Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling.

Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc - that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.

Identification of Novel ß-Tubulin Inhibitors Using a Combined In Silico/In Vitro Approach.

Due to their potential as leads for various therapeutic applications, including as antimitotic and antiparasitic agents, the development of tubulin inhibitors offers promise for drug discovery. In this study, an in silico pharmacophore-based virtual screening approach targeting the colchicine binding site of ß-tubulin was employed. Several structure- and ligand-based models for known tubulin inhibitors were generated. Compound databases were virtually screened against the models, and prioritized hits from the SPECS compound library were tested in an in vitro tubulin polymerization inhibition assay for their experimental validation. Out of the 41 SPECS compounds tested, 11 were active tubulin polymerization inhibitors, leading to a prospective true positive hit rate of 26.8%. Two novel inhibitors displayed IC50 values in the range of colchicine. The most potent of which was a novel acetamide-bridged benzodiazepine/benzimidazole derivative with an IC50 = 2.9 µM. The screening workflow led to the identification of diverse inhibitors active at the tubulin colchicine binding site. Thus, the pharmacophore models show promise as valuable tools for the discovery of compounds and as potential leads for the development of cancer therapeutic agents.

Two-step isolation of the two major paraconic acids of Cetraria islandica.

The lichen Cetraria islandica is traditionally used as a demulcent for the symptomatic treatment of irritations of the mouth and throat and associated dry cough, as well as for the treatment of temporary loss of appetite. In addition to depsides and depsidones, thalli contain paraconic acids, a group of secondary metabolites commonly found in lichens and fungi. Among those, protolichesterinic acid has shown promising pharmacological activities. However, the efficient isolation of paraconic acids is quite complex due to their very similar chemical structures and their weak ultraviolet absorption. In the present work, a two-step isolation protocol of protolichesterinic acid and lichesterinic acid from a complex paraconic acid mixture is described using Sephadex LH20 column chromatography and fast centrifugal partition chromatography. Final purities higher than 95% and recoveries above 50% are achieved. Additionally, reliable qualitative techniques for detecting and differentiating paraconic acids are described. Finally, some data on compound stability and enantiomeric purity are shown.

Determination of Phytochemical Contents in Extracts from Different Growth Stages of Oroxylum indicum Fruits Using HPLC-DAD and QAMS Methods.

Flavones are major compounds found in several parts of Oroxylum indicum (O. indicum). The quantification of multiple components by one marker (QAMS) method and the high-performance liquid chromatography (HPLC) method were developed for the quantitative analysis of extracts from the young fruits, green mature fruits, dry pod coats and seeds of O. indicum. Oroxin A, oroxin B and chrysin-7-O-glucuronide were identified in the O. indicum extracts. Oroxylin A and 5-hydroxymethylfurfural were isolated and structurally identified from the pod coat and young fruit extracts, respectively. From the HPLC analysis of the seven major flavones in the extracts, baicalin was the major compound in all extracts investigated (0.4-11% w/w of the extract). All flavone contents were low in the young fruit extract (<1% w/w of the extract). The green mature fruit and dry pod coat extracts showed similar constituent compositions. They contained small amounts of baicalin and oroxylin A, which were found only in these two extracts. Oroxylin A could be used as a marker to indicate the maturity of O. indicum fruits, while 5-hydroxymethylfurfural could be used as a marker for the young fruits. Baicalin was found to be a suitable single marker to calculate the contents of all flavones in the O. indicum extracts.

Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells.

We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.

Quantification of Silymarin in Silybi mariani fructus: Challenging the Analytical Performance of Benchtop vs. Handheld NIR Spectrometers on Whole Seeds.

The content of the flavonolignan mixture silymarin and its individual components (silichristin, silidianin, silibinin A, silibinin B, isosilibinin A, and isosilibinin B) in whole and milled milk thistle seeds (Silybi mariani fructus) was analyzed with near-infrared spectroscopy. The analytical performance of one benchtop and two handheld near-infrared spectrometers was compared. Reference analysis was performed with HPLC following a Soxhlet extraction (European Pharmacopoeia) and a more resource-efficient ultrasonic extraction. The reliability of near-infrared spectral analysis determined through partial least squares regression models constructed independently for the spectral datasets obtained by the three spectrometers was as follows. The benchtop device NIRFlex N-500 performed the best both for milled and whole seeds with a root mean square error of CV between 0.01 and 0.17%. The handheld spectrometer MicroNIR 2200 as well as the microPHAZIR provided a similar performance (root mean square error of CV between 0.01 and 0.18% and between 0.01 and 0.23%, respectively). We carried out quantum chemical simulation of near-infrared spectra of silichristin, silidianin, silibinin, and isosilibinin for interpretation of the results of spectral analysis. This provided understanding of the absorption regions meaningful for the calibration. Further, it helped to better separate how the chemical and physical properties of the samples affect the analysis. While the study demonstrated that milling of samples slightly improves the performance, it was deemed to be critical only for the analysis carried out with the microPHAZIR. This study evidenced that rapid and nondestructive quantification of silymarin and individual flavonolignans is possible with miniaturized near-infrared spectroscopy in whole milk thistle seeds.

Design and Validation of a Sensitive Multisteroid LC-MS/MS Assay for the Routine Clinical Use: One-Step Sample Preparation with Phospholipid Removal and Comparison to Immunoassays.

Steroid analysis in clinical laboratories is dominated by immunoassays (IAs) that have a high sample turnover but are inherently limited in trueness, precision, and sensitivity. Liquid chromatography coupled to mass spectrometry (LC-MS/MS) has proved to be a far more capable tool, delivering better sensitivity, specificity, and the possibility of parallel analysis of multiple steroids and metabolites, providing the endocrinologist with more reliable and comprehensive diagnostic information. An LC-MS/MS assay with gradient elution over less than eight minutes and a one-step sample preparation combining protein precipitation with phospholipid removal of off-line solid-phase extraction was developed and validated. It allowed the quantification of 11-deoxycorticosterone (11-DOC), 11-deoxycortisol (11-DF), 17-OH-progesterone (17P), 21-deoxycortisol (21-DF), androstenedione (ANDRO), aldosterone (ALDO), corticosterone (CC), cortisol (CL), cortisone (CN), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), estradiol (E2), progesterone (PROG), and testosterone (TES) in human serum. Interday imprecision was generally better than 15%, trueness was proven by recovery experiments with ISO 17034-certified reference materials, proficiency testing (UK NEQAS), and measuring serum reference standards. In-house comparison against IVD-CE-certified immunoassays (IA) for 17P, ANDRO, CL, DHEAS, E2, PROG, and TES was conducted by assessing leftover routine patient samples and purpose-built patient serum pools. None of the compared routine IAs were meeting the standards of the LC-MS/MS. Insufficient overall comparability was found for ANDRO and 17P (mean bias > +65%). Accuracy limitations at lower concentrations were present in IAs for PROG, E2, and TES.

Bioassay-Guided Isolation of Anti-Inflammatory Constituents of the Subaerial Parts of Cyperus articulatus (Cyperaceae).

Based on data from a previous ethnobotanical study in northern Angola, phytochemical investigations into the methanolic rhizomes and roots extract of Cyperus articulatus, monitored by in vitro assays, resulted in the recovery of 12 sesquiterpenes, 3 stilbenes, 2 phenolic acids, 1 monoterpene, and 1 flavonoid. Among them, 14 compounds were isolated for the first time from this species. Their inhibitory potential against nitric oxide (NO) production, as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, was evaluated in LPS-treated J774A.1 murine macrophages. Especially, both stilbene dimer trans-scirpusin B and trimer cyperusphenol B showed promising inhibitory activity against the production of the inflammatory mediator, NO, in a concentration-dependent manner (10−1 µM). The obtained data are the first results confirming the anti-inflammatory potential of C. articulatus and support its indigenous use as a traditional remedy against inflammation-related disorders.

Plumericin prevents intestinal inflammation and oxidative stress in vitro and in vivo.

Inflammatory bowel diseases (IBDs) are characterized by an inflammatory and oxidative stress condition in the intestinal tissue. In this study, we evaluated the effect of plumericin, one of the main bioactive components of Himatanthus sucuuba (Woodson) bark, on intestinal inflammation and oxidative stress, both in vitro and in vivo. The effect of plumericin (0.5-2 µM) in vitro was evaluated in rat intestinal epithelial cells (IEC-6) treated with lipopolysaccharides from E. coli (10 µg/mL) plus interferon-γ (10 U/mL). Moreover, a 2,4,6-dinitrobenzene sulfonic acid (DNBS)-induced colitis model was used to evaluate the anti-inflammatory and antioxidant activity of plumericin (3 mg/kg) in vivo. The results showed that plumericin significantly reduces intestinal inflammatory factors such as tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase expression, and nitrotyrosine formation. Plumericin also inhibited nuclear factor-κB translocation, reactive oxygen species (ROS) release, and inflammasome activation. Moreover, plumericin activated the nuclear factor erythroid-derived 2 pathway in IEC-6. Using the DNBS-induced colitis model, a significant reduction in the weight loss and in the development of the macroscopic and histologic signs of colon injury, together with a reduced inflammatory and oxidative stress state, were observed in plumericin-treated mice. These results indicate that plumericin exerts a strong anti-inflammatory and antioxidant activity. Thus, it might be a candidate for the development of a new pharmacologic approach for IBDs treatment.

Effect of Non-Volatile Constituents of Elsholtzia ciliata (Thunb.) Hyl. from Southern Vietnam on Reactive Oxygen Species and Nitric Oxide Release in Macrophages.

The extract of Elsholtzia ciliata aerial parts was subjected to bio-guided isolation using the intercellular ROS reduction in J774A.1 macrophages to monitor the anti-oxidative activity. Fifteen compounds were isolated from the active fractions including eleven flavonoids (vitexin, pedalin, luteolin-7-O-ß-d-glucopyranoside, apigenin-5-O-ß-d-glucopyranoside, apigenin-7-O-ß-d-glucopyranoside, chrysoeriol-7-O-ß-d-glucopyranoside, 7,3'-dimethoxyluteolin-6-O-ß-d-glucopyranoside, luteolin, 5,6,4'-trihydroxy-7,3'-dimethoxyflavone, 5-hydroxy-6,7-dimethoxyflavone (compound 13), 5-hydroxy-7,8-dimethoxyflavone); three hydroxycinnamic acid derivatives (caffeic acid, 4-(E)-caffeoyl-l-threonic acid, 4-O-(E)-p-coumaroyl-l-threonic acid) and one fatty acid (α-linolenic acid). The biological evaluation of these compounds (10-2.5 µm) indicated that all of them exerted good antioxidant and anti-inflammatory activities, in particular compound 13.

A Comprehensive Review on Chemotaxonomic and Phytochemical Aspects of Homoisoflavonoids, as Rare Flavonoid Derivatives.

Homoisoflavonoids (3-benzylidene-4-chromanones) are considered as an infrequent flavonoid class, possessing multi-beneficial bioactivities. The present study gives an overview on phytochemical aspects of homoisoflavonoids, including utilized plant species, parts, extracts, and separation techniques. Overall, these compounds have mainly been isolated and identified from bulbs and rhizomes of the plants belonging to Asparagaceae and Fabaceae families, particularly the genera of Ophiopogon, Dracaena, Scilla, Polygonatum, and Caesalpinia.

Anti-Cancer Activity and Phenolic Content of Extracts Derived from Cypriot Carob (Ceratonia siliqua L.) Pods Using Different Solvents.

Extracts derived from the Ceratonia siliqua L. (carob) tree have been widely studied for their ability to prevent many diseases mainly due to the presence of polyphenolic compounds. In this study, we explored, for the first time, the anti-cancer properties of Cypriot carobs. We produced extracts from ripe and unripe whole carobs, pulp and seeds using solvents with different polarities. We measured the ability of the extracts to inhibit proliferation and induce apoptosis in cancer and normal immortalized breast cells, using the MTT assay, cell cycle analysis and Western Blotting. The extracts' total polyphenol content and anti-oxidant action was evaluated using the Folin-Ciocalteu method and the DPPH assay. Finally, we used LC-MS analysis to identify and quantify polyphenols in the most effective extracts. Our results demonstrate that the anti-proliferative capacity of carob extracts varied with the stage of carob maturity and the extraction solvent. The Diethyl-ether and Ethyl acetate extracts derived from the ripe whole fruit had high Myricetin content and also displayed specific activity against cancer cells. Their mechanism of action involved caspase-dependent and independent apoptosis. Our results indicate that extracts from Cypriot carobs may have potential uses in the development of nutritional supplements and pharmaceuticals.

Comprehensive polyphenolic profiling in promising resistant grapevine hybrids including 17 novel breeds in northern Italy.

BACKGROUND: A promising way to overcome the susceptibility of Vitis vinifera L. to fungal diseases is the integration of genetic resistance by the interspecific crossing between V. vinifera varieties and resistant species. However, the products of such hybrids are still not accepted by customers, particularly due to their organoleptic characteristics, not least influenced by their polyphenolic profile. RESULTS: A total of 58 resistant breeding lines, 41 from international programs and 17 new progeny individuals, were grown in one untreated vineyard to exclude any variances by climatic and pedologic conditions or vineyard practice. A total of 60 polyphenols (including acids, anthocyanins, flavonols, flavan-3-ols, and stilbenoids) were determined in grapevine berries by ultrahigh-performance liquid chromatography-mass spectrometry in two consecutive years. The overall profiles were rather consistent (variation P > 0.05) within the two harvests, with the exceptions of epicatechin and caftaric acid. Anthocyanin diglucosides were found in ten of the red breeding lines, malvidin-3,5-O-diglucoside being predominant in nine of them. Total polyphenol content of the unknown progeny individuals and international breeding lines was comparable, with the exception of significantly increased amounts of gallic acid and some flavonoids. CONCLUSION: The comprehensive study reported herein of the polyphenolic profile of hybrids from international breeding programs, but also of new breeds from private initiatives, all cultivated in the same vineyard, will support the selection of promising candidates for further breeding programs to overcome impairment due to undesired sensory characteristics of new highly resistant varieties.

Antiausterity Activity of Secondary Metabolites from the Roots of Ferula hezarlalehzarica against the PANC-1 Human Pancreatic Cancer Cell Line.

Human pancreatic cancer is one of the most aggressive types of cancer, with a high mortality rate. Due to the high tolerance of such cancer cells to nutrient starvation conditions, they can survive in a hypovascular tumor microenvironment. In this study, the dichloromethane extract of the roots of Ferula hezarlalehzarica showed potent preferential cytotoxic activity with a PC50 value of 0.78 µg/mL. Phytochemical investigation of this extract led to the isolation of 18 compounds, including one new sesquiterpenoid (6) and one new monoterpenoid (18). All isolated compounds were evaluated for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells by employing an antiausterity strategy. Among them, ferutinin (2) was identified as the most active compound, with a PC50 value of 0.72 µM. In addition, the real-time effect of ferutinin (2) and compound 6 against PANC-1 cells, exposed to a nutrient-deprived medium (NDM), showed cell shrinkage, leading to cancer cell death within a short period of exposure. Compounds 2 and 6 also inhibited colony formation of PANC-1 cells. The present study indicates that the dichloromethane extract of the roots of F. hezarlalehzarica is a rich source of bioactive compounds for targeting PANC-1 cells.

Labdane-Type Diterpenes from the Aerial Parts of Rydingia persica: Their Absolute Configurations and Protective Effects on LPS-Induced Inflammation in Keratinocytes.

Phytochemical investigations of an extract of the aerial parts of Rydingia persica led to the isolation of 14 labdane-type diterpenoids, of which compounds 1-5, 8, and 12-14 turned out to be new natural products, while the remaining compounds were isolated for the first time from the genus Rydingia. Their structures were elucidated using 1D- and 2D-NMR and mass spectrometry, and their absolute configurations were determined by quantum chemical calculation methods. Furthermore, DP4+ NMR chemical shift probability calculations were performed for compounds 12-14, in order to elucidate the orientation of the ambiguous chiral center at C-15, prior to absolute configuration determination. The methanol extract of the aerial parts of R. persica along with subfractions obtained and selected isolated compounds were evaluated for their effects on inflammation-related factors such as nitrotyrosine formation, IL-6 release, and TNF-α release, along with tight-junction proteins claudin-1 and occludin expression in LPS-stimulated HaCaT cells. Occludin and claudin-1 are tight-junction proteins, which play a pivotal role in wound repair mechanisms. Overall, the subfractions and compounds isolated showed moderate to high activity, indicating that labdane-type diterpenoids contribute to the anti-inflammatory and wound-healing activity of R. persica.

Purification of thonningianins A and B and four further derivatives from Thonningia sanguinea by one- and two-dimensional centrifugal partition chromatography.

Thonningia sanguinea is a parasitic herb widely used in traditional African medicine. Dihydrochalcone glucosides (unsubstituted, substituted with hexahydroxydiphenoyl or galloyl moieties) are the main constituents in the subaerial parts of this plant. In the present study, purification of the six major compounds from a methanol extract of the plant's subaerial parts was achieved by centrifugal partition chromatography. A first dimension centrifugal partition chromatography separation with the solvent system methyl tert-butyl ether/1,2-dimethoxyethane/water (1:2:1) in the ascending mode enabled the isolation of the two major bioactive compounds thonningianin A and B from 350 mg of methanol extract within only 16 min with respectable yields (25.7 and 21.1 mg), purities (87.1 and 85%), and recoveries (71.2 and 70.4%). Using a multiple heart-cutting strategy, the remaining four major dihydrochalcone glucosides of the extract were further separated in a second dimension centrifugal partition chromatography with the solvent system ethyl acetate/1,2-dimethoxyethane/water (2:1:1) in the descending mode with high purities (88.9-98.8%).

Towards eco-friendly secondary plant metabolite quantitation: Ultra high performance supercritical fluid chromatography applied to common vervain (Verbena officinalis L.).

This report presents the first ultra high performance supercritical fluid chromatography diode array detector based assay for simultaneous determination of iridoid glucosides, flavonoid glucuronides, and phenylpropanoid glycosides in Verbena officinalis (Verbenaceae) extracts. Separation of the key metabolites was achieved in less than 7 min on an Acquity UPC2 Torus Diol column using a mobile phase gradient comprising subcritical carbon dioxide and methanol with 0.15% phosphoric acid. Method validation for seven selected marker compounds (hastatoside, verbenalin, apigenin-7-O-glucuronide, luteolin-7-O-glucuronide, apigenin-7-O-diglucuronide, verbascoside, and luteolin-7-O-diglucuronide) confirmed the assay to be sensitive, linear, precise, and accurate. Head-to-head comparison to an ultra high performance liquid chromatography comparator assay did prove the high orthogonality of the methods. Quantitative result equivalence was evaluated by Passing-Bablok-correlation and Bland-Altman-plot analysis. This cross-validation revealed, that one of the investigated marker compound peaks was contaminated in the ultra high performance liquid chromatography assay by a structurally related congener. Taken together, it was proven that the ultra high performance supercritical fluid chromatography instrument setup with its orthogonal selectivity is a true alternative to conventional reversed phase liquid chromatography in quantitative secondary metabolite analysis. For regulatory purposes, assay cross-validation with highly orthogonal methods seems a viable approach to avoid analyte overestimation due to coeluting, analytically indistinguishable contaminants.

Differentiation between Cistus L. (Sub-) Species (Cistaceae) Using NMR Metabolic Fingerprinting.

The genus Cistus is taxonomically complex, as taxonomic classification of individual species based on morphological criteria is often difficult and ambiguous. However, specific species contain valuable natural products, especially terpenoids and polyphenols, which exert various biological effects and might therefore be used for treatment of a broad array of disorders. Hence, a fast and reliable method for clear identification of different Cistus (sub-) species is required. Approaches for analysis of secondary metabolite profiles, e.g., with NMR, might remedy the challenging classification of Cistus (sub-) species and help to identify specific markers for differentiation between them. In the present study, 678 samples from wild-growing Cistus populations, including 7 species and 6 subspecies/varieties thereof, were collected in 3 years from populations in 11 countries all over the Mediterranean basin. Samples were extracted with buffered aqueous methanol and analysed with NMR. From the resulting 1D-1H-NOESY and J-Res profile spectra, marker signals or spectral regions for the individual (sub-) species were identified with multivariate statistical tools. By examining the NMR profiles of these extracts, we were able to identify discriminators and specific markers for the investigated Cistus (sub-) species. Various influencing factors, like (sub-) species, wild harvestings of different populations from several countries, numerous collection sites, different years, and cultivation in greenhouses have been considered in this work. As the here identified markers are independent from these influencing factors, the results can be considered a robust model and might be used for future differentiation between Cistus (sub-) species.

A New Diterpene and Anti-inflammatory Sesquiterpene Lactones from Sigesbeckia orientalis.

Sigesbeckia orientalis, more commonly referred to as Herba Sigesbeckiae or Xi Xian Cao in traditional Chinese medicine and hy thiêm in traditional Vietnamese medicine, is used in China and Vietnam to treat inflammatory diseases such as arthritis, rheumatism, and joint pain. In initial investigations, the dichloromethane extract from the aerial parts of S. orientalis showed distinct inhibitory effects on the release of interleukin-8 in human neutrophils. Therefore, the purpose of the present study was the phytochemical investigation of the bioactive dichloromethane extract and the in vitro analysis of the effects of the isolated compounds on interleukin-8, interleukin-1ß, tumor necrosis factor-α, and monocyte chemoattractant protein 1 release, and surface expression of adhesion molecules (CD11a, CD11b, and CD62L) in lipopolysaccharide-stimulated human neutrophils to identify the active principle(s). The separation of the bioactive dichloromethane extract using various chromatographic techniques led to the isolation of nine compounds. Their chemical structures were elucidated from nuclear magnetic resonance and mass spectrometry data. One diterpene, 17(13 → 14)-abeo-ent-3S*,13S*,16-trihydroxystrob-8(15)-ene, was identified as a new natural product. Three germacranolide sesquiterpene lactones inhibited interleukin-8 production with IC50 values between 1.6 and 6.3 µM, respectively, and tumor necrosis factor-α production with IC50 values between 0.9 and 3.3 µM, respectively. Furthermore, they significantly inhibited interleukin-1ß and monocyte chemoattractant protein 1 production and diminished the effects of lipopolysaccharide on the surface expression of the adhesion molecules CD11a, CD11b, and CD62L. These findings support the traditional use of S. orientalis in the treatment of inflammatory diseases.

Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction.

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature's treasures, however, could be used more effectively. Yet, reliable pipelines for the large-scale target prediction of natural products are still rare. We developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs)-a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17ß-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target predictions and guidance on using the respective tools.