Corrigendum: An integrative serum pharmacology-based approach to study the anti-tumor activity of B. Paniculatum aqueous bulb extract on the human hepatocellular carcinoma cell line BEL-7404.

[This corrects the article DOI: 10.3389/fphar.2020.01261.].

Cannabinoids: Recent Updates on Public Perception, Adverse Reactions, Pharmacokinetics, Pretreatment Methods and Their Analysis Methods.

Cannabinoids (CBDs) have been traditionally used as a folk medicine. Recently, they have been found to exhibit a high pharmacological potential. However, they are addicted and are often abused by drug users, thereby, becoming a threat to public safety. CBDs and their metabolites are usually found in trace levels in plants or in biological matrices and, are therefore not easy to be detected. Advances have been made toward accurately analyzing CBDs in plants or in biological matrices. This review aims at elucidating on the consumption of CBDs as well as its adverse effects and to provide a comprehensive overview of CBD pretreatment and detection methods. Moreover, novel pretreatment methods such as microextraction, Quick Easy Cheap Effective Rugged Safe and online technology as well as novel analytic methods such as ion-mobility mass spectrometry, application of high resolution mass spectrometry in nontarget screening are summarized. In addition, we discuss and compare the strengths and weaknesses of different methods and suggest their future prospect.

A systematic approach to decode the mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC).

Cornus Officinalis (Cornus), the dried pulp of mature Cornus, is used to treat liver diseases. However, the pharmacological mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC) has not been systematically studied. The chemical compounds and the bioactive chemical compounds of Cornus were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Cards database was used to explore the targets in liver cancer pathogenesis. The disease-drug Venn diagram was constructed using the VENN 2.1 and the STRING database was used to analyze protein-protein Interaction Network (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R package. Molecular docking was performed using Discovery Studio were assessed using Pymol and Discovery Studio 2016. Cell survival of BEL-7404 cells treated by Hydroxygenkwanin (HGK) were valued through CCK-8 assay. Expressions of caspase-3 and cleaved PARP was detected through Western blot. Pharmacological network diagrams of the Cornus compound-target network and HCC-related target network were successfully constructed. A total of 20 active compounds, 1841 predicted biological targets of Cornus, and 7100 HCC-related targets were identified. 37 target genes between Cornus and HCC were screened trough the network pharmacology. Molecular docking studies suggested that HGK has the highest affinity with caspase-3. HGK could induce apoptosis of HCC cells and significantly activate the caspase-3 protease activity in BEL-7404. This study systematically elaborated the mechanism of Cornus in the treatment of HCC and provided a new perspective to exploit Antineoplastic from Cornus.

Systems Pharmacology-Based Identification of Mechanisms of Action of Bolbostemma paniculatum for the Treatment of Hepatocellular Carcinoma.

BACKGROUND Traditional Chinese medicine has widely used Bolbostemma paniculatum to treat diseases, including cancer, but its underlying mechanisms remain unclear. The present study aimed to elucidate the potential pharmacological mechanisms of "Tu Bei Mu" (TBM), the Chinese name for Bolbostemmatis Rhizoma, the dry tuber of B. paniculatum, for the treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS The active components and putative therapeutic targets of TBM were explored using SwissTargetPrediction, Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and Search Tool for Interactions of Chemicals (STITCH). The HCC-related target database was built using DrugBank, DisGeNet, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). A protein-protein interaction network of the common targets was constructed, based on the matches between TBM potential targets and HCC-related targets, using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the cluster networks were used to elucidate the biological functions of TBM. RESULTS Pharmacological network diagrams of the TBM compound-target network and HCC-related target network were successfully constructed. A total of 22 active components, 191 predicted biological targets of TBM, and 3775 HCC-related targets were identified. Through construction of an HCC-related target database and a protein-protein interaction network of the common targets, TBM was predicted to be effective in treating HCC mainly through the PI3K-Akt, HIF-1, p53, and PPAR signaling pathways. CONCLUSIONS The PI3K/Akt, HIF1, p53, and PPAR pathways may play vital roles in TBM treatment of HCC. Also, the potential anti-cancer effect of TBM on HCC appears to stem from the synergetic effect of multiple targets and mechanisms.

The distribution and changes of glycoalkaloids in potato tubers under different storage time based on MALDI-TOF mass spectrometry imaging.

Glycoalkaloids (GAs) are toxic secondary metabolites in potatoes, which are harmful to human body. The storage time has a great influence on the biosynthesis and distribution of GAs. In present study, an imaging mass microscope (iMScope) was used to investigate the distribution and changes of GAs in potato tubers under different storage time (0, 10, 15, 20, 30, 40 and 60 days). We established a growth model with logistic equation to evaluate the growth trends of four major GAs in sprout, periderm and medulla. The results showed that the growth rate and relative contents of four GAs in sprout and periderm were significantly higher than that in medulla. In addition, four GAs also presented different change trends. For dehydrosolanine and α-solanine, rapid growth period of these two GAs in sprout (about at the day 23, similar to these in medulla) was later than which period in periderm (about at the day 17), while rapid growth of dehydrochaconine and α-chaconine appeared at almost the same time (about at the day 20). Based on the biosynthesis and metabolism of GAs, we have made possible explanations for these results. This study is useful for comprehending the metabolism of GAs in different parts and monitoring food safety in potatoes.

An Integrative Serum Pharmacology-Based Approach to Study the Anti-Tumor Activity of B. paniculatum Aqueous Bulb Extract on the Human Hepatocellular Carcinoma Cell Line BEL-7404.

The herb Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae family), also known as Tu-Bei-Mu (TBM) in Chinese, has shown curative effects to treat several types of cancer as an adjunctive therapy. Thereby we intend to find its effect on the human hepatocellular carcinoma (HCC) and to understand the pharmacological mechanism behind it. In this study, an integrative serum pharmacology-based approach linking serum pharmacology and bioinformatics prediction was employed. Firstly, we used the serum taken introgastrically from the rats dministered by TBM aqueous bulb extract to culture the HCC cell line BEL-7404 and detect its anti-tumor effects. Secondly, the TBM putative targets were predicted using the ETCM database and known therapeutic targets of NPC were collected from the OMIM database. Then, a TBM-HCC putative targets network was constructed using the DAVID and STRING databases. Thirdly, key gene targets were obtained based on topological analysis and pathway enrichment analysis. The expression of 4 representative key targets were validated by Western blotting. As a result, 36 TBM targets and 26 known therapeutic targets of HCC were identified. These key targets were found to be frequently involved in 13 KEGG pathways and 4 biological processes. The expression of four representative key targets: TP53, CASP3, BCL2 and BAX further supports the suppression of TBM on HCC. In general, our study shows the curative effects of TBM against HCC. By using this integrative approach, we may find novel potential therapeutic targets to suppress HCC using TBM as an adjunctive therapy. And it could also help us understand the mechanism of HCC treatments in response to TBM.

Interaction Effects between Doxorubicin and Hernandezine on the Pharmacokinetics by Liquid Chromatography Coupled with Mass Spectrometry.

Doxorubicin (DOX) is an effective anti-tumor drug widely used in clinics. Hernandezine (HER), isolated from a Chinese medicinal herb, has a selective inhibitory effect on DOX multidrug resistance, making DOX more effective in treating cancer. The aim of this study was to investigate the effect of the interaction of HER and DOX on pharmacokinetics. Male Sparague-Dawley rats were randomly divided into three groups: a single DOX group, a single HER group, and a combination group. Plasma concentrations of DOX and HER were determined by the LC-MS/MS method at specified time points after administration, and the main pharmacokinetic parameters were estimated. The results showed that there were significant differences in the Cmax and AUC0-∞ of DOX in the single drug group and combined drug group, indicating that HER could improve the absorption of DOX. However, DOX in combination, in turn, reduced the free drug concentration of HER, possibly because DOX enhanced the HER drug-protein binding effect. The results could be used as clinical guidance for DOX and HER to avoid adverse reactions.

Supercritical fluid chromatography-a technical overview and its applications in medicinal plant analysis: an update covering 2012-2018.

Medicinal plants with complex matrices are endowed with a wide scope of biological activities. The separation, quantification, characterization and purification of bioactive components from herbal medicine extracts have always challenged analysts. Fortunately, the advancement of various emerging techniques has provided potent support for improving the method selectivity, sensitivity and run speeds in medicinal plant analyses. In recent years, the advent of new-generation supercritical fluid chromatography (SFC) instruments and a wide diversity of column chemistries, coupled with the intrinsic technical features of SFC, have made it an alternative and prominent analytical platform in the medicinal plant research area. This work aims to give a comprehensive overview of the fundamentals, technical advancement and investigating parameters of SFC in combination with three prevalent detectors. Moreover, the latest research progress of SFC applications in medicinal plant analyses is illuminated, with focus on herbal medicine-related SFC papers on the analytical and preparative scale that were published during the period of 2012 to December 2018. The most relevant applications were classified based on the constituents to be analysed. As for the respective research cases, analytical protocols and data processing strategies were provided, along with the indicated restrictions or superiority of the method; thus, the current status of SFC in medicinal plant analysis was presented.

Deciphering the Pharmacological Mechanism of the Herb Radix Ophiopogonis in the Treatment of Nasopharyngeal Carcinoma by Integrating iTRAQ-Coupled 2-D LC-MS/MS Analysis and Network Investigation.

The herb Radix Ophiopogonis (RO) has been used effectively to treat nasopharyngeal carcinoma (NPC) as an adjunctive therapy. Due to the complexity of the traditional Chinese herbs, the pharmacological mechanism of RO's action on NPC remains unclear. To address this problem, an integrative approach bridging proteome experiments with bioinformatics prediction was employed. First, differentially expressed protein profile from NPC serum samples was established using isobaric tag for relative and absolute quantification (iTRAQ) coupled 2-D liquid chromatography (LC)-MS/MS analysis. Second, the RO putative targets were predicted using Traditional Chinese Medicines Integrated Database and known therapeutic targets of NPC were collected from Drugbank and OMIM databases. Then, a network between RO putative targets and NPC known therapeutic targets was constructed. Third, based on pathways enrichment analysis, an integrative network was constructed using DAVID and STRING database in order to identify potential candidate targets of RO against NPC. As a result, we identified 13 differentially expressed proteins from clinical experiments compared with the healthy control. And by bioinformatics investigation, 12 putative targets of RO were selected. Upon interactions between experimental and predicted candidate targets, we identified three key candidate targets of RO against NPC: VEGFA, TP53, and HSPA8, by calculating the nodes' topological features. In conclusion, this integrative pharmacology-based analysis revealed the anti-NPC effects of RO might be related to its regulatory impact via the PI3K-AKT signaling pathway, the Wnt signaling pathway, and the cAMP signaling pathway by targeting VEGFA, TP53, and HSPA8. The findings of potential key targets may provide new clues for NPC's treatments with the RO adjunctive therapy.

Chemical constituents of Eleutherococcus sessiliflorus extract and its sedative-hypnotic effect.

The present study was designed to investigate the chemical constituents and bioactivities of the roots of Eleutherococcus sessiliflorus (E. sessiliflorus). The compounds were isolated through various chromatography techniques and elucidated by mass spectrometric (MS), 1D- and 2D-NMR analyses. The sedative-hypnotic effect of E. sessiliflorus ethanol extract and its fractions (acetic ether, n-butanol and water fraction) were also investigated. In the chemical constituent study, one new compound, 3-ethyl-5-hydroxy-3-(hydroxymethyl) pentyl-3-(3,4-dihydroxyphenyl) acrylate and fourteen known compounds were isolated and identified. The chromatographic fingerprint of E. sessiliflorus was established by UPLC-PDA-MS/MS analysis. In bioactivity study, it was found that the water fraction of E. sessiliflorus extract could prolong pentobarbital-induced sleeping time more than that of the other fractions of E. sessiliflorus extract in mice, which provided a basis for future study on sedative-hypnotic effect of the chemical constituents in E. sessiliflorus.

Simultaneous determination and pharmacokinetics of four triterpenoids by ultra high performance liquid chromatography with tandem mass spectrometry after the oral administration of Acanthopanax sessiliflorus (Rupr. et Maxim) Seem extract.

A specific, simple, and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method utilizing the Triple Quad system has been developed and validated for the simultaneous determination and pharmacokinetic study of four triterpenoid components of Acanthopanax sessiliflorus in rat plasma. The components are 22-α-hydroxychiisanogenin, chiisanogenin, (1R,11α)1,4-epoxy-11-hrdroxy-3,4-secolupane-20(30)-ene-3,28-dioic acid, and 22-α-hydroxychiisanoside. Sample preparation involved a liquid-liquid extraction of the analytes with ethyl acetate. Chromatographic separation was accomplished using an Agilent SB-C18 column (1.8 µm, 2.1 mm × 50 mm) with 2.0 min isocratic elution. The compounds were detected with a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode and an ESI source in negative mode. The method was linear for all analytes over the investigated range, with all determined correlation coefficients exceeding 0.9906. The limit of quantification of each analyte was lower than 1 ng/mL. The intraday and interday precisions were less than 14.9%, and the accuracy ranged from -10.2 to 11.8%. The mean recoveries of the analytes were higher than 80.0%, and the matrix effects were between 100.4 and 107.1%. These results may contribute to determining the mechanism of action and guiding the clinical application of Acanthopanax sessiliflorus.

Four new diterpenoids isolated from the Euphorbia rapulum.

Four new diterpenoids named 1-epi-9-hydroxydepressin (1), 1-epi-8-hydroxydepressin (2), 2,13,9-trihydroxy-labda-8(17),12(E),14-triene (3) and tagalsin I (4) were isolated from Euphorbia rapulum. The structures of these compounds were elucidated by means of various spectroscopic methods. All the isolated compounds were evaluated for cytotoxic activities against HepG2, MCF-7, and C6 cell lines, and compound 4 showed moderate selective activity against MCF-7 cell line with an IC50 value of 31.8 µM.

In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists.

OBJECTIVES: Kadsura longipedunculata (KL) has been widely used for the treatment of insomnia in traditional Chinese medicine. The aim of this study was to explore the mechanism of the sedative and hypnotic effects of KL. MATERIALS AND METHODS: The content of KL was evaluated by HPLC-TOF-MS, and a potential target was found and used to construct its 3D structure to screen for potential ligands among the compounds in KL by using bioinformatics analysis, including similarity ensemble approach (SEA) docking, homology modeling, molecular docking and ligand-based pharmacophore. The PCPA-induced insomnia rat model was then applied to confirm the potential targets related to the sedative effects of KL by performing the forced swimming test (FST), the tail suspension test (TST) and the measurement of target-related proteins using western blotting and immunofluorescence. RESULTS: Bioinformatics analysis showed that most of lignan compounds in KL were optimal ligands for the 5-HT1A receptor (5-HT1AR), and they were found to be potential targets related to sedative effects; the main lignan content of KL extracts was characterized by HPLC-TOF-MS, with 7 proposed lignans detected. Administration of KL could significantly reduce FST and TST immobility time in the PCPA-induced 5HT-depleted insomnia rat model. The expressions of proteins related to the 5-HT1AR pathway were regulated by extracts of KL in a concentration-dependent manner, indicating that extracts of KL had 5-HT1AR agonist-like effects. CONCLUSION: In silico analysis and experimental validation together demonstrated that lignan extracts from KL can target 5-HT1AR in insomniac rats, which could shed light on its use as a potential 5-HT1AR agonist drug.

[Studies on chemical constituents of Syringa veutina].

OBJECTIVE: To study the chemical constituents of Syringa veutina Kom. METHODS: The constituents were isolated and repeatedly purified on silica and Sephadex LH-20 column chromatography. They were dentified and structurally elucidated by spectral analysis. RESULTS: Seven compounds were obtained. They were identified as Syningin(1), Liriodendrin(2), (+) -Medioresinol di-O-beta-D-glucopyranosied (3), Rutin(4), Quercetin 3-O-beta-D-glucopyranoside (5), Kaempferol-3-O-beta-D-glucopyranosied (6), D-mannitol (7). CONCLUSION: Compound 2 and 3 were isolated from this genus for the first time. Compound 4, 5, 6 and 7 were isolated from this plant for the first time.

[Determination of the cucurbitacins from Cucubita pepo cv dayangua by HPLC].

OBJECTIVE: To establish an HPLC method for the simultaneous determination of four bioactive cucurbitacins in Cucubita pepo cv Dayangua. METHODS: The HPLC chromatography was carried out with a lineal gradient programming and detection wavelength at 215 nm. Kromasil C8 column (150 mm x 4.6 mm ID, 5 microm)was used. The mobile phase was acetonitrile-water (containing 2.0% HAc) and the flow rate was 1.0 ml/min. RESULTS: The linear range of 23, 24-dihydrocucurbitacin F was 0.28-5.6 microg/ml (r = 0.9978), 23, 24-dihydrocucurbitacin D 0.39-7.8 microg/ml (r = 0.9986), cucurbitacin B 0.304-6.08 microg/ml (r = 0.9983), cucurbitacin E 2. 52 -50. 4 microg/ml (r = 0.9998). The method was accurate with variation less than 5% and recovery more than 95%. CONCLUSION: The method is successfully applied to determination of the four cucurbitacins from Cucubita pepo cv dayangua.