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Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimer’s brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the mechanisms underlying those benefits are still not fully understood. In order to explain the beneficial effects on metformin treatment, various metabolomics analyses have been applied to investigate the metabolic alterations in response to metformin treatment, and significant systemic metabolome changes were observed in biofluid, tissues, and cells. In this review, we compare the latest metabolomic research including clinical trials, animal models, and in vitro studies comprehensively to understand the overall changes of metabolome on metformin treatment.

An effective and previously demonstrated screening method for active constituents in natural products using LC-MS coupled with a bioassay was reported in our earlier studies. With this, the current investigation attempted to identify bioactive constituents of Scutellaria baicalensis through LC-MS coupled with a bioassay. Peaks at broadly 17–20 and 24–25 min on the MS chromatogram displayed an inhibitory effect on NO production in lipopolysaccharide-induced BV2 microglia cells. Similarly, peaks at roughly 17–19 and 22 min showed antioxidant activity with an 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)/2,2-diphenyl-1- picrylhydrazyl (DPPH) assay. For confirmation of LC-MS coupled with a bioassay, nine compounds (1–9) were isolated from an MeOH extract of S. baicalensis. As we predicted, compounds 1, 8, and 9 significantly reduced lipopolysaccharide (LPS)-induced NO production in BV2 cells. Likewise, compounds 5, 6, and 8 exhibited free radical-scavenging activities with the ABTS/DPPH assay. In addition, the structural similarity of the main components was confirmed by analyzing the total extract and EtOAc fractions through molecular networking. Overall, the results suggest that the method comprised of LC-MS coupled with a bioassay can effectively predict active compounds without an isolation process, and the results of molecular networking predicted that other components around the active compound node may also be active.

No abstract

Abstract:It is well known that activated microglia produce nitric oxide (NO), which has an important role in the pathophysiology of several neurodegenerative diseases such as Alzheimer's disease. In the course of searching for novel therapeutic agents from medicinal plants against neuroinflammatory diseases, the methanolic extract of Tetrapanax papyriferus was found to have significant NO inhibitory activity in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Nine oleanane-type triterpenes, including two new compounds, epipapyriogenin C-3-O-β-D-glucopyranoside (6) and 11-O-butylpapyrioside LIIc (9), were isolated from the leaves and stems of Tetrapanax papyriferus. The structures of these compounds were elucidated with 1D-and 2D-NMR and MS data. Among these ∆ 11,13 oleanane-type triterpenes, compound 3 showed significant NO inhibitory activity in BV-2 cells, reducing the LPS-induced expression of COX-2 and pro-inflammatory cytokines such as TNF-α and IL-6. Compounds 7 and 9 also showed NO inhibitory activities among the ∆ 12 oleanane-type triterpene saponins. These results show that oleanane-type triterpenes isolated from T. papyriferus could be a potential natural resource of NO inhibitors used in the treatment of neurodegenerative disorders.

Microbial cocultivation has been applied as a strategy to induce the biosynthesis of specialized metabolites. However, most previous studies have focused on competitive interactions between test strains. During our LC-MS-based chemical screening of randomized cocultures of Basidiomycetous fungi, we discovered that the coculture of Phellinus orientoasiaticus (Hymenochaetaceae) and Xylodon f laviporus (Schizoporaceae) induces multiple metabolites, although they did not show any competitive morphology. Targeted isolation yielded three new sesquiterpenes (1−3) along with five known analogues (4−8). The structures of the isolates were determined by MS and NMR experiments as well as electronic circular dichroism analysis. LC-MS analysis suggested that cyclohumulanoids of illudane-, sterpurane-, and tremulane-type scaffolds (1−7) were produced by P. orientoasiaticus, whereas a drimane-type sesquiterpene (8) was produced by X. f laviporus. None of the isolates exhibited antifungal activity or cytotoxicity, and compounds 1−7 exhibited NO production of LPS-treated RAW276.4 cells in a range of 15.9% to 38.0% at 100 μM.

This study was conducted to further investigate bioactive molecules from Sophora tonkinensis that can inhibit proprotein convertase substilisin/kexin type 9 (PCSK9) expression. After interpreting NMR spectroscopic data and MS spectral data of all isolates, a new naturally occurring compound, 6-hydroxy-vitexin-2″- O -rhamnoside ( 7 ), was identified along with 30 known compounds. The calculation of the gauge-including atomic orbital (GAIO) and electronic circular dichroism (ECD) proposed the absolute configuration of 17 as (2 S ,3 R )-methyl-2-(4-hydroxybenzyl)tartrate by comparing the calculated ECD with experimental data. All isolates were tested for their inhibitory effects on PCSK9 mRNA expression. Of the tested compounds, (+) - isolariciresinol ( 12 ) inhibited PCSK9 expression via downregulation of HNF1α and SREBPs.