A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

Zhang, Xiaojing; Hu, Huihui; Luo, Jingxiong; Deng, Hong‐Wei; Yu, Pei; Zhang, Zaijun; Zhang, Gaoxiao; Shan, Luchen; Wang, Yuqiang

doi:10.1248/bpb.b17-00313

Cited by 26 publications

(42 citation statements)

References 30 publications

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“…Thus, a series of novel derivatives of Danshensu have been developed. Pharmacological investigations have shown that these derivatives prevent myocardial ischemia injury in the heart, confirming their therapeutic potential in heart diseases [256][257][258][259][260][261] . Additionally, the combination of Danshensu and other agents, such as hydroxysafflor yellow A [262] , paeonol [263,264] , and puerarin [265,266] , shows synergistic cardioprotective effects, thus providing additional options for the clinical uses of Danshensu.…”

Section: Cardioprotective Effects Of Danshensu Derivatives and Preparmentioning

confidence: 66%

Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics

2018

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Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics.

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Section: Cardioprotective Effects Of Danshensu Derivatives and Preparmentioning

confidence: 66%

Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics

2018

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“…More recently, we have demonstrated that DT-010 was able to enhance the chemotherapeutic efficacy of doxorubicin in tumor cells ( Wang et al, 2016 ). Additionally, DT-010 could offer cardioprotection and neuroprotection against Parkinson’s disease-related neurotoxins ( Hu et al, 2016 ; Zhang et al, 2017 ). However, the neuroprotective effects of DT-010 in cellular models associated with AD have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

A Novel Tetramethylpyrazine Derivative Prophylactically Protects against Glutamate-Induced Excitotoxicity in Primary Neurons through the Blockage of N-Methyl-D-aspartate Receptor

Mak

et al. 2018

Front. Pharmacol.

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The over-activation of NMDA receptor via the excessive glutamate is believed to one of the most causal factors associated with Alzheimer’s disease (AD), a progressive neurodegenerative brain disorder. Molecules that could protect against glutamate-induced neurotoxicity may hold therapeutic values for treating AD. Herein, the neuroprotective mechanisms of dimeric DT-010, a novel derivative of naturally occurring danshensu and tetramethylpyrazine, were investigated using primary rat cerebellar granule neurons (CGNs) and hippocampal neurons. It was found that DT-010 (3–30 μM) markedly prevented excitotoxicity of CGNs caused by glutamate, as evidenced by the promotion of neuronal viability as well as the reversal of abnormal morphological changes. While its parent molecules did not show any protective effects even when their concentration reached 50 μM. Additionally, DT-010 almost fully blocked intracellular accumulation of reactive oxygen species caused by glutamate and exogenous oxidative stimulus. Moreover, Western blot results demonstrated that DT-010 remarkably attenuated the inhibition of pro-survival PI3K/Akt/GSK3β pathway caused by glutamate. Ca2+ imaging with Fluo-4 fluorescence analysis further revealed that DT-010 greatly declined glutamate-induced increase in intracellular Ca2+. Most importantly, with the use of whole-cell patch clamp electrophysiology, DT-010 directly inhibited NMDA-activated whole-cell currents in primary hippocampal neurons. Molecular docking simulation analysis further revealed a possible binding mode that inhibited NMDA receptor at the ion channel, showing that DT-010 favorably binds to Asn602 of NMDA receptor via arene hydrogen bond. These results suggest that DT-010 could be served as a novel NMDA receptor antagonist and protect against glutamate-induced excitotoxicity from blocking the upstream NMDA receptors to the subsequent Ca2+ influx and to the downstream GSK3β cascade.

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“…Research finds that the Nrf2-ARE signaling pathway is closely related to improving myocardial I/R injury. Meanwhile, Nrf2 is an important transcription factor in cell to reduce ROS (22). Our results suggest that the effects of hyperoxia liquid induced Nrf2-ARE signaling pathway in CPB induced rat model.…”

Section: Discussionmentioning

confidence: 56%

The effects of hyperoxia liquid regulate cardiopulmonary bypass‑induced myocardial damage through the Nrf2‑ARE signaling pathway

Han³

et al. 2018

Mol Med Report

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The aim of the present study was to investigate the protective role of hyperoxia liquid in regulating cardiopulmonary bypass (CPB)‑induced myocardial damage and its possible underlying mechanism. In the CPB‑induced rat model, hyperoxia liquid enhanced left ventricular ejection fraction (LVEF), reduced the left ventricular internal dimension systole (LVIDs) level, inhibited malondialdehyde levels, increased superoxide dismutase, glutathione (GSH) and GSH peroxidase levels, suppressed heart cell apoptosis, and induced the nuclear factor erythroid 2‑related factor 2 (Nrf2) and heme oxygenase‑1 (HO‑1) signaling pathway. Then, ML385, a Nrf2 inhibitor, was used to attenuate the effect of hyperoxia liquid on LVEF and LVIDs levels, oxidative stress and heart cell apoptosis in the CPB‑induced rat model. Collectively, the results of the present study demonstrated that the protective role of hyperoxia liquid may regulate oxidative stress in a CPB‑induced rat model through the Nrf2‑antioxidant response element signaling pathway.

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A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

Cited by 26 publications

References 30 publications

Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics

Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics

A Novel Tetramethylpyrazine Derivative Prophylactically Protects against Glutamate-Induced Excitotoxicity in Primary Neurons through the Blockage of N-Methyl-D-aspartate Receptor

The effects of hyperoxia liquid regulate cardiopulmonary bypass‑induced myocardial damage through the Nrf2‑ARE signaling pathway

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