Metabolic profiles revealed anti-ischemia-reperfusion injury of Yangxinshi tablet in Rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia-reperfusion (I/R) injury is a serious injury that is resulted from the recovery of blood supply after myocardial ischemia. Yangxinshi tablet is a compound Chinese herbal preparation and often used to alleviate the myocardial ischemia in clinical, but its protective mechanism of anti-myocardial ischemia reperfusion injury remains unclear. The objective of this study was to evaluate the anti-I/R injury effect of Yangxinshi tablet on a myocardial I/R rat model and to identify serum biomarker metabolites associated with I/R based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF/MS) metabolomic method, and explore the metabolic mechanism of anti-I/R injury of Yangxinshi tablet. MATERIALS AND METHODS: Unsupervised principle component analysis highlighted significant differences in the metabolome of the myocardial I/R, healthy control and drug-treated rats. Partial least squares-discriminant analysis revealed 25 metabolites as the most potential biomarker metabolites discriminating the myocardial I/R rats and control rats. Most of the metabolites were primarily involved in oxidative stress, energy metabolism, fatty acid metabolism, amino acid metabolism. These metabolites were validated by assessing the efficacy after intragastric administration of Yangxinshit ablet to the myocardial I/R rat model. RESULTS: Based on metabolomic results, the action mechanism of anti-I/R injury of Yangxinshi tablet was concluded as follows: (1) enhance the ability of scavenging free radicals and reactive oxygen species in vivo; (2) provide energy for myocardium via accelerating the intracellular carnitine transportion to accelerate the oxidation of fatty acid and (3) attenuate ceramide to reduce cardiomyocyte apoptosis. CONCLUSIONS: Yangxinshi tablet has cardio-protection effects on I/R rats via regulation of multiple metabolic pathways involving in oxidative stress, energy metabolism, fatty acid, and amino acid metabolisms. This study will be meaningful for its clinical application and valuable for further exploring the action mechanism of Yangxinshi tablet.

Metabolic analysis of the antidepressive effects of Yangxinshi Tablet in a vascular depression model in mice.

In recent years, vascular depression has become the focus of international attention. Yangxinshi Tablet (YXST) is usually used in cthe linic for the treatment of arrhythmia and heart failure, but we found that it also has antidepressive effects. The objective of the study was to identify biomarkers related to vascular depression in hippocampus and explore the antidepressive effects of YXST on the mouse model. Untargeted metabolomics based on UHPLC-Q-TOF/MS was applied to identify significantly differential biomarkers between the model group and control group. Unsupervised principal component analysis (PCA) was used to scan the tendency of groups and partial least squares-discriminant analysis (PLS-DA) to distinguish between the vascular depressive mice and the sham. PCA stores showed clear differences in metabolism between the vascular depressive mice and sham groups. The PLS-DA model exhibited 38 metabolites as the biomarkers to distinguish the vascular depressive mice and the sham. Further, YXST significantly regulated 22 metabolites to normal levels. The results suggested that YXST has a comprehensive antidepressive effect on vascular depression via regulation of multiple metabolic pathways including amino acid, the tricarboxylic acid cycle and phosphoglyceride metabolisms. These findings provide insight into the pathophysiological mechanism underlying vascular depression and the mechanism of YXST.

Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism.

Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. In addition, dioscin a natural steroidal saponin isolated from Chinese medicinal herbs, enhanced the serotonergic system and produced anti-depressant effect by enhancing 5-HT levels in hippocampus. What is more, this finding was verified by metabolic analyses of hippocampus, indicating 5-HT related metabolic pathway was involved in the pathogenesis of endotoxemia induced acute neuro-inflammation. Moreover, neuro-inflammation and neurogenesis within hippocampus were indexed using quantitative immunofluorescence analysis of GFAP DCX and Ki67, as well as real-time RT-PCR analysis of some gene expression levels in hippocampus. Our in vivo and in vitro studies show dioscin protects hippocampus from endotoxemia induced cascade neuro-inflammation through neurotransmitter 5-HT and HMGB-1/TLR4 signaling pathway, which accounts for the dioscin therapeutic effect in behavioral tests. Therefore, the current findings suggest that dioscin could be a potential approach for the therapy of endotoxemia induced acute neuro-inflammation.

Metabonomic identification of the effects of the Zhimu-Baihe saponins on a chronic unpredictable mild stress-induced rat model of depression.

The herbal pair Zhimu-Baihe (Zhimu: Anemarrhena asphodeloides; Baihe: Lilium brownii var. viridulum) is a traditional Chinese medicament used for the treatment of depression. However, the relevant mechanisms of action has not been clarified. This study investigated the anti-depressant activity of the total saponins from Zhimu and Baihe and the mechanisms underlying using a chronic unpredictable mild stress (CUMS)-induced rat model of depression. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was applied to determine the levels of three monoamine neurotransmitters, 5-hydroxytryptamine (5-HT), noradrenaline (NE) and dopamine (DA), in the rat hippocampus. Optimized pretreatment of samples and mass spectrometry conditions were used to analyse the metabonomic profile of the hippocampus. The 5-HT and NE levels in the CUMS group were reduced compared with the control group, whereas all groups had similar DA levels. The metabonomic profile of the hippocampus revealed 32 differential metabolites between the CUMS and control group, among which 18 metabolites were significantly recovered in the Anemarrhena saponins and Lilium saponins (AL) combination intervention group. These results suggested an anti-depressant effect of AL. Moreover, 24 metabolites in AL group were better recovered compared with the Anemarrhena saponins (AS) or Lilium saponins (LS) intervention groups, suggesting a synergetic effect of AS and LS in the treatment of depression. The anti-depressant effect might be related to the regulation of several metabolic pathways, including monoamine neurotransmitter synthesis (especially 5-HT and NE), and amino acid, fatty acid, and phospholipid metabolism in rats.