Effects of Buyang Huanwu Decoction on Intestinal Barrier, Intestinal Flora, and Trimethylamine Oxide in Rats with Heart Failure.

OBJECTIVE: To explore the mechanisms of Buyang Huanwu Decoction (BYHWD) modulating the gut microbiome and trimethylamine oxide (TAMO) to exert cardioprotective effects. METHODS: Ligation of the left anterior descending coronary artery was performed in rats to induce heart failure (HF). Except for the sham-operation group (n=10), 36 operation-induced models were randomized into 3 groups using a random number table (n=12 in each group): the model group, the BYHWD group (15.02 g/kg BYHWD), and the positive group (4.99 g/kg metoprolol succinate). After 4-week treatment (once daily by gavage), echocardiography was applied to evaluate the cardiac function and the Tei index (the ratio of ventricular isovolumic contraction time (IVCT) and isovolumic diastolic time (IVRT) to ejection time (ET)) was calculated; hematoxylin-eosin (HE) staining was observed to characterize the pathology of the myocardium and small intestinal villi. D-lactic acid was detected by an enzyme-linked immunosorbent assay (ELISA). Expressions of occludin, claudin-1, and zonula occludens (ZO-1) were detected by Western blot. 16S ribosomal ribonucleic acid (16S rRNA) sequencing was used to explore the changes in the intestinal flora. TMAO was detected via liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In the echocardiography, the Tei index was considerably lower in the positive and BYHWD groups compared with the model group (P<0.05). Besides, BYHWD improved the pathology of myocardium and small intestine of HF rats and lowered the D-lactic acid content in the serum, when compared with the model group (P<0.05). BYHWD also improved the expression of occludin and claudin-1 (P<0.05); in the gut microbiota analysis, BYHWD slowed down modifications in the structure distribution of gut microbiota and regulated the diversity of intestinal flora in HF rats. The content of TMAO in the serum was significantly lowered by BYWHT compared with the model group (P<0.05). CONCLUSION: BYHWD may delay progression of HF by enhancing the intestinal barrier structure, and regulating intestinal flora and TAMO.

Serum proteomic analysis reveals the cardioprotective effects of Shexiang Baoxin Pill and Suxiao Jiuxin Pill in a rat model of acute myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Shexiang Baoxin Pill (SBP) and Suxiao Jiuxin Pill (SJP) are traditional Chinese medicines used to treat cardiovascular disease (CVD) in China. However, the mechanism of their therapeutic effect on CVD has not been clearly elucidated yet. AIMS: The aim of this study is to investigate the cardioprotective effect of SBP and SJP in the treatment of acute myocardial infarction (AMI) model rats by applying serum proteomic approach. MATERIALS AND METHODS: The rat model of AMI was generated by ligating the left anterior descending coronary artery. 42 rats were randomly divided into four groups: sham-operating (Sham, n = 10) group, model (Mod, n = 8) group, Shexiang Baoxin pills pretreatment (SBP, n = 12) group and Suxiao Jiuxin pills pretreatment (SJP, n = 12) group. Data Independent Acquisition (DIA) proteomic approach was utilized to investigate the serum proteome from the rat individuals. The differentially expressed proteins were subsequently obtained with bioinformatic analysis. RESULTS: DIA-MS identified 415 proteins within 42 samples, and 84 differentially expressed proteins may contribute to the therapeutic effects of SBP and SJP. GOBP and KEGG pathway analysis of 84 differentially expressed proteins revealed that the proteins were mainly involved in platelet activation and adhesion processes. All 84 differentially expressed proteins presented the same changing tendency in the SBP and SJP groups when compared with the Mod group. Among these 84 proteins, 25 proteins were found to be related to CVD. Among these 25 proteins, ACTB, ACTG1, FGA, FGB, FGG, PF4 and VWF were found to be involved in platelet aggregation and activation. FN1, HSPA5 and YWHAZ were associated with adhesion. CONCLUSIONS: The results of our study suggest that the cardioprotective effects of SBP and SJP are achieved through the modulation of focal adhesion, platelet activation pathways.

Exploring biological basis of Syndrome differentiation in coronary heart disease patients with two distinct Syndromes by integrated multi-omics and network pharmacology strategy.

BACKGROUND: Traditional Chinese Medicine (TCM) is distinguished by Syndrome differentiation, which prescribes various formulae for different Syndromes of same disease. This study aims to investigate the underlying mechanism. METHODS: Using a strategy which integrated proteomics, metabolomics study for clinic samples and network pharmacology for six classic TCM formulae, we systemically explored the biological basis of TCM Syndrome differentiation for two typical Syndromes of CHD: Cold Congealing and Qi Stagnation (CCQS), and Qi Stagnation and Blood Stasis (QSBS). RESULTS: Our study revealed that CHD patients with CCQS Syndrome were characterized with alteration in pantothenate and CoA biosynthesis, while more extensively altered pathways including D-glutamine and D-glutamate metabolism; alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism, were present in QSBS patients. Furthermore, our results suggested that the down-expressed PON1 and ADIPOQ might be potential biomarkers for CCQS Syndrome, while the down-expressed APOE and APOA1 for QSBS Syndrome in CHD patients. In addition, network pharmacology and integrated analysis indicated possible comorbidity differences between the two Syndromes, that is, CCQS or QSBS Syndrome was strongly linked to diabetes or ischemic stroke, respectively, which is consistent with the complication disparity between the enrolled patients with two different Syndromes. These results confirmed our assumption that the molecules and biological processes regulated by the Syndrome-specific formulae could be associated with dysfunctional objects caused by the Syndrome of the disease. CONCLUSION: This study provided evidence-based strategy for exploring the biological basis of Syndrome differentiation in TCM, which sheds light on the translation of TCM theory in the practice of precision medicine.

[Shensong Yangxin Capsules in the adjuvant treatment of stable angina pectoris:a Meta-analysis and trial sequential analysis].

To systemically evaluate the benefits and side effects of Shensong Yangxin Capsules( SYC) in the adjuvant treatment of stable angina pectoris( SAP). Chinese and English databases( PubMed,EMbase,the Cochrane Library,CBM,CNKI,VIP,Wan Fang database) were retrieved to collect the randomized controlled trials( RCTs) about therapeutic efficacy of SYC combined with routine drug( trial group) vs routine drug( control group) in the treatment of SAP. The methodological quality of the RCTs was evaluated based on the cochrane risk of bias assessment tool. The data were extracted and Meta-analyzed by Reviewer Manager 5. 3. TSA 0. 9 software was used for trial sequential analysis( TSA) of the total effective rate of symptoms improvement. A total of 15 RCTs with 1 316 participants were included. RESULTS:: of Meta-analysis showed that the total effective rate of angina symptoms improvement( RR = 1. 15,95% CI[1. 09,1. 21],P<0. 001) of trial group were significantly higher than those of control group,with statistical significance,the total effective rate of electrocardiograms( ECG) improvement( RR = 1. 10,95% CI[0. 94,1. 29],P = 0. 25) of trial group were significantly higher than those of control group,but the difference was not statistically significant. After treatment,the improvement of the total time of 24 h general ischemia( SMD =-1. 21,95%CI[-1. 97,-0. 45],P = 0. 002),the ST-segment depression amplitude( SMD =-1. 30,95%CI [-1. 52,-1. 09],P<0. 001),the duration of angina pectoris attack( SMD =-1. 16,95% CI[-1. 36,-0. 95],P< 0. 001),the angina pectoris attack every week( SMD =-0. 80,95%CI[-1. 10,-0. 50],P<0. 001),the onsumption of nitroglycerin every week( SMD=-0. 72,95%CI[-1. 05,-0. 39],P<0. 001) in the trial group were better than that of the control group,and the difference was statistically significant. Besides,the improvement of the blood lipid and high sensitivity C reactive protein( hs-CRP) in the trial group were better than those of the control group after treatment,and the difference was statistically significant( P< 0. 001). Funnel plots and Egger's linear regression showed that there was no publication bias. By sensitivity analysis,it showed that the results of this study were stable and reliable. No obvious adverse drug reactions were observed in all studies. TSA analysis showed that the evidence of Meta-analysis was reliable. SYC combined with routine Western medicine treatment for SAP can improve the total effective rate of angina pectoris,reduce 24 h total ischemia time,ST segment depression amplitude,duration of angina pectoris attack,frequency of angina pectoris attack and nitroglycerin dosage,and also can improve blood lipid and hs-CRP levels.

Integrative analysis reveals distinct subtypes with therapeutic implications in KRAS-mutant lung adenocarcinoma.

BACKGROUND: KRAS-mutant lung adenocarcinomas (LUADs) are heterogeneous and frequently occur in smokers. The heterogeneity of KRAS-mutant LUAD has been an obstacle for the drug discovery. METHODS: We integrated multiplatform datatypes and identified two corresponding subtypes in the patients and cell lines. We further characterized the features of these two subtypes and performed drug screening to identify subtype-specific drugs. Finally, we used the defining features of the KRAS subtypes for drug sensitivity prediction. FINDINGS: Patient-Subtype 1 (PS1) was characterized by increased smoking-related mutational signature activity, a low tumor-infiltrating lymphocyte (TIL)-associating score and STK11/KEAP1 co-mutations. Patient-Subtype 2 (PS2) was characterized by an increased smoking-related methylation signature activity, a high TIL-associating score and increased KRAS dependency. The cell line subtypes faithfully recapitulated all the patients' features. Drug screening of the two cell line subtypes yielded several potential candidates, such as cytarabine and enzastaurin for Cell-line-Subtype 1 (CS1) and a BTK inhibitor QL-XII-61 for Cell-line-Subtype 2 (CS2). The defining features, such as smoking-related methylation signature, were significantly associated with the sensitivity to several drugs. INTERPRETATION: The heterogeneity of KRAS-mutant LUAD is associated with smoking-related genomic and epigenomic aberration along with other features such as immunogenicity, KRAS dependency and STK11/KEAP1 co-mutations. These features might be used as biomarkers for drug sensitivity prediction. FUND: This research was funded by the Young Scientists Fund of the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, China and the Education and Research Foundation for Young Scholars of Education Department of Fujian Province, China.