Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

Random forest for spatialization of daily evapotranspiration (ET0) in watersheds in the Atlantic Forest.

The importance of daily data on reference evapotranspiration (ET0) has increased in recent years due to its relevance in planning and decision making regarding irrigated agriculture, water production, and forest restoration. Facing the scarcity of this information measured in loco, the study of interpolation methods capable of representing ET0 becomes important. Therefore, this study aimed to evaluate the adequacy of the Random Forest (RF) method in the spatialization of ET0 in the watersheds of the Mid-South region of the Espírito Santo State, located within the Atlantic Forest biome, Brazil. From this study, it was found that the RF method is the most suitable one for ET0 spatialization when compared to the Angular distance weighting (ADW) and the inverse distance weighting (IDW) techniques. Also, the spatializations carried out by this method were transformed into databases in a grid format and made available online. Furthermore, the RF database was also compared to other ET0 grid databases, and it was concluded that the RF database also carried out a better performance than the other ones.

Quinolizidine Alkaloids from Cylicomorpha solmsii.

Five new quinolizidine alkaloids were isolated from the leaves of Cylicomorpha solmstii (Urb.) Urb. (Caricaceae) and named cylicomorphins A-E (1-5). They all are ester derivatives of the same basic quinolizidine skeleton bearing hydroxy, methyl, and ethanoic acid substituents. Their structures were mainly established by NMR spectroscopy, and the absolute configuration is proposed on the basis of VCD data and Mosher ester derivatization. Compound 5 displayed cytotoxicity in the 10 µM range against an HCT-116 cell line.

Spectro-temporal analysis of the Paraopeba River water after the tailings dam burst of the Córrego do Feijão mine, in Brumadinho, Brazil.

Remote sensing is an important tool for environmental assessment, especially in the event of disasters such as the tailings dam burst at the Córrego do Feijão mine, located in the Paraopeba River basin, Brazil. Thus, this study aimed to carry out a spectro-temporal analysis of the Paraopeba River water given the dam burst, using multispectral images from the MSI sensor onboard Sentinel-2 satellites. For this analysis, sections along the river were defined by the creation of buffers, with 10-km intervals each, starting from the origin of the burst. For each section, the average visible to near-infrared (NIR) reflectance values per band and the Normalized Difference Water Index (NDWI) were obtained. We found that the red edge and NIR bands (B5, B6, B7, B8, and B8A) showed higher reflectance values when compared to the visible bands in the months immediately after the disaster, especially in the first 20 km. In these months, negative NDWI values were also found for almost all sections downstream, demonstrating the large volume of mining tailings in the Paraopeba River. The seasonal variation of the observed values indicates the resuspension of the material deposited at the river bottom with the beginning of the rainy season. Finally, we highlight the usefulness of the MSI/Sentinel-2 red edge and NIR bands for further studies on the monitoring from space of water bodies subjected to contamination by large amounts of mud with iron ore tailings and contaminants, as occurred in the state of Minas Gerais, southeastern Brazil.

Multivariate statistics for spatial and seasonal quality assessment of water in the Doce River basin, Southeastern Brazil.

This study employed multivariate statistical techniques in one of the main river basins in Brazil, the Doce River basin, to select and evaluate the most representative parameters of the current water quality aspects, and to group the stations according to the similarity of the selected parameters, for both dry and rainy seasons. Data from 63 qualitative monitoring stations, belonging to the Minas Gerais Water Management Institute network were used, considering 38 parameters for the hydrological year 2017/2018. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used to reduce the total number of variables and to group stations with similar characteristics, respectively. Using PCA, four principal components were selected as indicators of water quality, explaining the cumulative variance of 68% in the rainy season and 65% in the dry season. The HCA grouped the stations into four groups in the rainy season and three groups in the dry season, showing the influence of seasonality on the grouping of stations. Moreover, the HCA made it possible to differentiate water quality stations located in the headwaters of the basin, in the main river channel, and near urban centers. The results obtained through multivariate statistics proved to be important in understanding the current water quality situation in the basin and can be used to improve the management of water resources because the collection and analysis of all parameters in all monitoring stations require greater availability of financial resources.

Comparison of the Phytochemical Composition of Serenoa repens Extracts by a Multiplexed Metabolomic Approach.

Phytochemical extracts are highly complex chemical mixtures. In the context of an increasing demand for phytopharmaceuticals, assessment of the phytochemical equivalence of extraction procedures is of utmost importance. Compared to routine analytical methods, comprehensive metabolite profiling has pushed forward the concept of phytochemical equivalence. In this study, an untargeted metabolomic approach was used to cross-compare four marketed extracts from Serenoa repens obtained with three different extraction processes: ethanolic, hexanic and sCO2 (supercritical carbon dioxide). Our approach involved a biphasic extraction of native compounds followed by liquid chromatography coupled to a high-resolution mass spectrometry based metabolomic workflow. Our results showed significant differences in the contents of major and minor compounds according to the extraction solvent used. The analyses showed that ethanolic extracts were supplemented in phosphoglycerides and polyphenols, hexanic extracts had higher amounts of free fatty acids and minor compounds, and sCO2 samples contained more glycerides. The discriminant model in this study could predict the extraction solvent used in commercial samples and highlighted the specific biomarkers of each process. This metabolomic survey allowed the authors to assess the phytochemical content of extracts and finished products of S. repens and unequivocally established that sCO2, hexanic and ethanolic extracts are not chemically equivalent and are therefore unlikely to be pharmacologically equivalent.

Addition of non-invasive ventilatory support to combined aerobic and resistance training improves dyspnea and quality of life in heart failure patients: a randomized controlled trial.

OBJECTIVE: To test the hypothesis that combined aerobic and resistance training and non-invasive ventilatory support result in additional benefits compared with combined aerobic and resistance training alone in heart failure patients. DESIGN: A randomized, single-blind, controlled study. SETTING: Cardiac rehabilitation center. PARTICIPANTS: A total of 46 patients with New York Heart Association class II/III heart failure were randomly assigned to a 10-week program of combined aerobic and resistance training, plus non-invasive ventilatory support ( n = 23) or combined aerobic and resistance training alone ( n = 23). METHODS: Before and after intervention, results for the following were obtained: 6-minute walk test, forced vital capacity, forced expiratory volume at one second, maximal inspiratory muscle pressure, and maximal expiratory muscle pressure, with evaluation of dyspnea by the London Chest Activity of Daily Living scale, and quality of life with the Minnesota Living With Heart Failure questionnaire. RESULTS: Of the 46 included patients, 40 completed the protocol. The combined aerobic and resistance training plus non-invasive ventilatory support, as compared with combined aerobic and resistance training alone, resulted in significantly greater benefit for dyspnea (mean change: 4.8 vs. 1.3, p = 0.004), and quality of life (mean change: 19.3 vs. 6.8, p = 0.017 ). In both groups, the 6-minute walk test improved significantly (mean change: 45.7 vs. 44.1, p = 0.924), but without a statistically significant difference. CONCLUSION: Non-invasive ventilatory support combined with combined aerobic and resistance training provides additional benefits for dyspnea and quality of life in moderate heart failure patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02384798. Registered 03 April 2015.

Could the acid-base status of Antarctic sea urchins indicate a better-than-expected resilience to near-future ocean acidification?

Increasing atmospheric carbon dioxide concentration alters the chemistry of the oceans towards more acidic conditions. Polar oceans are particularly affected due to their low temperature, low carbonate content and mixing patterns, for instance upwellings. Calcifying organisms are expected to be highly impacted by the decrease in the oceans' pH and carbonate ions concentration. In particular, sea urchins, members of the phylum Echinodermata, are hypothesized to be at risk due to their high-magnesium calcite skeleton. However, tolerance to ocean acidification in metazoans is first linked to acid-base regulation capacities of the extracellular fluids. No information on this is available to date for Antarctic echinoderms and inference from temperate and tropical studies needs support. In this study, we investigated the acid-base status of 9 species of sea urchins (3 cidaroids, 2 regular euechinoids and 4 irregular echinoids). It appears that Antarctic regular euechinoids seem equipped with similar acid-base regulation systems as tropical and temperate regular euechinoids but could rely on more passive ion transfer systems, minimizing energy requirements. Cidaroids have an acid-base status similar to that of tropical cidaroids. Therefore Antarctic cidaroids will most probably not be affected by decreasing seawater pH, the pH drop linked to ocean acidification being negligible in comparison of the naturally low pH of the coelomic fluid. Irregular echinoids might not suffer from reduced seawater pH if acidosis of the coelomic fluid pH does not occur but more data on their acid-base regulation are needed. Combining these results with the resilience of Antarctic sea urchin larvae strongly suggests that these organisms might not be the expected victims of ocean acidification. However, data on the impact of other global stressors such as temperature and of the combination of the different stressors needs to be acquired to assess the sensitivity of these organisms to global change.

Comprehensive mass spectrometric metabolomic profiling of a chemically diverse collection of plants of the Celastraceae family.

Natural products exhibit interesting structural features and significant biological activities. The discovery of new bioactive molecules is a complex process that requires high-quality metabolite profiling data to properly target the isolation of compounds of interest and enable their complete structural characterization. The same metabolite profiling data can also be used to better understand chemotaxonomic links between species. This Data Descriptor details a dataset resulting from the untargeted liquid chromatography-mass spectrometry metabolite profiling of 76 natural extracts of the Celastraceae family. The spectral annotation results and related chemical and taxonomic metadata are shared, along with proposed examples of data reuse. This data can be further studied by researchers exploring the chemical diversity of natural products. This can serve as a reference sample set for deep metabolome investigation of this chemically rich plant family.

Integration of Wnt-inhibitory activity and structural novelty scoring results to uncover novel bioactive natural products: new Bicyclo[3.3.1]non-3-ene-2,9-diones from the leaves of Hymenocardia punctata.

In natural products (NPs) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1,600 NEs, previously analyzed by UHPLC-HRMS2 metabolite profiling was screened for Wnt pathway regulation. The results of the biological screening drove the selection of a subset of 30 non-toxic NEs with an inhibitory IC50 ≤ 5 µg/mL. To increase the chance of finding structurally novel bioactive NPs, Inventa, a computational tool for automated scoring of NEs based on structural novelty was used to mine the HRMS2 analysis and dereplication results. After this, four out of the 30 bioactive NEs were shortlisted by this approach. The most promising sample was the ethyl acetate extract of the leaves of Hymenocardia punctata (Phyllanthaceae). Further phytochemical investigations of this species resulted in the isolation of three known prenylated flavones (3, 5, 7) and ten novel bicyclo[3.3.1]non-3-ene-2,9-diones (1, 2, 4, 6, 8-13), named Hymenotamayonins. Assessment of the Wnt inhibitory activity of these compounds revealed that two prenylated flavones and three novel bicyclic compounds showed interesting activity without apparent cytotoxicity. This study highlights the potential of combining Inventa's structural novelty scores with biological screening results to effectively discover novel bioactive NPs in large NE collections.

A Sample-Centric and Knowledge-Driven Computational Framework for Natural Products Drug Discovery.

The ENPKG framework organizes large heterogeneous metabolomics data sets as a knowledge graph, offering exciting opportunities for drug discovery and chemodiversity characterization.

TICI: a taxon-independent community index for eDNA-based ecological health assessment.

Global biodiversity is declining at an ever-increasing rate. Yet effective policies to mitigate or reverse these declines require ecosystem condition data that are rarely available. Morphology-based bioassessment methods are difficult to scale, limited in scope, suffer prohibitive costs, require skilled taxonomists, and can be applied inconsistently between practitioners. Environmental DNA (eDNA) metabarcoding offers a powerful, reproducible and scalable solution that can survey across the tree-of-life with relatively low cost and minimal expertise for sample collection. However, there remains a need to condense the complex, multidimensional community information into simple, interpretable metrics of ecological health for environmental management purposes. We developed a riverine taxon-independent community index (TICI) that objectively assigns indicator values to amplicon sequence variants (ASVs), and significantly improves the statistical power and utility of eDNA-based bioassessments. The TICI model training step uses the Chessman iterative learning algorithm to assign health indicator scores to a large number of ASVs that are commonly encountered across a wide geographic range. New sites can then be evaluated for ecological health by averaging the indicator value of the ASVs present at the site. We trained a TICI model on an eDNA dataset from 53 well-studied riverine monitoring sites across New Zealand, each sampled with a high level of biological replication (n = 16). Eight short-amplicon metabarcoding assays were used to generate data from a broad taxonomic range, including bacteria, microeukaryotes, fungi, plants, and animals. Site-specific TICI scores were strongly correlated with historical stream condition scores from macroinvertebrate assessments (macroinvertebrate community index or MCI; R2 = 0.82), and TICI variation between sample replicates was minimal (CV = 0.013). Taken together, this demonstrates the potential for taxon-independent eDNA analysis to provide a reliable, robust and low-cost assessment of ecological health that is accessible to environmental managers, decision makers, and the wider community.

Archaeological evidence of an ethnographically documented Australian Aboriginal ritual dated to the last ice age.

In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of GunaiKurnai Aboriginal Elders, we undertook archaeological excavations at Cloggs Cave in the foothills of the Australian Alps. In GunaiKurnai Country, caves were not used as residential places during the early colonial period (mid-nineteenth century CE), but as secluded retreats for the performance of rituals by Aboriginal medicine men and women known as 'mulla-mullung', as documented by ethnographers. Here we report the discovery of buried 11,000- and 12,000-year-old miniature fireplaces with protruding trimmed wooden artefacts made of Casuarina wood smeared with animal or human fat, matching the configuration and contents of GunaiKurnai ritual installations described in nineteenth-century ethnography. These findings represent 500 generations of cultural transmission of an ethnographically documented ritual practice that dates back to the end of the last ice age and that contains Australia's oldest known wooden artefacts.

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.

Assessment, regionalization, and modeling rainfall erosivity over Brazil: Findings from a large national database.

In this study, we used a large national database to assess the rainfall erosivity (RE) patterns in time and space over the Brazilian territory. Thereby, RE and erosivity density (ED) values were obtained for 5166 rainfall gauges. Also, the concentration of the RE throughout the year and the RE's gravity center locations were analyzed. Finally, homogeneous regions regarding RE values were delimited and estimative regression models were established. The results show that Brazil's mean annual RE value is 5620 MJ mm ha-1 h-1 year-1, with considerable spatial variation over the country. The highest RE magnitudes were found for the north region, while the northeast region shows the lowest values. Regarding the RE's distribution throughout the year, in the southern region of Brazil, it is more equitable, while in some spots of the northeastern region, it is irregularly concentrated in specific months. Further analyses revealed that for most of the months, the RE's gravity centers for Brazil are in the Goiás State and that they present a north-south migration pattern throughout the year. Complementarily, the ED magnitudes allowed the identification of high-intensity rainfall spots. Additionally, the Brazilian territory was divided into eleven homogeneous regions regarding the RE patterns and for each defined region, a regression model was established and validated. These models' statistical metrics were considered satisfactory and, thus, can be used to estimate RE values for the whole country using monthly rainfall depths. Finally, all database produced are available for download. Therefore, the values and maps shown in this study are relevant for improving the accuracy of soil loss estimates in Brazil and for the establishment of soil and water conservation planning on a national scale.

Leaf metabolic traits reveal hidden dimensions of plant form and function.

The metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization-a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function.

Proteasome inhibitors from Neoboutonia melleri.

Thirty new cycloartane derivatives (1-3, 5-12, 14-32) have been isolated from the leaves of Neoboutonia melleri. Their novelty stems from the loss of one of the C-4 methyl groups (1-3, 5-12, 14-25, and 32) and from the presence of an "extra" carbon atom in the side chain (1-3, 5-12, 14-20, 26-29, and 30-32). Furthermore, compound 32 possesses a rare triterpene skeleton with the cyclopropane ring fused onto C-1 and C-10, instead of C-9 and C-10. The structures were determined by spectrometric means, chemical correlations, and X-ray crystallography of derivative 1c. The substitution pattern in ring A, with a cyclopropyl ring conjugated with an α,ß-unsaturated carbonyl moiety, confers to the molecule a particular reactivity, giving rise to a formal inversion of the stereochemistry of the cyclopropane ring under UV irradiation. These compounds showed an interesting level of activity on the proteasome pathway, thus motivating their evaluation as possible anticancer agents. The large number of isolated compounds permitted a structure-activity relationship analysis, which showed that the presence of the two enone functions was a requirement for the activity.

Quality assessment of commercial Magnoliae officinalis Cortex by ¹H-NMR-based metabolomics and HPLC methods.

INTRODUCTION: The quality control of Magnoliae officinalis Cortex, a commonly used traditional Chinese medicine, is currently based on the assay of the two active compounds, honokiol and magnolol, by TLC or HPLC. OBJECTIVE: To compare ¹H-NMR-based metabolomics with the HPLC method for controlling the quality of Magnoliae officinalis Cortex. To identify the metabolites contributing to the differences between the samples and to discriminate different medicinal parts and geographic origins of these samples by ¹H-NMR-based metabolomics. METHODOLOGY: ¹H-NMR and several multivariate analysis techniques were applied to analyse the extracts of 18 batches of Magnoliae officinalis Cortex commercial samples, and the contents of honokiol and magnolol in these samples were determined by HPLC. The correlation analysis between the data from ¹H-NMR and HPLC was performed with the mixOmics software based on an unsupervised method. RESULTS: Honokiol and magnolol were the main compounds responsible for the discrimination of samples from different batches, thus proving that the choice of these two compounds as markers for quality assessment by HPLC is relevant. The two sources of Magnoliae officinalis Cortex recorded in the Chinese Pharmacopoeia, Magnolia officinalis and Magnolia officinalis var. biloba, could be differentiated from ¹H-NMR data, but the pattern recognition analysis by PLS-DA was unsuccessful in discriminating samples from various geographical origins. CONCLUSION: The combination of ¹H-NMR that gives a comprehensive profile of the metabolites and HPLC that targets two biomarkers is an efficient means for a better quality control of Magnoliae officinalis Cortex.

Inventa: A computational tool to discover structural novelty in natural extracts libraries.

Collections of natural extracts hold potential for the discovery of novel natural products with original modes of action. The prioritization of extracts from collections remains challenging due to the lack of a workflow that combines multiple-source information to facilitate the data interpretation. Results from different analytical techniques and literature reports need to be organized, processed, and interpreted to enable optimal decision-making for extracts prioritization. Here, we introduce Inventa, a computational tool that highlights the structural novelty potential within extracts, considering untargeted mass spectrometry data, spectral annotation, and literature reports. Based on this information, Inventa calculates multiple scores that inform their structural potential. Thus, Inventa has the potential to accelerate new natural products discovery. Inventa was applied to a set of plants from the Celastraceae family as a proof of concept. The Pristimera indica (Willd.) A.C.Sm roots extract was highlighted as a promising source of potentially novel compounds. Its phytochemical investigation resulted in the isolation and de novo characterization of thirteen new dihydro-ß-agarofuran sesquiterpenes, five of them presenting a new 9-oxodihydro-ß-agarofuran base scaffold.