Publications by authors named "Jean-Luc Wolfender"

188 Publications

Feature-Based Molecular Networking-An Exciting Tool to Spot Species of the Genus with Hidden Photosensitizers.

Metabolites 2021 Nov 19;11(11). Epub 2021 Nov 19.

Institute of Pharmacy, Pharmacognosy, Center for Molecular Biosciences (CMBI), University of Innsbruck, CCB-Innrain 80/82, 6020 Innsbruck, Austria.

Fungi have developed a wide array of defense strategies to overcome mechanical injuries and pathogen infections. Recently, photoactivity has been discovered by showing that pigments isolated from produce singlet oxygen under irradiation. To test if this phenomenon is limited to dermocyboid Cortinarii, six colourful species belonging to different classical subgenera (i.e., , , , , and ) were investigated. Fungal extracts were explored by the combination of in vitro photobiological methods, UHPLC coupled to high-resolution tandem mass spectrometry (UHPLC-HRMS), feature-based molecular networking (FBMN), and metabolite dereplication techniques. The fungi   () and   () exhibited promising photobiological activity in a low concentration range (1-7 µg/mL). Using UHPLC-HRMS-based metabolomic tools, the underlying photoactive principle was investigated. Several monomeric and dimeric anthraquinones were annotated as compounds responsible for the photoactivity. Furthermore, the results showed that light-induced activity is not restricted to a single subgenus, but rather is a trait of species of different phylogenetic lineages and is linked to the presence of fungal anthraquinones. This study highlights the genus as a promising source for novel photopharmaceuticals. Additionally, we showed that putative dereplication of natural photosensitizers can be done by FBMN.
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http://dx.doi.org/10.3390/metabo11110791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619139PMC
November 2021

Combination of Pseudo-LC-NMR and HRMS/MS-Based Molecular Networking for the Rapid Identification of Antimicrobial Metabolites From .

Front Mol Biosci 2021 22;8:725691. Epub 2021 Oct 22.

School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

An endophytic fungal strain isolated from a seagrass endemic to the Mediterranean Sea () was studied in order to identify its antimicrobial constituents and further characterize the composition of its metabolome. It was identified as by in-depth phylogenetic analyses. The ethyl acetate extract of that strain exhibited antimicrobial activities and an ability to inhibit quorum sensing of . To perform this study with a few tens of mg of extract, an innovative one-step generic strategy was devised. On one side, the extract was analyzed by UHPLC-HRMS/MS molecular networking for dereplication. On the other side, semi-preparative HPLC using a similar gradient profile was used for a single-step high-resolution fractionation. All fractions were systematically profiled by H-NMR. The data were assembled into a 2D contour map, which we call "pseudo-LC-NMR," and combined with those of UHPLC-HRMS/MS. This further highlighted the connection within structurally related compounds, facilitated data interpretation, and provided an unbiased quantitative profiling of the main extract constituents. This innovative strategy led to an unambiguous characterization of all major specialized metabolites of that extract and to the localization of its bioactive compounds. Altogether, this approach identified 22 compounds, 13 of them being new natural products and six being inhibitors of the quorum sensing mechanism of and . Minor analogues were also identified by annotation propagation through the corresponding HRMS/MS molecular network, which enabled a consistent annotation of 27 additional metabolites. This approach was designed to be generic and applicable to natural extracts of the same polarity range.
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http://dx.doi.org/10.3389/fmolb.2021.725691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569130PMC
October 2021

Alkyl-Quinolones derivatives as potential biomarkers for Pseudomonas aeruginosa infection chronicity in Cystic Fibrosis.

Sci Rep 2021 Oct 20;11(1):20722. Epub 2021 Oct 20.

Université de Lyon, Lyon, France.

In Cystic Fibrosis (CF), a rapid and standardized definition of chronic infection would allow a better management of Pseudomonas aeruginosa (Pa) infections, as well as a quick grouping of patients during clinical trials allowing better comparisons between studies. With this purpose, we compared the metabolic profiles of 44 in vitro cultures of Pa strains isolated from CF patients at different stages of infection in order to identify metabolites differentially synthetized according to these clinical stages. Compounds produced and secreted by each strain in the supernatant of a liquid culture were analysed by metabolomic approaches (UHPLC-DAD-ESI/QTOF, UV and UPLC-Orbitrap, MS). Multivariate analyses showed that first colonization strains could be differentiated from chronic colonization ones, by producing notably more Alkyl-Quinolones (AQs) derivatives. Especially, five AQs were discriminant: HQC5, HQNOC7, HQNOC7:1, db-PQS C9 and HQNOC9:1. However, the production of HHQ was equivalent between strain types. The HHQ/HQNOC9:1 ratio was then found to be significantly different between chronic and primo-colonising strains by using both UV (p = 0.003) and HRMS data (p = 1.5 × 10). Our study suggests that some AQ derivatives can be used as biomarkers for an improved management of CF patients as well as a better definition of the clinical stages of Pa infection.
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http://dx.doi.org/10.1038/s41598-021-99467-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528811PMC
October 2021

Liquid-Liquid Chromatography Separation of Guaiane-Type Sesquiterpene Lactones from Regel & Schmalh. and Evaluation of Their In Vitro Cytotoxic and Melanin Inhibitory Potential.

Int J Mol Sci 2021 Oct 3;22(19). Epub 2021 Oct 3.

Independent Laboratory of Natural Products Chemistry, Medical University of Lublin, 20-093 Lublin, Poland.

Regel & Schmalh. is a perennial plant used in Kazakh traditional folk medicine to treat epilepsy, neurosis, rheumatism, gastroduodenal ulcers, dyspepsia, wounds, abscesses or tumors. The aim of this work was to isolate series of sesquiterpene lactones from a crude methanolic root extract and investigate their in vitro cytotoxic potential against androgen-dependent prostate cancer LNCaP and epithelial prostate PNT2 cells, as well as to evaluate their melanin production inhibitory effects in murine melanoma B16F10 cells stimulated with α-melanocyte-stimulating hormone (αMSH). Two new (penninervin P and penninervin Q) and five known (olgin, laferin, olgoferin, oferin and daucoguainolactone F) guaiane-type sesquiterpene lactones were isolated with the use of a simple and fast liquid-liquid chromatography method. Olgin and laferin showed the most promising cytotoxic effects in LNCaP cells (IC of 31.03 and 23.26 μg/mL, respectively). Additionally, olgin, laferin, olgoferin, and oferin (10 μg/mL) potently impaired melanin release (40.67-65.48% of αMSH + cells) without influencing the viability of B16F10 cells. In summary, our findings might indicate that guaiane-type sesquiterpene lactones from could be regarded as promising candidates for further research in discovering new therapeutic agents with anti-prostate cancer and skin depigmentation properties.
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http://dx.doi.org/10.3390/ijms221910717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509705PMC
October 2021

Characterization of Quorum Sensing Inhibitors from the Endophyte and Evaluation of Their Antivirulence Effects by Metabolomics.

Microorganisms 2021 Aug 25;9(9). Epub 2021 Aug 25.

School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.

The opportunistic pathogen is one of the "critical priority pathogens" due to its multidrug resistance to a wide range of antibiotics. Its ability to invade and damage host tissues is due to the use of quorum sensing (QS) to collectively produce a plethora of virulence factors. Inhibition of QS is an attractive strategy for new antimicrobial agents because it disrupts the initial events of infection without killing the pathogen. Highly diverse microorganisms as endophytes represent an under-explored source of bioactive natural products, offering opportunities for the discovery of novel QS inhibitors (QSI). In the present work, the objective was to explore selective QSIs within a unique collection of fungal endophytes isolated from the tropical palm . The fungi were cultured, extracted, and screened for their antibacterial and specific anti-QS activities against . The endophytic strain was prioritized for scaled-up fractionation for its selective activity, leading to the isolation of eight compounds in a single step. Among them, two pyran-derivatives were found to be responsible for the QSI activity, with an effect on some QS-regulated virulence factors. Additional non-targeted metabolomic studies on documented their effects on the production of various virulence-related metabolites.
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http://dx.doi.org/10.3390/microorganisms9091807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465504PMC
August 2021

Hypoglycemic active principles from the leaves of Bauhinia holophylla: Comprehensive phytochemical characterization and in vivo activity profile.

PLoS One 2021 24;16(9):e0258016. Epub 2021 Sep 24.

Faculty of Sciences, São Paulo State University (UNESP), Bauru, São Paulo, Brazil.

Bauhinia holophylla leaves, also known as "pata-de-vaca", are traditionally used in Brazil to treat diabetes. Although the hypoglycemic activity of this medicinal plant has already been described, the active compounds responsible for the hypoglycemic activity have not yet been identified. To rapidly obtain two fractions in large amounts compatible with further in vivo assay, the hydroalcoholic extract of B. holophylla leaves was fractionated by Vacuum Liquid Chromatography and then purified by medium pressure liquid chromatography combined with an in vivo Glucose Tolerance Test in diabetic mice. This approach resulted in the identification of eleven compounds (1-11), including an original non-cyanogenic cyanoglucoside derivative. The structures of the isolated compounds were elucidated by nuclear magnetic resonance and high-resolution mass spectrometry. One of the major compounds of the leaves, lithospermoside (3), exhibited strong hypoglycemic activity in diabetic mice at the doses of 10 and 20 mg/kg b.w. and prevents body weight loss. The proton nuclear magnetic resonance (1H NMR) quantification revealed that the hydroalcoholic leaves extract contained 1.7% of lithospermoside (3) and 3.1% of flavonoids. The NMR analysis also revealed the presence of a high amount of pinitol (4) (9.5%), a known compound possessing in vivo hypoglycemic activity. The hypoglycemic properties of the hydroalcoholic leaves extract and the traditional water infusion extracts of the leaves of B. holophylla seem thus to be the result of the activity of three unrelated classes of compounds. Such results support to some extent the traditional use of Bauhinia holophylla to treat diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462688PMC
November 2021

Kaempferol-3-O-α-(3,4-di-E-p-coumaroyl)-rhamnopyranoside from Nectandra oppositifolia releases Ca from intracellular pools of Trypanosoma cruzi affecting the bioenergetics system.

Chem Biol Interact 2021 Nov 16;349:109661. Epub 2021 Sep 16.

Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, SP, 09210-180, Brazil. Electronic address:

Phytochemical analysis of EtOH extract from leaves of Nectandra oppositifolia afforded three flavonoids: kaempferol (1), kaempferol-3-O-α-rhamnopyranoside (2) and kaempferol-3-O-α-(3,4-di-E-p-coumaroyl)-rhamnopyranoside (3), which were characterized by NMR and ESI-HRMS. When tested against the protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, flavonoids 1 and 3 were effective to kill the trypomastigotes with IC values of 32.0 and 6.7 μM, respectively, while flavonoid 2 was inactive. Isolated flavonoids 1-3 were also tested in mammalian fibroblasts and showed CC values of 24.8, 48.7 and 153.1 μM, respectively. Chemically, these results suggested that the free aglycone plays an important role in the bioactivity while the presence of p-coumaroyl unities linked in the rhamnoside unity is important to enhance the antitrypanosomal activity and reduce the mammalian cytotoxicity. The mechanism of cellular death was investigated for the most potent flavonoid 3 in the trypomastigotes using fluorescent and luminescent-based assays. It indicated that this compound induced neither permeabilization of the plasma membrane nor depolarization of the membrane electric potential. However, early time incubation (20 min) with flavonoid 3 resulted in a constant elevation of the Ca levels inside the parasite. This effect was followed by a mitochondrial imbalance, leading to a hyperpolarization and depolarization of the mitochondrial membrane potential, with reduction of the ATP levels. During this time, the levels of reactive oxygen species levels (ROS) were unaltered. The leakage of Ca from the intracellular pools can affect the bioenergetics system of T. cruzi, leading to the parasite death. Therefore, flavonoid 3 can be a useful tool for future studies against T. cruzi parasites.
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http://dx.doi.org/10.1016/j.cbi.2021.109661DOI Listing
November 2021

Isolation and Identification of Isocoumarin Derivatives With Specific Inhibitory Activity Against Wnt Pathway and Metabolome Characterization of .

Front Chem 2021 12;9:664489. Epub 2021 Aug 12.

School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland.

The Wnt signaling pathway controls multiple events during embryonic development of multicellular animals and is carcinogenic when aberrantly activated in adults. Breast cancers are dependent on Wnt pathway overactivation mostly through dysregulation of pathway component protein expression, which necessitates the search for therapeutically relevant compounds targeting them. Highly diverse microorganisms as endophytes represent an underexplored field in the therapeutic natural products research. In the present work, the objective was to explore the chemical diversity and presence of selective Wnt inhibitors within a unique collection of fungi isolated as foliar endophytes from the long-lived tropical palm . The fungi were cultured, extracted with ethyl acetate, and screened for their effects on the Wnt pathway and cell proliferation. The endophytic strain was prioritized for scaled-up fractionation based on its selective activity. Application of geometric transfer from analytical HPLC conditions to semi-preparative scale and use of dry load sample introduction enabled the isolation of 15 pure compounds in a single step. Among the molecules identified, five are original natural products described for the first time, and six are new to this species. An active fraction obtained by semi-preparative HPLC was re-purified by UHPLC-PDA using a 1.7 µm phenyl column. 75 injections of 8 µg were necessary to obtain sufficient amounts of each compound for structure elucidation and bioassays. Using this original approach, in addition to the two major compounds, a third minor compound identified as ()-(-)-5-hydroxymellein (18) was obtained, which was found to be responsible for the significant Wnt inhibition activity recorded. Further studies of this compound and its structural analogs showed that only 18 acts in a highly specific manner, with no acute cytotoxicity. This compound is notably selective for upstream components of the Wnt pathway and is able to inhibit the proliferation of three triple negative breast cancer cell lines. In addition to the discovery of Wnt inhibitors of interest, this study contributes to better characterize the biosynthetic potential of .
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http://dx.doi.org/10.3389/fchem.2021.664489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397479PMC
August 2021

Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma.

Cancers (Basel) 2021 Aug 6;13(16). Epub 2021 Aug 6.

School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.

Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.
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http://dx.doi.org/10.3390/cancers13163978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391235PMC
August 2021

Using Porcine Jejunum Ex Vivo to Study Absorption and Biotransformation of Natural Products in Plant Extracts: as a Case Study.

Metabolites 2021 Aug 14;11(8). Epub 2021 Aug 14.

School of Pharmaceutical Sciences, University of Geneva, Centre Médical Universitaire, Rue Michel-Servet 1, 1211 Geneva, Switzerland.

Herbal preparations (HPs) used in folk medicine are complex mixtures of natural products (NPs). Their efficacy in vivo after ingestion depends on the uptake of the active ingredient, and, in some cases, their metabolites, in the gastrointestinal tract. Thus, correlating bioactivities measured in vitro and efficacy in vivo is a challenge. An extract of rich in different types of isoflavones was used to evaluate the capacity of viable porcine small intestine ex vivo to elucidate the absorption of HP constituents, and, in some cases, their metabolites. The identification and transport of permeants across the jejunum was monitored by liquid chromatography-mass spectrometry (LC-MS), combining targeted and untargeted metabolite profiling approaches. It was observed that the C-glycoside isoflavones were stable and crossed the intestinal membrane, while various O-glycoside isoflavones were metabolized into their corresponding aglycones, which were then absorbed. These results are consistent with human data, highlighting the potential of using this approach. A thorough investigation of the impact of absorption and biotransformation was obtained without in vivo studies. The combination of qualitative untargeted and quantitative targeted LC-MS methods effectively monitored a large number of NPs and their metabolites, which is essential for research on HPs.
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http://dx.doi.org/10.3390/metabo11080541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398828PMC
August 2021

Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity.

Br J Pharmacol 2021 Dec 9;178(23):4708-4725. Epub 2021 Sep 9.

Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.

Background And Purpose: Individualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. To avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-burdensome tools for real-time phenotyping of CYP2D6 could significantly contribute to precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using an LC-high-resolution mass spectrometry-based metabolomic approach.

Experimental Approach: Plasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over 7 days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants.

Key Results: We report four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared with the control session (n = 37). Semi-quantitative analysis showed that the largest decrease (-85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Mean relative intensities of these ions were significantly higher in the CYP2D6 normal-ultrarapid metabolizer group (n = 37) compared with the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6-deficient individuals compared with other volunteers.

Conclusion And Implications: The applied untargeted metabolomic strategy identified potential novel markers capable of semi-quantitatively predicting CYP2D6 activity, a promising discovery for personalized medicine.
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http://dx.doi.org/10.1111/bph.15651DOI Listing
December 2021

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.

Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of -desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.
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http://dx.doi.org/10.3390/ijms22126467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235637PMC
June 2021

, a Treatment for Uncontrolled Hypertension. Pilot Comparative Intervention.

Plants (Basel) 2021 May 19;10(5). Epub 2021 May 19.

Antenna Foundation, Avenue de la Grenade 24, 1207 Geneva, Switzerland.

In Iraq, in 2019, there were about 1.4 million Internally Displaced Persons (IDP); medical treatments were often interrupted. The feasibility of using () decoction to curb hypertension was evaluated. A multicentric comparative pilot intervention for 121 participants with high blood pressure (BP) (≥140/90 mmHg) was conducted. Participants of the intervention group (with or without conventional medication) received decoction on a dose regimen starting from 10 grams per day. BP was measured five times over six weeks. The major active substances were chemically quantified. Results: After 6 weeks, 61.8% of participants from the intervention group ( = 76) reached the target BP < 140/90 mmHg, compared to 6.7% in the control group ( = 45). In the intervention group, a mean (±SD) reduction of 23.1 (±11.8) mmHg and 12.0 (±11.2) for systolic and diastolic BP, respectively, was observed, while in the control group the reduction was 4.4 (±10.2)/3.6 (±8.7). The chemical analysis of the starting dose indicated a content of 36 mg of total anthocyanins and 2.13 g of hibiscus acid. The study shows the feasibility of using HS decoction in IDP's problematic framework, as hibiscus is a safe, local, affordable, and culturally accepted food product.
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http://dx.doi.org/10.3390/plants10051018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160910PMC
May 2021

Constituents of (L.) Greene Leaves with Potent Antioxidant Capacity: A Feature-Based Molecular Network Dereplication Approach.

Pharmaceutics 2021 May 10;13(5). Epub 2021 May 10.

Laboratory of Liquid Chromatography (Labcrol), Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, Brazil.

(L.) Greene (Fabaceae/Caesalpiniaceae) is a herbaceous plant that is widely distributed throughout the Americas. Plants from this genus have been used in traditional medicine as a laxative, to heal wounds, and to treat ulcers, snake and scorpion bites. In the present study, we investigated the chemical composition of leaves through a mass spectrometry molecular network approach. The oxygen radical absorbance capacity (ORAC) for the ethanolic extract, enriched fractions and isolated compounds was assessed. Overall, thirty-five compounds were annotated for the first time in . Thirty-two of them were reported for the first time in the genus. The isolated compounds 9, 12, 24 and 33 showed an excellent antioxidant capacity, superior to the extract and enriched fractions. Bond dissociation energy calculations were performed to explain and sustain the antioxidant capacity found. According to our results, the leaves of represent a promising source of potent antioxidant compounds.
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http://dx.doi.org/10.3390/pharmaceutics13050681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150882PMC
May 2021

Feature-Based Molecular Network-Guided Dereplication of Natural Bioactive Products from Leaves of (Willd.) Hochr.

Metabolites 2021 Apr 29;11(5). Epub 2021 Apr 29.

Laboratory of Liquid Chromatography, Institute of Exact and Natural Sciences, Federal University of Pará, Belem 66075-110, Brazil.

is a species known to have a high content of tannins. Accordingly, its preparations are used in southern Pará, Brazil, for their anti-inflammatory and antimicrobial activities, but so far, its chemical profile composition remains essentially unknown. We herein describe the compounds present in a hydro-acetonic extract from leaves as revealed by dereplication via ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry. The data were combined with spectral organization, spectral matching through the Global Natural Products Social platform, in silico annotation and taxonomical ponderation. Several types of phenolic compounds were identified such as gallic acids, flavan-3-ols and flavone-like compounds. From these, 5 have been recently reported by our group, whereas 44 are reported here for the first time in this tree species, and 41 (out of 49) for this genus. The results highlight the possible role of as a renewable source for natural bioactive products with potential pharmaceutical applications.
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http://dx.doi.org/10.3390/metabo11050281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147077PMC
April 2021

Identification of Potential Antiseizure Agents in using Zebrafish and Mouse Epilepsy Models.

ACS Chem Neurosci 2021 05 29;12(10):1791-1801. Epub 2021 Apr 29.

School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva 4, Switzerland.

The resin of the tree Flueck. (synonym: ; Burseraceae), also known as "frankincense", is a traditional remedy used for central nervous system disorders in East Africa. Here we report the evaluation of its antiseizure activity in zebrafish and mouse epilepsy models to identify novel antiseizure compounds. The resin was extracted by solvents of increasing polarity. The hexane extract demonstrated the strongest antiseizure activity and was therefore subjected to bioactivity-guided isolation, which leaded to the isolation of eight terpene derivatives. A new prenylbicyclogermacrene derivative () was isolated along with seven other compounds (, -). Among them, the triterpene β-boswellic acid () showed the strongest activity and reduced 90% of pentylenetetrazole (PTZ)-induced seizures at 100 μg/mL. In parallel to , a commercial extract of was also evaluated and showed moderate bioactivity (45% reduction at 30 μg/mL). The extract of was subjected to targeted isolation of other boswellic acid derivatives (-), which were evaluated for antiseizure activity in comparison with . In the whole series, β-boswellic acid () was the most active (60% reduction at 200 μM), and its potency was also confirmed with its purchased standard (). Pure nanoparticles of and a commercially formulated extract of were tested in a PTZ-kindling mouse seizure model. This notably revealed that the administration reduced seizures by 50% in this mouse model, which was consistent with its detection and quantification in plasma and brain samples. This study and the preclinical evaluation performed indicate that β-boswellic acid, common to various species of , has some potential as an antiseizure agent.
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http://dx.doi.org/10.1021/acschemneuro.1c00044DOI Listing
May 2021

Coumarins from Simonk.: Isolation by Liquid-Liquid Chromatography and Potential Anxiolytic Activity Using an In Vivo Zebrafish Larvae Model.

Int J Mol Sci 2021 Feb 12;22(4). Epub 2021 Feb 12.

Independent Laboratory of Natural Products Chemistry, Medical University of Lublin, 20-093 Lublin, Poland.

Different types of anxiety disorders have become the number one mental health issue in developed countries. The search for new, safer and effective drug-like molecules among naturally derived substances faces two difficulties: an efficient method of isolation compounds with a high-purity and high-throughput animal model for activity assay. Thus, the aim of the present study was to isolate by liquid-liquid chromatography high-purity rare coumarins from the fruits of Simonk. and evaluate their anxiolytic effect (defined as reversed thimotaxis) using a 5-days post-fertilization (dpf) larvae model. Liquid-liquid chromatography enabled the isolation of one simple hydroxycoumarin (devenyol) and four pyranocoumarins (cis-khellactone, d-laserpitin, isolaserpitin and octanoyllomatin). The anxiolytic effect was defined as a decrease in the time spent in the boundaries of the living space (also described as reversed thigmotaxis). Our results show that all isolated courmarins exerted a significant influence on the anxiety behavior (anxiolytic activity) in the zebrafish larvae model. According to our knowledge, this is the first report of anxiolytic activity of pyranocoumarins and devenyol.
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http://dx.doi.org/10.3390/ijms22041829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918798PMC
February 2021

Metabolite profile of Nectandra oppositifolia Nees & Mart. and assessment of antitrypanosomal activity of bioactive compounds through efficiency analyses.

PLoS One 2021 25;16(2):e0247334. Epub 2021 Feb 25.

Center of Natural Sciences and Humanities, Federal University of ABC, Santo Andre, Sao Paulo, Brazil.

EtOH extracts from the leaves and twigs of Nectandra oppositifolia Nees & Mart. shown activity against amastigote forms of Trypanosoma cruzi. These extracts were subjected to successive liquid-liquid partitioning to afford bioactive CH2Cl2 fractions. UHPLC-TOF-HRMS/MS and molecular networking were used to obtain an overview of the phytochemical composition of these active fractions. Aiming to isolate the active compounds, both CH2Cl2 fractions were subjected to fractionation using medium pressure chromatography combined with semi-preparative HPLC-UV. Using this approach, twelve compounds (1-12) were isolated and identified by NMR and HRMS analysis. Several isolated compounds displayed activity against the amastigote forms of T. cruzi, especially ethyl protocatechuate (7) with EC50 value of 18.1 μM, similar to positive control benznidazole (18.7 μM). Considering the potential of compound 7, protocatechuic acid and its respective methyl (7a), n-propyl (7b), n-butyl (7c), n-pentyl (7d), and n-hexyl (7e) esters were tested. Regarding antitrypanosomal activity, protocatechuic acid and compound 7a were inactive, while 7b-7e exhibited EC50 values from 20.4 to 11.7 μM, without cytotoxicity to mammalian cells. These results suggest that lipophilicity and molecular complexity play an important role in the activity while efficiency analysis indicates that the natural compound 7 is a promising prototype for further modifications to obtain compounds effective against the intracellular forms of T. cruzi.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906415PMC
August 2021

Spatial and evolutionary predictability of phytochemical diversity.

Proc Natl Acad Sci U S A 2021 01;118(3)

Laboratory of Functional Ecology, Institute of Biology, University of Neuchâtel, CH-2000 Neuchâtel, Switzerland;

To cope with environmental challenges, plants produce a wide diversity of phytochemicals, which are also the source of numerous medicines. Despite decades of research in chemical ecology, we still lack an understanding of the organization of plant chemical diversity across species and ecosystems. To address this challenge, we hypothesized that molecular diversity is not only related to species diversity, but also constrained by trophic, climatic, and topographical factors. We screened the metabolome of 416 vascular plant species encompassing the entire alpine elevation range and four alpine bioclimatic regions in order to characterize their phytochemical diversity. We show that by coupling phylogenetic information, topographic, edaphic, and climatic variables, we predict phytochemical diversity, and its inherent composition, of plant communities throughout landscape. Spatial mapping of phytochemical diversity further revealed that plant assemblages found in low to midelevation habitats, with more alkaline soils, possessed greater phytochemical diversity, whereas alpine habitats possessed higher phytochemical endemism. Altogether, we present a general tool that can be used for predicting hotspots of phytochemical diversity in the landscape, independently of plant species taxonomic identity. Such an approach offers promising perspectives in both drug discovery programs and conservation efforts worldwide.
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http://dx.doi.org/10.1073/pnas.2013344118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826413PMC
January 2021

A Cytotoxic Porphyrin from North Pacific Brittle Star .

Mar Drugs 2020 Dec 29;19(1). Epub 2020 Dec 29.

Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland.

Triple-negative breast cancer (TNBC) represents the deadliest form of gynecological tumors currently lacking targeted therapies. The ethanol extract of the North Pacific brittle star presented promising anti-TNBC activities. After elimination of the inert material, the active extract was submitted to a bioguided isolation approach using high-resolution semipreparative HPLC-UV, resulting in one-step isolation of an unusual porphyrin derivative possessing strong cytotoxic activity. HRMS and 2D NMR resulted in the structure elucidation of the compound as (3,4)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid. Never identified before in Ophiuroidea, porphyrins have found broad applications as photosensitizers in the anticancer photodynamic therapy. The simple isolation of a cytotoxic porphyrin from an abundant brittle star species we describe here may pave the way for novel natural-based developments of targeted anti-cancer therapies.
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http://dx.doi.org/10.3390/md19010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824513PMC
December 2020

A Mass Spectrometry Based Metabolite Profiling Workflow for Selecting Abundant Specific Markers and Their Structurally Related Multi-Component Signatures in Traditional Chinese Medicine Multi-Herb Formulae.

Front Pharmacol 2020 3;11:578346. Epub 2020 Dec 3.

School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

In Traditional Chinese Medicine (TCM), herbal preparations often consist of a mixture of herbs. Their quality control is challenging because every single herb contains hundreds of components (secondary metabolites). A typical 10 herb TCM formula was selected to develop an innovative strategy for its comprehensive chemical characterization and to study the specific contribution of each herb to the formula in an exploratory manner. Metabolite profiling of the TCM formula and the extract of each single herb were acquired with liquid chromatography coupled to high-resolution mass spectrometry for qualitative analyses, and to evaporative light scattering detection (ELSD) for semi-quantitative evaluation. The acquired data were organized as a feature-based molecular network (FBMN) which provided a comprehensive view of all types of secondary metabolites and their occurrence in the formula and all single herbs. These features were annotated by combining MS/MS-based spectral match, manual evaluation of the structural consistency in the FBMN clusters, and taxonomy information. ELSD detection was used as a filter to select the most abundant features. At least one marker per herb was highlighted based on its specificity and abundance. A single large-scale fractionation from the enriched formula enabled the isolation and formal identification of most of them. The obtained markers allowed an improved annotation of associated features by manually propagating this information through the FBMN. These data were incorporated in the high-resolution metabolite profiling of the formula, which highlighted specific series of related components to each individual herb markers. These series of components, named multi-component signatures, may serve to improve the traceability of each herb in the formula. Altogether, the strategy provided highly informative compositional data of the TCM formula and detailed visualizations of the contribution of each herb by FBMN, filtered feature maps, and reconstituted chromatogram traces of all components linked to each specific marker. This comprehensive MS-based analytical workflow allowed a generic and unbiased selection of specific and abundant markers and the identification of multiple related sub-markers. This exploratory approach could serve as a starting point to develop more simple and targeted quality control methods with adapted marker specificity selection criteria to given TCM formula.
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http://dx.doi.org/10.3389/fphar.2020.578346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756971PMC
December 2020

Tackling Virulence by Mulinane-Like Diterpenoids from .

Biomolecules 2020 12 2;10(12). Epub 2020 Dec 2.

Laboratoire de Microbiologie Signaux et Microenvironnement, Normandie Université, Université de Rouen Normandie, LMSM EA4312, 27000 Évreux, France.

is an important multidrug-resistant human pathogen by dint of its high intrinsic, acquired, and adaptive resistance mechanisms, causing great concern for immune-compromised individuals and public health. Additionally, resilience lies in the production of a myriad of virulence factors, which are known to be tightly regulated by the quorum sensing (QS) system. Anti-virulence therapy has been adopted as an innovative alternative approach to circumvent bacterial antibiotic resistance. Since plants are known repositories of natural phytochemicals, herein, we explored the anti-virulence potential of , a medicinal plant from the Taira Atacama community (Calama, Chile), against . Interestingly, extract (E) conferred a significant protection for human lung cells and nematodes towards pathogenicity. The production of key virulence factors was decreased upon E exposure without affecting growth. In addition, E was able to decrease QS-molecules production. Furthermore, metabolite profiling of E and its derived fractions achieved by combination of a molecular network and in silico annotation allowed the putative identification of fourteen diterpenoids bearing a mulinane-like skeleton. Remarkably, this unique interesting group of diterpenoids seems to be responsible for the interference with virulence factors as well as on the perturbation of membrane homeostasis of . Hence, there was a significant increase in membrane stiffness, which appears to be modulated by the cell wall stress response ECFσ SigX, an extracytoplasmic function sigma factor involved in membrane homeostasis as well as virulence.
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http://dx.doi.org/10.3390/biom10121626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761567PMC
December 2020

Identification and dereplication of endophytic Colletotrichum strains by MALDI TOF mass spectrometry and molecular networking.

Sci Rep 2020 11 13;10(1):19788. Epub 2020 Nov 13.

Université Paris-Saclay, CNRS, Institut de Chimie Des Substances Naturelles, UPR 2301, Avenue de la Terrasse, 91198, Gif-sur-Yvette, France.

The chemical diversity of biologically active fungal strains from 42 Colletotrichum, isolated from leaves of the tropical palm species Astrocaryum sciophilum collected in pristine forests of French Guiana, was investigated. The collection was first classified based on protein fingerprints acquired by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) correlated with cytotoxicity. Liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS) data from ethyl acetate extracts were acquired and processed to generate a massive molecular network (MN) using the MetGem software. From five Colletotrichum strains producing cytotoxic specialized metabolites, we predicted the occurrence of peptide and cytochalasin analogues in four of them by MN, including a similar ion clusters in the MN algorithm provided by MetGem software. Chemoinformatics predictions were fully confirmed after isolation of three pentacyclopeptides (cyclo(Phe-Leu-Leu-Leu-Val), cyclo(Phe-Leu-Leu-Leu-Leu) and cyclo(Phe-Leu-Leu-Leu-Ile)) and two cytochalasins (cytochalasin C and cytochalasin D) exhibiting cytotoxicity at the micromolar concentration. Finally, the chemical study of the last active cytotoxic strain BSNB-0583 led to the isolation of four colletamides bearing an identical decadienamide chain.
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http://dx.doi.org/10.1038/s41598-020-74852-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666161PMC
November 2020

In Vitro Anti-Inflammatory Activity in Arthritic Synoviocytes of Root Extracts and Its Unusual Dimeric Flavonoids.

Molecules 2020 Nov 9;25(21). Epub 2020 Nov 9.

School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva-4, Switzerland.

is a plant commonly used for the treatment of kidney stones, arthritis and pain in traditional Brazilian medicine. Different in vitro and in vivo activities, ranging from antinociceptive to anti-, have been reported for the dichloromethane root extract of (DCMAB) and isolated compounds. This work aimed to assess the in vitro anti-inflammatory activity in arthritic synoviocytes of the DCMAB, the hydroethanolic extract (HEAB) and three dimeric flavonoids isolated from the DCMAB. These compounds, brachydin A (), B () and C (), were isolated both by medium pressure liquid and high-speed counter current chromatography. Their quantification was performed by mass spectrometry on both DCMAB and HEAB. IL-1β activated human fibroblast-like synoviocytes were incubated with both extracts and isolated compounds to determine the levels of pro-inflammatory cytokine IL-6 by enzyme-linked immunosorbent assay (ELISA). DCMAB inhibited 30% of IL-6 release at 25 µg/mL, when compared with controls while HEAB was inactive. IC values determined for and were 3-fold higher than . The DCMAB activity seems to be linked to higher proportions of compounds and in this extract. These observations could thus explain the traditional use of roots in the treatment of osteoarthritis.
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http://dx.doi.org/10.3390/molecules25215219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665123PMC
November 2020

Paecilosetin Derivatives as Potent Antimicrobial Agents from .

J Nat Prod 2020 10 6;83(10):2915-2922. Epub 2020 Oct 6.

Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198, Gif-sur-Yvette, France.

Fifty-seven entomopathogenic microorganisms were screened against human pathogens and subjected to mass spectrometry molecular networking based dereplication. BSNB-1250, shown to produce potentially novel biologically active metabolites, was grown on a large scale on potato dextrose agar, and paecilosetin () and five new analogues (-) were subsequently isolated. The structures of the new compounds were elucidated using 1D and 2D NMR. The absolute configurations of compounds - were determined using Mosher ester derivatives (, , ), comparison of experimental and calculated ECD spectra (- and ), and single-crystal X-ray diffraction analysis (). Compounds and exhibited strong antibacterial activity against MSSA and MRSA with MIC values of 1-2 μg/mL.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00444DOI Listing
October 2020

Phosphatidylcholines from eggs activate an immune response in Arabidopsis.

Elife 2020 09 28;9. Epub 2020 Sep 28.

Department of Plant Molecular Biology, University of Lausanne, Lausanne, Switzerland.

Recognition of conserved microbial molecules activates immune responses in plants, a process termed pattern-triggered immunity (PTI). Similarly, insect eggs trigger defenses that impede egg development or attract predators, but information on the nature of egg-associated elicitors is scarce. We performed an unbiased bioactivity-guided fractionation of eggs of the butterfly . Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry of active fractions led to the identification of phosphatidylcholines (PCs). PCs are released from insect eggs, and they induce salicylic acid and HO accumulation, defense gene expression and cell death in , all of which constitute a hallmark of PTI. Active PCs contain primarily C16 to C18-fatty acyl chains with various levels of desaturation, suggesting a relatively broad ligand specificity of cell-surface receptor(s). The finding of PCs as egg-associated molecular patterns (EAMPs) illustrates the acute ability of plants to detect conserved immunogenic patterns from their enemies, even from seemingly passive structures such as eggs.
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http://dx.doi.org/10.7554/eLife.60293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521926PMC
September 2020

Insights on the Structural and Metabolic Resistance of Potato () Cultivars to Tuber Black Dot ().

Front Plant Sci 2020 20;11:1287. Epub 2020 Aug 20.

School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.

Black dot is a blemish disease of potato tubers caused by the phytopathogenic fungus . Qualitative resistance (monogenic) that leads to the hypersensitive response has not been reported against black dot, but commercial potato cultivars show different susceptibility levels to the disease, indicating that quantitative resistance (polygenic) mechanisms against this pathogen exist. Cytological studies are essential to decipher pathogen colonization of the plant tissue, and untargeted metabolomics has been shown effective in highlighting resistance-related metabolites in quantitative resistance. In this study, we used five commercial potato cultivars with different susceptibility levels to black dot, and studied the structural and biochemical aspects that correlate with resistance to black dot using cytological and untargeted metabolomics methods. The cytological approach using semithin sections of potato tuber periderm revealed that colonizes the tuber periderm, but does not penetrate in cortical cells. Furthermore, skin thickness did not correlate with disease susceptibility, indicating that other factors influence quantitative resistance to black dot. Furthermore, suberin amounts did not correlate with black dot severity, and suberin composition was similar between the five potato cultivars studied. On the other hand, the untargeted metabolomics approach allowed highlighting biomarkers of infection, as well as constitutive and induced resistance-related metabolites. Hydroxycinnamic acids, hydroxycinnamic acid amides and steroidal saponins were found to be biomarkers of resistance under control conditions, while hydroxycoumarins were found to be specifically induced in the resistant cultivars. Notably, some of these biomarkers showed antifungal activity against . Altogether, our results show that quantitative resistance of potatoes to black dot involves structural and biochemical mechanisms, including the production of specialized metabolites with antifungal properties.
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http://dx.doi.org/10.3389/fpls.2020.01287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468465PMC
August 2020

Production of Highly Active Antiparasitic Compounds from the Controlled Halogenation of the Crude Plant Extract.

J Nat Prod 2020 09 9;83(9):2631-2640. Epub 2020 Sep 9.

School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland (ISPSW), University of Geneva, CMU, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.

Direct halogenation of phenolic compounds present in the CHCl extract of the roots of was investigated to enhance chemodiversity. The approach is based on eco-friendly reactions using NaBr, NaI, and NaCl in aqueous media to generate multiple "unnatural" halogenated natural products from crude extracts. The halogenation reactions, monitored by UHPLC-PDA-ELSD-MS, were optimized to generate mono-, di-, or trihalogenated derivatives. To isolate these compounds, the reactions were scaled up and the halogenated analogues were isolated by semipreparative HPLC-UV and fully characterized by NMR and HR-MS data. All of the original 16 halogenated derivatives were evaluated for their antiparasitic activities against the parasites and . Compounds presenting selective antiparasitic activities against one or both parasites with IC values comparable to the reference were identified.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00433DOI Listing
September 2020

Symphytum officinale L.: Liquid-liquid chromatography isolation of caffeic acid oligomers and evaluation of their influence on pro-inflammatory cytokine release in LPS-stimulated neutrophils.

J Ethnopharmacol 2020 Nov 31;262:113169. Epub 2020 Jul 31.

Department of Pharmacognosy, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115, Iasi, Romania; Biothermodynamics, TUM School of Life and Food Sciences Weihenstephan, Technical University of Munich, 85354, Freising, Germany. Electronic address:

Ethnopharmacological Relevance: Symphytum officinale L. (comfrey, Boraginaceae) has been traditionally used for millennia in joint distortions, myalgia, bone fractures and hematomas. However, key activity-determining constituents and molecular mechanisms underlying its use have not been completely elucidated.

Aim Of The Study: The objective of this study was to isolate and identify the major compounds from a hydroethanolic root extract of S. officinale and evaluate their antioxidant potential, alongside their effect on the cytokine production of ex vivo stimulated neutrophils, thus providing scientific support for the traditional use of comfrey root.

Material And Methods: Four caffeic acid oligomers were isolated from comfrey roots by liquid-liquid chromatography, their structures being established by MS and NMR analyses. In vitro antioxidant evaluation was performed by DPPH and ABTS assays. The cytotoxicity of isolated compounds was established by flow cytometry. The effect on cytokine release, such as interleukin (IL)-1β, IL-8 and tumor necrosis factor alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated neutrophils was determined by enzyme-linked immunosorbent assay (ELISA).

Results: The main constituents found in comfrey root were represented by four caffeic acid oligomers, namely globoidnan B (1), rabdosiin (2), rosmarinic acid (3) and globoidnan A (4). Rabdosiin, globoidnans A and B were isolated for the first time from S. officinale. In the in vitro antioxidant tests, compound 2 was the most active, with EC values in DPPH and ABTS assays of 29.14 ± 0.43 and 11.13 ± 0.39, respectively. Neutrophils' viability over the tested concentration domain of 12.5-50 μM was not altered. At 50 μM, all compounds significantly inhibited IL-1β release, with compound 3 (45.60% release vs. LPS stimulated neutrophils) being the most active, followed by compounds 1 (53.85%), 2 (69.89%) and 4 (60.68%).

Conclusions: The four caffeic acid oligomers reported in S. officinale root may contribute to the overall anti-inflammatory activity for which comfrey preparations are used in traditional medicine.
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http://dx.doi.org/10.1016/j.jep.2020.113169DOI Listing
November 2020

Generation of Stilbene Antimicrobials against Multiresistant Strains of through Biotransformation by the Enzymatic Secretome of .

J Nat Prod 2020 08 24;83(8):2347-2356. Epub 2020 Jul 24.

School of Pharmaceutical Sciences, University of Geneva, CMU, Rue Michel Servet 1, 1211 Geneva 4, Switzerland.

The biotransformation of a mixture of resveratrol and pterostilbene was performed by the protein secretome of Several reaction conditions were tested to overcome solubility issues and to improve enzymatic activity. Using MeOH as cosolvent, a series of unusual methoxylated compounds was generated. The reaction was scaled-up, and the resulting mixture purified by semipreparative HPLC-PDA-ELSD-MS. Using this approach, 15 analogues were isolated in one step. Upon full characterization by NMR and HRMS analyses, eight of the compounds were new. The antibacterial activities of the isolated compounds were evaluated in vitro against the opportunistic pathogens and . The selectivity index was calculated based on cytotoxic assays performed against human liver carcinoma cells (HepG2) and the human breast epithelial cell line (MCF10A). Some compounds revealed remarkable antibacterial activity against multidrug-resistant strains of with moderate human cell line cytotoxicity.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00071DOI Listing
August 2020
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