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Background: Doxorubicin (DOX) is one of the most widely used antitumor drugs. However, continuous DOX treatment would cause crucial cardiotoxicity side effect, accompanied with the accumulation of reactive oxygen species (ROS), impaired mitochondrial functions and increased cardiomyocyte death. Sheng-Mai-San (SMS), a traditional Chinese medicine widely used for cardiovascular diseases, has been clinically used to counteract cardiotoxicity of DOX, yet the underlying mechanism is largely unknown. Methods: We utilized JC-1 assay to examine the effects of SMS and its components under DOX treatment in rat cardiomyocytes (H9c2 cells), and further investigated the functional mechanisms of active components in SMS formula via transcriptome sequencing, bioinformatics analysis and molecular experiments. Results: We identified three functional components of SMS in protecting cardiomyocytes from DOX-induced damages and revealed the coordinated regulatory mechanisms of these components, namely ginsenoside Rh2 (Rh2), Ophiopogonin D (OpD) and Schisandrin B (SchB). We found that Rh2 mainly acts to restore mitochondrial functions and to decrease ROS generation by enhancing fatty acid metabolism and antioxidant activity, OpD has assistive roles in mitochondrial function repair, and SchB mainly functions by inhibiting cell death, as well as activating cytoskeleton and ECM organization. Conclusion: This study provides supporting evidence for the clinical application of SMS to reduce the cardiotoxicity effects of DOX treatment, and also sheds light for the mechanistic studies of traditional Chinese medicine.

Background/Aims: Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years and has accumulated considerable knowledge concerning the in vivo efficacy of targeting complicated diseases. TCM formulae are a mixture of hundreds of chemical components with multiple potential targets, essentially acting as a combination therapy of multi-component drugs. However, the obscure substances and the unclear molecular mechanisms are obstacles to their further development and internationalization. Therefore, it is necessary to develop new modern drugs based on the combination of effective components in TCM with exact clinical efficacy. In present study, we aimed to detect optimal ratio of the combination of effective components based on Sheng-Mai-San for myocardial ischemia. Methods: On the basis of preliminary studies and references of relevant literature about Sheng-Mai-San for myocardial ischemia, we chose three representative components (ginsenoside Rb1 (G), ruscogenin (R) and schisandrin (S)) for the optimization design studies. First, the proper proportion of the combination was explored in different myocardial ischemia mice induced by isoproterenol and pituitrin based on orthogonal design. Then, the different proportion combinations were further optimized through uniform design in a multi-model and multi-index mode. Finally, the protective effect of combination was verified in three models of myocardial ischemia injured by ischemia/reperfusion, chronic intermittent hypoxia and acute infarction. Results: The optimized combination GRS (G: 6 mg/kg, R: 0.75 mg/kg, S: 6 mg/kg) obtained by experimental screening exhibited a significant protective effect on myocardial ischemia injury, as evidenced by decreased myocardium infarct size, ameliorated histological features, decreased myocardial myeloperoxidase (MPO) and malondiadehyde (MDA), calcium overload, and decreased serum lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), cardiac troponin I (cTn-I) activity. In addition, the interactions of three components in combination GRS were also investigated. The combination, compared to G, R and S, could significantly reduce the concentration of serum CK-MB and cTn-I, and decrease myocardial infarct size, which demonstrated the advantages of this combination for myocardial ischemia. Conclusion: Our results demonstrated that the optimized combination GRS could exert significant cardioprotection against myocardial ischemia injury with similar effect compared to Sheng Mai preparations, which might provide some pharmacological evidences for further development of new modern Chinese drug for cardiovascular diseases basing on traditional Chinese formula with affirmative therapeutic effect.

Ethnopharmacological relevance YiQiFuMai Powder Injection (YQFM), a traditional Chinese medicine prescription re-developed based on Sheng-Mai-San, is a classical and traditional therapeutic for clinical heart failure (HF) and angina. However, its potential mechanism against HF remains unclear. Aim of the study The present study observes the therapeutic role of YQFM and mechanisms underlying its effects on coronary artery ligation (CAL)-induced myocardial remodeling (MR) and HF. Methods MR and HF were induced by permanent CAL for 2 weeks in ICR mice. Then mice were treated with YQFM (0.13 g/kg, 0.26 g/kg and 0.53 g/kg) once a day until 2 weeks later. Cardiac structure and function were evaluated by echocardiography. Serum lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) were measured by biochemical kits and cardiomyocyte morphology was assessed by hematoxylin-eosin (HE) staining. Myocardial hydroxyproline (HYP), serum amino-terminal pro-peptide of pro-collagen type III (PIIINP), and Masson's trichrome staining were employed to evaluate cardiac fibrosis. Circulating level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was tested by ELISA kit to predict prognosis of CAL-induced HF. Effects of YQFM on the mitogen-activated protein kinases (MAPKs) pathway after CAL operation was evaluated by Western blotting and immunohistochemistry assay. Results YQFM (0.53 g/kg) improved the left ventricular (LV) function and structure impairment after 2 weeks in CAL mice. YQFM administration also decreased LDH and CK activities, circulating levels of MDA, PIIINP, NT-proBNP, and HYP contents. Moreover, YQFM ameliorated cardiac injury and fibrosis. Furthermore, YQFM (0.53 g/kg) inhibited the myocardial phosphorylation of MAPKs in HF mice. Conclusion Our findings suggest that YQFM attenuates CAL-induced HF via improving cardiac function, attenuating structure damage, oxidative stress, necrosis, collagen deposition, and fibrosis. In addition, YQFM ameliorates cardiac remodeling and HF, partially through inhibiting the MAPKs signaling pathways. These data provide insights and mechanisms into the widely application of YQFM in patients with HF, MI and other ischemic heart diseases. [ABSTRACT FROM AUTHOR]

Sheng-Mai-San is a multi-component traditional Chinese herbal preparation. Due to the fact granulated additives, such as starch, carboxymethyl cellulose, lactose and raw herbal powder may alter the content of the bioactive markers in the herbal products, a developed ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was used to measure the herbal biomarkers of ginsenoside Rb1, Rb2, Rc, Rd, Re, Rg1, Rh1, compound K, ophiopogonin D and schizandrin from the Sheng-Mai-San herbal formulation. Besides, scanning electron microscopy (SEM) was used to observe the morphology of the herbal granular powders. Light microscopy with Congo red and iodine-KI reagent staining was used to identify the cellulose fiber and cornstarch added to pharmaceutical herbal products. The swelling power (SP), water solubility index (WSI), and crude fiber analysis were used to determine the contents of cellulose fiber and cornstarch in pharmaceutical herbal products. In this study, we developed a novel skill to assess the quantification of appended cornstarch in pharmaceutical herbal products using Aperio ImageScope software. Compared with the traditional cornstarch analysis, our analysis method is a rapid, simple and conversion process which could be applied to detect the percentage of added cornstarch in unknown powder products. The various range of the herbal content for the five pharmaceutical manufacturers varied by up to several hundreds-fold. The physical examination reveals that the morphology of the herbal pharmaceutical products is rough and irregular with sharp layers. This study provides a reference standard operating procedure guide for the quality control of the Chinese herbal pharmaceutical products of Sheng-Mai-San. [ABSTRACT FROM AUTHOR]

Sheng-Mai-San (SMS), a well-known Chinese medicinal plant formula, is widely used for the treatment of cardiac diseases characterized by deficiency of Qi and Yin syndrome. A mouse chronic intermittent hypoxia (CIH) model was established to mimic the primary clinical features of deficiency of Qi and Yin syndrome. Mice experienced CIH for 28 days (nadir 7% to peak 8% oxygen, 20 min per day), resulting in left ventricle (LV) dysfunction and structure abnormalities. After administration of SMS (0.55, 1.1, and 5.5 g·kg −1 ·d −1 ) for four weeks, improved cardiac function was observed, as indicated by the increase in the ejection fraction from the LV on echocardiography. SMS also preserved the structural integrity of the LV against eccentric hypotrophy, tissue vacuolization, and mitochondrial injury as measured by histology, electron microscopy, and ultrasound assessments. Mechanistically, the antioxidant effects of SMS were demonstrated; SMS was able to suppress mitochondrial apoptosis as indicated by the reduction of several pro-apoptotic factors (Bax, cytochrome c , and cleaved caspase-3) and up-regulation of the anti-apoptosis factor Bcl-2. In conclusion, these results demonstrate that SMS treatment can protect the structure and function of the LV and that the protective effects of this formula are associated with the regulation of the mitochondrial apoptosis pathway. [ABSTRACT FROM AUTHOR]

Abstract: Sheng-Mai-San (SMS), a traditional Chinese multiherbal formula, is widely used in clinic for the treatment of myocardial ischemia (MI) in China. Recently, it has been shown that the change of neurotransmitters in central nervous system is closely related to the pathogenesis of MI, whether SMS might affect the neurotransmitters at central nervous system in MI patients has not been studied yet. In this study, a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous determination of two types of neurotransmitters (neuropeptides and monoaminergic neurotransmitters) in rat brain tissue was developed. The instrument was operated under the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive ion mode. A good linear relationship with coefficients ≥0.99 was achieved over the concentration ranges of 10–1000ngmL−1 for 5-hydroxytryptamine (5-HT) and norepinephrine (NE); 2–250ngmL−1 for methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK). Quantification limit for 5-HT and NE was 4.0ngmL−1; and 2.0ngmL−1 for M-ENK and L-ENK. The intra- and inter-day precision was less than 15% and accuracy was within ±15%. The analysis revealed significant reductions at the levels of 5-HT (p <0.01), NE (p <0.01), M-ENK (p <0.05) and L-ENK (p <0.01) in the MI group compared to the control group. These findings demonstrate that myocardial ischemia reduces the concentrations of 5-HT, NE, M-ENK and L-ENK in rat brains, while SMS shows protective effects on MI associated with reversing these four neurotransmitters to sham levels. [Copyright &y& Elsevier]

An integrated strategy based on experimental designs for the development, optimization and validation of the fingerprint method of Sheng-Mai-San by MEKC has been described. Orthogonal and sequential uniform designs were employed to select important experimental parameters and optimize CE conditions. Method validation was performed in terms of injection precision, sample stability test and robustness testing. Additionally, conventional modeling method was used to predict the optimum separation conditions for comparative purpose. The strategy described can also be utilized for fingerprint development in the quality control of other herbal medicines. [ABSTRACT FROM AUTHOR]

Abstract: Sheng-Mai-San (SMS) is a famous traditional Chinese medicine (TCM) recipe, containing Radix Ginseng (Panax ginseng C.A. Mey., Araliaceae), Radix Ophiopogonis (Ophiopogon japonicus (Thunb.) Ker-Gawl., Liliaceae) and Fructus Schisandrae (Schisandra chinensis (Turcz.) Baill., Magnoliaceae), and has been used more than one thousand years. In this research, pharmacokinetics of one component of this TCM recipe was studied. Schizandrin is the main absorbed effective ingredient of Fructus Schisandrae and its pharmacokinetics were studied following oral administration of pure schizandrin, Fructus Schisandrae aqueous extract, and SMS decoction in rats with approximately the same dose of 5mg/kg. At different time points (0, 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12h) after administration, the concentrations of schizandrin in rat plasma were determined by LC–MS, and main pharmacokinetic parameters were estimated. It was found that both AUC0-tn and T 1/2 of schizandrin in Fructus Schisandrae aqueous extract and in SMS decoction were increased significantly (p <0.05) comparing with that in monomer. The content assay also revealed that the concentrations of lignans would increase when SMS decocting, comparing with Fructus Schisandrae. These results indicate that some ingredients in SMS may increase the dissolution of schizandrin when decocting in vitro, and delay its elimination and enhance its bioavailability in rat. [Copyright &y& Elsevier]

The traditional Chinese medicine prescription "Sheng-Mai-San (SMS)" has been used for treating patients with coronary heart disease for a long time and was found to have antioxidative effects. Here, we applied adriamycin (doxorubicin, ADR), a highly effective anticancer agent, as an inducer to establish the animal model of dose-related cardiomyopathy due to inhibition of nucleic acid as well as protein synthesis, formation of free radicals, and lipid peroxidation. The objective of this study was to investigate the protective effects of SMS on adriamycin-induced cardiomyopathy. Wistar rats were divided into four groups: CONT (control), ADR, SMS, and ADR + SMS. ADR (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks and SMS was administered via a feeding tube throughout the mouth once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5-week post-treatment period, the hearts of the rats were surgically removed for the study of synthesis rates of DNA, RNA and proteins. Besides myocardial antioxidants, lipid peroxidation and morphological ultrastructure were also evaluated. Three weeks after the treatment, cardiomyopathy and congestive heart failure were characterized according to assessment in ascites, congested liver, depressed cardiac function and myocardial cell damage. The results demonstrated that nucleic acid as well as protein synthesis was inhibited, while lipid peroxidation was increased. Myocardial glutathione peroxidase (GSHPx) activity was decreased and electron microscopic examination revealed myocardial lesion indicative of ADR-induced cardiomyopathy. In contrast, administration of SMS before and concurrent with ADR significantly attenuated the myocardial effects. It also lowered mortality as well as the amount of ascites. In addition, indexes in myocardial GSHPx, macromolecular biosynthesis and superoxide dismutase activities were increasing, with a concomitant decrease in lipid peroxidation and preserved myocardial ultrastructure. These results indicated that SMS may be partially protective against ADR-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background/aims: Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years and has accumulated considerable knowledge concerning the in vivo efficacy of targeting complicated diseases. TCM formulae are a mixture of hundreds of chemical components with multiple potential targets, essentially acting as a combination therapy of multi-component drugs. However, the obscure substances and the unclear molecular mechanisms are obstacles to their further development and internationalization. Therefore, it is necessary to develop new modern drugs based on the combination of effective components in TCM with exact clinical efficacy. In present study, we aimed to detect optimal ratio of the combination of effective components based on Sheng-Mai-San for myocardial ischemia., Methods: On the basis of preliminary studies and references of relevant literature about Sheng-Mai-San for myocardial ischemia, we chose three representative components (ginsenoside Rb1 (G), ruscogenin (R) and schisandrin (S)) for the optimization design studies. First, the proper proportion of the combination was explored in different myocardial ischemia mice induced by isoproterenol and pituitrin based on orthogonal design. Then, the different proportion combinations were further optimized through uniform design in a multi-model and multi-index mode. Finally, the protective effect of combination was verified in three models of myocardial ischemia injured by ischemia/reperfusion, chronic intermittent hypoxia and acute infarction., Results: The optimized combination GRS (G: 6 mg/kg, R: 0.75 mg/kg, S: 6 mg/kg) obtained by experimental screening exhibited a significant protective effect on myocardial ischemia injury, as evidenced by decreased myocardium infarct size, ameliorated histological features, decreased myocardial myeloperoxidase (MPO) and malondiadehyde (MDA), calcium overload, and decreased serum lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), cardiac troponin I (cTn-I) activity. In addition, the interactions of three components in combination GRS were also investigated. The combination, compared to G, R and S, could significantly reduce the concentration of serum CK-MB and cTn-I, and decrease myocardial infarct size, which demonstrated the advantages of this combination for myocardial ischemia., Conclusion: Our results demonstrated that the optimized combination GRS could exert significant cardioprotection against myocardial ischemia injury with similar effect compared to Sheng Mai preparations, which might provide some pharmacological evidences for further development of new modern Chinese drug for cardiovascular diseases basing on traditional Chinese formula with affirmative therapeutic effect., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Sheng-Mai-San is a multi-component traditional Chinese herbal preparation. Due to the fact granulated additives, such as starch, carboxymethyl cellulose, lactose and raw herbal powder may alter the content of the bioactive markers in the herbal products, a developed ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was used to measure the herbal biomarkers of ginsenoside Rb₁, Rb₂, Rc, Rd, Re, Rg₁, Rh₁, compound K, ophiopogonin D and schizandrin from the Sheng-Mai-San herbal formulation. Besides, scanning electron microscopy (SEM) was used to observe the morphology of the herbal granular powders. Light microscopy with Congo red and iodine-KI reagent staining was used to identify the cellulose fiber and cornstarch added to pharmaceutical herbal products. The swelling power (SP), water solubility index (WSI), and crude fiber analysis were used to determine the contents of cellulose fiber and cornstarch in pharmaceutical herbal products. In this study, we developed a novel skill to assess the quantification of appended cornstarch in pharmaceutical herbal products using Aperio ImageScope software. Compared with the traditional cornstarch analysis, our analysis method is a rapid, simple and conversion process which could be applied to detect the percentage of added cornstarch in unknown powder products. The various range of the herbal content for the five pharmaceutical manufacturers varied by up to several hundreds-fold. The physical examination reveals that the morphology of the herbal pharmaceutical products is rough and irregular with sharp layers. This study provides a reference standard operating procedure guide for the quality control of the Chinese herbal pharmaceutical products of Sheng-Mai-San.