A multilocus-dendritic boronic acid functionalized magnetic nanoparticle for capturing circulating tumor cells in the peripheral blood of mice with metastatic breast cancer.

BACKGROUND: Dynamic fluctuation of circulating tumor cells (CTCs) can serve as an indicator of tumor progression. However, the sensitive isolation of CTCs remains extremely challenging due to their rarity and heterogeneity. Against this dilemma, dendritic boronic acid-modified magnetic nanoparticles (MNPs) were prepared in this study, and polyethyleneimine (PEI) was utilized as a scaffold to significantly increase the number of boronic acid moieties. Then the novel developed material was applied to monitor the number of CTCs in mice with metastatic breast cancer to evaluate the therapeutic effects of matrine (Mat), doxorubicin (Dox), and Mat in combination with Dox. RESULTS: Compared to the low binding capacity of a single boronic acid ligand, dendritic boronic acid shows enhanced sensitivity in binding to sialic acid (SA), which is overexpressed in CTCs. The results showed that the capture efficiency of this modified material could achieve 94.7% and successfully captured CTCs in blood samples from mice with metastatic breast cancer. The CTC counts were consistent with the results of the pathologic examination, demonstrating the reliability and utility of the method. SIGNIFICANCE: The dendritic boronic acid nanomaterials prepared in this study showed high specificity, sensitivity, and accuracy for cancer cell capture. The approach is expected to provide new insights into cancer diagnosis, personalized therapy, and optimization of treatment regimens.

Cytotoxic xanthones from Garcinia pedunculata fruits.

Eight previously undescribed and seven known xanthones were isolated from the fruits of Garcinia pedunculata Roxb. The structures were identified by a variety of spectroscopic methods as well as by comparison with the literature. The isolates showed appreciable cytotoxicity against three human tumor cell lines (HepG2, A549, and MCF-7). Pedunculaxanthone G exhibited inhibitory activities with IC50 values of 12.41, 16.51, and 15.45 µM against the cancer cell lines and induced cell apoptosis in HepG2 cells.

FD-DE: Differential Evolution with fitness deviation based adaptation in parameter control.

Differential Evolution (DE) is arguably one of the most powerful stochastic optimization algorithms for different optimization applications, however, even the state-of-the-art DE variants still have many weaknesses. In this study, a new powerful DE variant for single-objective numerical optimization is proposed, and there are several contributions within it: First, an enhanced wavelet basis function is proposed to generate scale factor F of each individual in the first stage of the evolution; Second, a hybrid trial vector generation strategy with perturbation and t-distribution is advanced to generate different trial vectors regarding different stages of the evolution; Third, a fitness deviation based parameter control is proposed for the adaptation of control parameters; Fourth, a novel diversity indicator is proposed and a restart scheme can be launched if necessary when the quality of the individuals is detected bad. The novel algorithm is validated using a large test suite containing 130 benchmarks from the universal test suites on single-objective numerical optimization, and the results approve the big improvement in comparison with several well-known state-of-the-art DE variants. Moreover, our algorithm is also validated under real-world optimization applications, and the results also support its superiority.

Accurate determination for lipidomics based on LC-tandem-MS parameters modeling, prediction, and database: Monitoring the progression of hepatocellular carcinoma.

The unavailability of adequate lipid reference standards is a major challenge for accurate quantitative analysis of lipidomics. Based on the discovery of regularity and predictability for lipids in chromatography-mass spectrometry behaviors, "target compound-structure correlation-analytical parameter database" protocol and "modeling-prediction" strategy were carried out to calculate the relative coefficients of analytical parameters within each subclass. Then the relevant LC-tandem-MS parameters of unknown lipids were predicted and a quantification parameter database for 4081 lipids was established and validated. Reference standards-independent accurate determination for lipidomics was achieved with the parameter's database and applied to monitor the change of lipid metabolism in the plasma of whole course of health-hepatitis-cirrhosis-hepatocellular carcinoma (HCC). Combined Student's t test, orthogonal partial least squares discrimination analysis (OPLS-DA) and binary logistic regression-ROC analysis, lipid biomarkers for differentiating health from each disease and differentiating different stages of disease were identified and the pathogenesis of HCC was preliminarily clarified. The established methodology would shed light on comprehensive and accurate quantitative lipidomics and exploring the pathomechanism and potential therapeutic targets of HCC.

A multidimensional strategy for uncovering comprehensive quality markers of Schisandra chinensis (Turcz.) Baill based on pharmacodynamics and chemical properties.

BACKGROUND: Quality control of Traditional Chinese Medicines (TCMs) has improved greatly, but there is still a lack of a convincing quality evaluation system for TCMs. Developing quality control markers of TCMs based on pharmacodynamics instead of content has been an attractive approach. However, on account of neglecting phytochemistry attributes of TCMs, part of effective markers might be short of specificity and inconvenient for detecting in production manufacture, which is adverse to control the quality of TCMs systematically. PURPOSE: To build a novel and multidimensional quality assessment approach for TCMs based on pharmacodynamics and chemical properties. METHODS: Schisandra chinensis (Turcz.) Baill (S. chinensis) was used as an example and a rat depression model was built by using a chronic unpredictable mild stress procedure. For identifying the antidepressive components of S. chinensis, we elucidated its antidepressant mechanism in first-step by using quantitative RT-PCR and immunoblotting techniques. And accordingly, correlation analysis between ingredients in vivo with target proteins and anti-inflammation experiments in vitro were carried out. On the other hand, HPLC fingerprint combinations with diverse chemometrics methods were applied to analyze 14 preparations of S. chinensis to obtain its characteristic chemical information. Finally, we ascertained the quality control markers of S. chinensis by integrating the efficacious and characteristic constituents. RESULTS: Our research indicated that S. chinensis treated depression by relieving disordered monoaminergic system and ameliorating neuroinflammation. Five effective substances (schisandrol A, schisandrin A, gomisin N, schisandrin B, and schisandrin C) were screened out according to their potential anti-depression efficacy. Besides, 21 common ingredients and 4 representative constituents of S. chinensis were identified by chemical analysis, whereas only 2 characteristic quantitative markers (schisandrol A, schisandrol B) were ultimately ascertained based on previous studies. CONCLUSION: 6 components, schisandrol A, schisandrin A, gomisin N, schisandrin B, schisandrin C, and schisandrol B, possessed efficacy, measurability, and specificity, were selected as the comprehensive markers for quality control of S. chinensis. We proposed a multidimensional strategy for identifying comprehensive quality markers for TCMs in this study.

Induction of P-glycoprotein expression by dandelion in tumor and heart tissues: Impact on the anti-tumor activity and cardiotoxicity of doxorubicin.

BACKGROUND: Previously, we have investigated the anti-tumor activity and mechanism through which dandelion acts against triple-negative breast cancer (TNBC). However, traditional Chinese medicine is mostly accepted as an adjunct therapy during chemotherapy in clinical practice. So far, little is known about the effects of dandelion in conjunction with chemotherapeutic drugs. PURPOSE: To investigate the effects of dandelion on the anti-tumor activity and cardiotoxicity of doxorubicin (DOX), and to further explore the molecular mechanisms through which these effects occur. STUDY DESIGN: At the beginning of this study, dandelion was observed to alleviate DOX-induced cardiotoxicity and reduce the anti-tumor activity of DOX. Subsequently, we investigated whether the resistance to DOX mediated by P-glycoprotein was involved in the above effects. METHODS: The cardioprotective effect of dandelion was investigated on DOX-treated mice by histological analysis, myocardial enzyme assays, and an untargeted metabolomics study based on LC-Q-TOF/MS. TNBC cell lines and 4T1 tumor-bearing mice were employed to investigate the combined anti-tumor activity. Laser scanning confocal microscope and a flow cytometry analysis were employed to measure the intracellular accumulation of DOX. A specific, sensitive, and rapid LC-MS/MS method was developed to detect the efflux of DOX from cells. Expression of P-glycoprotein in mouse tumor and heart tissues was detected via Western blotting analysis. RESULTS: Dandelion was found to significantly alleviate DOX-induced cardiotoxicity, as was evidenced by improved cardiomyocyte morphology, decreased LDH and CK-MB release, and adjusted metabolic biomarker levels. However, in vitro and in vivo studies showed that dandelion could reduce the anti-tumor activity of DOX. This counteraction was achieved by activating of the drug efflux transporter P-glycoprotein, thereby promoting the efflux of DOX from cells and reducing the intracellular accumulation of DOX. Moreover, the activation of P-glycoprotein by dandelion in mouse heart tissue was also observed, thus suggesting that the decrease of cardiac DOX accumulation plays an important role in the cardioprotective effect of dandelion. CONCLUSION: Dandelion can activate the P-glycoprotein in heart and tumor tissues, which ameliorates DOX-induced cardiotoxicity but attenuates DOX cytotoxicity toward TNBC. Our findings have important implications for the correct clinical use of dandelion.

Material Basis Elucidation and Quantification of Dandelion through Spectrum-Effect Relationship Study between UHPLC Fingerprint and Antioxidant Activity via Multivariate Statistical Analysis.

The excessive expression of reactive oxygen species is closely connected to many diseases. Considerable studies have demonstrated dandelion as well as its ingredients exhibited antioxidant activity. However, specific material basis reflecting the antioxidant activity has not been comprehensively investigated. In this study, a spectrum-effect relationship study on dandelion between fingerprinting and antioxidant activity was analyzed in detail, while a UHPLC quantification method developed and completely validated for simultaneous determination of active ingredients in dandelion. With the establishment of dandelion fingerprints of different regions, 24 common peaks were characterized. The classic FRAP method and ABTS methods were then used to detect their antioxidant activity. Partial least squares regression analysis, bivariate correlation analysis and grey correlation method were used to accomplish the spectrum-effect relationship. Eventually, the ingredients with antioxidant activity which could be considered as candidate quality markers of dandelion were discovered through spectrum-effect relationship analysis. The six compounds including caftaric acid, chlorogenic acid, caffeic acid, chicoric acid, isochlorogenic acid A, and isochlorogenic acid C were quantitatively determined. The developed UHPLC assay method was accurate, precise, and reliable. The study has elucidated the antioxidant material basis of dandelion and provided a scientific basis for the quality control of dandelion.

Isotope labelled in suit derivatization-extraction integrated system for amine/phenol submetabolome analysis based on nanoconfinement effect: Application to lung cancer.

Amine/phenol submetabolome has shown critical role in clinical cancer screening and therapy. In suit derivatization has widely applied in the analysis of amine/phenol submetabolome by LC/MS for simplifying the pretreatment procedures, improving the separation and sensitivity. However, the complexity of biological matrix and trace amount of metabolites in plasma that lead to the limited detection coverage, poor repeatability and low extraction efficiency are still issues for in suit derivatization. Herein, we proposed an isotope labelled in suit derivatization-extraction integrated system for targeted analysis of all the metabolites in amine/phenol submetabolome with high efficiency and repeatability by LC-MS. The processes of in suit derivatization, alkalization and extraction were performed simultaneously in the nanopores highly dispersed between the carbon nanofibers based on the nanoconfinement effect. Isotope labelling derivatization (ILD) reagents benzoyl chloride (BzCl) and BzCl-d5 were used to enhance the accuracy of identification and relative quantification. The detection sensitivity was increased up to 5.91-fold and detection coverage was enhanced more than 25% compared with conventional derivatization method. After systematical validation, the established methodology was applied to profile the amine/phenol submetabolome of human plasma and 1498 metabolites were screened out, among which, 1004 (67.02%) were positively or putatively identified. Furthermore, 106 amine/phenol metabolites exhibited significant difference between lung cancer patients and healthy controls by using multiple data processing methods. Taken together, the isotope labelled in suit derivatization-extraction integrated system was a useful approach for the analysis of amine/phenol submetabolome in plasma with broad metabolome coverage, simple pretreatment steps, high detection sensitivity and accuracy, and could be a potential tool for clinical biomarker discovery of disease.

Uncovering the mechanisms of dandelion against triple-negative breast cancer using a combined network pharmacology, molecular pharmacology and metabolomics approach.

BACKGROUND: Taraxacum mongolicum, also called dandelion, has been used for thousands of years as a remedy for mammary abscess, mammary gland hyperplasia, and various other diseases afflicting the breast. In modern pharmacological research, dandelion has been proven to be effective against triple-negative breast cancer (TNBC). However, the mechanisms of this anti-tumor effect have not been fully elucidated. PURPOSE: The aim of this investigation was to understand the multi-target mechanisms through which dandelion counteracts TNBC via a network pharmacology strategy as well as to validate its effectiveness by means of molecular pharmacology and metabolomics assessments. METHODS: A liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (LC-Q-TOF/MS) was employed to identify the absorbed components of dandelion in rat plasma. The network pharmacology-based prediction was utilized to uncover the potential mechanisms through which dandelion counteracts TNBC, during which potential targets were identified and pathway enrichment analysis was performed. Subsequently, TNBC cells and 4T1 tumor-bearing mice were used to further verify the molecular mechanisms of dandelion. RESULTS: Twelve active compounds were identified in rat plasma, which were connected with 50 TNBC-related targets. The pathway enrichment showed that dandelion could treat TNBC through regulating a series of biological processes involving cell cycle and metabolism. Experimentally, flow cytometry analysis revealed that dandelion could arrest the G0/G1 and G2/M cell cycles in 4T1 cells. Further western blot analysis evidenced that the protein expression of kinase 6 (CDK6) as well as cyclins B1 and B2 in mice tumor tissue were suppressed by dandelion. In addition, cell metabolomics analysis revealed the changes in the endogenous metabolite levels that result from dandelion treatments, such as the downregulation of arginine and spermine levels. All these findings were consistent with the predicted targets and pathways. CONCLUSION: This study comprehensively demonstrates the multi-target mechanisms of dandelion against TNBC using network pharmacology, molecular pharmacology, and metabolomics approaches. These findings will provide important stepping stones for further mechanism investigations and may lead to the development of highly effective dandelion-based treatments for TNBC.

Discovery of pulmonary fibrosis inhibitor targeting TGF-ß RI in Polygonum cuspidatum by high resolution mass spectrometry with in silico strategy.

Pulmonary fibrosis (PF) is an irreversible lung disease that is characterized by excessive scar tissue with a poor median survival rate of 2-3 years. The inhibition of transforming growth factor-ß receptor type-I (TGF-ß RI) by an appropriate drug may provide a promising strategy for the treatment of this disease. Polygonum cuspidatum (PC) is a well-known traditional Chinese herbal medicine which has an anti-PF effect. Accordingly, a combination of high resolution mass spectrometry with an in silico strategy was developed as a new method to search for potential chemical ingredients of PC that target the TGF-ß RI. Based on this strategy, a total of 24 ingredients were identified. Then, absorption, distribution, metabolism, and excretion (ADME)-related properties were subsequently predicted to exclude compounds with potentially undesirable pharmacokinetics behaviour. Molecular docking studies on TGF-ß RI were adopted to discover new PF inhibitors. Eventually, a compound that exists in PC known as resveratrol was proven to have excellent biological activity on TGF-ß RI, with an IC50 of 2.211 µM in vitro. Furthermore, the complex formed through molecular docking was tested via molecular dynamics simulations, which revealed that resveratrol had strong interactions with residues of TGF-ß RI. This study revealed that resveratrol has significant potential as a treatment for PF due to its ability to target TGF-ß RI. In addition, this research demonstrated the exploration of natural products with excellent biological activities toward specific targets via high resolution mass spectrometry in combination with in silico technology is a promising strategy for the discovery of novel drugs.

Analytical comparability assessment on glycosylation of ziv-aflibercept and the biosimilar candidate.

Ziv-aflibercept (aflibercept) is a recombinant fusion protein which combines the portions of human vascular endothelial growth factor receptors extracellular domains fused to the Fc portion of human IgG1. It is a highly sialylated glycoprotein with 5 N-glycosylation sites. In this study, a comprehensive strategy for comparability study of the complex glycosylation was developed between aflibercept and the biosimilar candidate including the investigations on N-glycosylation sites, site occupancy, site-specific glycoforms, released glycans and sialic acids. The results indicated that same N-glycosylation sites were identified, site occupancy were 100% except N68 site, site-specific glycoforms and released glycans showed similar glycan species, contents of NANA were at a same level for two products. Minor differences were found between two products. The biosimilar candidate presented lower level of aglycosylation, lower level of glycans containing one terminal sialic acid, higher level of glycans containing two terminal sialic acids, higher level of G0F and Man5, lower level of G1F and G2F compared with aflibercept. However, further studies exhibited no differences were observed in the cell-based biological potency and Fc effector function. Moreover, the biosimilar candidate showed a similar pharmacokinetics curve and bioequivalence compared with aflibercept.

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.

"Modeling-Prediction" Strategy for Deep Profiling of Lysophosphatidic Acids by Liquid Chromatography-Mass Spectrometry: Exploration Biomarkers of Breast Cancer.

Lysophosphatidic acids (LPAs) are important bioactive phospholipids consisting of various species involved in a wide array of physiological and pathological processes. However, LPAs were rarely identified in untargeted lipidomics studies because of the incompatibility with analytical methods. Moreover, in targeted studies, the coverages of LPAs remained unsatisfactorily low due to the limitation of reference standards. Herein, a "modeling-prediction" workflow for deep profiling of LPAs by liquid chromatography-mass spectrometry was developed. Multiple linear regression models of qualitative and quantitative parameters were established according to features of fatty acyl tails of the commercial standards to predict the corresponding parameters for unknown LPAs. Then 72 multiple reaction monitoring (MRM) transitions were monitored simultaneously and species of LPA 14:0, LPA 16:1, LPA 18:3, LPA 20:3 and LPA 20:5 were firstly characterized and quantified in plasma. Finally, the workflow was applied to explore the changes of LPAs in plasma of breast cancer patients compared with healthy volunteers. Multi-LPAs indexes with strong diagnostic ability for breast cancer were identified successfully using Student's t- test, orthogona partial least-squares discrimination analysis (OPLS-DA) and logistic regression- receiver operating characteristic (ROC) curve analysis. The proposed workflow with high sensitivity, high accuracy, high coverage and reliable identification would be a powerful complement to untargeted lipidomics and shed a light on the analysis of other lipids.

A stepwise integrated multi-system to screen quality markers of Chinese classic prescription Qingzao Jiufei decoction on the treatment of acute lung injury by combining 'network pharmacology-metabolomics-PK/PD modeling'.

BACKGROUND: Previously, we have investigated the therapeutic mechanism of Qingzao Jiufei Decoction (QZJFD), a Chinese classic prescription, on acute lung injury (ALI), however, which remained to be further clarified together with the underlying efficacy related compounds for quality markers (Q-markers). HYPOTHESIS/PURPOSE: To explore Q-markers of QZJFD on ALI by integrating a stepwise multi-system with 'network pharmacology-metabolomics- pharmacokinetic (PK)/ pharmacodynamic (PD) modeling'. METHODS: First, based on in vitro and in vivo component analysis, a network pharmacology strategy was developed to identify active components and potential action mechanism of QZJFD on ALI. Next, studies of poly-pharmacology and non-targeted metabolomics were used to elaborate efficacy and verify network pharmacology results. Then, a comparative PK study on active components in network pharmacology was developed to profile their dynamic laws in vivo under ALI, suggesting Q-marker candidates. Next, quantified analytes with marked PK variations after modeling were fitted with characteristic endogenous metabolites along drug concentration-efficacy-time curve in a PK-PD modeling to verify and select primary effective compounds. Finally, Q-markers were further chosen based on representativeness among analytes through validity analysis of PK quantitation of primary effective compounds. RESULTS: In virtue of 121 and 33 compounds identified in vitro and in vivo, respectively, 33 absorbed prototype compounds were selected to construct a ternary network of '20 components-47 targets-113 pathways' related to anti-ALI of QZJFD. Predicted mechanism (leukocytes infiltration, cytokines, endogenous metabolism) were successively verified by poly-pharmacology and metabolomics. Next, 18 measurable components were retained from 20 analytes by PK comparison under ALI. Then, 15 primary effective compounds from 18 PK markers were further selected by PK-PD analysis. Finally, 9 representative Q-markers from 15 primary effective compounds attributed to principal (chlorogenic acid), ministerial (methylophiopogonanone A, methylophiopogonanone B), adjuvant (sesamin, ursolic acid, amygdalin), conductant drugs (liquiritin apioside, liquiritigenin and isoliquiritin) in QZJFD, were recognized by substitutability and relevance of plasmatic concentration at various time points. CONCLUSION: 9 Q-markers for QZJFD on ALI were identified by a stepwise integration strategy, moreover, which was a powerful tool for screening Q-makers involved with the therapeutic action of traditional Chinese medicine (TCM) prescription and promoting the process of TCM modernization and scientification.

Integrated study of metabolomics and gut metabolic activity from ulcerative colitis to colorectal cancer: The combined action of disordered gut microbiota and linoleic acid metabolic pathway might fuel cancer.

Colorectal cancer (CRC) is one of the most serious complications of ulcerative colitis (UC). Altered gut microbiota is implicated in the development of CRC and metabolic perturbations are often associated with changes in the gut microbiome composition. Given the links between gut microbiome and the metabolic profiles in the body, an approach involving ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) metabolomics and 16S rDNA sequencing technology was applied to trace the development UC into CRC in rats. The study identified 11 differential metabolites related to both UC and CRC, which mainly referred to the linoleic acid metabolism. Among these, linoleic acid and 12­hydroxy­8,10-octadecadienoic acid could serve as key biomarkers for the development of UC into CRC. Besides, a significant change was observed in the microflora structure during the development from UC to CRC; this mainly involved a gradual increase in Escherichia-Shigella and a gradual decrease in Lactobacillus. In addition, Pearson's correlation analysis revealed strong correlations between intestinal microflora-related metabolites and specific intestinal microflora, which indicated both of them can promote the transition of UC to CRC. The results of the present study provided positive support for the involvement of intestinal microflora and host metabolism in the pathophysiological mechanism that is responsible for the development of UC into CRC. This information can help understand the risk for CRC that accompanies a diagnosis of UC and also provide different means of targeting these differential metabolites and intestinal microbiota to avoid UC-induced CRC.

Acute lung injury therapeutic mechanism exploration for Chinese classic prescription Qingzao Jiufei Decoction by UFLC-MS/MS quantification of bile acids, fatty acids and eicosanoids in rats.

Acute lung injury (ALI) is a common and complex inflammatory disease, which has been reasonably associated with carboxyl-containing metabolites in our preliminary non-targeted metabolomic strategy. Qingzao Jiufei Decoction (QZJFD), a classic prescription, is widely used in the treatment of pulmonary inflammatory injuries. Successively, in this targeted project, to fill in the research gap and exposit the therapeutic mechanism of QZJFD on ALI, considering the structure similarity and bioactivity correlation, 21 bile acids, 11 fatty acids and 19 eicosanoids were profiled simultaneously in plasma, lung, bronchoalveolar lavage fluid, spleen and feces from rats utilizing a novel ultraperformance liquid chromatography-mass spectrometry approach. As a result, potential biomarkers and ALI characteristic metabolomic spectrums were obtained to distinguish different physical states using discriminative similarity threshold as 0.65 for clinical application. After treatment with QZJFD, obvious reversing ability for various biomarker levels was observed in different bio-samples, providing insights into the systemic intervention of QZJFD on ALI by regulating bile acid synthesis, fatty acid synthesis and eicosanoid metabolism. Conclusively, this investigation represented more information on the comprehensive therapeutic action of QZJFD on ALI involving with multi-targets and multi-pathways for clinical application and traditional Chinese medicine modernization.

Qualitative and quantitative analysis of pyrrolizidine alkaloids for the entire process quality control from Senecio scandens to Senecio scandens-containing preparations by high performance liquid chromatography-tandem mass spectrometry.

Senecio scandens as a commonly used traditional Chinese medicine that is used alone or in combination with other herbs in preparations such as QianBai BiYan tablets has attracted much attention because of its hepatotoxic pyrrolizidine alkaloids. Nowadays, most studies for pyrrolizidine alkaloids are only performed on herbs or a preparation, however, production of preparations is a dynamic process, control of toxic impurities for raw materials, or finished products cannot monitor the production process dynamically. Thus, in this study, qualitative and quantitative analysis of pyrrolizidine alkaloids for the entire process quality control from S. scandens to its preparations was carried out with HPLC-MS/MS for the first time, which was more comprehensive and dynamic than the previous single-layer analysis. First, the species of pyrrolizidine alkaloids in S. scandens were analyzed, and the characteristic fragmentation rules of pyrrolizidine alkaloids containing common parent nucleus were found, which can be used to identify these components rapidly in the future. Then, a quantitative method for S. scandens to QianBai BiYan tablets and other nine S. scandens-containing preparations was established, and after the medication safety speculation, all of them met the relevant safety requirements. After that, in order to ensure the stability and controllable of drug quality, the limit of pyrrolizidine alkaloids in preparations was determined according to the safe dosage that is stipulated to be the same as raw materials. Finally, the factors causing the content change of pyrrolizidine alkaloids in S. scandens from different source were studies, which can provide theoretical basis for selecting suitable raw materials for production.

A systematic strategy for screening therapeutic constituents of Schisandra chinensis (Turcz.) Baill infiltrated blood-brain barrier oriented in lesions using ethanol and water extracts: a novel perspective for exploring chemical material basis of herb medicines.

Schisandra chinensis, a widely used Chinese herbal medicine, was considered as central nervous system (CNS) drug for years. Both ethanol extracts (EES) and water extracts (WES) of it were applied clinically. Unfortunately, the difference of their efficacy and even effective material foundation of S. chinensis remains obscure. In this study, to explore the active constituents of S. chinensis, we compared pharmacodynamics and chemical profiles in vitro/in vivo of EES/WES for the first time using multiple chemical analysis, pharmacological and data processing approaches. It was proved that there was no significant difference in the anti-depressive effects between WES and EES. However, the contents of most components in vitro and in plasma were higher in EES than those in WES, which was unconvincing for their similar efficacy. Therefore, we further explored components of S. chinensis targeted onto brain and the results showed that 5 lignans were identified with definite absorptivity respectively both in EES and WES caused by the limitation of blood-brain barrier. Moreover, bioinformatic analysis predicted their anti-depressive action. Above all, the systematic strategy screened 5 brain-targeted effective substances of S. chinensis and it was suggested that exploring the components into nidi would promote the studies on herbs effective material basis.

Metabolomic profile perturbations of serum, lung, bronchoalveolar lavage fluid, spleen and feces in LPS-induced acute lung injury rats based on HPLC-ESI-QTOF-MS.

Acute lung injury (ALI) is a clinically common and serious disease, underscoring the urgent need for clarification of its pathogenesis. According to traditional Chinese medicine (TCM) theories on the "lung-spleen-intestine axis" and its correlation with ALI, a high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) metabolomic platform was applied to identify biomarkers from five bio-samples of control and model rats challenged with intratracheally administered lipopolysaccharide (LPS) based on multivariate mathematical statistical analysis. As a result, 19, 24, 24, 15 and 29 altered metabolites were identified in serum, lung, bronchoalveolar lavage fluid (BALF), spleen and feces samples, respectively. Metabolic pathway analysis showed that linoleic acid, sphingolipid, glycerophospholipid and bile acid metabolism pathways were mainly altered by ALI. Additionally, ROC curves were applied to assess the specificity and sensitivity of the biomarkers. ALI characteristic metabolomic spectra were then established to differentiate the control from the model group with a similarity discriminative threshold of 0.7. Additionally, to compare the metabolomic profiles of the five bio-samples and establish metabolic similarities and differences among them, correlation analysis was conducted in order to delineate an objective law of endogenous linkage along the lung-spleen-intestine axis. Therefore, this study provides insights into the mechanisms involved in ALI from a metabolomics perspective, which can be applied in characterization of the mechanism and early disease detection. Graphical abstract.

A new oleanane type pentacyclic triterpenoid saponin from the husks of xanthoceras sorbifolium bunge and its neuroprotection on PC12 cells injury induced by Aß25-35.

A new triterpenoid saponin (1), 3-O-[ß-D-glucopyranosyl(1→6)]-(2'-angeloyl)-ß-D-glucopyranosyl-28-O-ß-D-glucopyranosyl(1→6)[α-L-rhamnopyranosyl(1→2)-ß-D-glucopyranosyl]-21-O-acetyl-16-deoxybarringtogenol C, together with four known saponins (2 ∼ 5) were isolated from the husks of Xanthoceras sorbifolium Bunge. Their structures were characterized by HR-ESI-MS, 1D-NMR, 2D-NMR spectra and chemical methods. Compound 1 exhibited excellent neuroprotection on PC12 cells injury induced by Aß25-35 at the doses of 150 µmol/L and 200 µmol/L. The cell viabilities were (76.18 ± 2.09) % and (76.02 ± 3.20) %, respectively.[Formula: see text].