The Material Basis and Mechanism of Xuefu Zhuyu Decoction in Treating Stable Angina Pectoris and Unstable Angina Pectoris.

METHODS: Firstly, we used a network proximity approach to calculate and compare the effectiveness of the formula with that of Western drugs for each type of angina, including all targets and intersecting targets, from a topological perspective. Secondly, we compared the mechanisms of action of the two angina pectoris at three levels and five aspects, including conventional and modular analysis approaches. Thirdly, based on the unique functions of each angina in the complex heterogeneous network, we designed a reverse process for finding the material basis using dynamic, static, and enriched items as well as a total item. Finally, the designed inverse process, material basis, and mechanism of action were validated. RESULTS: The target network of Xuefu Zhuyu decoction is closer to the target network of each type of angina than that of Western drugs, and the intersection targets have a closer proximity. Comparison of the mechanisms of action showed that stable angina and unstable angina had 158 common targets, while the unique targets were 34 and 1, respectively. Modularity analysis showed that the GO similarity of target modules was highly correlated with KEGG similarity. We ended up with 67 compounds upregulated for stable angina and 47 compounds upregulated for unstable angina. Our results were validated by literature mining, high-volume molecular docking, and miRNA enrichment analysis. CONCLUSIONS: For both types of angina pectoris, Xuefu Zhuyu decoction is superior to Western drugs. A comparison of various aspects led to the unique mechanisms of action, from which the material basis of each type of angina was deduced.

A systematic strategy for uncovering quality marker of Asari Radix et Rhizoma on alleviating inflammation based chemometrics analysis of components.

Asari Radix et Rhizoma (Asarum), a traditional Chinese medicine (TCM), has been applied in clinical generally. However, due to the lack of valid methods for Asarum quality control, inhomogenous quality and therapy issues have become severe with each passing day. In this study, we aimed to establish a comprehensive multi-system to explore the quality control markers underlying pharmaceutical effects based on chemometrics analysis on the total ingredients of Asarum. In brief, DNA barcoding technology was used to screen out the unadulterated herbs in the 15 batches Asarum collected from different origins. Then, the chemical profiles of volatile/nonvolatile components of 10 batches Asarum with definite resource were obtained by HPLC Q-TOF/MS and GC/MS. Combination with chemometrics methods, 14 characteristic ingredients and 4 qualitative and quantitative markers were figured out preliminarily. Moreover, correlation analysis between the characteristic ingredients and the cytokines integrating the virtual targets prediction of network pharmacology, 3 potential bioactive substance were ascertained. In conclusion, l-asarinin, 2-Methoxy-4-vinylphenol and safrole were considered as the potent candidates for quality control markers based on the comprehensive understanding for therapeutic effects and the chemical information of Asarum, which provided a novel perspective of the development for the quality control of TCM.

An integrated serum and urinary metabonomic research of Rhizoma Curcumae-Rhizoma Sparganii drug pair in hysteromyoma rats based on UPLC-Q-TOF-MS analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Curcumae and Rhizoma Sparganii (RCRS), a celebrated traditional Chinese medicine drug pair, has been used to treat hysteromyoma (HY). AIM OF THE STUDY: We aimed to identify the endogenous biomarkers of RCRS against HY. MATERIALS AND METHODS: HY rat model was established by injecting intramuscularly estradiol benzoate and progesterone injection from inner thigh in sequence. Body weight, uterus morphological indexes, immunohistochemistry (IHC) and hematoxylin and eosin (HE) staining experiments were used to evaluate the efficacy of RCRS (The rats were treated with RCRS extract, which was made by soxhlet reflux method. The rats were administrated intragastrically with 2 mL of RCRS extract). UPLC-Q-TOF-MS based metabonomics was adopted to analyze the serum and urine biomarkers from HY rats before and after RCRS treatment. Principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were utilized to identify differences of metabolic profiles in rats among the four groups. RESULTS: 16 potential biomarkers from serum and 18 potential biomarkers from urine in both positive and negative mass spectrometry detection modes were identified, primarily related to Linoleic acid metabolism and Glyoxylate and dicarboxylate metabolism. RCRS drug pair has therapeutic effects on rats with HY via the regulation of multiple metabolic pathways. CONCLUSIONS: This study provides a useful method to get insight into the integrated metabonomic mechanism of RCRS drug pair on HY rats.

Quantitative metabolomics for investigating the value of polyamines in the early diagnosis and therapy of colorectal cancer.

As an important biomarker for cancer, polyamine levels in body fluid could be employed for monitoring the colorectal cancer (CRC), however the role of polyamines in the development and therapeutics phases of CRC remains uncertain. In this paper, the relationship between polyamines and CRC development and therapeutics had been investigated by the study of changes in plasma polyamine levels during the precancerous, developmental and treatment phases of CRC. After inducing CRC in Wistar rats by intraperitoneal injection of 1, 2-dimethylhydrazine, the animals were given a traditional Chinese medicine, Aidi injections. Firstly, the polyamine levels in the plasma of CRC, healthy and medicated rats were measured by UHPLC-MS/MS assay. In addition, Lasso regression analysis was used for screening and confirming the key markers, which can be employed for distinguishing the healthy and CRC rats as well as the CRC and medication rats. The results obtained showed that polyamine metabolism had been disrupted by CRC but returned to normal levels following Aidi injections and, in particular, putrescine and agmatine were closely correlated with CRC. Our results demonstrate the potential value of plasma polyamine metabolic profiling during the early diagnosis and medical treatment of CRC. Also, the integrated method of polyamine metabolite target analysis and lasso regression analysis can be applied in metabolomics for seeking the differential metabolites.

GC-MS method for determination and pharmacokinetic study of seven volatile constituents in rat plasma after oral administration of the essential oil of Rhizoma Curcumae.

Rhizoma Curcumae (RC) is perennial herbaceous plant mainly present in China, India and Malaysiabelong, which is belong to the family Zingiberaceae. The rhizomes of RC have been used as a famous traditional Chinese medicine for the treatment of syndrome of blood stasis. A selective, sensitive and accurate gas chromatography-mass spectroscopy (GC-MS) method was developed and validated in this paper for the simultaneous determination and pharmacokinetic study of α-Pinene, 1,8-Cineole, Borneol, ß-Elemene, Curcumol, Germacrone, and Curdione in rat plasma. The GC-MS system was operated under selected ion monitoring (SIM) mode using a DB-5 (30m×0.25mm (ID)×0.25µm (film thickness)) column. Linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability were used to validate the current GC/MS assay. The lowest limit of quantifications (LLOQ) of α-Pinene, 1,8-Cineole, Borneol, ß-Elemene, Curcumol, Germacrone, Curdione were 2.71ng/mL, 7.76ng/mL, 3.37ng/mL, 21.68ng/mL, 40.21ng/mL, 24.84ng/mL and 47.78ng/mL respectively. After oral administration 1.0g/kg of RC rhizomes to the rats, the maximum plasma concentration (Cmax) was 34.72±9.97ng/mL for α-Pinene, 99.86±5.54ng/mL for 1,8-Cineole, 16.10±3.37ng/mL for Borneol, 248.98±86.19ng/mL for ß-Elemene, 673.75±104.15ng/mL for Curcumol, 2353.64±637.83ng/mL for Germacrone and 2420.04±708.51ng/mL for Curdione. The time to reach the maximum plasma concentration (Tmax) was 2.33±0.29h for α-Pinene, 0.67±0.29h for 1,8-Cineole, 1.33±0.58h for Borneol, 1.83±0.76h for ß-Elemene, 0.83±0.29h for Curcumol, 0.89±0.98h for Germacrone and 1.17±0.76h for Curdione. In this study, a validated GC-MS method for simultaneous determination of seven volatile oil compounds in rat plasma after oral administration of the extract of RC rhizomes and research on their pharmacokinetics was validated. The recovery and stability results were satisfactory in this study.

An integrative investigation of the toxicity of Aconiti kusnezoffii radix and the attenuation effect of its processed drug using a UHPLC-Q-TOF based rat serum and urine metabolomics strategy.

Aconiti kusnezoffii radix (AKR), the root of Aconitum kusnezoffii Reichb., is commonly used in the treatment of the rheumatoid arthritis. However, the clinical application is limited due to its potential toxicity. Therefore, to investigate the mechanism of its potential neurotoxicity and nephrotoxicity, a comprehensive metabolomics study combined with serum biochemistry and histopathology measurements was carried out. A UHPLC-Q-TOF mass spectrometry based metabolomics approach was applied to characterize the AKR toxicity, while the toxicity attenuation effects of Aconiti kusnezoffii radix cocta (AKRC) on Wistar rats were also investigated. Two chromatographic techniques involving reversed-phase chromatography and hydrophilic interaction chromatography were combined for the serum and urine detection, which balanced the integrity and selectivity of the two matrices. Principal component analysis was used to determine the groups, and principal component analysis discriminant analysis was carried out to confirm the important variables. Then, the developed integrative toxicity evaluation method was applied to assess the toxicity of AKR and the attenuation effect of AKRC. The highly sensitive and specific toxic biomarkers, which can provide practical bases were identified for the diagnosis of the neurotoxicity and nephrotoxicity induced by AKR. In all, a total of 19 putative biomarkers were characterized, and related metabolic pathways were identified. The study demonstrated that the established metabolomics strategy is a powerful approach for investigating the mechanisms of herbal toxicity and the attenuation effect of a processing method and would provide medical solutions for other toxic herbal medications and further clinical evidence on how AKR improves symptoms of rheumatoid arthritis patients.

An Investigation on the Quantitative Structure-Activity Relationships of the Anti-Inflammatory Activity of Diterpenoid Alkaloids.

Diterpenoid alkaloids are extracted from plants. These compounds have broad biological activities, including effects on the cardiovascular system, anti-inflammatory and analgesic actions, and anti-tumor activity. The anti-inflammatory activity was determined by carrageenan-induced rat paw edema and experimental trauma in rats. The number of studies focused on the determination, quantitation and pharmacological properties of these alkaloids has increased dramatically during the past few years. In this work we built a dataset composed of 15 diterpenoid alkaloid compounds with diverse structures, of which 11 compounds were included in the training set and the remaining compounds were included in the test set. The quantitative chemistry parameters of the 15 diterpenoid alkaloids compound were calculated using the HyperChem software, and the quantitative structure-activity relationship (QSAR) of these diterpenoid alkaloid compounds were assessed in an anti-inflammation model based on half maximal effective concentration (EC50) measurements obtained from rat paw edema data. The QSAR prediction model is as follows: log ( E C 50 ) = - 0.0260 × SAA + 0.0086 × SAG + 0.0011 × VOL - 0.0641 × HE - 0.2628 × LogP - 0.5594 × REF - 0.2211 × POL - 0.1964 × MASS + 0.088 × BE + 0.1398 × HF (R² = 0.981, Q² = 0.92). The validated consensus EC50 for the QSAR model, developed from the rat paw edema anti-inflammation model used in this study, indicate that this model was capable of effective prediction and can be used as a reliable computational predictor of diterpenoid alkaloid activity.

Use of the local false discovery rate for identification of metabolic biomarkers in rat urine following Genkwa Flos-induced hepatotoxicity.

Metabolomics is concerned with characterizing the large number of metabolites present in a biological system using nuclear magnetic resonance (NMR) and HPLC/MS (high-performance liquid chromatography with mass spectrometry). Multivariate analysis is one of the most important tools for metabolic biomarker identification in metabolomic studies. However, analyzing the large-scale data sets acquired during metabolic fingerprinting is a major challenge. As a posterior probability that the features of interest are not affected, the local false discovery rate (LFDR) is a good interpretable measure. However, it is rarely used to when interrogating metabolic data to identify biomarkers. In this study, we employed the LFDR method to analyze HPLC/MS data acquired from a metabolomic study of metabolic changes in rat urine during hepatotoxicity induced by Genkwa flos (GF) treatment. The LFDR approach was successfully used to identify important rat urine metabolites altered by GF-stimulated hepatotoxicity. Compared with principle component analysis (PCA), LFDR is an interpretable measure and discovers more important metabolites in an HPLC/MS-based metabolomic study.