Shenxiang Suhe pill improves cardiac function through modulating gut microbiota and serum metabolites in rats after acute myocardial infarction.

CONTEXT: Shenxiang Suhe pill (SXSH), a traditional Chinese medicine, is clinically effective against coronary heart disease, but the mechanism of cardiac-protective function is unclear. OBJECTIVE: We investigated the cardiac-protective mechanism of SXSH via modulating gut microbiota and metabolite profiles. MATERIALS AND METHODS: Sprague-Dawley (SD) male rats were randomly divided into 6 groups (n = 8): Sham, Model, SXSH (Low, 0.063 g/kg; Medium, 0.126 g/kg; High, 0.252 g/kg), and Ato (atorvastatin, 20 mg/kg). Besides the Sham group, rats were modelled with acute myocardial infarction (AMI) by ligating the anterior descending branch of the left coronary artery (LAD). After 3, 7, 14 days' administration, ultrasound, H&E staining, serum enzymic assay, 16S rRNA sequencing were conducted to investigate the SXSH efficacy. Afterwards, five groups of rats: Sham, Model, Model-ABX (AMI with antibiotics-feeding), SXSH (0.126 g/kg), SXSH-ABX were administrated for 14 days to evaluate the gut microbiota-dependent SXSH efficacy, and serum untargeted metabolomics test was performed. RESULTS: 0.126 g/kg of SXSH intervention for 14 days increased ejection fraction (EF, 78.22%), fractional shortening (FS, 109.07%), and aortic valve flow velocities (AV, 21.62%), reduced lesion area, and decreased serum LDH (8.49%) and CK-MB (10.79%). Meanwhile, SXSH upregulated the abundance of Muribaculaceae (199.71%), Allobaculum (1744.09%), and downregulated Lactobacillus (65.51%). The cardiac-protective effect of SXSH was disrupted by antibiotics administration. SXSH altered serum metabolites levels, such as downregulation of 2-n-tetrahydrothiophenecarboxylic acid (THTC, 1.73%), and lysophosphatidylcholine (lysoPC, 4.61%). DISCUSSION AND CONCLUSION: The cardiac-protective effect and suggested mechanism of SXSH could provide a theoretical basis for expanding its application in clinic.

Dual-screening of anti-inflammatory and antioxidant active ingredients of shenxiang suhe pill and its potential multi-target therapy for coronary heart disease.

BACKGROUND: Shenxiang Suhe Pill (SXSHP), a Chinese medicine formula, is widely used in clinic to treat coronary heart disease (CHD). However, due to the complex composition of SXSHP, its underlying mechanisms and pharmacodynamic properties are still unknown. In this paper, we try to define the compounds of SXSHP by dual-screening the active ingredients with anti-inflammation and antioxidant effects and predict its multi-target-pathway in CHD therapy using network pharmacology. METHODS: The chemical constituents in SXSHP were analyzed by UPLC/Q-TOF. Then, the active ingredients with the anti-inflammation and antioxidant effects were dual-screened by in vitro experiments. Ingenuity pathway analysis (IPA) was used to analyze and predict the potential targets and pathways of the anti-inflammatory and antioxidant effects of SXSHP. RESULTS: A total of 38 chemical constituents were identified in SXSHP, among which we screened six anti-inflammatory compounds: luteolin, isorhamnetin-3-O-beta-d-glucoside, 4-hydroxy-3-methoxycinnamaldehyde, benzoic acid, kaempferol-3-O-glucuronide acid, and blumeatin; and five antioxidant compounds: vanillin, eugenol, muscone, luteolin, and asiatic acid. IPA showed that eugenol, muscone, and 4-hydroxy-3-methoxycinnamaldehyde were closely related to the HIF-1 and IL-15 signaling pathways, which protect against oxidative stress and inflammation, respectively. CONCLUSIONS: Among the 38 ingredients in SXSHP, the anti-inflammatory pharmacological effects of isorhamnetin-3-O-beta-d-glucoside, blumeatin and 4-hydroxy-3-methoxycinnamaldehyde were reported for the first time. According to the network pharmacology analysis, eugenol, 4-hydroxy-3-methoxycinnamaldehyde and muscone are involved in the antioxidant HIF-1 pathway and the anti-inflammatory IL-15 pathway, and that may be the mechanism of SXSHP in the treatment of CHD.

A Review of Danshen Combined with Clopidogrel in the Treatment of Coronary Heart Disease.

OBJECTIVE: Danshen, the root of Salvia miltiorrhiza Bunge, is a traditional herbal medicine in China, which has been used to treat irregular menstruation, cold hernia, and abdominal pain for thousands of years. Danshen is frequently used in combination with drugs to treat cardiovascular diseases. Clopidogrel is a commonly used drug for treating coronary heart disease, but clopidogrel resistance restricts its development. Therefore, the clinical efficacy of Danshen combined with clopidogrel treats coronary heart disease and the relationship between Danshen and clopidogrel metabolism enzymes is suggested for future investigations. MATERIALS AND METHODS: The information was collected by searching online databases, and the RevMan 5.3 software was used to perform meta-analysis. RESULTS: Twenty-two articles, including 2587 patients, were enrolled after the evaluation. Meta-analysis showed that Danshen combined with clopidogrel was more effective than clopidogrel alone in treating coronary heart disease by improving clinical curative effect, reducing the frequency of angina pectoris, improving electrocardiogram results, shortening the duration of angina pectoris, and easing adverse reactions. Danshen inhibited carboxylesterase 1 and most enzyme of cytochrome P450, especially cytochrome P450 1A2, which may affect the metabolism of clopidogrel. CONCLUSION: Danshen combined with clopidogrel may compensate for individual differences of clopidogrel resistance among individuals in the treatment of coronary heart disease. Meanwhile, the inhibitory effect of Danshen on cytochrome P450 and carboxylesterase 1 could be partly responsible for the synergistic and attenuating effects of Danshen combined with clopidogrel.

Anti-coagulative and gastrointestinal motility regulative activities of Fructus Aurantii Immaturus and its effective fractions.

OBJECTIVE: Fructus Aurantii Immaturus (FAI) has been used in the treatment of gastrointestinal disorders (GIDs) in traditional Chinese medicine (TCM) for thousands of years, which also has been found to have effects on cardiovascular diseases (CVDs) in recent years. The current study aimed at investigating the anti-coagulative and gastrointestinal motility regulative activities of different fractions isolated from FAI, which may have both effects on gastrointestinal and cardiovascular systems, in the manners of network pharmacology analysis and experiments in vivo and in vitro. METHODS: We obtained water decoction, volatile oils, alkaloids and flavonoids from FAI, which were identified by gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC). Network pharmacological analysis was used to explore the relationship between the various types of chemical constituents, gene target and biological pathways of FAI. Then, the effective fractions in terms of anti-coagulative and gastrointestinal motility regulative activities were investigated by the experiment of rabbit intestinal smooth muscles contraction, mice small intestine propulsion rate and blood-clotting time, and verified by the blood stasis model. RESULTS: From the Network pharmacological analysis, the flavonoids were predicted to be the main active ingredients on gastrointestinal and cardiovascular systems. Experimental results also showed that flavonoids could significantly increase the small intestine propulsion rate and extend the blood-clotting time of mice. The Flavonoids could alleviate the increased fractional shortening (FS), left ventricular outflow, hematocrit and fibrinogen, and ameliorate the pathological changes of myocardial tissues caused by blood stasis. CONCLUSION: These findings indicated that flavonoids in FAI might be the main effective fractions on gastrointestinal motility and anti-coagulation.

[Effects of Xue-Bi-Jing combined with forsythia suspension on the liver gene expression levels of rats with sepsis model].

OBJECTIVE: To study the effects of "XUE BI JING plus LIANQIAO" injection on gene expression levels of rats with sepsis model. METHODS: One hundred and twenty rats were randomly divided into sham operation group, sepsis model group, Te-neng group and "XUE BI JING plus forsythia suspension" group. The sepsis model of rats was prepared by "CLP" method. Tai neng group was treated by peritoneal injection Imipenem/ Cilastatin (0.18 g/kg); "XUE BI JING plus LIANQIAO" group was treated by peritoneal injection Imipenem/ Cilastatin (0.18 g/kg) plus "xue-bi-jing" (10 ml/kg) and "liang ge san" (18 g/200 g) by intragastric administration 2 times a day; the sham operation group and model group were treated by peritoneal injection of normal saline (10 ml/kg). The survival rates at 48h and 72h were observed for all groups. The gene expression levels of livers in all groups were detected by BiostarR-40s chip. The NCBI database was used to inquest Gene function and class. RESULTS: The survival rates at 48h and 72h in "XUE BI JING+ forsythia suspension" group were 83.3% and 76.7% which were significantly higher than those (30.0% and 16.7%) in sepsis model group and those (60.0% and 33.3%) in Te-neng group (P < 0.01). Model group/control group have 305 differential expression genes with 159 up-regulation genes and 146 down-regulation genes. Tai-neng group/model group have 386 differential expression genes with 206 up-regulation genes and 180 down-regulation genes. "XUE BI JING plus forsythia suspension" group/model group have 342 differential expression genes with 102 up-regulation genes and 240 downregulation genes. The genes with up-regulation in model group/ control group and with down-regulation in"XUE BI JING plus forsythia suspension" group/model group were 24. The genes with down-regulation in the model group/ sham operation group and with up-regulation in "XUE BI JING plus forsythia suspension"group/model group were 16. CONCLUSION: "XUE BI JING plus forsythia suspension" can reduce the mortality of rats with sepsis, which could be due to the expression of relative regulation genes.

[A gene chip study of "Jun Du Yan Bingzhi" on liver in a sepsis model of rat].

OBJECTIVE: To study the effect of "Jun Du Yan Bingzhi" on genic change in liver of a sepsis rat model by gene chip technique, in order to study the mechanism of the action of the drug on the gene level. METHODS: Ninety rats were randomly divided into normal control group, model group and "Jun Du Yan Bingzhi" group, with 30 rats in each group. Sepsis was reproduced by cecal ligation and puncture (CLP) method. In "Jun Du Yan Bingzhi" group the rats were treated with intraperitoneal injection of imipenem/cilastatin (0.18 g/kg), Xuebijing injection (10 ml/kg) and gavage of "Liangge San" (15 ml/kg). In the control group and model group intraperitoneal physiological saline (10 ml/kg) was given; Survival time, and 48-hour and 72-hour survival rates of every group were observed, and changes in liver genes were examined with BiostarR-40 s chip. The ratio of Cy3/Cy5 > or =2.0 or < or =0.5 was used to screen differential genes, and NCBI database was used to identity the function of differential genes. RESULTS: The 48-hour and 72-hour survival rate of "Jun Du Yan Bingzhi" group was significantly higher than that of model group (83.3% vs. 30.0%, 76.7% vs. 17.7%, both P<0.01), 305 differential genes were found in model/control groups, with up-regulation in 159, down-regulation in 146, 500 differential genes were found in "Jun Du Yan Bingzhi" group/model group, with up-regulation in 292, down-regulation in 208, model group/control group up-regulation and "Jun Du Yan Bingzhi" group/model group down-regulation were 48, model group/control group down-regulation and "Jun Du Yan Bingzhi" group/model group up-regulation were 63. CONCLUSION: "Jun Du Yan Bingzhi" can degrade the 48-hour and 72-hour death rate of sepsis rat, through control immunization related, inflammation, signal transduction transcription regulation, cell cycle, apoptosis, substance metabolism, translation/processing/modify/degradation of protein, differentiation/proliferation/growth of cell related gene, promote multisystem function of sepsis rat to recover normal.