Molecular mechanism of Xiaohuoluo wan for rheumatoid arthritis by integrating in vitro and in vivo chemomics and network pharmacology.

The cause of rheumatoid arthritis (RA) is unclear. Xiaohuoluo wan (XHLW) is a classical Chinese medicine that is particularly effective in the treatment of RA. Given the chemical composition of XHLW at the overall level has been little studied and the molecular mechanism for the treatment of RA is not clear, we searched for the potential active compounds of XHLW and explored their anti-inflammatory mechanism in the treatment of RA by flexibly integrating the high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based in vitro and in vivo chemomics, network pharmacology, and other means. The results of the study identified that the active compounds of XHLW, such as alkaloids, nucleosides, and fatty acids, may play an anti-inflammatory role by regulating key targets such as IL-2, STAT1, JAK3, and MAPK8, inducing immune response through IL-17 signaling pathway, T-cell receptor, FoxO, tumor necrosis factor (TNF), and so forth, inhibiting the release of inflammatory factors and resisting oxidative stress and other pathways to treat RA. The results of this study provide referable data for the screening of active compounds and the exploration of molecular mechanisms of XHLW in the treatment of RA.

Environmental control programs the emergence of distinct functional ensembles from unconstrained chemical reactions.

Many approaches to the origin of life focus on how the molecules found in biology might be made in the absence of biological processes, from the simplest plausible starting materials. Another approach could be to view the emergence of the chemistry of biology as process whereby the environment effectively directs "primordial soups" toward structure, function, and genetic systems over time. This does not require the molecules found in biology today to be made initially, and leads to the hypothesis that environment can direct chemical soups toward order, and eventually living systems. Herein, we show how unconstrained condensation reactions can be steered by changes in the reaction environment, such as order of reactant addition, and addition of salts or minerals. Using omics techniques to survey the resulting chemical ensembles we demonstrate there are distinct, significant, and reproducible differences between the product mixtures. Furthermore, we observe that these differences in composition have consequences, manifested in clearly different structural and functional properties. We demonstrate that simple variations in environmental parameters lead to differentiation of distinct chemical ensembles from both amino acid mixtures and a primordial soup model. We show that the synthetic complexity emerging from such unconstrained reactions is not as intractable as often suggested, when viewed through a chemically agnostic lens. An open approach to complexity can generate compositional, structural, and functional diversity from fixed sets of simple starting materials, suggesting that differentiation of chemical ensembles can occur in the wider environment without the need for biological machinery.

[Analysis of potential pharmacodynamic material basis of Euonymus alatus in treatment of nephritis based on integrated chemomics and network biology].

This paper was aimed to explore the potential pharmacodynamics effect of Euonymus alatus in the treatment of nephritis based on integrated chemomics and network biology. The chemical constituent database of E. alatus was constructed by consulting litera-ture and using online database. The chemical constituents were identified by UPLC-Q-TOF/HRMS~E and UNIFI software. On this basis, a series of comparisons, molecular docking studies and in-depth analysis of the chemical constituents and nephritis disease targets were carried out with use of network biology method, and the potential pharmacodynamic effect of E. alatus for the treatment of nephritis was investigated by reviewing the existing. In this study, 62 chemical constituents were collected in the database of chemical consti-tuents of E. alatus, and 24 chemical constituents were identified by mass spectrum. Subsequently, based on the network biology me-thod, 22 important chemical constituents and 5 key targets were obtained by reverse screening. Molecular docking study showed that a total of 11 chemical constituents such as quercetin, kaempferol, and catechinmay be the potential material basis for E. alatus in the treatment of nephritis. Starting with chemomics and using the technology of network biology, we established a network interaction model between drug components and disease targets in this study. Through the interaction between targets in complex networks, we can find the key targets easily and quickly. By docking the key targets with small drug molecules, we can screen out the potential pharmacodynamic components, providing a reference for the follow-up study of active ingredients.

Chemomic and chemometric approach based on ultra-fast liquid chromatography with ion trap time-of-flight mass spectrometry to reveal the difference in the chemical composition between Da-Cheng-Qi decoction and its three constitutional herbal medicines.

Da-Cheng-Qi decoction (DCQT) is a traditional purgative Chinese decoction with a history of 2000 years. To study the effect of interactions between the ingredients on the overall chemical composition of DCQT, a chemomic and chemometric approach based on ultra-fast liquid chromatography with ion trap time-of-flight mass spectrometry was developed and validated. After mixing and decocting all four ingredients to make the DCQT, the concentrations of some chemicals are significantly different from those in single herb decoction and 24 of them were identified and tentatively characterized by comparing their data with those of standard compounds or literature data. No new chemicals were formed during mixing and decoction. Our findings indicated that there are interactions between these natural medicines during the mixing and preparation process. The 24 identified chemicals could be used as chemical markers for optimizing prescription and evaluation of consistent quality, and the strategy in the present study could be applied for other multiherb formulae.

A quantitative chemomics strategy for the comprehensive comparison of Murraya paniculata and M. exotica using liquid chromatography coupled with mass spectrometry.

Murrayae Folium et Cacumen (MFC) is a traditional Chinese medicine (TCM) derived from two plant species, Murraya exotica L. and Murraya paniculata (L.) Jack, as recorded in the Chinese Pharmacopoeia. However, there is no research available on the comprehensive analysis and comparison of the chemical constituents of these two species. In the present study, an integrated LC-MS-based quantitative metabolome strategy was proposed to conduct a comprehensive and in-depth qualitative and quantitative analysis and comparison of the chemome of M. exotica and M. paniculata. Firstly, the universal chemical information of two plants was obtained by quadrupole-time-of-flight mass spectrometry (Q-TOF-MS) combined with hybrid triple quadrupole-linear ion trap mass spectrometry (Qtrap-MS). Subsequently, a UNIFI in house database, the proposed fragmentation patterns, and a quantitative structure chromatographic retention relationship (QSRR) model were integrated for the rapid, comprehensive, and accurate structural elucidation of the chemical constituents of these two species. Thirdly, a large-scale quantitation method was established using scheduled multiple reaction monitoring mode (sMRM) and 76 primary components were selected as quantitative markers for the method validation. The obtained dataset was then subjected for multivariate statistical analysis to comprehensive comparison of these two plants. As a result, a total of 209 and 212 compounds were identified from M. exotica and M. paniculata, respectively. Among them, 103 common constituents were disclosed in both plants. The multivariate statistical analysis and absolute quantitative analysis revealed noticeable differences in the contents of specific chemical constituents between these two plants. The higher quantity constituents in M. exotica are 7-methoxycoumarins, while polymethoxylated flavonoids are the major constituents in M. paniculata. The common compounds accounted for approximately 80 % of the quantitative components in both plants, which provides a theoretical basis for their common use as the official source of MFC. In sum, the established quantitative chemomics strategy supplies an effective means for comprehensive chemical comparison of multi-source TCMs.

Integrating UPLC-QE-Orbitrap-MS technology and network pharmacological method to reveal the mechanism of Bailemian capsule to relieve insomnia.

Bailemian capsule (BLMC) is a Chinese patent drug for treating insomnia with excellent curative effects. But there are few researches on it. In this research, a rapid separation and identification method using UPLC-QE-Orbitrap-MS was established, and 228 identified compounds were separated within 18 min. The structures of compounds were preliminarily determined by comparing the retention time and fragmentation law. Furthermore, multiple databases were used to integrate the compound targets of BLMC and the disease targets related to insomnia. After the intersection of the two sets of targets, a protein-protein interaction network and a drug-target-disease pharmacological network were established, then using the DAVID database to perform GO analysis and KEGG analysis on the common targets to find related pathways. Finally, a total of 289 common targets and 136 pathways were found to participate in the mechanism.

Chemomics-based marker compounds mining and mimetic processing for exploring chemical mechanisms in traditional processing of herbal medicines, a continuous study on Rehmanniae Radix.

Exploring processing chemistry, in particular the chemical transformation mechanisms involved, is a key step to elucidate the scientific basis in traditional processing of herbal medicines. Previously, taking Rehmanniae Radix (RR) as a case study, the holistic chemome (secondary metabolome and glycome) difference between raw and processed RR was revealed by integrating hyphenated chromatographic techniques-based targeted glycomics and untargeted metabolomics. Nevertheless, the complex chemical transformation mechanisms underpinning the holistic chemome variation in RR processing remain to be extensively clarified. As a continuous study, here a novel strategy by combining chemomics-based marker compounds mining and mimetic processing is proposed for further exploring the chemical mechanisms involved in herbal processing. First, the differential marker compounds between raw and processed herbs were rapidly discovered by untargeted chemomics-based mining approach through multivariate statistical analysis of the chemome data obtained by integrated metabolomics and glycomics analysis. Second, the marker compounds were mimetically processed under the simulated physicochemical conditions as in the herb processing, and the final reaction products were chemically characterized by targeted chemomics-based mining approach. Third, the main chemical transformation mechanisms involved were clarified by linking up the original marker compounds and their mimetic processing products. Using this strategy, a set of differential marker compounds including saccharides, glycosides and furfurals in raw and processed RR was rapidly found, and the major chemical mechanisms involved in RR processing were elucidated as stepwise transformations of saccharides (polysaccharides, oligosaccharides and monosaccharides) and glycosides (iridoid glycosides and phenethylalcohol glycosides) into furfurals (glycosylated/non-glycosylated hydroxymethylfurfurals) by deglycosylation and/or dehydration. The research deliverables indicated that the proposed strategy could advance the understanding of RR processing chemistry, and therefore may be considered a promising approach for delving into the scientific basis in traditional processing of herbal medicines.

Mechanism of Tripterygium wilfordii tablets for the treatment of rheumatoid arthritis based on integrated chemomics and network pharmacology / 国际药学研究杂志

Objective: To explore the mechanism of Leigongteng Pian(Tripterygium wilfordii tablets)for the treatment of rheumatoid arthritis(RA)based on chemomics and network pharmacology. Method: UPLC-Q-TOF/HRMS was used to analyze the chemical constituents of Tripterygium wilfordii tablets under the positive and negative ion modes. Thereafter,the ingredient targets of Tripterygium wilfordii tablets were predicted by Swiss Target Prediction and Pharm- Mapper databases,and the targets of RA diseases were obtained by Traditional Chinese Medicine Systems Pharmacology (TCMSP),Therapeutic Target Database(TTD)and Comparative Toxicogenomics Database(CTD). By taking the inter-section of ingredient targets and disease targets,the direct common targets of Tripterygium wilfordii tablets for the treat- ment of rheumatoid arthritis were obtained. Then the GeneMANIA database was used to obtain indirect targets,and the software of Cytoscape 3.7.1 was used to construct the protein-protein interaction(PPI)networks of potential targets,by which the key targets were screened. Enrichment of gene function and pathways of all potential targets were conducted by Gene Ontology(GO)database and Kyoto Encyclopedia of Genes and Genomes(KEGG)database to explore the mecha- nism of Tripterygium wilfordii tablets for the treatment of rheumatoid arthritis. Results: Thirtyone chemical constituents of Tripterygium wilfordii tablets were screened out and sixtysix potential targets were predicted. Twentyseven active com- ponents in the Tripterygium wilfordii tablets might be important components for the treatment of rheumatoid arthritis as in- dicated by the reverse screening. At the same time,five core targets were screened out,which might be involved in the key pathways that actively participate in the intervention and adjustion of rheumatoid arthritis. Conclusion: In this study,we found that the active components in Tripterygium wilfordii tablets could exert important biological effects via multiple targets and pathways,and these targets and pathways are all involved with the inflammation and immune regula- tion of RA.

Discovery of quality markers and quality evaluation of Poria cocos based on “in vitro-in vivo” multidimensional chemical group associated network / 中草药

Objective: The quality markers of Poria cocos were identified based on the “in vitro-in vivo” multidimensional chemical group associated network and in vivo pharmacokinetics, and the mass spectrometry method for quantitative detection of quality markers was established to evaluate the quality of P. cocos. Methods: A quantitative analysis method of triterpenoids in P. cocos was established by ultra-high performance liquid chromatography-triple quadruple tandem mass spectrometry (UHPLC-MS/MS) while dioscin was chosen as internal reference substance. The pharmacokinetic curves of active ingredients in vivo were drawn. Seven quality markers of P. cocos including dehydrotumulosic acid, tumulosic acid, and poricoic acid B were identified based on the results of pharmacokinetics. The content of high content components and quality markers in 10 batches of P. cocos were detected and used as variables for cluster analysis of 10 batches of P. cocos. Results: There were differences in the results of clustering analysis with different indexes as variables in evaluating the quality of P. cocos. Conclusion: To a certain extent, the method of quality control of P. cocos with high content components is one-sided. In order to comprehensively and accurately control the quality of P. cocos, it is necessary to take into full account the in vivo and in vitro changes and the in vivo dynamic process of P. cocos composition, and select the effective quality markers related to its pharmacodynamics for its quality control.

Mechanism of anti-inflammatory for Dengtaiye Tablets based on integrated network pharmacology and chemomics / 中草药

Objective To investigate the anti-inflammatory mechanism of the alkaloids in Dengtaiye Tablets (DTYT) based on the network pharmacology and chemomics. Methods The main indole alkaloids in the DTYT from Folium Alstoniae Scholaris were identified by UPLC-Q/TOF. The network pharmacology coupled with virtual docking technology and bioinformatics analysis were carried out for screening the key protein targets and pathways. Western blotting was utilized for evaluating the phosphorylation level of the primary node proteins in BEAS-2B cells inflammatory model induced by LPS. Results Twelve indole alkaloids were found in DTYT extract, which act on different protein targets, such as PDPK1 (PDK1), MAPK1 (ERK2), and MAPK8 (JNK1) respectively, and reduce the level of ERK2, JNK1, and IKK phosphorylation induced by LPS. Conclusion As the Q-markers of anti-inflammatory, the indole alkaloids contained in DTYT inhibited the PDK1/AKT/NF-κB and MAPK pathways, which present potential molecular mechanisms for the treatment of chronic bronchitis of DTYT.