plantMASST - Community-driven chemotaxonomic digitization of plants.

Understanding the distribution of hundreds of thousands of plant metabolites across the plant kingdom presents a challenge. To address this, we curated publicly available LC-MS/MS data from 19,075 plant extracts and developed the plantMASST reference database encompassing 246 botanical families, 1,469 genera, and 2,793 species. This taxonomically focused database facilitates the exploration of plant-derived molecules using tandem mass spectrometry (MS/MS) spectra. This tool will aid in drug discovery, biosynthesis, (chemo)taxonomy, and the evolutionary ecology of herbivore interactions.

Identification of novel dimers and chemical profiling of acid amide alkaloids in Piper nigrum.

Peppers (Piper nigrum L.) are distinguished by their pungent flavor and aroma. Piperine is a major acid-amide alkaloid with a piperidine ring that gives pepper its flavor and scent. In plant metabolomics research, the accessibility of the chemical standards is critical for scientific credibility. We isolated and identified 10 novel dimers of acid amide alkaloids (9-15 and 20-22), along with 12 known monomers (1-6) and dimers (7, 8, 16-19) from black pepper. Subsequently, we found the distribution of monomers and dimers of acid amide alkaloids in black and white peppers by twenty-two acid amide alkaloids which we obtained using the molecular networking technique and multivariate analysis to reveal the molecular relationships between the acid amide alkaloids in black and white peppers. Our research delved into the chemical diversity of acid amide alkaloids in black and white peppers, which could help inform future culinary and potential medicinal utilization of pepper.

Panaxydol extracted from Panax ginseng inhibits NLRP3 inflammasome activation to ameliorate NASH-induced liver injury.

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome exacerbates liver inflammation and fibrosis in nonalcoholic steatohepatitis (NASH), suggesting that development of inflammasome inhibitor can become leading candidate to ameliorate NASH. Panax ginseng (P. ginseng) contains numerous bioactive natural components to reduce inflammation. This study aims to identify inhibitory components of P. ginseng for NLRP3 inflammasome activation. We separated polar and non-polar fractions of P. ginseng and tested modulation of NLRP3 inflammasome, and then identified pure component for inflammasome inhibitor which ameliorates diet-induced NASH. Non-polar P. ginseng fractions obtained from ethyl acetate solvent attenuated IL-1ß secretion and expression of active caspase-1. We revealed that panaxydol (PND) is pure component to inhibit NLRP3 inflammasome activation. PND blocked inflammasome cytokines release, pyroptotic cell death, caspase-1 activation and specking of inflammasome complex. Inhibitory effect of PND was specific to NLRP3-dependent pathway via potential interaction with ATP binding motif of NLRP3. Moreover, in vivo studies showed that PND plays beneficial roles to reduce tissue inflammations through disruption of NLRP3 inflammasome and to ameliorate the development of NASH. These results provide new insight of natural products, panaxydol, for NLRP3 inflammasome inhibitor and could offer potential therapeutic candidate for reliving NASH.

Open access repository-scale propagated nearest neighbor suspect spectral library for untargeted metabolomics.

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 MS/MS spectra originating from published untargeted metabolomics experiments. Entries in this library, or "suspects," were derived from unannotated spectra that could be linked in a molecular network to an annotated spectrum. Annotations were propagated to unknowns 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 for download or for data analysis through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

Triterpenoid saponins from Camellia sinensis roots with cytotoxic and immunomodulatory effects.

Camellia sinensis L. (Theaceae) leaves have been used as a beverage in both Eastern and Western cultures for a long time, while its root has not been intensively studied. In this study, seven undescribed triterpenoid saponins (1-7) and twelve known saponins (8-19) with different combinations of substituents, such as oxygenated isoprenyl substituents and sugar moieties, and lengths of sugar chains, were isolated from the C. sinensis roots. Their structures were unequivocally determined using one- and two-dimensional nuclear magnetic resonance data and acid hydrolysis analysis. Investigation of the biological activities of isolated compounds revealed that only those without functional acetyl groups exhibited cytotoxic activities against mouse and human cancer cells (B16F10) and human cervical cancer cell line (HeLa) at 50 µM. Compounds with an aldehyde group at C-23 of aglycone showed immunomodulatory activity against Th1 and Th17 cells at 10 µM. Ten compounds with biological activities from C. sinensis roots extracts, including three previously undescribed ones (3, 6, and 7), were identified.

Effect of pre-fragmentation on efficacy and safety for phacoemulsification in femtosecond laser-assisted cataract surgery: a non-randomized clinical trial.

Background: Ultrasound energy during phacoemulsification results in the endothelial cell loss of cornea. Crystallin lens fragmentation with softening before phacoemulsification can be used with femtosecond laser-assisted cataract surgery (FLACS) device. Methods: This non-randomized clinical trial included patients who underwent cataract surgery and not had corneal opacity. Patients who were not possible to apply the interface on the ocular surface, were excluded. Each subject was allowed to decide the surgical method by himself/herself. Cataract surgery was performed with FLACS (groups I and II) or conventional surgical technique (group III). The FLACS group was further subdivided into two groups according to whether a lens softening procedure was performed (group I) or not (group II). The nuclear density of cataract was objectively classified by Pentacam nuclear staging (PNS), preoperatively. Surgical parameters including total phacoemulsification time (TPT), cumulative dissipated energy (CDE), and the balanced salt solution (BSS) volume consumed, were measured during the surgery. Postoperative visual outcomes were evaluated at three months after the surgery, and corneal endothelial cell count (ECC) loss were calculated based on ECC measured before the surgery and two months after the surgery. Results: Eighty-nine eyes from 89 patients were enrolled. Fifty-three were treated using FLACS (groups I; quadrant pattern with softening of pre-fragmentation, n=31 and II; sextant pattern without softening of pre-fragmentation, n=22) and 36 (group III) with the conventional manual technique. The FLACS groups (groups I and II) had statistically significant lower TPT (P<0.001), CDE (P<0.001), and BSS volumes (P<0.001) used in the nucleus removal step compared to group III. Furthermore, ECC loss in groups I (4.59%±2.57%) and II (6.10%±3.30%) were also statistically lower compared to group III (13.49%±10.55%, P<0.001). From subgroup analysis with the PNS 2, group I showed lower pre-fragmentation time, lower CDE, lower BSS volume used during nucleus removal, and lower ECC loss compared to group II (all P<0.001). Conclusions: Pre-fragmentation using FLACS may reduce intraoperative ultrasound energy and intraocular manipulations compared to conventional cataract surgery.

Antiviral Mechanisms of Saucerneol from Saururus chinensis against Enterovirus A71, Coxsackievirus A16, and Coxsackievirus B3: Role of Mitochondrial ROS and the STING/TKB-1/IRF3 Pathway.

Enterovirus A71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus B3 (CVB3) are pathogenic members of the Picornaviridae family that cause a range of diseases, including severe central nervous system complications, myocarditis, and pancreatitis. Despite the considerable public health impact of these viruses, no approved antiviral treatments are currently available. In the present study, we confirmed the potential of saucerneol, a compound derived from Saururus chinensis, as an antiviral agent against EV71, CVA16, and CVB3. In the in vivo model, saucerneol effectively suppressed CVB3 replication in the pancreas and alleviated virus-induced pancreatitis. The antiviral activity of saucerneol is associated with increased mitochondrial ROS (mROS) production. In vitro inhibition of mROS generation diminishes the antiviral efficacy of saucerneol. Moreover, saucerneol treatment enhanced the phosphorylation of STING, TBK-1, and IRF3 in EV71- and CVA16-infected cells, indicating that its antiviral effects were mediated through the STING/TBK-1/IRF3 antiviral pathway, which was activated by increased mROS production. Saucerneol is a promising natural antiviral agent against EV71, CVA16, and CVB3 and has potential against virus-induced pancreatitis and myocarditis. Further studies are required to assess its safety and efficacy, which is essential for the development of effective antiviral strategies against these viruses.

Camellia japonica Root Extract Increases Antioxidant Genes by Induction of NRF2 in HeLa Cells.

Camellia japonica L. (Theaceae) has been used for medicinal and cosmetic purposes in East Asian countries. Most functional components were obtained from the upper parts of the tree, such as leaves, flowers, or seeds. Here, we report a functional effect of the 80% methanolic extract of C. japonica root (CJRE) on antioxidative stress in HeLa cells. The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor that triggers the induction of oxidative stress-relating genes and drug detoxification. As result, CJRE showed a strong anti-radical scavenging effect in a dose-dependent manner. In addition, the induction of antioxidant response elements (ARE)-luciferase activity was maximized at CJRE 200 µg/mL. Furthermore, CJRE induced the mRNA levels of HO-1 and NQO1 by the nuclear NRF2 accumulation. As a possible mechanism of Nrf2 activation, the phosphorylation of p38 and ERK1/2 signaling might fortify the NRF2 induction as well as its stability. However, the phosphorylation of AKT is rather decreased. Taken together, CJRE may potentiate the antioxidant effects by increasing the NRF2 signaling through MAP kinase signaling and the properties of its radical scavenging activity. Thus, CJRE could apply for other medicinal and cosmetic purposes.

Mass spectrometry data on specialized metabolome of medicinal plants used in East Asian traditional medicine.

Traditional East Asian medicine not only serves as a potential source of drug discovery, but also plays an important role in the healthcare systems of Korea, China, and Japan. Tandem mass spectrometry (MS/MS)-based untargeted metabolomics is a key methodology for high-throughput analysis of the complex chemical compositions of medicinal plants used in traditional East Asian medicine. This Data Descriptor documents the deposition to a public repository of a re-analyzable raw LC-MS/MS dataset of 337 medicinal plants listed in the Korean Pharmacopeia, in addition to a reference spectral library of 223 phytochemicals isolated from medicinal plants. Enhanced by recently developed repository-level data analysis pipelines, this information can serve as a reference dataset for MS/MS-based untargeted metabolomic analysis of plant specialized metabolites.

Hierarchical network analysis of co-occurring bioentities in literature.

Biomedical databases grow by more than a thousand new publications every day. The large volume of biomedical literature that is being published at an unprecedented rate hinders the discovery of relevant knowledge from keywords of interest to gather new insights and form hypotheses. A text-mining tool, PubTator, helps to automatically annotate bioentities, such as species, chemicals, genes, and diseases, from PubMed abstracts and full-text articles. However, the manual re-organization and analysis of bioentities is a non-trivial and highly time-consuming task. ChexMix was designed to extract the unique identifiers of bioentities from query results. Herein, ChexMix was used to construct a taxonomic tree with allied species among Korean native plants and to extract the medical subject headings unique identifier of the bioentities, which co-occurred with the keywords in the same literature. ChexMix discovered the allied species related to a keyword of interest and experimentally proved its usefulness for multi-species analysis.

Investigation of Chemical Profiles of Different Parts of Morus alba Using a Combination of Molecular Networking Methods with Mass Spectral Data from Two Ionization Modes of LC/MS.

Plants produce numerous secondary metabolites with diverse physicochemical properties. Because different parts of a single plant produce various components, several spectroscopic methods are necessary to inspect their chemical profiles. Mass spectral data are recognized as one of the most useful tools for analyzing components with a wide range of polarities. However, interpreting mass spectral data generated from positive and negative ionization modes is a challenging task because of the diverse chemical profiles of secondary metabolites. Herein, we combine and analyze mass spectral data generated in two ionization modes to detect as many metabolites as possible using the molecular networking approach. We selected different parts of a single plant, Morus alba (Moraceae), which are used in the functional food and medicinal herb industries. The mass spectral data generated from two ionization modes were combined and analyzed using various molecular networking workflows. We confirmed that our approach could be applied to simultaneously analyze the different types of secondary metabolites with different physicochemical properties.

Cluster Analysis of Medicinal Plants and Targets Based on Multipartite Network.

Network-based methods for the analysis of drug-target interactions have gained attention and rely on the paradigm that a single drug can act on multiple targets rather than a single target. In this study, we have presented a novel approach to analyze the interactions between the chemicals in the medicinal plants and multiple targets based on the complex multipartite network of the medicinal plants, multi-chemicals, and multiple targets. The multipartite network was constructed via the conjunction of two relationships: chemicals in plants and the biological actions of those chemicals on the targets. In doing so, we introduced an index of the efficacy of chemicals in a plant on a protein target of interest, called target potency score (TPS). We showed that the analysis can identify specific chemical profiles from each group of plants, which can then be employed for discovering new alternative therapeutic agents. Furthermore, specific clusters of plants and chemicals acting on specific targets were retrieved using TPS that suggested potential drug candidates with high probability of clinical success. We expect that this approach may open a way to predict the biological functions of multi-chemicals and multi-plants on the targets of interest and enable repositioning of the plants and chemicals.

α-Glucosidic hydroquinone derivatives from Viburnum erosum.

Six undescribed compounds (1-6) were isolated from the leaves of Viburnum erosum along with four known compounds 7-10. The structures were determined by NMR and MS spectroscopic analyses, and their absolute configurations were established by chemical and spectroscopic methods. Compounds 1-6 were α-glucosidic hydroquinone derivatives with different linear monoterpenoid structures. Compounds 1-10 were also evaluated for their tyrosinase inhibitory activities, and 10 showed potent inhibition of tyrosinase enzyme with IC50 value of 37.9 µM compared to 47.6 µM of the positive control (ß-arbutin).

Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3-/- mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.

Targeted Isolation of Cytotoxic Sesquiterpene Lactones from Eupatorium fortunei by the NMR Annotation Tool, SMART 2.0.

Small Molecular Accurate Recognition Technology (SMART 2.0) has recently been introduced as a NMR-based machine learning tool for the discovery and characterization of natural products. We attempted targeted isolation of sesquiterpene lactones from Eupatorium fortunei with the aid of structural annotation by SMART 2.0 and chemical profiling. Eight germacrene-type (1-7 and 10) and two eudesmane-type sesquiterpene lactones (8 and 9) were isolated from the whole plant of Eupatorium fortunei. With the guidance of the results of the subfractions from E. fortunei obtained by SMART 2.0, their cytotoxic activities were evaluated against five cancer cells (SKOV3, A549, PC3, HEp-2, and MCF-7). Compounds 4 and 8 exhibited IC50 values of 3.9 ± 1.2 and 3.9 ± 0.6 µM against prostate cancer cells, PC3, respectively. Compound 7 showed good cytotoxicity with IC50 values of 5.8 ± 0.1 µM against breast cancer cells, MCF-7. In the present study, the rapid annotation of the mixture of compounds in a fraction by the NMR-based machine learning tool helped the targeted isolation of bioactive compounds from natural products.

Morin Hydrate Inhibits Influenza Virus entry into Host Cells and Has Anti-inflammatory Effect in Influenza-infected Mice.

Influenza virus is the major cause of seasonal and pandemic flu. Currently, oseltamivir, a potent and selective inhibitor of neuraminidase of influenza A and B viruses, is the drug of choice for treating patients with influenza virus infection. However, recent emergence of oseltamivir-resistant influenza viruses has limited its efficacy. Morin hydrate (3,5,7,2',4'-pentahydroxyflavone) is a flavonoid isolated from Morus alba L. It has antioxidant, anti-inflammatory, neuroprotective, and anticancer effects partly by the inhibition of the NF-кB signaling pathway. However, its effects on influenza virus have not been studied. We evaluated the antiviral activity of morin hydrate against influenza A/Puerto Rico/8/1934 (A/PR/8; H1N1) and oseltamivir-resistant A/PR/8 influenza viruses in vitro. To determine its mode of action, we carried out time course experiments, and time of addition, hemolysis inhibition, and hemagglutination assays. The effects of the co-administration of morin hydrate and oseltamivir were assessed using the murine model of A/PR/8 infection. We found that morin hydrate reduced hemagglutination by A/PR/8 in vitro. It alleviated the symptoms of A/PR/8-infection, and reduced the levels of pro-inflammatory cytokines and chemokines, such as TNF-α and CCL2, in infected mice. Co-administration of morin hydrate and oseltamivir phosphate reduced the virus titers and attenuated pulmonary inflammation. Our results suggest that morin hydrate exhibits antiviral activity by inhibiting the entry of the virus.

The Rapid Discrimination and Quality Assessment of Three Zanthoxylum Species Using 1H NMR Spectrometry.

The husks and fruits of Zanthoxylum species (Rutaceae) are the popular pungent and spicy ingredients of foods and the traditional medicines in many countries. Three Zanthoxylum species, Z. bungeanum, Z. schinifolium, and Z. piperitum, are distributed and intermixed with each other as "Zanthoxyli Pericarpium" in Korean markets. In the present study, we analyzed the ethyl acetate-soluble and nonpolar fractions of Zanthoxylum samples by 1H NMR spectrometry and performed a multivariate analysis for finding the discriminant markers between three species. Xanthoxylin was identified as the metabolic marker for the discrimination of Zanthoxylum species and quantified by the qNMR approach.

Targeted Isolation of Lignans from Trachelospermum asiaticum Using Molecular Networking and Hierarchical Clustering Analysis.

High-resolution-mass-spectrometry (HR-MS) methods rapidly provide extensive structural information for the isolation of metabolites in natural products. However, they may occasionally provide more information than required and interfere with the targeted analysis of natural products. In this study, we aimed to selectively isolate lignans from Trachelospermum asiaticum by applying the Global Natural Product Social Molecular Networking (GNPS) platform and hierarchical clustering analysis (HCA). T. asiaticum, which contains lignans, triterpenoids and flavonoids that possess various biological activities, was analyzed in a data-dependent acquisition (DDA) analysis mode using HR-MS. The preprocessed MS spectra were applied not only to GNPS for molecular networking but also to HCA based on similarity patterns between two nodes. The combination of these two methods reliably helped in the targeted isolation of lignan-type metabolites, which are expected to possess potent anti-cancer or anti-inflammatory activities.

A new phenolic compound from Phedimus middendorffianus with antiproliferative activity.

A new phenolic compound (1) and together with 12 known compounds-eight flavonoids (2 ∼ 9), two phenolic compounds (10 and 11) and two benzoic acid (12 and 13)-were isolated from Phedimus middendorffianus (Maxim.). The structures of all compound were determined on the basis of spectroscopic (MS and NMR) analyses. Compounds 4, 5, 7 and 11 ∼ 13 were showed anti-proliferative activities against MCF-7 than PC-3 cell line. Also compound 12 and 13 showed the significant cytotoxic activities against two cancer cell lines, PC-3 and MCF-7.

Exploring novel secondary metabolites from natural products using pre-processed mass spectral data.

Many natural product chemists are working to identify a wide variety of novel secondary metabolites from natural materials and are eager to avoid repeatedly discovering known compounds. Here, we developed liquid chromatography/mass spectrometry (LC/MS) data-processing protocols for assessing high-throughput spectral data from natural sources and scoring the novelty of unknown metabolites from natural products. This approach automatically produces representative MS spectra (RMSs) corresponding to single secondary metabolites in natural sources. In this study, we used the RMSs of Agrimonia pilosa roots and aerial parts as models to reveal the structural similarities of their secondary metabolites and identify novel compounds, as well as isolation of three types of nine new compounds including three pilosanidin- and four pilosanol-type molecules and two 3-hydroxy-3-methylglutaryl (HMG)-conjugated chromones. Furthermore, we devised a new scoring system, the Fresh Compound Index (FCI), which grades the novelty of single secondary metabolites from a natural material using an in-house database constructed from 466 representative medicinal plants from East Asian countries. We expect that the FCIs of RMSs in a sample will help natural product chemists to discover other compounds of interest with similar chemical scaffolds or novel compounds and will provide insights relevant to the structural diversity and novelty of secondary metabolites in natural products.