Integration of Metabolomics With Pharmacodynamics to Elucidate the Anti-myocardial Ischemia Effects of Combination of Notoginseng Total Saponins and Safflower Total Flavonoids

Abstract

Notoginseng (Sanqi), the roots and rhizomes of Panax notoginseng and safflower, the flowers of Carthamus tinctorius, are widely used traditional Chinese medicines (TCMs) for the treatment of cardiovascular diseases. Positive evidences have fueled growing acceptance for cardioprotective effects of the combination of the notoginseng total saponins and safflower total flavonoids (CNS) against myocardial ischemia (MI). However, the underlying cardioprotective mechanisms of CNS are still obscured. Metabolomics is a comprehensive tool for investigating biological mechanisms of disease, monitoring therapeutic outcomes, and advancing drug discovery and development. Herein, we investigated the cardioprotective effects of CNS on the isoproterenol (ISO)-induced MI rats by using plasma and urine metabolomics based on ultra-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) and multiple pharmacodynamics approaches. The results showed that pretreatment with CNS could attenuate the cardiac injury resulting from ISO, as evidenced by decreasing the myocardial infarct size, converting the echocardiographic, histopathological, and plasma biochemical abnormalities, and reversing the perturbations of plasma and urine metabolic profiles, particularly for the 55.0 mg/kg dosage group. In addition, 44 metabolites were identified as the potential MI biomarkers, mainly including a range of free fatty acids (FFAs), sphingolipids, and glycerophospholipids. CNS pretreatment group may robustly ameliorate these potential MI-related biomarkers. The accumulation of LysoPCs and FFAs, caused by PLA2, may activate NF-κB pathway and increase proinflammatory cytokines. However, our results showed that CNS at 55.0 mg/kg dosage could maximally attenuate the NF-κB signaling pathway, depress the expressions of TNF-α, IL-6, IL-1β, and PLA2. The results suggested that the anti-inflammatory property of CNS may contribute to its cardioprotection against MI. Our results demonstrate that the integrating of metabolomics with pharmacodynamics provides a reasonable approach for understanding the therapeutic effects of TCMs and CNS provide a potential candidate for prevention and treatment of MI.

Comparative Study on Excretive Characterization of Main Components in Herb Pair Notoginseng-Safflower and Single Herbs by LC–MS/MS

“…20110301) was deposited at Modern Research Center for Traditional Chinese Medicine, Peking University (Beijing, China). SF was prepared following the protocol reported by Meng, in which the content of HSYA was 10.53% [10]. The ratio of NS and SF was 6:5 in CNS.…”

“…Notoginseng Radix et Rhizoma (notoginseng) in combination with Carthami Flos (safflower), has been commonly used for the prevention and treatment of cardiovascular diseases [9,10]. Notoginseng is an important Chinese medicinal herb utilized for the treatment of pectoris and coronary artery disease [11,12,13,14].…”

“…The combination of NS and SF (CNS) could enhance their protective effects against myocardial ischemic injury in our previous studies [10]. The synergistic effects of herbal combination can be achieved by improving the pharmacokinetic profile, including absorption, distribution, metabolism, and excretion [21,22,23,24,25].…”

Large Volume Direct Injection Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry-Based Comparative Pharmacokinetic Study between Single and Combinatory Uses of Carthamus tinctorius Extract and Notoginseng Total Saponins

“…Myocardial ischemia-induced infarction is one of the leading causes of human death worldwide. The benefits of either Carthamus tinctorius extract (CTE) or notoginseng total saponins (NGTS) towards myocardial ischemia injury on rats have been well defined, and more interestingly, previous studies have demonstrated that better cardio-protective effects were observed when using their combination preparation (CNP) [1][2][3]. However, the underlying synergetic mechanisms of CTE and NGTS combination, their pharmacokinetic (PK) interactions in particular, still remain unclear.…”

“…Our previous pharmacological evaluations optimized a relatively low dosage CNP for the anti-myocardial ischemia effect [2]. Furthermore, the cocktail method usually suffers from extensive CYP450 crossover within the probe substrates [7].…”