Our inability to effectively “drug” targets such as MYC for therapeutic purposes requires the development of new approaches. We report on the implementation of a phenotype-based assay for monitoring MYC expression in multiple myeloma cells. The open reading frame (ORF) encoding an unstable variant of GFP was engineered immediately downstream of the MYC ORF using CRISPR/Cas9, resulting in co-expression of both proteins from the endogenous MYC locus. Using fluorescence readout as a surrogate for MYC expression, we implemented a pilot screen in which ∼10,000 compounds were prosecuted. Among known MYC expression inhibitors, we identified cardiac glycosides and cytoskeletal disruptors to be quite potent. We demonstrate the power of CRISPR/Cas9 engineering in establishing phenotype-based assays to identify gene expression modulators.

Pomace, the press residue from different fruits accumulating as waste product in food industry, contains high amounts of secondary metabolites that could be utilized for health-related applications. This study aims at evaluating the potential of pomaces of apricot, bilberry, and elderberry to serve as a source for endothelial nitric oxide synthase (eNOS)-activating compounds. Five extracts obtained from the lyophilized pomace of apricot and elderberry with solvents of different polarity were found to enhance A23187-stimulated eNOS activity when tested at 50 μg/mL in an [14C]-l-arginine to [14C]-l-citrulline conversion assay in the human endothelium-derived cell line EA.hy926 (p < 0.05). The bioassay-guided fractionation of the extracts obtained with methanol/water (70:30) led to several active fractions from apricot pomace (p < 0.05) and elderberry pomace (p < 0.01). Liquid chromatography-mass spectrometry-based chemical analysis of the extracts and active fractions pointed mainly to triterpenoic acids as active compounds. One particular dihydroxytriterpenoic acid, characteristic for elderberry, was enriched as the main compound in the two most active fractions and might serve as a promising lead structure for further studies.

INTRODUCTION:TRPA1 is an excitatory ion channel and is involved in sensory processes including thermal (cold) nociception, and inflammatory pain.In the stomach TRPA1 modulates motility by delaying gastric emptying.The allicin in garlic is a strong activator of the TRPA1 channel.AIM: To characterize the sensations induced by intragastric application of allicin-containing garlic powder and to evaluate the effect of intragastric garlic powder on gastric tone and mechanosensitivity.METHODS: A 3-luminal tube with a barostat balloon was used for measurement of proximal gastric tone, gastric distension, and infusion of test solutions.The allicin content of a commercially available garlic powder was determined by HPLC (0.5%) and stability of allicin for at least 60 minutes after dilution of the powder was confirmed in vitro.After an initial open label dose finding with 1g, 2g, 3.75 g and 7.5 g garlic powder, 2 g garlic powder (10 mg allicin) in 10 ml H 2 O, was considered to induce moderate but constant sensation.This concentration was used hereafter in 7 volunteers to evaluate gastric sensation, tone, and mechanosensitivity in a double blind, placebo controlled manner.After a conditioning gastric distension, a bolus of 2 g garlic in 10 ml water or placebo was injected into the stomach.Continuous gastric tone and symptoms (graded symptom questionnaire with 7 symptoms, 5 grades per question; every 5 minutes) were recorded for 15 minutes, followed by stepwise distension.After another bolus injection of placebo/garlic, symptom evaluation, tone measurement and balloon distension was repeated.Aggregate symptom perception scores were calculated and areas under the curve were computed.During tone measurement, balloon volumes were determined in the 5 minutes before and after injection of test solutions and differences between placebo and garlic were determined.A p-value <0.05 was considered significant.RESULTS: Bolus injection of garlic caused immediate epigastric symptoms, mean aggregate symptom score (AUC in 15 minutes) was 106±49 vs. 35±30 after placebo (p=0.01).Garlic induced significant epigastric pressure, stinging, and warmth (p<0.01 vs. placebo), while the symptoms cramps, satiety, nausea and pain were not significantly different after placebo administration (p>0.05).Tone measurement in the five minutes before and after injection showed a significant dramatic increase of balloon volume after garlic (627±349 ml vs -145±120 ml; p<0.02).Symptom scores induced by mechanical distension (NS) and balloon volumes during distensions (NS) were not significantly different after garlic and placebo.SUMMARY: Garlic containing allicin induces immediate epigastric symptoms of pressure, stinging and warmth and decreases proximal gastric tone but does not influence mechanosensitivity.TRPA1 is a receptor that is involved in gastric sensation and motility. Su1640

Background TRPA1 is an excitatory ion channel and is involved in sensory processes including thermal nociception and inflammatory pain. The allicin in garlic is a strong activator of the TRPA1 channel. Aim To evaluate the effect of intragastric garlic powder containing allicin on perception, gastric tone, and mechanosensitivity. Methods An infusion-barostat balloon assembly was used for infusion of test solutions, for distension, and to measure proximal gastric compliance and tone. After an initial open label dose finding with 1 g, 2 g, 3.75 g, and 7.5 g commercially available garlic powder, a bolus of 2 g garlic powder (11 mg allicin)/60 mL H2O was considered to induce moderate but constant sensation and was used hereafter in a placebo-controlled, single-dose, double-blind, randomized study in 7 volunteers to evaluate gastric sensation, tone, and mechanosensitivity. Key Results Bolus injection of garlic caused immediate epigastric symptoms, mean aggregate symptom scores (AUC in 15 minutes) were 106 +/- 49 vs. 35 +/- 30 after placebo (P = 0.01). Garlic induced significant epigastric pressure, stinging, and warmth (P < 0.01 vs. placebo), while intensity of cramps, satiety, nausea, and pain was not significantly different to placebo (P > 0.05). Garlic induced an immediate, short lived fundic relaxation (balloon volume 627 +/- 349 mL vs. -145 +/- 120 mL; P < 0.02). No effect of allicin on proximal gastric mechanosensitivity and compliance was observed (NS). Conclusion and Inferences Garlic containing allicin induces immediate epigastric symptoms of pressure, stinging, and warmth and induces fundic relaxation but does not influence mechanosensitivity or compliance. TRPA1 is a receptor that is involved in gastric sensation and motility.

Secondary metabolites from lichens are known for exhibiting various biological effects such as anti-inflammatory, antioxidant and antibacterial activities. Despite this wide range of reported biological effects, their impact on the formation of advanced glycation end products (AGEs) remains vastly unexplored. The latter are known contributors to lifestyle and age-related diseases such as Alzheimer and Parkinson. Moreover, the development of atherosclerosis and arterial stiffness is causally linked to the formation of AGEs. With this in mind, the present work evaluated the inhibitory effects of secondary lichen metabolites on the formation of pentosidine-like AGEs' by using an in vitro, Maillard reaction based, fluorescence assay. Overall, thirty-seven natural and five synthetically modified compounds were tested, eighteen of which exhibiting IC50 values in the range of 0.05 to 0.70 mM. This corresponds to 2 to 32 fold of the inhibitory activity of aminoguanidine. Targeting one major inhibiting mechanism of AGEs formation, all compounds were additionally evaluated on their radical scavenging capacities in an DPPH assay. Furthermore, as both AGEs' formation and hypertension are major risk factors for atherosclerosis, compounds that were available in sufficient amounts were also tested for their vasodilative effects. Overall, and though some of the active compounds were previously reported cytotoxic, present results highlight the interesting potential of secondary lichen metabolites as anti-AGEs and vasodilative agents.

Apple pomace is a waste product of the apple manufacturing industry that has been in the focus of life sciences as it represents a low-cost source of fruit-derived compounds. High fruit consumption is associated with beneficial health effects, and therefore, apple pomace and its constituents raise therapeutic interest. The present work reviews (i) the chemical constituents of apple pomace, (ii) optimized extraction methods of apple pomace compounds, and (iii) biological activities of apple pomace. Current evidence of apple pomace influence on digestion and metabolism, cholesterol and triglyceride homeostasis, diabetes, and sex hormones is summarized. Furthermore, studies regarding its antioxidative, anti-inflammatory, antiproliferative, antibacterial and antiviral effects are presented. The review concludes that apple pomace is an underutilized waste product of the apple industry with the potential of being processed for its nutritional and pharmaceutical value.

Until the early 19th century, medicinal plants were the most important and irreplaceable sources of therapeutics.With the development of plant chemistry since the 18th century, culminating in the isolation of morphine 1805 by the apothecary F.W.A. Sertürner, attention finally turned to single substances, their derivatives and synthetic molecules, which could be quickly produced on an industrial level and were thought to be better controllable in terms of dosage, efficacy and side effects.In the progress of this development, many medicinal plants fell into oblivion, were not further investigated or not even studied.During the last decades, scientific interest has turned again to medicinal plants, as research in tradition, compounds and composition might reveal new opportunities for future challenges and essential medicinal needs, not only under the aspect of "soft therapeutics", but also as a source of clearly effective resources for the treatment of diseases, including serious diseases, with presently unsatisfying therapeutic solutions.Today, we have new methods and much more opportunity to explore the composition of plants under the aspect of their efficacy more deeply than ever before.This knowledge can now be linked to pharmacological and clinical studies, to allow a much better understanding of herbal medicines, their pharmacological (incl.toxicological) effects and their effectiveness.In contrast to most synthetic chemical ingredients and isolated pure substances of biogenic origin, the active ingredient of herbal medicines is a multicomponent mixture with high quality demands.The ad-

Lymph node metastasis of breast cancer is a clinical marker of poor prognosis. Yet, there exist no therapies targeting mechanisms of intravasation into lymphatics. Herein we report on an effect of the antidyslipidemic drug fenofibrate with vasoprotective activity, which attenuates breast cancer intravasation in vitro, and describe the potential mechanisms. To measure intravasation in a 3-dimensional co-culture model MDA-MB231 and MCF-7 breast cancer spheroids were placed on immortalised lymphendothelial cell (LEC) monolayers. This provokes the formation of circular chemorepellent induced defects (CCIDs) in the LEC barrier resembling entry ports for the intravasating tumour. Furthermore, the expression of adhesion molecules ICAM-1, CD31 and FAK was investigated in LECs by western blotting as well as cell-cell adhesion and NF-kappa B activity by respective assays. In MDA-MB231 cells the activity of CYP1A1 was measured by EROD assay. Fenofibrate inhibited CCID formation in the MDA-MB231/LEC- and MCF-7/LEC models and the activity of NF-kappa B, which in turn downregulated ICAM-1 in LECs and the adhesion of cancer cells to LECs. Furthermore, CD31 and the activity of FAK were inhibited. In MDA-MB231 cells,fenofibrate attenuated CYP1A1 activity. Combinations with other FDA-approved drugs, which reportedly inhibit different ion channels, attenuated CCID formation additively or synergistically. In summary, fenofibrate inhibited NF-kappa B and ICAM-1, and inactivated FAK, thereby attenuating tumour intravasation in vitro. A combination with other FDA-approved drugs further improved this effect. Our new concept may lead to a novel therapy for cancer patients.

inger & Kopp 960), the response to the call for papers dedicated to Max Wichtl in recognition of his outstanding and continuous tribute to pharmacognostic research was overwhelming. For this reason we are pleased to present a second double issue with the same dedication. We previously reported on the milestones of Max Wichtlʼs academic career. In all his functions and positions, be it as vice-president and president of the Society for Medicinal Plant and Natural Product Research (GA) or editor of Planta Medica, his ‘Viennese charm’ and ‘Prussian sense of duty’ were as much appreciated as his professional qualities. One important aspect in his life, however, was not mentioned before. Beside his dedication to pharmacognostic research, it is his talent to music and art which still keeps him so young (▶ Fig. 1). So, for decades he was engaged in the production of puppet theatres (Marionettentheater Schartenhof, G), and as connoisseur of W.A. Mozart. He translated the famous Mozart biography of Maynard Solomon: ‘Mozart. A Life’ into German (2005). After having retired Max Wichtl and his wife Traudl took residence close to Vienna. Even his close friends wonder how he manages to undertake this vast amount of personal entertainment activities, while never losing his pharmacognostic aims out of sight. As a critical opera-goer and expert in the genre he takes every opportunity to attend a good performance be it in Vienna, Salzburg or outside of Austria. Max, we wish you many further enjoyable years with pharmacognosy and music. In this issue a comprehensive review takes a historical look at the development of the field of “pharmacognosy”. With the first DNA-based method used to clearly distinguish a pharmaceutically used species from other ones, it is both relevant and exciting to look back at the long tradition focusing on the authentication and quality assurance of herbal medicines (Heinrich & Anagnostou 1110). In their review Sgamma et al. (1117) describe the introduction of DNA barcoding into the British Pharmacopoeia. A general trouble shooting chart is provided to guide the user through the problems that may be encountered. The development of authentication tests for wild-harvested Rhodiola rosea L. is used as a case study. A further review deals with the evaluation of the multi-tarCorrespondence Univ. Prof. i. R. Mag. Dr. Dr. h. c. Brigitte Kopp Department of Pharmacognosy, University of Vienna Althanstraße 14, 1090 Vienna, Austria brigitte.kopp@univie.ac.at

The traditionally used Central American medicinal plant Pluchea odorata, known as an anti-inflammatory and cancer cell growth-inhibiting remedy, was subjected to bioassay-guided isolation. Structure elucidation by 1D- and 2D-NMR and MS techniques supported by ECD and UV spectroscopic data revealed seven structurally previously undescribed and eight known eudesmane-type sesquiterpenes. Furthermore, one previously undescribed and one known phytol-like alcohol were identified. All compounds were tested for their cytotoxicity in cancer cells and for their anti-invasive effects. Among the eudesmanes, 3 alpha-(2',3'-epoxy-2'-methylbutyryloxy)-4 alpha-hydroxy-11-hydroperoxy-eudesm-6-en-8-one exhibited the most potent cytotoxic activity with an IC50 value of 8.8 mu M (after 48 h). Also in an in vitro model measuring the tumor-triggered breaching of the adjacent lymph endothelial cell barrier (3S*,4R*,5S*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2'-methylbutyryloxy)-4,7-dihydroxy-eudesm-11-en-8-one (IC75 = 47 mu M) and (3S*,4R*,5R*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2'-methylbutyryloxy)-4-acetyloxy-6-methoxy-11-hydroxy-eudesm-6-en-8-one (IC75 = 73 mu M) showed inhibitory activities. Furthermore, preliminary structure-activity relationships (SARs) of the eudesmanes were developed. (C) 2017 Elsevier Ltd. All rights reserved.

Inflammation is part of numerous pathological conditions, which are lacking satisfying treatment and effective concepts of prevention. A national research network project, DNTI, involving scientists from six Austrian universities as well as several external partners aimed to identify and characterize natural products capable of combating inflammatory processes specifically in the cardiovascular system. The combined use of computational techniques with traditional knowledge, high-tech chemical analysis and synthesis, and a broad range of in vitro, cell-based, and in vivo pharmacological models led to the identification of a series of promising anti-inflammatory drug lead candidates. Mechanistic studies contributed to a better understanding of their mechanism of action and delivered new knowledge on the molecular level of inflammatory processes. Herein, the used approaches and selected highlights of the results of this interdisciplinary project are presented.

An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this early step of metastatic progression.

BACKGROUND:The t(2;5)(p23;q35) chromosomal translocation results in the expression of the fusion protein NPM/ALK that when expressed in T-lymphocytes gives rise to anaplastic large cell lymphomas (ALCL). In search of new therapy options the dichloromethane extract of the ethnomedicinal plant Neurolaena lobata (L.) R.Br. ex Cass was shown to inhibit NPM/ALK expression.PURPOSE:Therefore, we analysed whether the active principles that were recently isolated and found to inhibit inflammatory responses specifically inhibit growth of NPM/ALK+ ALCL, leukaemia and breast cancer cells, but not of normal cells, and the intravasation through the lymphendothelial barrier.METHODS:ALCL, leukaemia and breast cancer cells, and normal peripheral blood mononuclear cells (PBMCs) were treated with isolated sesquiterpene lactones and analysed for cell cycle progression, proliferation, mitochondrial activity, apoptosis, protein and mRNA expression, NF-κB and cytochrome P450 activity, 12(S)-HETE production and lymphendothelial intravasation.RESULTS:In vitro treatment of ALCL by neurolenin B suppressed NPM/ALK, JunB and PDGF-Rβ expression, inhibited the growth of ALCL cells late in M phase, and induced apoptosis via caspase 3 without compromising mitochondrial activity (as a measure of general exogenic toxicity). Moreover, neurolenin B attenuated tumour spheroid intravasation probably through inhibition of NF-κB and CYP1A1.CONCLUSION:Neurolenin B specifically decreased pro-carcinogenic NPM/ALK expression in ALK+ ALCL cells and, via the inhibition of NF-kB signalling, attenuated tumour intra/extravasation into the lymphatics. Hence, neurolenin B may open new options to treat ALCL and to manage early metastatic processes to which no other therapies exist.

The major effects of arbuscular mycorrhizal fungi (AMF) colonization on plant growth, monoterpenoids and coumarins were determined in two genotypes of angelica (Angelica archangelica L., Apiaceae). Genetically uniform experimental plants were used, which was achieved by in vitro propagation of two genotypes (individual plants). The effects of Glomus mosseae (Funneliformis mosseae, BEG 12), Glomus intraradices (Rhizophagus intraradices, BB-E) and the AMF mixture Symbivit® were tested against a negative (without AMF and without additional phosphorus) and a positive (KH2PO4 without AMF) control in five plants per treatment. All in all 50 plants were investigated. Fifteen monoterpenoid and seven coumarin compounds were quantitatively determined in the rhizome and coarse root fractions by means of GC/MS using an internal standard. The sum of the monoterpenoids and coumarins was calculated. Concentrations of compounds rather slightly decreased upon inoculation with AMF when compared to the control. In contrast, biomass increased showing the highest amounts for plants treated with G. mosseae. These results finally caused a marked increase in yield for G. mosseae treated plants compared to the control. Phosphorus treatment led to the lowest yield with significant results for coumarins and in particular for osthole compared to G. mosseae treatment. This is also evidence of an independent effect from an increased phosphorus uptake due to root colonization by AMF. In summary, the results showed a marked increase in yield of all investigated compounds through treatment with G. mosseae compared to the control group, even if the level of significance was just barely missed presumably on account of the small sample size.

Pluchea odorata is ethno pharmaceutically used to treat inflammation-associated disorders. The dichloromethane extract (DME) was tested in the carrageenan-induced rat paw oedema assay investigating its effect on inflammation that was inhibited by 37%. Also an in vitro anti-neoplastic potential was reported. However, rather limited information about the bio-activity of purified compounds and their cellular mechanisms are available. Therefore, two of the most abundant eudesmanes in P. odorata were isolated and their anti-neoplastic and anti-intravasative activities were studied. HL-60 cells were treated with P. odorata compounds and metabolic activity, cell number reduction, cell cycle progression and apoptosis induction were correlated with relevant protein expression. Tumour cell intravasation through lymph endothelial monolayers was measured and potential causal mechanisms were analyzed by Western blotting. Compound PO-1 decreased the metabolic activity of HL-60 cells (IC50 = 8.9 μM after 72 h) and 10 μM PO-1 induced apoptosis, while PO-2 showed just weak anti-neoplastic activities at concentrations beyond 100 μM. PO-1 arrested the cell cycle in G1 and this correlated with induction of JunB expression. Independent of this mechanism 25 μM PO-1 decreased MCF-7 spheroid intravasation through the lymph endothelial barrier. Hence, PO-1 inhibits an early step of metastasis, impairs unrestricted proliferation and induces apoptosis at low micromolar concentrations. These results warrant further testing in vivo to challenge the potential of PO-1 as novel lead compound.

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

Pomace is an easy-accessible raw material for the isolation of fruit-derived compounds. Fruit consumption is associated with health-promoting effects, such as the prevention of cardiovascular disease. Increased vascular nitric oxide (NO) bioavailability, for example, due to an enhanced endothelial nitric oxide synthase (eNOS) activity, could be one molecular mechanism mediating this effect. To identify compounds from apple (Malus domestica Borkh.) pomace that have the potential to amplify NO bioavailability via eNOS activation, a bioassay-guided fractionation of the methanol/water (70:30) extract has been performed using the (14)C-L-arginine to (14)C-L-citrulline conversion assay (ACCA) in the human endothelium-derived cell line EA.hy926. Phytochemical characterization of the active fractions was performed using the spectrophotometric assessment of the total phenolic content, as well as TLC, HPLC-DAD-ELSD, and HPLC-MS analyses. Eleven triterpenoic acids, of which one is a newly discovered compound, were identified as the main constituents in the most active fraction, accompanied by only minor contents of phenolic compounds. When tested individually, none of the tested compounds exhibited significant eNOS activation. Nevertheless, cell stimulation with the reconstituted compound mixture restored eNOS activation, validating the potential of apple pomace as a source of bioactive components.

In 2007 the European Union has announced the "2020 directive" for the promotion of renewable energy resources and sustainable agricultural processes with a focus on biofuels. According to this directive in 2020 20% of energy is achieved by renewable resources, with agricultural processes being a large proportion. Poplar is an important energy crop in Europe. Growth and biomass are the primary parameters for studies in this system, with the aim to enhance the suitability of such commercial crops as renewable energy resources. The growth-promoting interaction of bacteria and the plant are of special interest. Colonization of endophytic bacteria in internal plant tissue can promote plant growth and stress resistance, and can enhance control of pathogens. In vitro grown explants of the poplar hybrid (female [Populus alba x (P. davidiana + P. simonii) x P. tomentosa]) free from culturable bacteria show significant differences in growth, root development and metabolic signature when compared to shoots inoculated with Paenibacillus sp. strain P22. We investigated the influence of this endophytic Paenibacillus isolate on the metabolism of poplar shoot explants, free from culturable endophytic bacteria, with gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS). Metabolite profiling of Paenibacillus-inoculated and non-inoculated poplar plants revealed a significant metabolic signature in the plant as a response to the presence of the bacteria.