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Abstract The cytotoxic effects of hyperatomarin-a prenylated phloroglucinol isolated from Hypericum annulatum Moris subsp. annulatum were assessed in a broad spectrum of tumor cell lines originating from leukemias, lymphomas and [...]

The aim of the study was to provide an in-depth characterization of the methanol-aqueous extract from the aerial parts of Gypsophila glomerata Pall. Ex Adams (Caryophyllaceae) (EGG) and to assess its protective potential on carbon tetrachloride (CCl4)-induced liver and kidney damage in male Wistar rats. Twenty-two flavonoid C-, O- and C,O--glycosides in EGG were annotated by mass spectrometry--based molecular networking; nine of them are reported in this species for the first time. Fourteen-day oral administration of EGG at a dose 200 mg kg−1 bm prevented significantly CCl4-induced liver injury, discerned by an amelioration of the markers of oxidative stress (GSH and MDA) and transaminase activity. EGG decreased the serum level of urea and creatinine as well. The observed improvement of biochemical parameters was supported by histopathological observations. The protective hepatorenal effects of EGG, rich in 2“-О-pentosyl-6-С-hexosyl-apigenin/luteolin/ methylluteolin and their acetyl- and methoxycinnamoyl-derivatives, were comparable with the effects of the positive control silymarin.

The content of the benzophenones, hypericophenonoside, neoannulatophenonoside, annulatophenonoside, annulat-ophenone, acetylannulatophenonoside and the xanthone derivative gentisein have been determined in aerial parts, leaves, flowers and stems of Hypericum annulatum Moris. Extraction of samples with methanol by magnetic stirring at room temperature allowed a good recovery of analytes (from 90.70% for gentisein to 103.81% for annulatophenonoside) and the precision of the entire procedure was <6.05%. The subsequent HPLC separation and quantification was achieved using a Hypersil ODS C18 column and UV detection at 290 nm. The mobile phase comprised methanol and 20 mm potassium dihydrogen phosphate (adjusted to a pH of 3.19 with o-phosphoric acid), and gradient elution mode was applied. The detection limits were 0.03, 0.02 and 0.001 µg/mL for hypericophenonoside, acetylannulatophenonoside and gentisein, respectively. The total amounts of the phenolic compounds assayed ranged from 10.92 mg/g in stems to 82.86 mg/g in leaves. Hypericophenonoside was the dominant benzophenone present in the majority of the plant samples, being present in amounts between 7.54 ± 0.25 mg/g in stems and 64.22 ± 2.44 mg/g in leaves. Hypericophenonoside accounted for up to 77.50% of the components found in the leaves, whereas annulatophenonoside (6.29 ± 0.15 mg/g) and acetylannulatophenonoside (8.95 ± 0.09 mg/g) were detected in much lower quantities. In contrast to leaves, flowers showed a tendency towards higher contents of gentisein (9.35 ± 0.07 mg/g) and neoannulatophenonoside (4.72 ± 0.04 mg/g) than the other parts assayed. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metabolic disorders (MDs) include disease states such as diabetes mellitus, obesity, dyslipidemia, hyperuricemia, etc., affecting about 30% of the planet's population. The purpose of the present study was to investigate the protective potential of Cicerbita alpina leaf extract (ECA) against chemically induced type 2 diabetes in Wistar rats. Additionally, some biochemical parameters in the blood serum and liver, as well as histopathological investigation, were also performed. Quantitative analysis of the major compounds in the used extract was performed using ultrahigh-performance liquid chromatography-diode array detection (UHPLC-DAD) analyses using the external standard method. C. alpina extract revealed a beneficial effect on MDs, lowering blood sugar levels and MDA quantity in the liver, increasing the reduced glutathione level, and increasing antioxidant enzyme activity. Cichoric acid (CA) (91.93 mg/g dry extract (de) ± 4.64 mg/g de) was found to be the dominant compound in the extract, followed by caftaric (11.36 ± 2.10 mg/g de), and chlorogenic acid (CGA) (9.25 ± 0.05 mg/g de). In conclusion, C. alpina leaf extract (ECA) is rich in caffeoyltartaric and caffeoylquinic acids and provides beneficial effects on the diabetic animal model.

Pelargonium graveolens L'Hèr. (Geraniaceae) is renowned for its traditional use as a flavor, ornamental and medicinal plant. This work aimed at an in-depth study of the phytochemical profiling and in vitro antioxidant and enzyme inhibition assessment of a methanol-aqueous extract from P. graveolens leaves. A UHPLC-HRMS analysis revealed more than 110 secondary metabolites, including 8 acyltartaric and 11 acylcitric/acylisocitric acids; 8 gallotannins; 36 flavonols, flavanones and methoxylated flavonoids together with 17 phenolic and aliphatic acids; and 21 phenolic acid glycosides. For the first time, acylcitric acids along with feruloyl- and coumaroyltartaric acids are reported in the species. The leaf extract actively scavenged 2,2-diphenyl-1-picrylhydrazyl DPPH (273.45 mg trolox equivalent (TE/g)) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS •+ ) radicals (531.97 mgTE/g) and showed a high reducing power: 431.32 mg TE/g Cupric reducing antioxidant capacity (CUPRAC) and 292.21 mg TE/g Ferric reducing antioxidant power (FRAP). It possessed a metal chelating capacity (13.44 ethylenediaminetetraacetic acid equivalent (EDTAE)/g) and contained 2.71 mmol TE/g in the phosphomolybdenum assay. The rose geranium extract exhibited high inhibition towards acetyl- and butyrylcholinesterase (2.80 and 2.20 mg galantamine equivalent (GALAE)/g, respectively) and tyrosinase (75.49 mg kojic acid equivalent (KAE)/g). It inhibited α-glucosidase and α-amylase (3.75 mmol and 0.79 acarbose equivalent (ACAE)/g, respectively) and lipase (28.91 mg orlistat equivalent (OE)/g). This study sheds light into the future potential application of the rose geranium in pharmaceutical and nutraceutical products.

Oxidative stress exerts multiple disruptive effects on cellular morphology and function and is a major detriment to age-related and pathological neurodegenerative processes. The present study introduces an evaluative and comparative investigation of the antioxidant and cytoprotective properties of a Prenanthes purpurea extract and its major constituent 3,5-dicaffeoylquinic acid (DiCQA) in an in vitro model of H 2 O 2 -induced neurotoxicity. Using validated in vitro and in silico approaches, we established the presence and concentration dynamics of cellular protection in a 24 h pretreatment regimen with the natural products. The conducted cytotoxicity studies and the automated Chou-Talalay analysis for studying drug interactions demonstrated a strong antagonistic effect of the tested substances against oxidative stimuli in an "on demand" manner, prevailing at the higher end of the concentration range. These findings were further supported by the proteomic characterization of the treatment samples, accounting for a more distinct neuroprotection provided by the pure polyphenol 3,5-DiCQA.

The metabolic syndrome and its associated co-morbidities have been recognized as predisposing risk factors for the development of metabolic-associated fatty liver disease (MAFLD). The present study reports on the beneficial effect of the Tanacetum balsamita methanol-aqueous extract (ETB) at 150 and 300 mg/kg bw on biochemical parameters related to oxidative stress, metabolic syndrome, and liver function in rat animal models with induced MAFLD. ETB was found to be non-toxic with LD50 > 3000 mg/kg and did not affect cell viability of hepatic HEP-G2 cells in a concentration up to 800 μg/mL. The pathology was established by a high-calorie diet and streptozotocin. Acarbose and atorvastatin were used as positive controls. At the higher dose, ETB reduced significantly ( p < 0.05) the blood glucose levels by about 20%, decreased lipase activity by 52%, total cholesterol and triglycerides by 50% and 57%, respectively, and restored the amylase activity and leukocytes compared to the MAFLD group. ETB ameliorated oxidative stress biomarkers reduced glutathione and malondialdehyde in a dose-dependent manner. At 300 mg/kg, the beneficial effect of the extract on antioxidant enzymes was evidenced by the elevated catalase, glutathione peroxidase, and superoxide dismutase activity by 70%, 29%, and 44%, accordingly, compared to the MAFLD rats. ETB prevents the histopathological changes related to MAFLD. ETB, rich in 3,5-dicafeoylquinic, chlorogenic, and rosmarinic acids together with the isorhamnetin- and luteolin-glucoside provides a prominent amelioration of MAFLD.

The genus Stachys L., one of the largest genera of the Lamiaceae family, is highly represented in Turkey. This study was conducted to determine the bio-pharmaceutical potential and phenolic contents of six different extracts from aerial parts of Stachys tundjeliensis. The obtained results showed that the ethanol extract exhibited the highest antioxidant activity in the antioxidant assays. Meanwhile, the ethanol extract displayed strong inhibitory activity against α-tyrosinase, the dichloromethane extract exhibited potent inhibition against butyrylcholinesterase, and the n-hexane extract against α-amylase. Based on ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry analysis, more than 90 secondary metabolites, including hydroxybenzoic acid, hydroxycinnamic acid, and their glycosides, acylquinic acids, phenylethanoid glycosides, and various flavonoids were identified or tentatively annotated in the studied S. tundjeliensis extracts. It was observed that the application of S. tundjeliensis eliminated H 2 O 2 -induced oxidative stress. It was determined that protein levels of phospho-nuclear factor kappa B (NF-κB), receptor for advanced glycation endproducts, and activator protein-1, which are activated in the nucleus, decreased, and the synthesis of matrix metalloproteinase (MMP)-2 and MMP-9 also decreased to basal levels. Overall, these findings suggest that S. tundjeliensis contains diverse bioactive compounds for the development of nutraceuticals or functional foods with potent biological properties., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Sideritis scardica Griseb, also known as "mountain tea" and "Olympus tea" (Lamiaceae family) is an endemic plant from the mountainous regions of the Balkan Peninsula. In this study, we focused on an in-depth phytochemical analysis of S. scardica infusion using ultra-high-performance liquid chromatography hyphenated with high-resolution mass spectrometry (UHPLC-HRMS). Quantitative determination of the main secondary metabolites was carried out by UHPLC-HRMS analyses using the external standard method. The results revealed more than 100 metabolites, including five sugar acids and saccharides, 21 carboxylic, hydroxybenzoic, hydroxycinnamic acids, and derivatives, 15 acylquinic acids, 10 phenylpropanoid glycosides, four iridoid glycosides, 28 flavonoids, seven fatty acids, and four organosulfur compounds. Furthermore, a dereplication and fragmentation patterns of five caffeic acids oligomers and four acylhexaric acids was performed for the first time in S. scardica . Regarding the quantitative analysis, the phenylethanoid verbascoside ( 53 ) (151.54 ± 10.86 mg/g lyophilized infusion, li), the glycosides of isoscutellarein ( 78 ) (151.70 ± 14.78 mg/g li), methylisoscutelarein ( 82 ) (107.4 ± 9.07 mg/g li), and hypolaetin ( 79 ) (78.33 ± 3.29 mg/g li), as well as caffeic acid ( 20 ) (87.25 ± 6.54 mg/g li), were found to be the major compounds in S. scardica infusion. The performed state-of-the-art phytochemical analysis of S. scardica provides additional knowledge for the chemical constituents and usage of this valuable medicinal plant.

Within this particular framework, the extracts obtained from Inula sarana using a variety of solvents, included n-hexane, ethyl acetate, dichloromethane (DCM), 70% ethanol, ethanol, and water. The extracts obtained from n-hexane, ethyl acetate, and DCM were then subjected to a specific method for their incorporation into β-cyclodextrin (β-CD). The establishment of complex formation was validated through the utilization of scanning electron microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR). The identification of phytochemical components was executed using UHPLC-HRMS. Furthermore, the total phenolic and flavonoid content was evaluated using the Folin-Ciocalteu assay and the AlCl 3 method. Subsequently, the determination of antioxidant capacity was conducted utilizing DPPH, ABTS, CUPRAC, Frap, PBD, and MCA assays. The enzyme inhibitory activities of the samples (extracts and β-CD complexes) were also examined by AChE, BChE, tyrosinase, α-glucosidase, and α-amylase. The findings indicated that water and 70% ethanol extracts contained the highest phenolic content. One hundred and fourteen bioactive compounds were identified by UHPLC-HRMS analysis. This study unveiled a substantial array of flavonoids, phenolic acid-hexosides and caffeoylhexaric acids within I. sarana , marking their initial identification in this context. Among the various extracts tested, the 70% ethanol extract stood out due to its high flavonoid content (jaceosidin, cirsiliol, and eupatilin) and hydroxybenzoic and hydroxycinnamic acid hexosides. This extract also displayed notably enhanced antioxidant activity, with ABTS, CUPRAC, and FRAP test values of 106.50 mg TE/g dry extract, 224.31 mg TE/g dry extract, and 110.40 mg TE/g, respectively. However, the antioxidant values of the complex extracts with β-CD were generally lower than those of the pure extracts, an observation warranting significant consideration. In terms of enzyme inhibition activity, the ethanol and 70% ethanol extracts exhibited higher inhibitory effects on AChE, tyrosinase, and α-glucosidase. Conversely, n-hexane displayed stronger inhibitory activity against BChE. The ethyl acetate extract demonstrated elevated amylase inhibitory activity. However, the antioxidant values of the complex extracts with β-CD were generally lower than those of the pure extracts, a noteworthy observation, while water and extracts from the I. sarana complex with β-CD exhibited minimal or negatable inhibitory activity against specific enzymes.

Oxidative stress is a common phenomenon of many liver disorders; it both affects patient survival and directly influences the applicability, effectiveness, and toxicity of drugs. In the pursuit of reliable natural remedies for hepatoprotection, this study reports on the complete phytochemical characterization, antioxidant, and hepatoprotective activities of the Prenanthes purpurea methanol-aqueous extract in an in vitro model of diclofenac-induced liver injury (DILI). An ultra high-performance liquid chromatography-high-resolution mass spectrometry analysis (UHPLC-HRMS) was conducted, delineating more than 100 secondary metabolites for the first time in the species, including a series of phenolic acid-hexosides, acylquinic, acylhydroxyquinic and acyltartaric acids, and flavonoids. Quinic acid, chlorogenic, 3,5-dicaffeoylquinic and 5-feruloylhydroxyquinic acid, caffeoyltartaric and cichoric acids, eryodictiol- O -hexuronide, and luteolin O -hexuronide dominated the phytochemical profile and most likely contributed to the observed hepatoprotective activity of the studied P. purpurea leaf extract. The potency and molecular basis of cellular protection were investigated in parallel with pure caffeoylquinic acids in a series of pretreatment experiments that verified the antiapoptotic and antioxidant properties of the natural products.

Alzheimer's disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone ( 3a-r ) or sulfonyl hydrazone ( 5a-l ) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds ( 3c and 3d ) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n , possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H 2 O 2 -induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c , 3d , and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c , 3d , and 3n were capable of penetrating the blood-brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c , 3d , and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

This study aimed at the evaluation of the antioxidant and cognitive-enhancing effect of methanol-aqueous extract from Helichrysum italicum ssp. italicum aerial parts. Significant radical scavenging activity (110.33 ± 3.47 and 234.70 ± 5.21 mg TE/g for DPPH and ABTS) and reducing power (354.23 ± 17.51 and 210.24 ± 8.68 mg TE/g for CUPRAC and FRAP) were observed. The extract showed average acetylcholinesterase and low butyrylcholinesterase inhibitory potential. H. italicum extract (200 mg/kg/po) administered in combination with galantamine (3 mg/kg/po) for 12 days significantly improved the memory and learning process compared with galantamine alone in the passive avoidance test. The effect was comparable to that of Ginkgo biloba extract (100 mg/kg/po). In deep secondary metabolite annotation of the extract by UHPLC-HRMS, more than 90 hydroxybenzoic and hydroxicinnamic acid-glycosides, phenylethanoid glycosides, a series of acylquinic and caffeoylhexaric acids, methoxylated derivatives of scutellarein, quercetagetin and 6-hydroxyluteolin, and prenylated phloroglucinol-α-pyrones were reported for the first time in H. italicum . Fragmentation patterns of four subclasses of heterodimer-pyrones were proposed. In-depth profiling of the pyrones revealed 23 compounds undescribed in the literature. Pyrones and acylphloroglucinols together with acylquinic acids could account for memory improvement. The presented research advanced our knowledge of H. italicum , highlighting the species as a rich source of secondary metabolites with cognitive-enhancing potential.

Echinops ritro L. (Asteraceae) is traditionally used in the treatment of bacterial/fungal infections and respiratory and heart ailments. The aim of this study was to evaluate the potential of extracts from E. ritro leaves (ERLE) and flowering heads (ERFE) as antioxidant and hepatoprotective agents on diclofenac-induced lipid peroxidation and oxidative stress under in vitro and in vivo conditions. In isolated rat microsomes and hepatocytes, the extracts significantly alleviated oxidative stress by increasing cell viability and GSH levels and reducing LDH efflux and MDA production. During in vivo experiments, the administration of the ERFE alone or in combination with diclofenac resulted in a significant increase in cellular antioxidant protection and a decrease in lipid peroxidation witnessed by key markers and enzymes. A beneficial influence on the activity of the drug-metabolizing enzymes ethylmorphine-N-demetylase and aniline hydroxylase in liver tissue was found. In the acute toxicity test evaluation, the ERFE showed no toxicity. In the ultrahigh-performance liquid chromatography-high-resolution mass spectrometry analysis, 95 secondary metabolites were reported for the first time, including acylquinic acids, flavonoids, and coumarins. Protocatechuic acid O -hexoside, quinic, chlorogenic and 3, 5-dicaffeoylquinic acid, apigenin; apigenin 7- O -glucoside, hyperoside, jaceosidene, and cirsiliol dominated the profiles. The results suggest that both extracts should be designed for functional applications with antioxidant and hepatoprotective capacity.

The study aimed at the metabolite profiling and evaluation of antioxidant and enzyme inhibitory properties of methanol extracts from flowers, leaves, and tubers of unexplored Eminium intortum (Banks & Sol.) Kuntze and E. spiculatum (Blume) Schott (Araceae). A total of 83 metabolites, including 19 phenolic acids, 46 flavonoids, 11 amino, and 7 fatty acids were identified by UHPLC-HRMS in the studied extracts for the first time. E. intortum flower and leaf extracts had the highest total phenolic and flavonoid contents (50.82 ± 0.71 mg GAE/g and 65.08 ± 0.38 RE/g, respectively). Significant radical scavenging activity (32.20 ± 1.26 and 54.34 ± 0.53 mg TE/g for DPPH and ABTS) and reducing power (88.27 ± 1.49 and 33.13 ± 0.68 mg TE/g for CUPRAC and FRAP) were observed in leaf extracts. E. intortum flowers showed the maximum anticholinesterase activity (2.72 ± 0.03 mg GALAE/g). E. spiculatum leaves and tubers exhibited the highest inhibition towards α-glucosidase (0.99 ± 0.02 ACAE/g) and tirosinase (50.73 ± 2.29 mg KAE/g), respectively. A multivariate analysis revealed that O -hydroxycinnamoylglycosyl- C -flavonoid glycosides mostly accounted for the discrimination of both species. Thus, E. intortum and E. spiculatum can be considered as potential candidates for designing functional ingredients in the pharmaceutical and nutraceutical industries.

Cicerbita alpina (L.) Wallr. is a perennial herbaceous plant in the tribe Cichorieae (Lactuceae), Asteraceae family, distributed in the mountainous regions in Europe. In this study, we focused on the metabolite profiling and the bioactivity of C. alpina leaves and flowering heads methanol-aqueous extracts. The antioxidant activity of extracts, as well as inhibitory potential towards selected enzymes, involving in several human diseases, including metabolic syndrome (α-glucosidase, α-amylase, and lipase), Alzheimer's disease, (cholinesterases: AChE, BchE), hyperpigmentation (tyrosinase), and cytotoxicity were assessed. The workflow comprised ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). UHPLC-HRMS analysis revealed more than 100 secondary metabolites, including acylquinic, acyltartaric acids, flavonoids, bitter sesquiterpene lactones (STLs), such as lactucin, dihydrolactucin, their derivatives, and coumarins. Leaves showed a stronger antioxidant activity compared to flowering heads, as well as lipase (4.75 ± 0.21 mg OE/g), AchE (1.98 ± 0.02 mg GALAE/g), BchE (0.74 ± 0.06 mg GALAE/g), and tyrosinase (49.87 ± 3.19 mg KAE/g) inhibitory potential. Flowering heads showed the highest activity against α-glucosidase (1.05 ± 0.17 mmol ACAE/g) and α-amylase (0.47 ± 0.03). The obtained results highlighted C. alpina as a rich source of acylquinic, acyltartaric acids, flavonoids, and STLs with significant bioactivity, and therefore the taxon could be considered as a potential candidate for the development of health-promoting applications.

Herein, a chemophenetic significance, based on the phenolic metabolite profiling of three Senecio ( S. hercynicus, S. ovatus , and S. rupestris ) and two Jacobaea species ( J. pancicii and J. maritima ), coupled to morphometric data, is presented. A set of twelve morphometric characters were recorded from each plant species and used as predictor variables in a linear discriminant analysis (LDA) model. From a total 75 observations (15 from each of the five species), the model correctly assumed their species' membership, except for 2 observations. Among the studied species, S. hercynicus and S. ovatus presented the greatest morphological similarity. A phytochemical profiling of phenolic specialized metabolites by UHPLC-Orbitrap-MS revealed 46 hydroxybenzoic, hydroxycinnamic, and acylquinic acids and their derivatives, 1 coumarin and 21 flavonoids. Hierarchical and PCA clustering applied to the phytochemical data corroborated the similarity of S. hercynicus and S. ovatus , observed in the morphometric analysis. This study contributes to the phylogenetic relationships between the tribe Senecioneae taxa and highlights the chemophenetic similarity/dissimilarity of the studied species belonging to Senecio and Jacobaea genera.

Asteraceae species Tanacetum balsamita L. (costmary) is renowned for its traditional usage as an aromatic, carminative and tonic plant. This work aimed at in-depth study of the phytochemical and in vitro biological profilings of methanol−aqueous extracts from the costmary leaves, flower heads and roots. An UHPLC-HRMS analysis revealed more than 100 secondary metabolites including 24 acylquinic acids, 43 flavonoid glycosides, aglycones and methoxylated derivatives together with 15 phenolic acids glycosides. For the first time, 91 compounds are reported in the costmary. The flower heads extract possessing the highest content of total phenolics and flavonoids, actively scavenged DPPH (84.54 ± 3.35 mgTE/g) and ABTS radicals (96.35 ± 2.22 mgTE/g), and showed the highest reducing potential (151.20 and 93.22 mg TE/g for CUPRAC and FRAP, respectively). The leaves extract exhibited the highest inhibition towards acetyl- and butyrylcholinesterase (2.11 and 2.43 mg GALAE/g, respectively) and tyrosinase (54.65 mg KAE/g). The root extract inhibited α-glucosidase (0.71 ± 0.07 mmol ACAE/g), α-amylase (0.43 ± 0.02 mmol ACAE/g) and lipase (8.15 ± 1.00 mg OE/g). At a concentration >2 µg/mL, a significant dose dependent reduction of cell viability towards THP-1 monocyte leukemic cells was observed. Costmary could be recommended for raw material production with antioxidant and enzyme inhibitory properties.

The bioactive content, antioxidant properties, and enzyme inhibition properties of extracts of Alcea fasciculiflora from Turkey prepared with different solvents (water, methanol, ethyl acetate) and extraction methods (maceration, soxhlet, homogenizer assisted extraction, and ultrasound assisted extraction) were examined in this study. UHPLC-HRMS analysis detected or annotated a total of 50 compounds in A. fasciculiflora extracts, including 18 hydroxybenzoic and hydroxycinnamic acids, 7 Hexaric acids, 7 Coumarins, 15 Flavonoids, and 3 hydroxycinnamic acid amides. The extracts had phenolic and flavonoid levels ranging from 14.25 to 24.87 mg GAE/g and 1.68 to 25.26 mg RE/g, respectively, in the analysis. Both DPPH and ABTS tests revealed radical scavenging capabilities (between 2.63 and 35.33 mg TE/g and between 13.46 and 76.27 mg TE/g, respectively). The extracts had reducing properties (CUPRAC: 40.38-78 TE/g and FRAP: 17.51-42.58 TE/g). The extracts showed metal chelating activity (18.28-46.71 mg EDTAE/g) as well as total antioxidant capacity (phosphomolybdenum test) (0.90-2.12 mmol TE/g). DPPH, ABTS, FRAP, and metal chelating tests indicated the water extracts to be the best antioxidants, while the ethyl acetate extracts had the highest overall antioxidant capacity regardless of the extraction technique. Furthermore, anti-acetylcholinesterase activity was identified in all extracts (0.17-2.80 mg GALAE/g). The water extracts and the ultrasound-assisted ethyl acetate extract were inert against butyrylcholinesterase, but the other extracts showed anti-butyrylcholinesterase activity (1.17-5.80 mg GALAE/g). Tyrosine inhibitory action was identified in all extracts (1.79-58.93 mg KAE/g), with the most effective methanolic extracts. Only the ethyl acetate and methanolic extracts produced by maceration and homogenizer aided extraction showed glucosidase inhibition (0.11-1.11 mmol ACAE/g). These findings showed the overall bioactivity of the different extracts of A. fasciculiflora and provided an overview of the combination of solvent type and extraction method that could yield bioactive profile and pharmacological properties of interest and hence, could be a useful reference for future studies on this species.

The biological activity of the aerial part and rhizomes of Primula auriculata were assessed for the first time. The biological activities (antioxidant properties, enzyme inhibition, and AGE inhibition) as well as the phenolic and flavonoid contents of the ethyl acetate, ethanol, hydro-ethanol and water extracts of P. auriculata aerial parts and rhizomes were determined. Cell viability assays and gelatin zymography were also performed for MMP-2/-9 to determine the molecular mechanisms of action. The gene expression for MMPs was described with RT-PCR. The levels of various proteins, including phospho-Nf-κB, BCL-2, BAX, p-53, and cyclin D1 as well as RAGE were measured using Western blot analysis. The hydro-ethanol extract of the aerial part possessed the highest phenolic (56.81 mg GAE/g) and flavonoid (63.92 mg RE/g) contents. In-depth profiling of the specialized metabolites by ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) allowed for the identification and annotation of 65 compounds, including phenolic acids and glycosides, flavones, flavonols, chalcones, dihydrochalcones, and saponins. The hydro-ethanol extract of the aerial parts (132.65, 180.87, 172.46, and 108.37 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) and the ethanol extract of the rhizomes (415.06, 638.30, 477.77, and 301.02 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) exhibited the highest free radical scavenging and reducing activities. The ethanol and hydro-ethanol extracts of both the P. auriculata aerial part and rhizomes exhibited higher inhibitory activity against acetylcholinesterase, while the hydro-ethanol extracts (1.16 mmol ACAE/g, for both the aerial part and rhizomes extracts) were more active in the inhibition of α-glucosidase. After the treatment of an HT-29 colorectal cancer cell line with the extracts, the apoptosis mechanism was initiated, the integrity of the ECM was remodeled, and cell proliferation was also taken under control. In this way, Primula extracts were shown to be potential drug sources in the treatment of colorectal cancer. They were also detected as natural MMP inhibitors. The findings presented in the present study appraise the bioactivity of P. auriculata , an understudied species. Additional assessment is required to evaluate the cytotoxicity of P. auriculata as well as its activity in ex vivo systems.

Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer's disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity.

This study focused on the biological evaluation and chemical characterization of Malabaila lasiocarpa Boiss. (M. lasiocarpa) (Family: Apiaceae). The phytochemical profile, antioxidant, enzyme inhibitory of the methanolic, aqueous, dichloromethane, hexane extracts were investigated. Based on UHPLC-HRMS analyses, a total of 101 peaks were annotated or identified for the first time in M. lasiocarpa extracts. They include hydroxybenzoic, hydroxycinnamic, acylquinic acids and their glycosides, C- and O-glycosyl and O-diglycosyl flavonoids. In addition, 10 simple mono- and disubstituted coumarins together with 10 furanocoumarins were tentatively annotated. The methanolic extract possessing the highest phenolic (24.36±0.60 mg gallic acid equivalent/g extract) and flavonoid (69.15±0.37 mg rutin equivalent/g extract) content also exhibited the strongest radical scavenging potential against 2,2-diphenyl-1 picrylhydrazyl (21.73±0.42 mg Trolox equivalent/g extract, respectively), and highest reducing capacity (57.81±0.97 and 28.00±0.40 mg Trolox equivalent/g extract, for cupric reducing antioxidant capacity and ferric reducing antioxidant power, respectively). The dichloromethane extract substantially depressed the tyrosinase (73.92±5.37 mg kojic acid equivalent/g extract), α-amylase (0.63±0.01 mmol acarbose equivalent/g extract) and α-glucosidase (0.69±0.02 mmol acarbose equivalent/g extract) enzymes. This study has produced critical scientific data on M. lasiocarpa which are potential contenders for the development of novel phyto-pharmaceuticals., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Small-scale photobioreactors (PBRs) in the inoculum stage were designed with internal (red or green) and external white LED light as an initial step of a larger-scale installation aimed at fulfilling the integral biorefinery concept for maximum utilization of microalgal biomass in a multifunctional laboratory. The specific growth rate of Scenedesmus obliquus (Turpin) Kützing biomass for given cultural conditions was analyzed by using MAPLE software. For the determination of total polyphenols, flavonoids, chlorophyll "a" and "b", carotenoids and lipids, UHPLC-HRMS, ISO-20776/1, ISO-10993-5 and CUPRAC tests were carried out. Under red light growing, a higher content of polyphenols was found, while the green light favoured the flavonoid accumulation in the biomass. Chlorophylls, carotenoids and lipids were in the same order of magnitude in both samples. The dichloromethane extracts obtained from the biomass of each PBR synergistically potentiated at low concentrations (0.01-0.05 mg/mL) the antibacterial activity of penicillin, fluoroquinolones or oregano essential oil against the selected food-borne pathogens ( Staphylococcus aureus , Escherichia coli and Salmonella typhimurium ) without showing any in vitro cytotoxicity. Both extracts exhibited good cupric ion-reducing antioxidant capacity at concentrations above 0.042-0.08 mg/mL. The UHPLC-HRMS analysis revealed that both extracts contained long chain fatty acids and carotenoids thus explaining their antibacterial and antioxidant potential. The applied engineering approach showed a great potential to modify microalgae metabolism for the synthesis of target compounds by S. obliquus with capacity for the development of health-promoting nutraceuticals for poultry farming.

This study evaluated the in vitro antineoplastic and antiviral potential and in vivo toxicity of twelve extracts with different polarity obtained from the herbaceous perennial plant Geum urbanum L. ( Rosaceae ). In vitro cytotoxicity was determined by ISO 10993-5/2009 on bladder cancer, (T-24 and BC-3C), liver carcinoma (HEP-G2) and normal embryonic kidney (HEK-293) cell lines. The antineoplastic activity was elucidated through assays of cell clonogenicity, apoptosis induction, nuclear factor kappa B p65 (NFκB p65) activation and total glutathione levels. Neutral red uptake study was applied for antiviral activity. The most promising G. urbanum extract was analyzed by UHPLC-HRMS. The acute in vivo toxicity analysis was carried out following OEDC 423. The ethyl acetate extract of aerial parts (EtOAc-AP) exhibited the strongest antineoplastic activity on bladder cancer cell lines (IC 50 = 21.33-25.28 µg/mL) by inducing apoptosis and inhibiting NFκB p65 and cell clonogenicity. EtOAc and n -butanol extracts showed moderate antiviral activity against human adenovirus type 5 and human simplex virus type I. Seventy four secondary metabolites (gallic and ellagic acid derivatives, phenolic acids, flavonoids, etc.) were identified in EtOAc-AP by UHPLC-HRMS. This extract induced no signs of acute toxicity in liver and kidney specimens of H-albino mice in doses up to 210 mg/kg. In conclusion, our study contributes substantially to the detailed pharmacological characterization of G. urbanum , thus helping the development of health-promoting phytopreparations.

Boerhavia diffusa is a great tropical plant and is widely used for various traditional purposes. In the present study, we examined the influence of solvents (dichloromethane, ethyl acetate, methanol and infusion (water)) on chemical composition and biological capabilities of B. diffusa . An UHPLC-HRMS method was used to determine the chemical characterization. The biological ability was examined for antioxidant, enzyme inhibitory and anti-cancer effects. To evaluate antioxidant effects, different chemical methods (ABTS, DPPH, CUPRAC, FRAP, metal chelating and phosphomolybdenum) were applied. With regard to enzyme inhibitory properties, cholinesterases, amylase, glucosidase and tyrosinase were used. The MDA-MB-231 breast cancer cell line was chosen to determine anticancer activity. Based on the UHPLC-HRMS analysis, 37 specialized metabolites were dereplicated and identified in the studied extracts. Results revealed the presence of 15 hydroxybenzoic, hydroxycinnamic, acylquinic acids, and their glycosides, one rotenoid, seven flavonoids, 12 fatty acids and two other glycosides. Among the tested extracts, the methanol extract showed a stronger antioxidant ability compared with other extracts. The methanol extract also showed the best inhibitory effects on tyrosinase and glucosidase. In the anti-cancer evaluation, the methanol extract showed stronger anticancer effects compared with water extract. In summary, our observations can contribute to the establishment of B. diffusa as a potential candidate for functional applications in the preparation.

Spondias species have been used in traditional medicine for different human ailments. In this study, the effect of different solvents (ethyl acetate, methanol, and water) and extraction methods (infusion, maceration, and Soxhlet extraction) on the enzyme inhibitory activity against acetylcholinesterase, butyrylcholinesterase, tyrosinase, α-amylase, α-glucosidase, and antioxidant properties of S. mombin and S. dulcis leaves and stem bark were evaluated. Ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) yield in the identification and/or annotation of 98 compounds showing that the main secondary metabolites of the plant are gallic and ellagic acids and their derivatives, ellagitannins, hydroxybenzoic, hydroxycinnamic, acylquinic acids and flavonols, flavanones, and flavanonols. The leaves infusion of both Spondias species showed highest inhibition against acetylcholinesterase (AChE) (10.10 and 10.45 mg galantamine equivalent (GALAE)/g, for S. dulcis and S. mombin , respectively). The ethyl acetate extracts of the stem bark of S. mombin and S. dulcis actively inhibited α-glucosidase. Methanolic extracts of the leaves and stem bark exhibited highest tyrosinase inhibitory action. Antioxidant activity and higher levels of phenolics were observed for the methanolic extracts of Spondias. The results suggested that the Spondias species could be considered as natural phyto-therapeutic agents in medicinal and cosmeceutical applications.

The genus Acacia (Family Leguminosae) is composed of several medicinal plants used for treating miscellaneous diseases. Amid the important members of this genus, A. nilotica and A. ataxacantha are widely employed for their tremendous healing properties. Hence, this present work aimed to determine the total phenolic and flavonoid contents and investigate the antioxidant, antiproliferative, anti-enzyme and antimicrobial potentials of methanolic and water extracts of leaves and stem bark of A. nilotica and A. ataxacantha obtained by maceration and ultrasonication. The total phenolic and flavonoid contents were obtained in the range of 33.35-116.60 mg GAE/g and 0.26-49.90 mg RE/g, respectively, with the methanolic leaf extracts of both species showing the highest contents. Moreover, the methanolic extracts were observed to display higher antioxidant potentials in almost all antioxidant assays performed compared to the water extracts (ABTS: 52.66-943.81 mg TE/g, DPPH: 8.51-493.90 mg TE/g, CUPRAC: 106.39-1193.75 mg TE/g; FRAP: 31.38-416.21 mg TE/g, and phosphomolybdenum: 0.90-4.17 mM TE/g). However, the water extracts were seen to be better metal chelators than the methanolic extracts (8.47-36.85 mg EDTAE/g). Additionally, all extracts were found to exhibit anti-tyrosinase (30.79-74.80 mg KAE/g) and anti-amylase (0.10-1.10 mM ACAE/g) properties. With the exception of a few extracts, glucosidase and acetylcholinesterase inhibitions (1.69-2.12 mg ACAE/g and 0.42-2.61 mg GALAE/g, respectively) were also demonstrated. While the methanolic extracts of both species showed antimicrobial potency against all the 18 tested microorganisms (gram positive, gram negative, and fungi), the water extracts were effective only against the gram positive bacteria. The extracts were also found to exhibit antiproliferative effects on SH-SY5Y human neuroblastoma cells, with the methanolic extracts showing higher cytotoxic potential than the water extracts. Therefore, this study showed these species to be good sources of antioxidants, enzyme inhibitors, antimicrobials and antiproliferative agents, which could be of great interest for their applications as natural bioactive ingredients in the development of pharmaceuticals and nutraceuticals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The widespread genus Cirsium Mill. (Asteraceae) is renowned in traditional medicine. In the present study, an innovative biochemometric-assisted metabolite profiling of the flower heads, aerial parts and roots of Cirsium appendiculatum Griseb. (Balkan thistle) in relation to their antioxidant and enzyme inhibitory potential was developed. The workflow combines ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) with partial least-square analysis to discriminate the herbal extracts and identify the most prominent biological activities. The annotation and dereplication of 61 secondary metabolites were evidenced, including 15 carboxylic (including hydroxybenzoic and hydroxycinnamic) acids and their glycosides, 11 acylquinic acids, 26 flavonoids and 9 fatty acids. All compounds were reported for the first time in the studied species. The root extract revealed the highest cupric and ferric reducing power (618.36 ± 5.17 mg TE/g and 269.89 ± 8.50 mg TE/g, respectively) and antioxidant potential in phosphomolybdenum (3.36 ± 0.15 mmol TE/g) as well as the most prominent enzyme inhibitory potential on α -glucosidase (0.72 ± 0.07 mmol ACAE/g), acetylcholinesterase (4.93 ± 0.25 mg GALAE/g) and butyrylcholinesterase (3.80 ± 0.26 mg GALAE/g). Nevertheless, the flower heads were differentiated by their higher metal chelating activity (32.53 ± 3.51 mg EDTAE/g) and total flavonoid content (46.59 ± 0.89 mgRE/g). The partial least-square discriminant and heat-map analysis highlighted the root extract as the most active and a promising source of bioactive compounds for the therapeutic industry.

Oleraceins are a class of indoline amide glycosides found in Portulaca oleracea L. (Portulacaceae), or purslane. These compounds are characterized by 5,6-dihydroxyindoline-2-carboxylic acid N -acylated with cinnamic acid derivatives, and many are glucosylated. Herein, hydromethanolic extracts of the aerial parts of purslane were subjected to UHPLC-Orbitrap-MS analysis, in negative ionization mode. Diagnostic ion filtering (DIF), followed by diagnostic difference filtering (DDF), were utilized to automatically filter out MS data and select plausible oleracein structures. After an in-depth MS 2 analysis, a total of 51 oleracein compounds were tentatively identified. Of them, 26 had structures, matching one of the already known oleracein, and the other 25 were new, undescribed in the literature compounds, belonging to the oleracein class. Moreover, based on selected diagnostic fragment ions, clustering algorithms and visualizations were utilized. As we demonstrate, clustering methods provide valuable insights into the mass fragmentation elucidation of natural compounds in complex mixtures.

The aim of the study was to provide an in-depth characterization of the methanol-aqueous extract from the aerial parts of Gypsophila glomerata Pall. Ex Adams (Caryophyllaceae) (EGG) and to assess its protective potential on carbon tetrachloride (CCl 4 )-induced liver and kidney damage in male Wistar rats. Twenty-two flavonoid C- , O - and C,O --glycosides in EGG were annotated by mass spectrometry--based molecular networking; nine of them are reported in this species for the first time. Fourteen-day oral administration of EGG at a dose 200 mg kg -1 bm prevented significantly CCl 4 -induced liver injury, discerned by an amelioration of the markers of oxidative stress (GSH and MDA) and transaminase activity. EGG decreased the serum level of urea and creatinine as well. The observed improvement of biochemical parameters was supported by histopathological observations. The protective hepatorenal effects of EGG, rich in 2"- О -pentosyl-6- С -hexosyl-apigenin/luteolin/ methylluteolin and their acetyl- and methoxycinnamoyl-derivatives, were comparable with the effects of the positive control silymarin., (© 2022 Bojana Dimitrova et al., published by Sciendo.)

In the current study, Achillea santolinoides and Achillea aleppica aeral parts and root were extracted with ethyl acetate, methanol, and water. Detailed phytochemical profiles were obtained using UHPLC-MS, yielding the identification of hydroxybenzoic and hydroxycinnamic acids, phenolic acid glycosides and sugar esters, acylquinic acids, O -glycosyl flavones and flavonols, and flavonoid aglycons, among others. The antioxidant properties and enzyme inhibitory activities of the extracts were assayed with in vitro tests. The phenolic content of the water extracts was significantly higher as compared to the ethyl acetate and methanol ones. A. aleppica aerial parts methanol extract possessed highest flavonoid content (49.18 mg rutin equivalent/g). Antioxidant properties assessment revealed that the methanol extract of A. santolinoides roots actively scavenged DPPH (54.11 mg TE/g) and ABTS radicals (112.53 mg TE/g) and possessed highest reducing potential (183.55 and 129.92 mg TE/g, for CUPRAC and FRAP, respectively). The ethyl acetate extracts of aerial parts and roots of both species showed highest inhibition against BuCHE (6.07-6.76 mg GALAE/g). The ethyl acetate extract of A. santolinoides aerial part showed highest inhibition against tyrosinase (73.00 mg KAE/g). These results showed that the tested Achillea species might represent novel phytotherapeutic avenues for the management of Alzheimer's disease and epidermal hyperpigmentation conditions, which are both associated with oxidative stress. This paper could shed light into future potential industrial applications using the tested Achillea species.

Rhaponticoides iconiensis (Hub.-Mor.) M.V.Agab. & Greuter. (Asteraceae) is an endemic species spread in several small populations in the province of Konya (Turkey). It is critically endangered with an extremely high risk of extinction. Recently, based on the molecular phylogenetic and eco geographical studies on Cardueae-Centaureinae, the genus Rhaponticoides Vaill. was separated from Centaurea L. Antioxidant properties and enzyme inhibition, as well as the phenolic and flavonoid contents, of the methanol (Soxhlet extraction and maceration) and water (infusion) extracts of R. iconiensis leaves, roots, and flower heads were determined. The methanol extracts of R. iconiensis leaves contained the highest amount of phenolic (52.37 and 54.37 mg gallic acid equivalent/g) and flavonoids (74.13 and 80.75 mg rutin equivalent/g). Accordingly, the leaves methanol extracts showed the highest antioxidant potential. Interestingly, the roots methanol extracts were the most potent acetylcholinesterase (4.75 mg galantamine equivalent/g) and butyrylcholinesterase inhibitors (5.26 and 5.14 mg galantamine equivalent/g). The leaves and roots methanol extracts exhibited high α-glucosidase (2.48-3.08 mmol acarbose equivalent/g) and α-amylase (0.17-0.70 mmol acarbose equivalent/g) inhibition. The highest tyrosinase inhibition was recorded for leaves methanol extracts (138.79 and 140.34 mg kojic acid equivalent/g). 87 natural products (including hydroxybenzoic, hydroxycinnamic and acylquinic acids, flavones, flavonols, flavanones and anthocyanins) were unambiguously identified or tentatively annotated in the studied extracts. Findings presented in the present study appraise the bioactivity of R. iconiensis, an understudied species., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Achyranthes aspera Linn. (Amaranthaceae), commonly known as the Prickly Chaff flower, is used as herbal medicine in the Ivorian's culture, Africa. Nonetheless, there is currently a paucity of scientific information on A. aspera from the Ivory Coast. Herein, the antioxidant activity of A. aspera extracts (methanol, dichloromethane, ethyl acetate and infusion) as well as the enzymatic inhibitory potentials towards key enzymes in human diseases, namely Alzheimer's disease, (cholinesterases: AchE and BChE), type 2 diabetes (α-glucosidase and α-amylase) and hyperpigmentation (tyrosinase) were assessed. The total phenolic (TPC) and flavonoid (TFC) content was determined using colorimetric methods and the individual compounds were characterized using ultra-high performance liquid chromatography coupled with hybrid quadrupole-Orbitrap high resolution mass spectrometry (UHPLC-HRMS). Furthermore, a network pharmacology analysis was conducted to predict putative targets of identified phenolic compounds. The highest TPC was observed in the infused extract (28.86 ± 0.12 mg GAE/g), while the dichloromethane extract (38.48 ± 1.48 mg RE/g) showed the highest level of TFC. UHPLC-HRMS analysis has revealed an abundance of fatty acids, flavonoids, phenols and acylquinic acids. Among tested extracts, the infused extract displayed the highest free radical quenching, reducing and metal-chelating ability. The extracts (except infusion) were effective as enzyme inhibitors against AChE, while only methanolic and infused extracts showed noteworthy anti-BChE effects. The methanolic extract showed a remarkable antityrosinase effect (56.24 ± 5.05 mg KAE/g), as well. Modest to moderate inhibitory activity was observed against α-amylase (all extracts) and α-glucosidase (only dichloromethane extract). Finally, the network pharmacology analysis suggested the carbonic anhydrase II enzyme as a putative target for explaining, at least in part, the traditional use of A. aspera preparations as diuretic and blood clotting agent. Data amassed herein tend to validate the use of A. aspera in traditional medicine, as well as act as a stepping stone for further studies in the quest for novel phytopharmaceuticals. In this context, it is desirable that this study will contribute to the validation of the traditional uses of this plant in the African herbal medicine, and to the valorization of the whole chain production of A. aspera , as a local and sustainable botanical resource.

Clinopodium vulgare L. (Lamiaceae) was used in the traditional Bulgarian medicine for treatment of wounds, diabetes and gastric ulcers. In this study we aimed at safety assessment of C. vulgare lyophilized water extract (CVE) characterized by ultra high-performance liquid chromatography-Orbitrap high resolution mass spectrometry (UHPLC-HRMS). The acute and sub-acute toxicity of CVE was determined in two rodent species (mice and rats), and two routes of administration - intraperitoneal (i.p.) and oral (p.o.). LD 50 (i.p.) , were found to be 675 mg/kg (mice) and 500 mg/kg (rats). An acute i. p. administration resulted in central nervous system toxic effects. LD 50 (p.o.) was higher than 2000 mg/kg for both species. In sub-acute oral administration, CVE did not exert any toxic effect on hematology, blood and urine biochemistry, and histomorphology in pancreas, liver, spleen and kidney. In addition, based on accurate masses, MS/MS and comparison with standards, a variety of flavonoids, caffeic acid oligomers and saponins were tentatively elucidated in CVE. Rosmarinic acid was the major compound. In conclusion, CVE did not cause hematological, biochemical and histopathological changes after oral administration and it is safe for internal use. The obtained UHPLC-HRMS profile revealed CVE as a new rich source of water soluble caffeic acid oligomers., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Glucuronide Oleanane-type Triterpenoid Carboxylic Acid 3,28-Bidesmosides (GOTCAB) are accumulated in Gypsophila L. roots. In the study we aimed at investigating the possible synergistic effects of Gypsophila trichotoma GOTCABs and cytostatic etoposide towards the Hodgkin lymphoma cell line HD-MY-Z. The combination effects with etoposide were evaluated using the symbolic mathematical software MAPLE. Liquid chromatography-mass spectrometry allowed the identification or tentative assignment of 28 core GOTCAB structures together with 6 monodesmosides in the root extract. Tested gypsogenin-based saponins possessed C-28 ester-bonded chain substituted with acetyl, cis/trans methoxycinnamoyl and both acetyl and sulfate groups. No cytotoxic effect was observed up to 20 μg/mL on normal mice fibroblasts (CCL-1 cell line) and lymphoma cells. Etoposide alone exerted IC 50 93 μg/mL. In the presence of acetylated saponins (20 μg/mL), a strong synergism (Fa = 0.8, CI = 0.1) was observed with IC 50 11 μg/mL. The combination induced apoptosis witnessed by caspase activation, elevated levels of cytosolic mono- and oligonucleosomes, and nuclear fragmentation together with discernible increase in ROS generation. The results emphasize the arabinose in the C-3 chain and acetylation pattern of the C-28 chain of the saponins as important structural features for cytotoxicity enhancing activity. Triterpenoid saponins are a valuable tool to improve the efficacy of cytostatics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The phytochemical, antiradical, and enzyme inhibition profile of three solvent extracts (ethyl acetate, methanol, water) of Origanum sipyleum were assessed. We also performed a pharmacological study in order to explore protective effects induced by extracts in inflamed colon. LC-MS analysis revealed that the extracts contained different classes of phenolics. The aqueous extract showed the highest antioxidant and acetylcholinesterase (AChE) inhibitory effects. Total phenol and flavonoid contents were highest in aqueous and ethyl acetate extract, respectively. All extracts were effective in reducing colon pro-oxidant and pro-inflammatory biomarkers. The extracts revealed also able to inhibit fungal and bacterial species involved in ulcerative colitis, including Candida albicans, Candida tropicalis, Staphylococcus aureus, and Staphylococcus thyphimurium. Finally, we also showed the antiproliferative effects exerted by the EA extracts on human colon cancer HCT116 cell line. Concluding, our results indicated that O. sipyleum extracts displayed promising therapeutic properties which warrants further validation. PRACTICAL APPLICATIONS: The present phytochemical and biological studies, including antioxidant, anti-inflammatory, and antimicrobic assessments, showed significant protective effects exerted by O. sipyleum extracts in an experimental model of ulcerative colitis. The results are intriguing and suggest potential applications O. sipyleum extracts as sources of natural agents for the management of clinical symptoms related to ulcerative colitis, characterized by increased burden of oxidative stress and microbiome dysbiosis., (© 2019 Wiley Periodicals, Inc.)

Three new prenyloxy chromanone derivatives, aucherine A-C (6, 7 and 9) as well as six known prenylated phloroglucinols (1-5 and 8) were isolated from the aerial parts of Hypericum aucheri Jaub. Et Spach. The structures of the isolated compounds were established by means of spectral techniques (HRESIMS, 1D and 2D NMR). The new compounds were tested on а panel of human tumor cell line using MTT assay. All tested compounds exerted moderate cytotoxicity with IC 50 values ranging from 19.6 to 57.8 μM. The influence of the new compounds on some key signaling molecules (procaspase-9 and Bcl-xL), implicated in the regulation of programmed cell death was assessed by Western blot analysis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Geigeria alata Benth. & Hook.f. ex Oliv. & Hiern (Asteraceae) is used in Sudanese folk medicine for treatment of diabetes. The study aimed to estimate the acute oral toxicity of trans-3,5-dicaffeoylquinic acid (3,5-diCQA) from G. alata roots and to assess its antihypeglycemic, antioxidant and antihypertensive effects on chemically-induced diabetic spontaneously hypertensive rats (SHRs). The structure of 3,5-diCQA was established by NMR and HRMS spectra. Type 2 diabetes was induced by intraperitoneal injection of streptozotocin. 3,5-diCQA was slightly toxic with LD 50  = 2154 mg/kg. At 5 mg/kg 3,5-diCQA reduced significantly (p < 0.05) the blood glucose levels by 42%, decreased the blood pressure by 22% and ameliorated the oxidative stress biomarkers reduced glutathione, malondialdehyde, and serum biochemical parameters. The beneficial effect on antioxidant enzymes was evidenced by the elevated glutathione peroxidase, glutathione reductase, and glutathione S-transferase activitiy in the livers of diabetic animals. 3,5-diCQA prevents the histopathological changes related to diabetes and hypertension. 3,5-diCQA was more potent α-glucosidase inhibitor (IC 50 27.24 μg/mL) than acarbose (IC 50 99.77 μg/mL). The antihyperglycemic action of the compound was attributed to the α-glucosidase inhibition. The beneficial effects of 3,5-diCQA on streptozotocin-induced diabetic hypertensive rats support the traditional use of G.alata for the management of diabetes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ethyl acetate (EA), methanol (MeOH), and aqueous extracts of aerial parts of Anthemis tinctoria var. pallida (ATP) and A. cretica subsp. tenuiloba (ACT) were investigated for their phenol and flavonoid content, antioxidant, and key enzyme inhibitory potentials. All extracts displayed antiradical effects, with MeOH and aqueous extracts being a superior source of antioxidants. On the other hand, EA and MeOH extracts were potent against AChE and BChE. Enzyme inhibitory effects against tyrosinase and α-glucosidase were observed, as well. We also studied Anthemis extracts in an ex vivo experimental neurotoxicity paradigm. We assayed extract influence on oxidative stress and neurotransmission biomarkers, including lactate dehydrogenase (LDH) and serotonin (5-HT), in isolated rat cortex challenged with K + 60 mM Krebs-Ringer buffer (excitotoxicity stimulus). An untargeted proteomic analysis was finally performed in order to explore the putative mechanism in the brain. The pharmacological study highlighted the capability of ACT water extract to blunt K + 60 mM increase in LDH level and 5-HT turnover, and restore physiological activity of specific proteins involved in neuron morphology and neurotransmission, including NEFMs, VAMP-2, and PKCγ, thus further supporting the neuroprotective role of ACT water extract.