Gut microbiota-based PK-PD study and molecular mechanism of Specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

An accurate and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry method was established and validated for the determination of nine bioactive compounds of Ligustri Lucidi Fructus in rat plasma. Separation was performed on Halo® C18 column with a mobile phase of acetonitrile and 0.1% formic acid in water. The eluate was detected by multiple reaction monitoring scanning operating in the negative ionization mode. This assay method was validated for selectivity, linearity, intra- and interday precision, accuracy, recovery, matrix effect, and stability, and all methodological parameters fulfilled the Food and Drug Administration criteria for bioanalytical validation. The established method was successfully applied to a comparative pharmacokinetic study of raw and wine-processed Ligustri Lucidi Fructus in rats for the first time. It was found that the AUC0-24 and Cmax value of salidroside, hydroxytyrosol, and nuezhenidic acid were increased significantly after processing, while the AUC0-24 and Cmax value of oleoside 11-methyl ester, 1'''-O-β-d-glucosylformoside, specnuezhenide, G13, oleonuezhenide, and oleanolic acid were decreased, which suggested that processing affects the absorption and bioavailability of Ligustri Lucidi Fructus. The results might be valuable for the clinical reasonable application and understanding the processing mechanism of Ligustri Lucidi Fructus.

Pharmacokinetic comparison of nine bioactive components in rat plasma following oral administration of raw and wine-processed Ligustri Lucidi Fructus by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry.

Cordycepin has recently received increased attention owing to its extensive pharmacological activity. Adenosine deaminase (ADA) is widely distributed in mammalian blood and tissues; as a result, cordycepin is quickly metabolized upon entering into the body and converted into the inactive metabolite 3'-deoxyinosine, thus limiting its activity when administered alone. We herein present a novel ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for screening ADA inhibitors against the metabolism of cordycepin. Cordycepin and 3'-deoxyinosine were chosen as substrate and product, respectively. A proper separation was achieved for all analytes within 3 min. 3'-Deoxyinosine was quantified in the presence or absence of potential ADA inhibitors to evaluate ADA activity. The assay can simultaneously determine substrate and product, with the endogenous substance and ADA inhibitors added not interfering in its activity. After optimizing the enzymatic incubation and UHPLC-MS/MS conditions, Km and Vmax values for ADA deamination of cordycepin were 95.18 ± 7.85 μm and 363.90 ± 12.16 μmol/min/unit, respectively. Oleanolic acid and ursolic acid from Ligustri Lucidi Fructus were chosen as ADA inhibitors with half maximal inhibitory concentration values of 21.82 ± 0.39 and 18.41 ± 0.14 μm, respectively. A non-competitive inhibition model was constructed and this assay can be used to screen other potential ADA inhibitors quickly and accurately.

A rapid assay to screen adenosine deaminase inhibitors from Ligustri Lucidi Fructus against metabolism of cordycepin utilizing ultra-high-performance liquid chromatography–tandem mass spectrometry

Abstract Zibushengfa Tablet is a widely consumed traditional Chinese medicine (TCM) prescription. However, its main bioactives remain unclear and its pharmacopeia quality-marker (Q-marker) is poorly characterized nowadays. The present study analyzed its lyophilized aqueous powder using ultra-high-performance liquid chromatography-quadrupole-orbitrap mass spectrometry. Through comparison with authentic standards in the library, 46 bioactives were putatively identified, including quinic acid, D-gluconic acid, gallic acid, protocatechuic acid, 5-caffeoylquinic acid, L-tryptophan, salidroside, (+)-catechin hydrate, caffeic acid, cryptochlorogenic acid, mangiferin, ferulic acid, myricetin-3-O-galactoside, 2,3,5,4’-tetrahydroxystilbene-2-O-glucoside, forsythoside B, myricitrin, rutin, hyperoside, acteoside, 3,4-dicaffeoylquinic acid, myricetin, senkyunolide A, isochlorogenic acid C, quercitrin, (+)-epipinoresinol, quercetin, biochanin A, calycosin, luteolin, wedelolactone, calycosin-7-O-glucoside, chrysoeriol, trans-cinnamic acid, formononetin, chrysin, 3,3’,4’,5,6,7,8-heptamethoxyflavone, Z-ligustilide, amentoflavone, tangeretin, hinokiflavone, emodin, physcion, linoleic acid, stearic acid, palmitic acid, and palmitic acid ethyl ester. Of these, four pairs of isomers were successfully differentiated using the newly established library-filtering strategy. On this basis, senkyunolide A, amentoflavone, quercetin, quercitrin, and wedelolactone are preliminarily suggested as additional quality-markers for the consideration by Pharmacopeia Committee, to prevent the possible adulterate. Graphical Abstract

Library-based UHPLC-Q-exactive-orbitrap-MS putative identification of isomeric and non-isomeric bioactives from Zibushengfa Tablet and pharmacopeia quality-marker chemistry

Abstract In this study, we assembled and annotated the chloroplast (cp) genomes of four Ligustrum species, L. sinense , L. obtusifolium , L. vicaryi , and L. ovalifolium ‘Aureum’. Including six other published Ligustrum species, we compared various characteristics such as gene structure, sequence alignment, codon preference, and nucleic acid diversity, and performed positive-selection genes screening and phylogenetic analysis. The results showed that the cp genome of Ligustrum was 162,185–166,800 bp in length, with a circular tetrad structure, including a large single-copy region (86,885–90,106 bp), a small single-copy region (11,446–11,499 bp), and a pair of IRa and IRb sequences with the same coding but in opposite directions (31,608–32,624 bp). This structure is similar to the cp genomes of most angiosperms. We found 132–137 genes in the cp genome of Ligustrum , including 89–90 protein-coding genes, 35–39 tRNAs, and 8 rRNAs. The GC content was 37.93–38.06% and varied among regions, with the IR region having the highest content. The single-nucleotide (A/T)n was dominant in simple-sequence repeats of the Ligustrum cp genome, with an obvious A/T preference. Six hotspot regions were identified from multiple sequence alignment of Ligustrum ; the ycf1 gene region and the clpP1 exon region can be used as potential DNA barcodes for the identification and phylogeny of the genus Ligustrum . Branch-site model and Bayes empirical Bayes (BEB) analysis showed that four protein-coding genes ( accD , clpP , ycf1 , and ycf2 ) were positively selected, and BEB analysis showed that accD and rpl20 had positively selected sites. A phylogenetic tree of Oleaceae species was constructed based on the whole cp genomes, and the results were consistent with the traditional taxonomic results. The phylogenetic results showed that genus Ligustrum is most closely related to genus Syringa . Our study provides important genetic information to support further investigations of the phylogenetic development and adaptive evolution of Ligustrum species. 

/pdf/complete-chloroplast-genomes-and-comparative-analysis-of-1y9yym1l.pdf

Complete chloroplast genomes and comparative analysis of Ligustrum species

Triterpenoids are one of the most active constituents in Ligustri Lucidi Fructus, but only oleanolic acid has been mostly studied. In recent years, a growing number of studies have shown that other triterpenes from Ligustri Lucidi Fructus also have various biological activities, so it is necessary to build up a detailed profile of the triterpenoids in Ligustri Lucidi Fructus. The chromatographic separation was performed on a C_(18) column(4.6 mm×250 mm, 5 μm) with mobile phase of methanol-acetonitrile-0.2% formic acid for gradient elution. The detection wavelength was set at 210 nm, with a flow rate of 0.5 mL·min~(-1), and the column temperature of 25 ℃. The HPLC fingerprint of triterpenoids in Ligustri Lucidi Fructus was built by testing 21 batches of samples from different sources. The structures of the total 15 common chromatographic peaks were elucidated with UHPLC-ESI-Orbitrap-MS/MS technique and six of them were identified as tormentic acid, pomolic acid, maslinic acid, botulin, oleanolic acid and ursolic acid by comparison to the reference substances. Under the same chromatographic condition, four main triterpenes(podocarboxylic acid, hawthorn acid, oleanolic acid and ursolic acid) were quantified and the results of system adaptability and methodology investigation all met the requirements of content determination. Meanwhile, with oleanolic acid(A) as the internal reference substance, quantitative analysis of multi-components by single marker(QAMS) method was used to analyze the above four components. The relative correction factor of oleanolic acid(B), hawthorn acid(C) and ursolic acid(D) to oleanolic acid was f_(B/A)=1.12, f_(C/A)=1.02 and f_(D/A)=0.88, respectively, and the relative retention values of these three to oleanolic acid was RRV_(B/A)=0.46, RRV_(C/A)=0.70 and RRV_(D/A)=1.03, respectively. The contents determined by two methods were similar. In conclusion, the method built in this paper is proved to be simple, reliable and specific for the simultaneous qualitative and quantitative analysis of the triterpenoids in Ligustri Lucidi Fructus, which can lay foundation for further assays of the triterpenoids in Ligustri Lucidi Fructus and the relative products.

[Qualitative and quantitative analysis on non-triterpenoids in Ligustri Lucidi Fructus].

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[Qualitative and quantitative analysis on non-triterpenoids in Ligustri Lucidi Fructus].