Compound danshen dripping pills normalize a reprogrammed metabolism of myocardial ischemia rats to interpret its time-dependent efficacy in clinic trials: a metabolomic study

Aa, Nan; Guo, Jiahua; Cao, Bei; Sun, Runbin; Ma, Xiaojing; Yang, Chong‐Ren; Zhou, Shuiping; Aa, Jiye; Yang, Zhaohui; Sun, He; Wang, Guangji

doi:10.1007/s11306-019-1577-3

Cited by 20 publications

(9 citation statements)

References 13 publications

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“…T 89 [also known as cardiotonic pills (CP), compound Danshen dripping pills in Chinese] is a widely used traditional Chinese medicine in China for treating ischemic angina pectoris, which consists of salvia miltiorrhiza (SM), panax notoginseng (PN), and Borneol. T 89 has passed phase II and is undergoing phase III clinical trials for prevention and treatment of ischemic cardiovascular disease by the United States Food and Drug Administration since 2016 ( Aa et al, 2019 ). Guo et al (2016) observed that T 89 pretreatment increased energy production and regulated the dominant energy metabolism mode accomplished with enhancing a metabolic shift toward fatty acid metabolism from glycolysis induced by ISO, which indicated that the regulation of energy metabolism was involved in the underling mechanism whereby T 89 exerted effect on myocardial ischemia.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

et al. 2021

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BackgroundT89, a traditional Chinese medicine, has passed phase II, and is undergoing phase III clinical trials for treatment of ischemic cardiovascular disease by the US FDA. However, the role of T89 on isoproterenol (ISO)-induced cardiac injury is unknown. The present study aimed to explore the effect and underlying mechanism of T89 on ISO-induced cardiac injury.MethodsMale Sprague-Dawley rats received subcutaneous injection of ISO saline solution at 24 h intervals for the first 3 days and then at 48 h intervals for the next 12 days. T89 at dose of 111.6 and 167.4 mg/kg was administrated by gavage for 15 consecutive days. Rat survival rate, cardiac function evaluation, morphological observation, quantitative proteomics, and Western blotting analysis were performed.ResultsT89 obviously improved ISO-induced low survival rate, attenuated ISO-evoked cardiac injury, as evidenced by myocardial blood flow, heart function, and morphology. Quantitative proteomics revealed that the cardioprotective effect of T89 relied on the regulation of metabolic pathways, including glycolipid metabolism and energy metabolism. T89 inhibited the enhancement of glycolysis, promoted fatty acid oxidation, and restored mitochondrial oxidative phosphorylation by regulating Eno1, Mcee, Bdh1, Ces1c, Apoc2, Decr1, Acaa2, Cbr4, ND2, Cox 6a, Cox17, ATP5g, and ATP5j, thus alleviated oxidative stress and energy metabolism disorder and ameliorated cardiac injury after ISO. The present study also verified that T89 significantly restrained ISO-induced increase of HSP70/HSP40 and suppressed the phosphorylation of ERK, further restored the expression of CX43, confirming the protective role of T89 in cardiac hypertrophy. Proteomics data are available via ProteomeXchange with identifier PXD024641.ConclusionT89 reduced mortality and improves outcome in the model of ISO-induced cardiac injury and the cardioprotective role of T89 is correlated with the regulation of glycolipid metabolism, recovery of mitochondrial function, and improvement of myocardial energy.

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Section: Introductionmentioning

confidence: 99%

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

et al. 2021

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“…The normal control group ( n = 8) remained undisturbed. Subsequently, the CUMS-induced rats were injected with ISO (8 mg/kg) for five days to form the CHD model ( Aa et al, 2019 ; Hu et al, 2020 ). The rat model for CHD with depression induced by CUMS and ISO was evaluated by measuring rat body weight change, open field test, sucrose preference test, and ST-segment of the electrocardiogram.…”

Section: Methodsmentioning

confidence: 99%

An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression

Zhang

Zhu

et al. 2021

Front. Pharmacol.

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Objectives: This study aimed to explore the mechanism of Xiong-Pi-Fang (XPF) in the treatment of coronary heart disease (CHD) with depression by an integrative strategy combining serum pharmacochemistry, network pharmacology analysis, and experimental validation.Methods: An ultrahigh performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) method was constructed to identify compounds in rat serum after oral administration of XPF, and a component-target network was established using Cytoscape, between the targets of XPF ingredients and CHD with depression. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to deduce the mechanism of XPF in treating CHD with depression. Finally, in a chronic unpredictable mild stress (CUMS)-and isoproterenol (ISO)-induced rat model, TUNEL was used to detect the apoptosis index of the myocardium and hippocampus, ELISA and western blot were used to detect the predicted hub targets, namely AngII, 5-HT, cAMP, PKA, CREB, BDNF, Bcl-2, Bax, Cyt-c, and caspase-3.Results: We identified 51 compounds in rat serum after oral administration of XPF, which mainly included phenolic acids, saponins, and flavonoids. Network pharmacology analysis revealed that XPF may regulate targets, such as ACE2, HTR1A, HTR2A, AKT1, PKIA, CREB1, BDNF, BCL2, BAX, CASP3, cAMP signaling pathway, and cell apoptosis process in the treatment of CHD with depression. ELISA analysis showed that XPF decreased Ang-II content in the circulation and central nervous system, inhibited 5-HT levels in peripheral circulation, and increased 5-HT content in the central nervous system and cAMP content in the myocardia and hippocampus. Meanwhile, western blot analysis indicated that XPF could upregulate the expression levels of PKA, CREB, and BDNF both in the myocardia and hippocampus. TUNEL staining indicated that the apoptosis index of myocardial and hippocampal cells increased in CUMS-and ISO-induced CHD in rats under depression, and XPF could increase the expression of Bcl-2, inhibit the expression of Bax, Cyt-c, and caspase-3, and rectify the injury of the hippocampus and myocardium, which exerted antidepressant and antimyocardial ischemia effects.Conclusion: Our study proposed an integrated strategy, combining serum pharmacochemistry and network pharmacology to investigate the mechanisms of XPF in treating CHD with depression. The mechanism of XPF in treating CHD with depression may be related to the activation of the cAMP signaling pathway and the inhibition of the apoptosis.

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“…Missing data were excluded before the analysis. After normalization against the IS, the data were evaluated using SIMCA-P 14.1 software (Umetrics, Umeå, Sweden) (21).…”

Section: Multivariate Statistical Analysismentioning

confidence: 99%

Plasma Metabolites Alert Patients With Chest Pain to Occurrence of Myocardial Infarction

et al. 2021

Front. Cardiovasc. Med.

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Myocardial infarction (MI) is one of the leading causes of death worldwide, and knowing the early warning signs of MI is lifesaving. To expand our knowledge of MI, we analyzed plasma metabolites in MI and non-MI chest pain cases to identify markers for alerting about MI occurrence based on metabolomics. A total of 230 volunteers were recruited, consisting of 146 chest pain patients admitted with suspected MI (85 MIs and 61 non-MI chest pain cases) and 84 control individuals. Non-MI cardiac chest pain cases include unstable angina (UA), myocarditis, valvular heart diseases, etc. The blood samples of all suspected MI cases were collected not longer than 6 h since the onset of chest pain. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry were applied to identify and quantify the plasma metabolites. Multivariate statistical analysis was utilized to analyze the data, and principal component analysis showed MI could be clearly distinguished from non-MI chest pain cases (including UA and other cases) in the scores plot of metabolomic data, better than that based on the data constructed with medical history and clinical biochemical parameters. Pathway analysis highlighted an upregulated methionine metabolism and downregulated arginine biosynthesis in MI cases. Receiver operating characteristic curve (ROC) and adjusted odds ratio (OR) were calculated to evaluate potential markers for the diagnosis and prediction ability of MI (MI vs. non-MI cases). Finally, gene expression profiles from the Gene Expression Omnibus (GEO) database were briefly discussed to study differential metabolites' connection with plasma transcriptomics. Deoxyuridine (dU), homoserine, and methionine scored highly in ROC analysis (AUC > 0.91), sensitivity (>80%), and specificity (>94%), and they were correlated to LDH and AST (p < 0.05). OR values suggested, after adjusting for gender, age, lipid levels, smoking, type II diabetes, and hypertension history, that high levels of dU of positive logOR = 3.01, methionine of logOR = 3.48, and homoserine of logOR = 1.61 and low levels of isopentenyl diphosphate (IDP) of negative logOR = −5.15, uracil of logOR = −2.38, and arginine of logOR = −0.82 were independent risk factors of MI. Our study highlighted that metabolites belonging to pyrimidine, methionine, and arginine metabolism are deeply influenced in MI plasma samples. dU, homoserine, and methionine are potential markers to recognize MI cases from other cardiac chest pain cases after the onset of chest pains. Individuals with high plasma abundance of dU, homoserine, or methionine have increased risk of MI, too.

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Compound danshen dripping pills normalize a reprogrammed metabolism of myocardial ischemia rats to interpret its time-dependent efficacy in clinic trials: a metabolomic study

Cited by 20 publications

References 13 publications

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

Quantitative Proteomics Reveal That Metabolic Improvement Contributes to the Cardioprotective Effect of T89 on Isoproterenol-Induced Cardiac Injury

An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression

Plasma Metabolites Alert Patients With Chest Pain to Occurrence of Myocardial Infarction

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