel Danshensu (DSS)/ Tetramethylpyrazine (TMP) derivative, exerts cardio-protective and anti-thrombolytic effects both in vitro and in vivo. However, ADTM is metabolized into (R)-3,4-Dihydroxyphenyllactic acid (DSS) and (3,5,6-Trimethylpyrazin-2-yl) methanol (TMP-OH) too rapidly to describe its pharmacokinetic behavior accurately. In this study, a rapid, sensitive, and simple high-performance liquid chromatography-ultraviolet detection method was developed and validated for concurrent DSS and TMP-OH determination, to quantify and evaluate ADTM pharmacokinetic behavior and compare the differences therein between three administration modes: a) Single intravenous (iv) ADTM administration; b) Combined sodium DSS and TMP-OH iv administration; c) Single sodium DSS or TMP-OH iv administration for the same dosage. The assay was validated according to the Food and Drug Administration guidelines and found to be suitable for the determination of plasma levels of therapeutic drugs. This method was successfully applied to DSS and TMP-OH pharmacokinetic studies after iv administration of ADTM, DSS, and TMP-OH in rats. Pharmacokinetic parameters showed significant differences in DSS but not TMP-OH between the three groups. These preclinical data will be useful for the design of subsequent trials of DSS derivatives.

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A novel Danshensu/tetramethylpyrazine derivative induces vasorelaxation on rat aorta and exerts cardioprotection in dogs

Cited by 7 publications

References 25 publications

A novel Danshensu/tetramethylpyrazine protects against Myocardial Ischemia Reperfusion Injury in rats

A novel Danshensu/tetramethylpyrazine protects against Myocardial Ischemia Reperfusion Injury in rats

Integrative omic and transgenic analyses reveal the positive effect of ultraviolet‐B irradiation on salvianolic acid biosynthesis through upregulation of SmNAC1

Concurrent Determination of Danshensu and Hydroxyl Ligustrazine in Rat Plasma Using High-Performance Liquid Chromatography and its Application to the Pharmacokinetic Study of ADTM, DSS and TMP-OH Following Intravenous Administration

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