Chemical profiling and quantification of flavones in several Pseudognaphalium and Gnaphalium species of Mexican gordolobo using UHPLC/PDA/MS.

The inflorescences of the Mexican gordolobo are used as a folk medicine to treat various respiratory diseases. Currently, the botanical species that bear the name Mexican gordolobo belong to the genera Gnaphalium and Pseudognaphalium. Despite a long history of traditional use, most Mexican gordolobo species have never been fully chemically characterized, and the range of constituents in the species has not been comprehensively reported. To establish a quality control and chemical characterization method, a total of 49 samples belonging to 18 species of Pseudognaphalium and four species of Gnaphalium were studied. Nine flavones were quantified using a UPLC-PDA method. The method was validated in terms of linearity (R2 > 0.99), precision (intra- and inter-day: 0.1-3.9%), accuracy (96-103%), detection limit (10 ng/mL), limit of quantification (25 ng/mL) and robustness. 3-Methylquercetin, luteolin, quercetin, 3,5-dihydroxy-6,7,8-trimethoxyflavone, apigenin and gnaphaliin A were present at relatively high levels in most of the samples analyzed. The samples of P. oxyphyllum and P. liebmannii showed the highest content of the 9 compounds analyzed. Whereas the samples of the 5 species of Gnaphalium showed the lowest levels, including non-detectable, of the 9 compounds quantified. This marks an important difference with Pseudognaphalium species. Furthermore, using UHPLC-ESI-QToF data with targeted and non-targeted approaches, 57 compounds, were identified in Mexican gordolobo samples. Flavonoids were the main group of compounds found in Mexican gordolobo.

Floral pigments and their perception by avian pollinators in three Chilean Puya species.

The Chilean Puya species, Puya coerulea var. violacea and P. chilensis bear blue and pale-yellow flowers, respectively, while P. alpestris considered to be their hybrid-derived species has unique turquoise flowers. In this study, the chemical basis underlying the different coloration of the three Puya species was explored. We first isolated and identified three anthocyanins: delphinidin 3,3',5'-tri-O-glucoside, delphinidin 3,3'-di-O-glucoside and delphinidin 3-O-glucoside; seven flavonols: quercetin 3-O-rutinoside-3'-O-glucoside, quercetin 3,3'-di-O-glucoside, quercetin 3-O-rutinoside, isorhamnetin 3-O-rutinoside, myricetin 3,3',5'-tri-O-glucoside, myricetin 3,3'-di-O-glucoside and laricitrin 3,5'-di-O-glucoside; and six flavones: luteolin 4'-O-glucoside, apigenin 4'-O-glucoside, tricetin 4'-O-glucoside, tricetin 3',5'-di-O-glucoside, tricetin 3'-O-glucoside and selagin 5'-O-glucoside, which is a previously undescribed flavone, from their petals. We also compared compositions of floral flavonoid and their aglycone among these species, which suggested that the turquoise species P. alpestris has an essentially intermediate composition between the blue and pale-yellow species. The vacuolar pH was relatively higher in the turquoise (pH 6.2) and pale-yellow (pH 6.2) flower species, while that of blue flower species was usual (pH 5.2). The flower color was reconstructed in vitro using isolated anthocyanin, flavonol and flavone at neutral and acidic pH, and its color was analyzed by reflectance spectra and the visual modeling of their avian pollinators. The modeling demonstrated that the higher pH of the turquoise and pale-yellow species enhances the chromatic contrast and spectral purity. The precise regulation of flower color by flavonoid composition and vacuolar pH may be adapted to the visual perception of their avian pollinator vision.

Morin loaded mesoporous molecular sieves as novel devices to the potential treatment of tumor pathologies.

Morin is an antioxidant and anticancer flavonoid, extracted from natural sources, that may exert beneficial effects for several pathologies. Despite this, the administration of morin represents a challenge due to its low aqueous solubility. Mesoporous silica materials have emerged as biocompatible tools for drug delivery, as their pore size can be modulated for maximum surface area to volume ratio. In this contribution, we evaluate the ability of iron-modified mesoporous materials, for morin loading and controlled delivery. The SBA-15 and MCM-41 sieves were synthesized and modified with iron (metal content 4.02 and 6.27 % wt, respectivily). Characterization by transmission electron microscopy, XRD and UV-Vis revealed adequate pore size and agglomerates of very small metallic nanospecies (nanoclusters), without larger iron oxide nanoparticles. FT-IR spectra confirmed the presence of silanol groups in the solid hosts, which can interact with different groups present in morin molecules. SBA-15 materials were more efficient in terms of morin loading capacity (LC) due to their larger pore diameter. LC was more than 35% for SBA-15 materials when adsorptions studies were carried out with 9 mg of drug. Antioxidant activity were assayed by using DPPH test. Free iron materials presented a significate improvement as antioxidants after morin incorporation, reaching a scavenging activity of almost a 90%. On the other hand, in iron modified mesoporous materials, the presence of morin did not affect the scavenging activity. The results could be related with the formation of a complex between the flavonoid and the iron. Finally, biosafety studies using normal epithelial cells revealed that neither the loaded nor the unloaded materials exerted toxicity, even at doses of 1 mg/ml. These findings expand knowledge about mesoporous materials as suitable carriers of flavonoids with the aim of improving therapies for a wide range of pathologies.

Polyphenol intake and gastric cancer: A case-control study in the Brazilian Amazon region.

BACKGROUND: Polyphenol intake has been associated with a decreased risk of some types of cancer, including gastric cancer (GC). However, few studies address this topic in the Latin American population. In the present study, we evaluated the association between polyphenol intake and the risk of GC in the Brazilian Amazon region. METHODS: A case-control study was conducted in Belém (Amazon region) from July 2017 to February 2021. A total of 193 GC cases and 194 controls of both sexes, between 18 and 75 years old, were included in the study. Dietary data were collected using a validated food-frequency questionnaire and polyphenol intake identified using the Phenol-Explorer database. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), with adjustement for potential confounders. RESULTS: Cases and controls had similar total polyphenol intake (356.4 mg/1000 kcal/d and 331.1 mg/1000 kcal/d, respectively; p = 0.086). After adjusting for potential confounders, high consumption of flavan-3-ols (highest vs. lowest tertile: OR 0.41, 95% CI 0.18-0.94) and hydroxybenzoic acids (highest vs. lowest tertile: OR 0.24, 95% CI 0.10-0.56) was associated with a decreased risk of GC. The opposite was true regarding the intake of flavones (OR 2.46, 95% IC 1.17-5.18) and other polyphenols (OR 2.54, 95% IC 1.16-5.54). When stratifying according to anatomical topography, we observed that the intake of total flavonoids, flavan-3-ols, and flavanones reduced the risk of cardia GC while that of hydroxybenzoic acids reduced the risk of non-cardia GC. In addition, the intake of flavones and other polyphenols was associated with an increased risk of non-cardia GC. According to histologic subtypes, hydroxybenzoic acid intake was associated with a reduced risk of intestinal-type GC (OR 0.21, 95% IC 0.07-0.64), while flavone consumption was associated with an increased risk of diffuse-type GC (OR 2.59, 95% IC 1.05-6.42). CONCLUSIONS: Our findings suggest that in the Brazilian Amazon region the high intake of flavan-3-ols and hydroxybenzoic acids is associated with a reduced risk of GC, suggesting a potential beneficial role of these compounds against GC.

New flavone, and cytotoxicity activity of Rauia resinosa ethanolic extract and constituents.

The ethanolic extract from leaves of Rauia resinosa, Rutaceae, provided a new flavone, 5-hydroxy-5',6,7-trimethoxy-3',4'-methylenedioxyflavone (1), in addition to four known compounds: 3',4',5,5',7-pentamethoxyflavone (2), 5,7,8-trimethoxy-3'4'-methylenedioxyflavone (3), 3',4',5,7,8-pentamethoxyflavone (4) and ß-sitosterol (5). The structures of all compounds were established on the basis of spectroscopic methods, mainly 1D and 2D NMR, UPLC-DAD-MS and UPLC-ESI-MS/MS, involving comparison with literature data. Cytotoxicity of leaves and stems extracts, their fractions and compounds (2), (3), (4) and (5) were evaluated against T24 (bladder carcinoma), TOV-21-G (ovarian adenocarcinoma) and HepG2 (liver carcinoma) cell lines.

High-Resolution Mass Spectrometry Identification and Characterization of Flavonoids from Fridericia chica Leaves Extract with Anti-Arbovirus Activity.

Plant extracts are complex mixtures that are difficult to characterize, and mass spectrometry is one of the main techniques currently used in dereplication processes. Fridericia chica is a species with medicinal uses in Latin American countries, used in the treatment of inflammatory and infectious diseases. Extracts of this plant species are characterized by the presence of anthocyanidins. In this study, using high-resolution mass spectrometry coupled with liquid chromatography, it was possible to determine the molecular formula of thirty-nine flavonoids. Fragmentation analysis, ultraviolet spectrum and nuclear magnetic resonance data allowed the partial characterization of the structures of these compounds. The spectral dataset allowed the identification of a series of flavones in addition to the desoxyanthocyanidins common in extracts of the species. The occurrence of some of the proposed structures is uncommon in extracts of species of the Bignoniaceae family, and they are reported for the first time in the extract of this species. Quantitative analyses of total flavonoids confirmed the high content of these constituents in the species, with 4.09 ± 0.34 mg/g of dry plant material. The extract under study showed low in vitro cytotoxicity with CC50 ≥ 296.7 ± 1.4 µg/mL for Vero, LLC-MK2 and MRC-5 cell lines. In antiviral activity assays, inhibition of the cytopathic effects of Dengue, Zika and Mayaro viruses was observed, with EC50 values ranging between 30.1 and 40.9 µg/mL. The best result was observed against the Mayaro virus, with an EC50 of 30.1 µg/mL.

Flavonols and Flavones as Potential anti-Inflammatory, Antioxidant, and Antibacterial Compounds.

Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with beneficial effects and reveal their underlying mechanisms. Flavonoids are phytoconstituents with anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial properties. Herein, we listed and contextualized various aspects of the protective effects of the flavonols quercetin, isoquercetin, kaempferol, and myricetin and the flavones luteolin, apigenin, 3',4'-dihydroxyflavone, baicalein, scutellarein, lucenin-2, vicenin-2, diosmetin, nobiletin, tangeretin, and 5-O-methyl-scutellarein. We presented their structural characteristics and subclasses, importance, occurrence, and food sources. The bioactive compounds present in our diet, such as fruits and vegetables, may affect the health and disease state. Therefore, we discussed the role of these compounds in inflammation, oxidative mechanisms, and bacterial metabolism; moreover, we discussed their synergism with antibiotics for better disease outcomes. Indiscriminate use of antibiotics allows the emergence of multidrug-resistant bacterial strains; thus, bioactive compounds may be used for adjuvant treatment of infectious diseases caused by resistant and opportunistic bacteria via direct and indirect mechanisms. We also focused on the reported mechanisms and intracellular targets of flavonols and flavones, which support their therapeutic role in inflammatory and infectious diseases.

The Argentine Mistletoes Ligaria cuneifolia (Ruiz & Pav.) Tiegh (Loranthaceae) and Phoradendron liga (Gillies ex Hook. & Arn.) Eichler (Santalaceae). Thirty Years of Research.

Ligaria cuneifolia (Ruiz & Pav.) Tiegh (Loranthaceae) and Phoradendron liga (Gillies ex Hook. & Arn.) Eichler (Santalaceae) are regarded as Argentine mistletoes based on their similarities with the European counterpart, Viscum album L. (Santalaceae). These two species are the most used medicinal plants to treat high blood pressure in the Argentinian population. To provide scientific grounds to their traditional use and therapeutic potential, they were selected as herbal drug candidates. The main findings would support the anti-hypertensive action, the anticholesterolemic and antioxidant features of L. cuneifolia, and immunomodulatory properties for both species. Quercetin-O-glycosides, galloyl glycosides, and proanthocyanidins are present in L. cuneifolia while P. liga shows C-glycosyl flavones and 3-deoxyproanthocyanidins. This review summarizes the phytochemical characterization, medicinal properties and reveals promising results warranting future efforts for further investigation.

Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones.

Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3'-5' exonuclease (ExoN).

Neuroprotective Effect of Luteolin-7-O-Glucoside against 6-OHDA-Induced Damage in Undifferentiated and RA-Differentiated SH-SY5Y Cells.

Luteolin is one of the most common flavonoids present in edible plants and its potential benefits to the central nervous system include decrease of microglia activation, neuronal damage and high antioxidant properties. The aim of this research was to evaluate the neuroprotective, antioxidant and anti-inflammatory activities of luteolin-7-O-glucoside (Lut7). Undifferentiated and retinoic acid (RA)-differentiated SH-SY5Y cells were pretreated with Lut7 and incubated with 6-hydroxydopamine (6-OHDA). Cytotoxic and neuroprotective effects were determined by MTT assay. Antioxidant capacity was determined by DPPH, FRAP, and ORAC assays. ROS production, mitochondrial membrane potential (ΔΨm), Caspase-3 activity, acetylcholinesterase inhibition (AChEI) and nuclear damage were also determined in SH-SY5Y cells. TNF-α, IL-6 and IL-10 release were evaluated in LPS-induced RAW264.7 cells by ELISA. In undifferentiated SH-SY5Y cells, Lut7 increased cell viability after 24 h, while in RA-differentiated SH-SY5Y cells, Lut7 increased cell viability after 24 and 48 h. Lut7 showed a high antioxidant activity when compared with synthetic antioxidants. In undifferentiated cells, Lut7 prevented mitochondrial membrane depolarization induced by 6-OHDA treatment, decreased Caspase-3 and AChE activity, and inhibited nuclear condensation and fragmentation. In LPS-stimulated RAW264.7 cells, Lut7 treatment reduced TNF-α levels and increased IL-10 levels after 3 and 24 h, respectively. In summary, the results suggest that Lut7 has neuroprotective effects, thus, further studies should be considered to validate its pharmacological potential in more complex models, aiming the treatment of neurodegenerative diseases.

Analysis of the Molecular Mechanisms by Flavonoids with Potential Use for Osteoporosis Prevention or Therapy.

BACKGROUND: Osteoporosis is the most common skeletal disorder worldwide. Flavonoids have the potential to alleviate bone alterations in osteoporotic patients with the advantage of being safer and less expensive than conventional therapies. OBJECTIVE: The main objective is to analyze the molecular mechanisms triggered in bone by different subclasses of flavonoids. In addition, this review provides an up-to-date overview of the cellular and molecular aspects of osteoporotic bones versus healthy bones, and a brief description of some epidemiological studies indicating that flavonoids could be useful for osteoporosis treatment. METHODS: The PubMed database was searched in 2001- 2021 using the keywords osteoporosis, flavonoids, and their subclasses such as flavones, flavonols, flavanols, isoflavones, flavanones and anthocyanins, focusing the data on the molecular mechanisms triggered in bone. RESULTS: Although flavonoids comprise many compounds that differ in structure, their effects on bone loss in postmenopausal women or in ovariectomized-induced osteoporotic animals are quite similar. Most of them increase bone mineral density and bone strength, which occur through an enhancement of osteoblastogenesis and osteoclast apoptosis, a decrease in osteoclastogenesis, as well as an increase in neovascularization on the site of the osteoporotic fracture. CONCLUSION: Several molecules of signaling pathways are involved in the effect of flavonoids on osteoporotic bone. Whether all flavonoids have a common mechanism or they act as ligands of estrogen receptors remains to be established. More clinical trials are necessary to know better their safety, efficacy, delivery and bioavailability in humans, as well as comparative studies with conventional therapies.

Synthesis and Evaluation of Trypanocidal Activity of Chromane-Type Compounds and Acetophenones.

American trypanosomiasis (Chagas disease) caused by the Trypanosoma cruzi parasite, is a severe health problem in different regions of Latin America and is currently reported to be spreading to Europe, North America, Japan, and Australia, due to the migration of populations from South and Central America. At present, there is no vaccine available and chemotherapeutic options are reduced to nifurtimox and benznidazole. Therefore, the discovery of new molecules is urgently needed to initiate the drug development process. Some acetophenones and chalcones, as well as chromane-type substances, such as chromones and flavones, are natural products that have been studied as trypanocides, but the relationships between structure and activity are not yet fully understood. In this work, 26 compounds were synthesized to determine the effect of hydroxyl and isoprenyl substituents on trypanocide activity. One of the compounds showed interesting activity against a resistant strain of T. cruzi, with a half effective concentration of 18.3 µM ± 1.1 and an index of selectivity > 10.9.

Phytochemical composition and biological screening of two Lophophytum species / Composición fitoquímica y cribado biológico de dos especies de Lophophytum

Lophophytum species are holoparasites that grow on tree roots. The objectives of the work were to explore the chemical composition of the tubers of two Lophophytum species and to analyze the antioxidant, anti-inflammatory and antilithiatic activity of their extracts using in vitro methods. The chemical composition was determined by histochemical, phytochemical and TLC tests. In addition, the profile of phenolic compounds was determined by HPLC-MS. The presence of secondary metabolites of recognized activity was demonstrated. The results of the HPLC-MS/MS allowed the tentative identification of catechin, luteolin and glycosides of eriodictyol, naringenin and luteolin in the extract of Lophophytum leandriand eriodictyol, naringenin, luteolin and their glycosylated derivatives in Lophophytum mirabile. The extracts showed promising antioxidant (DPPH, ABTS and ß-carotene-linoleic acid), anti-inflammatory (inhibition of 5-LOX) and anti-urolytic (by bioautographic TLC) activity. It is noteworthy that these are the first results of the phytochemical composition and biological activity of L. mirabile. However, in vivo studies are required to corroborate these activities.

Las especies de Lophophytumson holoparásitas que crecen en raíces de árboles. Los objetivos del trabajo fueron explorar la composición química del túber de dos especies de Lophophytum y analizar la actividad antioxidante, antiinflamatoria y antilitiásica de sus extractos usando métodos in vitro. La composición química se determinó mediante pruebas histoquímicas, fitoquímicas y por TLC. Además, se determinó el perfil de compuestos fenólicos por HPLC-MS/MS. Se demostró presencia de metabolitos secundarios de reconocida actividad. Los resultados del HPLC-MS/MS permitieron identificar tentativamente catequina, luteolina y glucósidos de eriodictiol, naringenina y luteolina en el extracto de Lophophytum leandriy eriodictiol, naringenina, luteolina y sus derivados glicosilados en Lophophytum mirabile. Los extractos mostraron prometedora actividad antioxidante (DPPH, ABTS y ß-caroteno-ácido linoleico), antiinflammatoria (inhibición de la 5-LOX) y antiurolitiásica (por TLC bioautográfica). Es de destacar que estos son los primeros resultados de composición fitoquímica y actividad biológica de L. mirabile. Sin embargo, se requieren estudios in vivo para corroborar dichas actividades.

Bioactive Diterpenes from the Brazilian Native Plant (Moquiniastrum pulchrum) and Their Application in Weed Control.

Even today, weeds continue to be a considerable problem for agriculture. The application of synthetic herbicides produces serious environmental consequences, and crops suffer loss of their activity due to the appearance of new resistant weed biotypes. Our aim is to develop new effective natural herbicides that improve the problem of resistance and do not harm the environment. This work is focused on a bioassay-guided isolation and the characterization of natural products present in Moquiniastrum pulchrum leaves with phytotoxic activity and its preliminary application in weeds. Moquiniastrum pulchrum was selected for two reasons: it is an abundant species in the Cerrado region (the second most important ecosystem in Brazil, after the Amazon)-the explanation behind its being a dominant species is a major focus of interest-and it has traditional employment in folk medicine. Six major compounds were isolated in this plant: one flavone and five diterpenes, two of which are described for the first time in the literature. Four of the six compounds exhibited phytotoxic activity in the bioassays performed. The results confirmed the phytotoxic potential of this plant, which had not been investigated until now.

Benzylated Dihydroflavones and Isoquinoline-Derived Alkaloids from the Bark of Diclinanona calycina (Annonaceae) and Their Cytotoxicities.

Diclinanona calycina R. E. Fries popularly known as "envira", is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of D. calycina was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in D. calycina as well as in the genus Diclinanona. The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (1); aporphine, anonaine (2); oxoaporphine, liriodenine (3); benzyltetrahydroisoquinolines, (S)-(+)-reticuline (4); dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (5); (+)-1S,2R-reticuline Nß-oxide (6); and (+)-1S,2S-reticuline Nα-oxide (7); tetrahydroprotoberberine, coreximine (8); and pavine, bisnorargemonine (9). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (10), dichamanetin (11), and a mixture of uvarinol (12) and isouvarinol (13). Compound 5 is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (10), and the mixture of uvarinol (12) and isouvarinol (13), which presented moderate cytotoxic activity against the tested cancer cell lines (<20.0 µg·mL-1) and low cytotoxicity against the non-cancerous cell line MRC-5 (>25.0 µg·mL-1). Dichamanetin (11) showed cytotoxic activity against HL-60 and HCT116 with IC50 values of 15.78 µg·mL-1 (33.70 µmol·L-1) and 18.99 µg·mL-1 (40.56 µmol·L-1), respectively while the mixture of uvarinol (12) and isouvarinol (13) demonstrated cytotoxic activity against HL-60, with an IC50 value of 9.74 µg·mL-1, and HCT116, with an IC50 value of 17.31 µg·mL-1. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound.

Bioassay-Guided Identification of the Antiproliferative Compounds of Cissus trifoliata and the Transcriptomic Effect of Resveratrol in Prostate Cancer Pc3 Cells.

The bioassay-guided fractionation of a CHCl3-MeOH extract from the stems of Cissus trifoliata identified an active fraction against PC3 prostate cancer cells. The treatment for 24 h showed an 80% reduction in cell viability (p ≤ 0.05) by a WST-1 assay at a concentration of 100 µg/mL. The HPLC-QTOF-MS analysis of the fraction showed the presence of coumaric and isoferulic acids, apigenin, kaempferol, chrysoeriol, naringenin, ursolic and betulinic acids, hexadecadienoic and octadecadienoic fatty acids, and the stilbene resveratrol. The exposure of PC3 cells to resveratrol (IC25 = 23 µg/mL) for 24 h induced significant changes in 847 genes (Z-score ≥ ±2). The functional classification tool of the DAVID v6.8 platform indicates that the underlying molecular mechanisms against the proliferation of PC3 cells were associated (p ≤ 0.05) with the process of differentiation and metabolism. These findings provide experimental evidence suggesting the potential of C. trifoliata as a promising natural source of anticancer compounds.

Anti-inflammatory Properties of Ethanolic Extract and 2″-O-ß-D-Glucopyranosyl-vitexin Obtained from Alternanthera tenella Colla Whole Plant.

Six flavonoids were identified and isolated from the ethanolic extract of Alternanthera tenella Colla (Amaranthaceae) whole plant (EEAT) including 2″-O-ß-D-glucopyranosyl-vitexin (A19). Flavonoids have anti-inflammatory activity; however, the 2″-O-ß-D-glucopyranosyl-vitexin anti-inflammatory property was not totally explored. The aim of the present study was to investigate the anti-inflammatory effects of ethanolic extract from A. tenella whole plant and isolated flavone C-glycoside A19 in models of inflammation. The oral administration (p.o.) of EEAT (30, 100, and 300 mg/kg), A19 (0.1, 1, and 10 mg/kg), and prednisolone (3 mg/kg) were tested against the carrageenan-induced paw edema in Swiss mice. The EEAT (100 mg/kg, p.o.), A19 (1 mg/kg, p.o.), and prednisolone (3 mg/kg, p.o.) were tested in the zymosan-articular inflammation, carrageenan-pleurisy, and complete Freund's adjuvant (CFA) models in Swiss mice. In silico analysis and search for structural relationships between vitexin derivatives flavones present in the EEAT and TNF-α inhibitors were performed. EEAT, A19, and prednisolone significantly inhibited (i) edema, mechanical hyperalgesia in carrageenan-induced paw inflammation; (ii) leukocyte migration and protein extravasation in carrageenan-induced pleurisy; (iii) knee edema, mechanical hyperalgesia, and leukocyte migration in articular inflammation induced by zymosan. Still the CFA induced the increase in myeloperoxidase and N-acetylglucosaminidase activities, EEAT, A19, and prednisolone significantly inhibited these enzymes. The in silico analysis showed that molecules with similar structure to apigenin and vitexin have a potential inhibition on the TNF system. This study confirms the anti-inflammatory properties of EEAT and A19. The C-glycosylated flavone A19 could be responsible for the EEAT anti-edematogenic and anti-hyperalgesic effects and a potential TNF-α inhibitor.

Natural isoflavonoids in invasive cancer therapy: From bench to bedside.

Cancer is a public health problem worldwide, and one of the crucial steps within tumor progression is the invasion and metastasis of cancer cells, which are directly related to cancer-associated deaths in patients. Recognizing the molecular markers involved in invasion and metastasis is essential to find targeted therapies in cancer. Interestingly, about 50% of the discovered drugs used in chemotherapy have been obtained from natural sources such as plants, including isoflavonoids. Until now, most drugs are used in chemotherapy targeting proliferation and apoptosis-related molecules. Here, we review recent studies about the effect of isoflavonoids on molecular targets and signaling pathways related to invasion and metastasis in cancer cell cultures, in vivo assays, and clinical trials. This review also reports that glycitein, daidzein, and genistein are the isoflavonoids most studied in preclinical and clinical trials and displayed the most anticancer activity targeting invasion-related proteins such as MMP-2 and MMP-9 and also EMT-associated proteins. Therefore, the diversity of isoflavonoids is promising molecules to be used as chemotherapeutic in invasive cancer. In the future, more clinical trials are needed to validate the effectiveness of the various natural isoflavonoids in the treatment of invasive cancer.

Protective effect of flavonoids from Passiflora edulis Sims on diabetic complications in rats.

OBJECTIVES: This study was carried out to evaluate the effects of flavonoids present in leaves of Passiflora edulis fruit on complications induced by diabetes in rats. METHODS: The extract of P. edulis leaf was obtained by 70% ethanol maceration. From the dry extract, the fractions were obtained by consecutive liquid-liquid partition with hexane, ethyl acetate and n-butanol. The content of isoorientin of ethyl acetate and n-butanol fractions was determined by ultra-performance liquid chromatography coupled with electrospray and triple quadrupole ionization (TQD) analysis in tandem mass spectrometry (UPLC-ESI-Tq-MS). Only Fr-BuOH was used to treat diabetic or not Wistar rats. Biochemical parameters, platelet aggregation and production of reactive species were evaluated. KEY FINDINGS: The UPLC-ESI-Tq-MS analysis revealed the presence of several flavonoids, among which we identified five possible flavonoids c-heterosides (luteolin-7-O-pyranosyl-3-O-glucoside, apigenin-6-8-di-C-glycoside, apigenin-6-C-arabinoside-8-C-glycoside, isoorientin, isovitexin). The diabetic rats (treated intraperitoneally with alloxan, 150 mg/kg) treated with Fr-BuOH (20 mg/kg/day for 90 days) presented improvement in blood glucose, serum levels of fructosamine, lipid profile and urea. Furthermore, the Fr-BuOH reduced both platelet aggregation and the production of oxidant species in diabetic animals. CONCLUSIONS: These results suggested that flavonoid C-glycosides present in the Fr-BuOH may be beneficial for the diabetic state, preventing complications induced by diabetes.

Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors.

Although the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC50 of 5 µM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.