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Shudage-4, an ancient and well-known formula in traditional Mongolian medicine comprising four different types of traditional Chinese medicine, is widely used in the treatment of gastric ulcers. However, the potential material basis and molecular mechanism of Shudage-4 in attenuating stress-induced gastric ulcers remain unclear. This study aimed to first explore the potential material basis and molecular mechanism of Shudage-4 in attenuating gastric ulcers in rats. The chemical constituents and transitional components in the blood of Shudage-4 were identified by ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS). The rat gastric ulcer model was induced by water immersion restraint stress (WIRS). The ulcer damage to gastric tissue was measured at the gross anatomical level and pathological level by hematoxylin-eosin (HE) staining of gastric tissue. RNA sequencing of gastric tissue and plasma metabolomics were performed to analyze the mechanism of Shudage-4 against gastric ulcers. A Pearson correlation analysis was performed to explore the association between serum metabolites and gene expression of gastric tissue. A total of 30 chemical constituents were identified in Shudage-4 by UPLC-TOF-MS. Among 30 constituents, 13 transitional components in the blood were considered as the potential material basis. Shudage-4 treatment had a significant effect on WIRS-induced gastric ulcers in rats. HE staining of gastric tissue illustrated that WIRS-induced ulcer damage was suppressed by Shudage-4 treatment. RNA sequencing of gastric tissue showed that 282 reversed expression genes in gastric tissue were related to Shudage-4 treatment, and gene set enrichment analysis revealed that Shudage-4 treatment significantly inhibited gene set expression related to reactive oxygen species (ROS), which was also validated by detecting rat gastric tissue MDA, GSH, SOD, GSH-Px, and CAT activities. The plasma metabolomic data demonstrated that 23 significantly differential metabolites were closely associated with the Shudage-4 treatment. The further multiomics joint analysis found that significantly upregulated 5 plasma metabolites in Shudage-4-treated rats compared to model rats were negatively correlated with gene set expression related to ROS in gastric tissue. Shudage-4 alleviated WIRS-induced gastric ulcers by inhibiting ROS generation, which was achieved by regulating plasma metabolites level. [ABSTRACT FROM AUTHOR]

A liquid chromatography−mass spectrometry method was developed for the simultaneous quantitation of (2R,3R)-Dihydromyricetin and Myricetin in rat plasma samples to facilitate analysis of samples collected after administration of SenDeng-4 medicine. The plasma was subjected to protein precipitation with HCl (containing 10% ascorbic acid) and analyzed using electrospray ionization mass spectrometry in selected ion monitoring mode with Paeoniflorin as an internal standard. Good linearity for the two compounds was observed. The intra- and inter-day precision of analysis was <10% for each compound. The present method was suitable for determining (2R,3R)-Dihydromyricetin and Myricetin in rat plasma after intravenous administration of SenDeng-4 to rats with sufficient sensitivity. [ABSTRACT FROM AUTHOR]

Nutmeg-5, which consists of Myristica fragrans Houtt., Aucklandia lappa Decne. , Inula helenium L. , Fructus Choerospondiatis and Piper longum L. , is an ancient and classic formula in traditional Mongolian medicine that is widely used in the treatment of ischemic heart disease. However, its material basis and pharmacological mechanisms remain to be fully elucidated. The aim of this study was to explore the potential material basis and molecular mechanism of Nutmeg-5 in improving cardiac remodeling after myocardial infarction (MI). The constituents of Nutmeg-5 absorbed into the blood were identified by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). A mouse MI model was induced in male Kunming mice by permanent ligation of the left anterior descending coronary artery (LDA) ligation. Echocardiography was performed to assess cardiac function. The protective effect of Nutmeg-5 and compound Danshen dripping pills as positive control medicine on post-MI cardiac remodeling was evaluated by tissue histology and determination of the serum protein levels of biomarkers of myocardial injury. RNA sequencing analysis of mouse left ventricle tissue was performed to explore the molecular mechanism of Nutmeg-5 in cardiac remodeling after MI. A total of 27 constituents absorbed into blood were identified in rat plasma following gavage administration of Nutmeg-5 (0.54 g/kg) for 1 h. We found that ventricular remodeling after MI was significantly improved after Nutmeg-5 treatment in mice, which was demonstrated by decreased mortality, better cardiac function, decreased heart weight to body weight and heart weight to tibia length ratios, and attenuated cardiac fibrosis and myocardial injury. RNA sequencing revealed that the protective effect of Nutmeg-5 on cardiac remodeling after MI was associated with improved heart metabolism. Further study found that Nutmeg-5 treatment could preserve the ultrastructure of mitochondria and upregulate gene expression related to mitochondrial function and structure. HIF-1α (hypoxia inducible factor 1, alpha subunit) expression was significantly upregulated in the hearts of MI mice and significantly suppressed in the hearts of Nutmeg-5-treated mice. In addition, Nutmeg-5 treatment significantly activated the peroxisome proliferator-activated receptor alpha signaling pathway, which was inhibited in the hearts of MI mice. Nutmeg-5 attenuates cardiac remodeling after MI by improving heart metabolism and preserving mitochondrial dysfunction by inhibiting HIF-1α expression in the mouse heart after MI. Working model for the protective effect of Nutmeg-5 on cardiac remodeling after MI by improving heart metabolism and preserving mitochondrial dysfunction by inhibiting HIF-1α expression in mice. [Display omitted] [ABSTRACT FROM AUTHOR]