A novel enzyme-based functional correlation algorithm for multi-omics reveals the potential mechanisms of traditional Chinese medicines: Taking Jian-Pi-Yi-Shen formula as an example.

The integrated analysis of host metabolome and intestinal microbiome is an opportunity to explore the complex therapeutic mechanisms of traditional Chinese medicines. Currently, researchers mainly employ various statistical correlation analytical methods to investigate metabolome-microbiome correlations. However, these conventional correlation techniques often focus on statistical correlations and their biological meanings are always ignored, especially the functional relevance between them. Here, we developed a novel enzyme-based functional correlation (EBFC) algorithm to further improve the interpretability and the identified scope of microbe-metabolite correlations based on the conventional Spearman's analysis. The proposed EBFC algorithm is successfully utilized to reveal the therapeutic mechanisms of Jian-Pi-Yi-Shen (JPYS) formula on the treatment of adenine-induced chronic kidney disease (CKD) rats. JPYS, a TCM formula for treating CKD, has beneficial clinical effects. We tentatively revealed the potential mechanism of JPYS for treating CKD rats from the perspective of the serum metabolome, gut microbiome, and their interactions. Specifically, 11 metabolites and 19 bacterial genera in the CKD rats were significantly regulated to approaching normal status after JPYS treatment, suggesting that JPYS could ameliorate the pathological symptoms of CKD rats by reshaping the disturbed metabolome and gut microbiota. Further correlation analysis between the significantly perturbed metabolites, microbiota, and the related enzymes provided more strong evidence for the study of host metabolism-microbiota interactions and the therapeutic mechanism of JPYS on CKD rats. In conclusion, these findings will help us to deeply understand the pathogenesis of CKD and provide new insights into the therapeutic mechanism of JPYS.

Chemical characterization and metabolic profiling of Xiao-Er-An-Shen Decoction by UPLC-QTOF/MS.

Background: Xiao-Er-An-Shen decoction (XEASD), a TCM formula composed of sixteen Chinese medicinal herbs, has been used to alleviate tic disorders (TD) in clinical practice for many years. However, the chemical basis underlying the therapeutic effects of XEASD in the treatment of TD remains unknown. Purpose: The present study aimed to determine the major chemical components of XEASD and its prototype compounds and metabolites in mice biological samples. Methods: The chemical constituents in XEASD were identified using ultra-high Performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Following this, XEASD was orally administered to mice, and samples of plasma, urine, feces, bile, and tissue were collected in order to identify effective compounds for the prevention or treatment of TD. Result: Of the total 184 compounds identified to be discriminated in the XEASD, comprising 44 flavonoids, 26 phenylpropanoids, 16 coumarins, 16 triterpenoids, 14 amino acids, 13 organic acids, 13 alkaloids, 13 ketones, 10 cyclic enol ether terpenes, 7 citrullines, 3 steroids, and 5 anthraquinones, and others. Furthermore, we summarized 54 prototype components and 78 metabolic products of XEASD, measured with biological samples, by estimating metabolic principal components, with four prototype compounds detected in plasma, 58 prototypes discriminated in urine, and 40 prototypes identified in feces. These results indicate that the Oroxylin A glucuronide from Citri reticulatae pericarpium (CRP) is a major compound with potential therapeutic effects identified in brain, while operating positive effect in inhibiting oxidative stress in vitro. Conclusion: In summary, our work delineates the chemical basis underlying the complexity of XEASD, providing insights into the therapeutic and metabolic pathways for TD. Various types of chemicals were explored in XEASD, including flavonoids, phenylpropanoids, coumarins, organic acids, triterpenoid saponins, and so on. This study can promote the further pharmacokinetic and pharmacological evaluation of XEASD.

HPLC-MS and Network Pharmacology Analysis to Reveal Quality Markers of Huo-Xue-Jiang-Tang Yin, a Chinese Herbal Medicine for Type 2 Diabetes Mellitus.

Huo-Xue-Jiang-Tang Yin (HXJTY) is a Chinese medicine formulation, which has been widely used for the treatment of various lipometabolism- and glycometabolism-related diseases in clinics. Currently, HXJTY is mainly prescribed to treat patients with type 2 diabetes mellitus (T2DM), yet its chemical and pharmacologic profiles remain to be elucidated. Here, the potential bioactive compound and action mechanism were investigated using chemical and network pharmacology analysis. A rapid HPLC-MS was employed to identify and quantify the component of HXJTY. On the basis of the identified chemical markers from HXJTY, a network pharmacology study, including target gene prediction and functional enrichment, was applied to screen out the main quality markers of HXJTY and explore its potential mechanism for the treatment of T2DM. The results showed that a total of 22 components were identified and quantified from HXJTY by HPLC-MS. Furthermore, 12 active components such as astragaloside IV, calycosin-7-O-ß-D-glucoside, hydroxysafflor yellow A, and others were proposed as quality markers of HXJTY for treating T2DM based on network pharmacology analysis. In addition, 125 corresponding possible therapeutic target genes of T2DM were obtained. These target genes are mainly related to peptidase activity, hydrolase activity, phosphatase activity, and cofactor binding, suggesting the involvement of PI3K-Akt, MAPK, AGE-RAGE, and Rap1 signaling pathways in HXJTY-treated T2DM. Our results may provide a useful approach to identify potential quality markers and molecular mechanism of HXJTY for treating T2DM.

Jian-Pi-Yi-Shen Regulates EPO and Iron Recycling Protein Expressions in Anemic Rats with Chronic Kidney Disease: Accumulation of Hypoxia Inducible Factor-2α via ERK Signaling.

Jian-Pi-Yi-Shen (JPYS), the traditional Chinese medicine (TCM) decoction, has been commonly used to treat chronic kidney disease (CKD) and its complications such as anemia. JPYS has been previously found to induce erythropoietin (EPO) production in HEK293T cells and CKD rats. However, the mechanism of JPYS in treating anemia of CKD rats has remained largely unknown. Here, we further extend our effort to investigate the translational control of hypoxia inducible factor- (HIF-) α protein via ERK signaling and the effect on iron recycling-related protein expression by JPYS, thus revealing the mechanism of JPYS in correcting anemia in CKD. Experimental CKD rats with anemia were induced by 5/6 nephrectomy. Rats were administrated orally with high dose (6.0 g/kg/d) and low dose (1.5 g/kg/d) of JPYS for 90 days. Serum hepcidin level was determined to evaluate iron homeostasis. The protein expressions of HIF-2α, erythropoietin (EPO), ferritin, and ferroportin (FPN) and the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. The results showed that JPYS treatment significantly ameliorated kidney function by reducing increased levels of blood urea nitrogen (BUN), serum creatinine (Scr), and urine protein (UPRO). Periodic acid-Schiff (PAS) and Masson staining observation showed that the renal pathological damage was restored in JPYS-treated CKD rats. In parallel, JPYS markedly improved CKD anemia through upregulation of red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT). JPYS stimulated EPO and HIF-2α protein expressions in both the kidney and liver of CKD rats. Furthermore, JPYS induced the phosphorylation of ERK1/2 protein. In addition, JPYS regulated protein expression of ferritin and FPN in both the liver and spleen of CKD rats and the serum level of hepcidin. In conclusion, JPYS induces the expression of EPO through ERK-mediated HIF-2α protein accumulation and regulates systemic iron recycling, supporting its role in promoting erythropoiesis and improvement of anemia in CKD.

Chemical characterisation and quantification of the major constituents in the Chinese herbal formula Jian-Pi-Yi-Shen pill by UPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

INTRODUCTION: Jian-Pi-Yi-Shen pill (JPYSP) is a Chinese medicine formula developed for the treatment of anaemic patients with chronic kidney disease (CKD). OBJECTIVE: To investigate the chemical profile of JPYSP in the treatment of renal anaemia. METHODS: A method coupling ultra-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) was established to characterise the chemical constituents present in JPYSP. Subsequently, a high-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (HPLC-QQQ-MS/MS) was developed to quantify the major constituents from the identified compounds related to the treatment of CKD and anaemia. RESULTS: A total of 71 compounds were tentatively identified from JPYSP, including saponins, flavonoids, sesquiterpenoids, coumarins, phenylpropanoids, anthranones, anthraquinones, tannins, phenolic acids and others. Amongst them, 12 compounds (i.e. astragaloside IV, calycosin, calycosin 7-O-glucoside, salvianolic acid A, rosmarinic acid, rhein, liquiritin, formononetin, atractylenolide I, dioscin, tanshinone IIA, and acteoside) were further quantified simultaneously by HPLC-QQQ-MS/MS. CONCLUSION: The newly developed approach is suitable for the chemical profiling analysis and quality control of JPYSP, and could lead to additional pharmacodynamic studies involving the components of JPYSP.

Metabolomics Reveals Effect of Zishen Jiangtang Pill, a Chinese Herbal Product on High-Fat Diet-Induced Type 2 Diabetes Mellitus in Mice.

A Chinese herbal decoction, Zishen Jiangtang Pill (ZJP), has been clinically prescribed to diabetic patients to prevent excessive blood sugar levels for decades. However, the potential mechanisms of this action have not been well investigated. The purpose of this study was to explore the metabolic variations in response to ZJP treatment for an animal model of obese type 2 diabetes. An UHPLC-Orbitrap/MS-based metabolomics tool was conducted to reveal the potential mechanisms of ZJP on diabetic mice. The treatment with ZJP significantly restored the increased levels of insulin, glucose and total cholesterol in high-fat diet mice. A total of 26 potential biomarkers were found and identified in serum samples, amongst which 24 metabolites were robustly affected and driven back to the control-like levels after ZJP treatment. By analyzing the metabolic pathways, glutathione metabolism, steroid hormone biosynthesis and glycerophospholipid metabolism were suggested to be closely involved in diabetes disease. From the above outcomes, it can be concluded that ZJP exhibits a promising anti-diabetic activity, largely due to the regulation of phospholipid metabolism, including phosphatidylcholines, lysophosphatidylcholines, and phosphatidylinositol.

Online Doppler Effect Elimination Based on Unequal Time Interval Sampling for Wayside Acoustic Bearing Fault Detecting System.

The railway occupies a fairly important position in transportation due to its high speed and strong transportation capability. As a consequence, it is a key issue to guarantee continuous running and transportation safety of trains. Meanwhile, time consumption of the diagnosis procedure is of extreme importance for the detecting system. However, most of the current adopted techniques in the wayside acoustic defective bearing detector system (ADBD) are offline strategies, which means that the signal is analyzed after the sampling process. This would result in unavoidable time latency. Besides, the acquired acoustic signal would be corrupted by the Doppler effect because of high relative speed between the train and the data acquisition system (DAS). Thus, it is difficult to effectively diagnose the bearing defects immediately. In this paper, a new strategy called online Doppler effect elimination (ODEE) is proposed to remove the Doppler distortion online by the introduced unequal interval sampling scheme. The steps of proposed strategy are as follows: The essential parameters are acquired in advance. Then, the introduced unequal time interval sampling strategy is used to restore the Doppler distortion signal, and the amplitude of the signal is demodulated as well. Thus, the restored Doppler-free signal is obtained online. The proposed ODEE method has been employed in simulation analysis. Ultimately, the ODEE method is implemented in the embedded system for fault diagnosis of the train bearing. The results are in good accordance with the bearing defects, which verifies the good performance of the proposed strategy.

Note: signal amplification and filtering with a tristable stochastic resonance cantilever.

This Note reports a tristable cantilever that exploits stochastic resonance (SR) phenomenon for a study of signal amplification and filtering. The tristable device system combines the benefits of bistable system (wide interwell spacing) and monostable system (smooth motion in potential). The prototype tristable cantilever exhibits 42 times root-mean-square amplitude, 35.86 dB power gain, advance of 15 dB signal-to-noise ratio, and twice fidelity at around 7.6 Hz as compared to the input signal. In a wide operating bandwidth [5.5 Hz, 8.2 Hz], the tristable SR cantilever outperforms the traditional monostable cantilever and bistable SR cantilever in these characteristics.

[Effect of jianxin pinglu pill on arrhythmia and aquaporin 4 expression in rats with myocardial ischemia/reperfusion injury].

OBJECTIVE: To explore the effect of jianxin pinglu pill (JPP) on arrhythmia and aquaporin 4 (AQP4) in rats with myocardial ischemia/reperfusion (I/R) injury. METHODS: The effects of JPP on arrhythmia, mortality and AQP4 on I/R injured rats model induced by blocking left coronary artery were observed using II lead of ECG, HE stain and AQP4 immunohistochemical stain. RESULTS: JPP showed significant effect in lowering the arrhythmia occurrence and mortality, reducing myocardial ischemic edema and injury, strengthening AQP4 expression in myocardial tissue. CONCLUSION: JPP has the effect of preventing I/R induced arrhythmia, it might be related with its action in up-regulating AQP4 expression level in myocardium and reducing the intracellular edema.