Pterodon emarginatus Seed Preparations: Antiradical Activity, Chemical Characterization, and In Silico ADMET Parameters of ß-caryophyllene and Farnesol.

The study of medicinal plants and their active compounds is relevant to maintaining knowledge of traditional medicine and to the development of new drugs of natural origin with lower environmental impact. From the seeds of the Brazilian plant Pterodon emarginatus, six different preparations were obtained: essential oil (EO), ethanol extract (EthE) prepared using the traditional method, and four extracts using solvents at different polarities, such as n-hexane, chloroform, ethyl acetate, and methanol (HexE, ChlE, EtAE, and MetE). Chemical characterization was carried out with gas chromatography, allowing the identification of several terpenoids as characteristic components. The two sesquiterpenes ß-caryophyllene and farnesol were identified in all preparations of Pterodon emarginatus, and their amounts were also evaluated. Furthermore, the total flavonoid and phenolic contents of the extracts were assessed. Successively, the antiradical activity with DPPH and ORAC assays and the influence on cell proliferation by the MTT test on the human colorectal adenocarcinoma (HT-29) cell line of the preparations and the two compounds were evaluated. Lastly, an in silico study of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) showed that ß-caryophyllene and farnesol could be suitable candidates for development as drugs. The set of data obtained highlights the potential medicinal use of Pterodon emarginatus seeds and supports further studies of both plant preparations and isolated compounds, ß-caryophyllene and farnesol, for their potential use in disease with free radical involvement as age-related chronic disorders.

Luteolin and Vernodalol as Bioactive Compounds of Leaf and Root Vernonia amygdalina Extracts: Effects on α-Glucosidase, Glycation, ROS, Cell Viability, and In Silico ADMET Parameters.

The aqueous decoctions of Vernonia amygdalina (VA) leaves and roots are widely used in traditional African medicine as an antidiabetic remedy. The amount of luteolin and vernodalol in leaf and root extracts was detected, and their role was studied regarding α-glucosidase activity, bovine serum albumin glycation (BSA), reactive oxygen species (ROS) formation, and cell viability, together with in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Vernodalol did not affect α-glucosidase activity, whereas luteolin did. Furthermore, luteolin inhibited the formation of advanced glycation end products (AGEs) in a concentration-dependent manner, whereas vernodalol did not reduce it. Additionally, luteolin exhibited high antiradical activity, while vernodalol demonstrated a lower scavenger effect, although similar to that of ascorbic acid. Both luteolin and vernodalol inhibited HT-29 cell viability, showing a half-maximum inhibitory concentration (IC50) of 22.2 µM (-Log IC50 = 4.65 ± 0.05) and 5.7 µM (-Log IC50 = 5.24 ± 0.16), respectively. Finally, an in silico ADMET study showed that both compounds are suitable candidates as drugs, with appropriate pharmacokinetics. This research underlines for the first time the greater presence of vernodalol in VA roots compared to leaves, while luteolin is prevalent in the latter, suggesting that the former could be used as a natural source of vernodalol. Consequently, root extracts could be proposed for vernodalol-dependent antiproliferative activity, while leaf extracts could be suggested for luteolin-dependent effects, such as antioxidant and antidiabetic effects.

The Use of Medicinal Plants in Blood Vessel Diseases: The Influence of Gender.

Data available in the literature on the use of herbal products to treat inflammation-related vascular diseases were considered in this study, while also assessing the influence of gender. To this end, the articles published in PubMed over the past 10 years that described the use of plant extracts in randomized clinical trials studying the effectiveness in vascular pathologies were analyzed. The difference in efficacy of plant-derived preparations in female and male subjects was always considered when reporting. The safety profiles of the selected plants were described, reporting unwanted effects in humans and also by searching the WHO database (VigiBase®). The medicinal plants considered were Allium sativum, Campomanesia xanthocarpa, Sechium edule, Terminalia chebula. Additionally, an innovative type of preparation consisting of plant-derived nanovesicles was also reported.

Anti-inflammatory, Antinociceptive, and Toxicological Properties of Uvaria comperei Stem Crude Extract and Fractions.

The present study was carried out to investigate the anti-inflammatory activity of a methanolic extract and fractions of Uvaria comperei stems. The crude extract was obtained by maceration of the powder in methanol and fractions by vacuum chromatography from the methanolic extract. To study the anti-inflammatory activity in vitro, red blood cell lysis inhibition assay and albumin denaturation inhibition were performed, while in vivo measurements of carrageenan-induced paw oedema and formalin-induced pain in albino mice were performed. Acute toxicity and cytotoxicity studies of the fraction F2 were performed, as well as its HPLC, and some biochemical parameters were quantified. Uvaria comperei crude extract (UCCE) at 250 and 500 µg/mL completely inhibited albumin denaturation, while decreasing 75.5% of heat blood cell lysis at 500 µg/mL. The fractions 128-136 (F3), 10-11 (F1), and 56-62 (F2) at 500 µg/mL displayed a significant anti-inflammatory activity with percentages of inhibition of 60.5, 67.4, and 100%, respectively. Administration of fraction F2 (25, 50, and 100 mg/kg, p.o.) produced a dose-dependent inhibition of formalin-induced pain of 60.2% at 50 mg/kg in the neurogenic phase (p < 0.05) and 70.2% at 25 mg/kg in the inflammatory phase (p < 0.05). Similarly, the time-dependent increase in carrageenan-induced paw circumference induced by carrageenan was inhibited by pretreatment with F2: 50% of inhibition at 25 mg/kg after 30 min (p < 0.05) and 96.5% inhibition at 25 mg/kg after 6 h (p < 0.05). In this research, the fraction F2 presented its maximum analgesic property at 50 mg/kg, while it presented the highest anti-inflammatory property at 25 mg/kg. The oral lethal median dose (LD50) of F2 was determined to be greater than 2000 mg/kg; further low cytotoxicity in RAW cells was also observed. Overall, this work shows that the methanolic crude extract and fractions, mainly F2, of Uvaria comperei stem have interesting anti-inflammatory properties.

Selected Plant-Derived Polyphenols as Potential Therapeutic Agents for Peripheral Artery Disease: Molecular Mechanisms, Efficacy and Safety.

Vascular diseases, such as peripheral artery disease (PAD), are associated with diabetes mellitus and a higher risk of cardiovascular disease and even death. Surgical revascularization and pharmacological treatments (mainly antiplatelet, lipid-lowering drugs, and antidiabetic agents) have some effectiveness, but the response and efficacy of therapy are overly dependent on the patient's conditions. Thus, the demand for new cures exists. In this regard, new studies on natural polyphenols that act on key points involved in the pathogenesis of vascular diseases and, thus, on PAD are of great urgency. The purpose of this review is to take into account the mechanisms that lead to endothelium dysfunction, such as the glycoxidation process and the production of advanced glycation end-products (AGEs) that result in protein misfolding, and to suggest plant-derived polyphenols that could be useful in PAD. Thus, five polyphenols are considered, baicalein, curcumin, mangiferin, quercetin and resveratrol, reviewing the literature in PubMed. The key molecular mechanisms and preclinical and clinical studies of each selected compound are examined. Furthermore, the safety profiles of the polyphenols are outlined, together with the unwanted effects reported in humans, also by searching the WHO database (VigiBase).

Magnolol and Luteolin Inhibition of α-Glucosidase Activity: Kinetics and Type of Interaction Detected by In Vitro and In Silico Studies.

Magnolol and luteolin are two natural compounds recognized in several medicinal plants widely used in traditional medicine, including type 2 diabetes mellitus. This research aimed to determine the inhibitory activity of magnolol and luteolin on α-glucosidase activity. Their biological profile was studied by multispectroscopic methods along with inhibitory kinetic analysis and computational experiments. Magnolol and luteolin decreased the enzymatic activity in a concentration-dependent manner. With 0.075 µM α-glucosidase, the IC50 values were similar for both compounds (~ 32 µM) and significantly lower than for acarbose (815 µM). Magnolol showed a mixed-type antagonism, while luteolin showed a non-competitive inhibition mechanism. Thermodynamic parameters suggested that the binding of magnolol was predominantly sustained by hydrophobic interactions, while luteolin mainly exploited van der Waals contacts and hydrogen bonds. Synchronous fluorescence revealed that magnolol interacted with the target, influencing the microenvironment around tyrosine residues, and circular dichroism explained a rearrangement of the secondary structure of α-glucosidase from the initial α-helix to the final conformation enriched with ß-sheet and random coil. Docking studies provided support for the experimental results. Altogether, the data propose magnolol, for the first time, as a potential α-glucosidase inhibitor and add further evidence to the inhibitory role of luteolin.

Effects of Croton lechleri sap (Sangre de Drago) on AGEs formation, LDL oxidation and oxidative stress related to vascular diseases.

The sap of Croton lechleri Müll. Arg. (Euphorbiaceae) is well-known in South American traditional medicine. This research investigated its activity against glycation and oxidative stress (glycoxidation) to estimate its usefulness in ROS-related diseases. The activity of the sap on albumin glycation, LDL oxidation and ROS formation was detected. C. lechleri sap inhibited BSA glycation and exhibited a protective effect against LDL oxidation; at the concentration of 0.8 µg/mL, it extended the Lag phase of almost 60%. Furthermore, the sap was studied on cell viability and ROS production in HUVEC showing valuable free-radical scavenging activity. In detail, the sap (1.0 and 10.0 µg/mL) significantly decreased the baseline level and H2O2-induced ROS production in HUVEC. This research showed for the first time the ability of C. lechleri sap to decrease the albumin glycation, LDL oxidation and ROS formation in HUVEC, supporting its potential in vascular diseases.

α-Glucosidase and advanced glycation end products inhibition with Vernonia amygdalina root and leaf extracts: new data supporting the antidiabetic properties.

OBJECTIVE: This study aims to investigate antidiabetic activity of several Vernonia amygdalina extracts to study their potential use in medicine. METHODS: Aqueous and ethanol extracts were obtained by maceration and Soxhlet extraction from roots and leaves of V. amygdalina. The extracts were tested as inhibitors of α-glucosidase activity and of advanced glycation end products (AGEs) formation. Further, radical scavenging activity was examined detecting the oxygen radical absorbance capacity, while the potential cytotoxicity of extracts was estimated with MTT assay. KEY FINDINGS: In aqueous and ethanol extracts, several polyphenolic compounds were identified; in detail, (-)-catechin and luteolin were found in leaf extracts, while caffeic acid, chlorogenic acid and the terpenoid vernodalol were recognized in root extracts. Regarding antidiabetic activity, the aqueous root extracts efficiently inhibited α-glucosidase activity in a concentration-dependent manner (IC50 = 5.6 µg/ml and 39.8 µg/ml, respectively of macerated and Soxhlet extracts), whereas those obtained from leaves exhibited lower potency. Furthermore, AGEs formation was reduced by all V. amygdalina extracts starting from 10 µg/ml. CONCLUSIONS: The aqueous extracts of V. amygdalina roots obtained by maceration and Soxhlet extraction show remarkable anti-α-glucosidase activity, and all extracts have favourable antiglycation and antioxidant activities.

α-Glucosidase and glycation inhibitory activities of Rumex lunaria leaf extract: a promising plant against hyperglycaemia-related damage.

Rumex lunaria L. is a Canarian medicinal plant, belonging to Polygonaceae. The potential antidiabetic activity of the methanolic extract of the leaves was investigated. For this purpose, the inhibition of α-glucosidase and albumin glycation by the extract was studied. Further, the anti-radical activity and the phytochemical composition were detected. The reduction of α-glucosidase activity was significant from 3 µg/mL, while the BSA glycation inhibition started from 100 µg/mL. Moreover, the extract exhibited a significant free-radical scavenger activity. Its phytochemical characterization showed the presence of carotenoids, phenolic and flavonoid compounds, whereas anthraquinones were not detected. C-flavonoid glycosides were identified and quercetin-O-hexoside-O-deoxyhexoside was the most detected (22.67 ± 0.02 mg/g). The findings indicate that the methanolic R. lunaria leaf extract has significant anti-α-glucosidase, anti-radical and anti-glycation activities. This research is the first showing the potential antidiabetic activity of R. lunaria.[Formula: see text].

Antiglycation Activity and HT-29 Cellular Uptake of Aloe-Emodin, Aloin, and Aloe arborescens Leaf Extracts.

Aloe arborescens is a relevant species largely used in traditional medicine of several countries. In particular, the decoction of leaves is prepared for various medicinal purposes including antidiabetic care. The aim of this research was the study of the antiglycation activity of two A. arborescens leaf extracts and isolated compounds: aloin and aloe-emodin. These phytoconstituents were quantitatively assessed in methanolic and hydroalcoholic extracts using high performance liquid chromatography (HPLC) analysis. In addition, the total phenolic and flavonoid contents were detected. In order to study their potential use in diabetic conditions, the antiglycation and antiradical properties of the two extracts and aloin and aloe-emodin were investigated by means of bovine serum albumin (BSA) and 1,1-diphenyl-2-picryl-hydrazil (DPPH) assays; further, their cytotoxicity in HT-29 human colon adenocarcinoma cells was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore, the ability of aloin and aloe-emodin to permeate the cellular membranes of HT-29 cells was determined in order to estimate their potential in vivo absorption. This assessment indicated that aloe-emodin can substantially pass through cell membranes (~20%), whereas aloin did not permeate into HT-29 cells. Overall, the data show that both the methanolic and the hydroalcoholic A. arborescens extracts determine significant inhibition of glycation and free-radical persistence, without any cytotoxic activity. The data also show that the antiglycation and the antiradical activities of aloin and aloe-emodin are lower than those of the two extracts. In relation to the permeability study, only aloe-emodin is able to cross HT-29 cellular membranes, showing the attitude to pass through the intestinal layer. Overall, the present data surely support the traditional use of A. arborescens leaf extracts against hyperglycemic conditions, while aloin and aloe-emodin as potential drugs need further study.

Cameroonian medicinal plants belonging to Annonaceae family: radical scavenging and antifungal activities.

The free-radical scavenging activity of ethanolic and methanolic extracts of leaves, stems and roots of Annona muricata, Monodora tenuifolia, Uvaria comperei, Uvaria muricata and Xylopia africana was evaluated using DPPH and ORAC assays. Further, phytochemical analysis, total phenolic and total flavonoid contents were also determined. Moreover, the antifungal activity of extracts was studied. The findings indicated that A. muricata and U. comperei extracts own antiradical activities and moderate antifungal properties.

New arylsparteine derivatives as positive inotropic drugs.

Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an Emax of 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having Emax of 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.

Croton lechleri sap and isolated alkaloid taspine exhibit inhibition against human melanoma SK23 and colon cancer HT29 cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Croton lechleri Mull. Arg. (Euphorbiaceae) is a traditional medicinal plant which produces a red sap, traditionally known as "Sangre de Drago"; it is used in folk medicine externally for wounds, fractures, and haemorrhoids, internally for intestinal and stomach ulcers and also for the empirical cure of cancers. MATERIALS AND METHODS: We investigated the effects of Croton lechleri sap and taspine in comparison with taxol and vinblastine on the growth of human cancer cell lines of SK23 (melanoma), LoVo and HT29 (colorectal cancer) using MTT and Trypan blue assays. Further, we studied cell cycle by flow cytometry and detected acetylated-α-tubulin by confocal microscope. RESULTS: Croton lechleri inhibited cell proliferation starting from 1 µg/mL in SK23 cells, whereas 10 times higher concentrations were required for growth inhibition of HT-29 and LoVo cell lines. Also taspine (0.1 µg/mL) inhibited the SK23 and HT29 cell proliferation. Further, assay was assessed on SK23 and HT29 cell lines with 24-48 h treatment with sap and taspine. Both sap and taspine inhibited cancer cell proliferation; taspine showed higher activity on SK23 cells, which was significantly increased after 48 h of SK23 treatment. Using confocal microscopy we observed that Croton lechleri (1 µg/mL) caused a loss of microtubule structure, whereas taspine (0.5 µg/mL) caused an increase in acetylated α-tubulin and a modification of cellular morphology, mainly in SK23 cells. Croton lechleri sap 10 and 50 µg/mL influence cell cycle; 50 µg/mL sap caused a dramatic reduction of cells in G(1)/G(0) and S phases with a great increase of subG(0) cells. CONCLUSIONS: The data showed that Croton lechleri and taspine could inhibit cell proliferation with higher potency against melanoma SK23 cells, supporting the empirical use of the sap as anticancer in ethnomedicine and taspine as a possible anticancer agent.

Age-dependent vasorelaxation of Casimiroa edulis and Casimiroa pubescens extracts in rat caudal artery in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaf and seed decoctions of Casimiroa spp. are used in Mexican traditional medicine to treat high blood pressure. Previous researches showed as Casimiroa extracts are able to induce relaxation of rat aortic and caudal arteries. To study the influence of the aging, we determined the vascular effect induced by extracts of Casimiroa edulis and Casimiroa pubescens in arterial tissues from young and old rats. MATERIALS AND METHODS: The activity of Casimiroa edulis extracts: hexanic-leaf (Ce5), methanolic-leaf (Ce6), hexanic-seed (Ce7) and methanolic-seed (Ce8), and Casimiroa pubescens: hexanic-leaf (Cp9), methanolic-leaf (Cp10), hexanic-seed (Cp11) and methanolic-seed (Cp12) were investigated in precontracted caudal arteries of young (4 months) and old (20 months) rats. RESULTS: The Casimiroa extracts tested at 20 µg/ml induced vasorelaxation in phenylephrine-precontracted arterial tissues both in young and old arterial tissues. Methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12) caused a higher relaxation in young than in old arterial tissues. Nifedipine (0.01 µM) did not change the vasorelaxation induced by Casimiroa edulis extract either in young and old rat arterial tissues. CONCLUSIONS: The vasorelaxation induced by Casimiroa edulis and Casimiroa pubescens extracts is decreased from aging since the effects were higher in young than in old rat arterial tissues. However, the methanolic-seed extracts of both plant species induced a relevant vasorelaxation also in old arterial tissues. Thus the results support the traditional use of Casimiroa decoctions as antihypertensive, also in elderly.

Vasorelaxation by extracts of Casimiroa spp. in rat resistance vessels and pharmacological study of cellular mechanisms.

AIM OF THE STUDY: Casimiroa spp. are Mexican plants traditionally used for treatment of hypertension. To study their antihypertensive action, we determined the arterial dilatation induced by extracts from leaves and seeds of Casimiroa calderoniae F. Chiang & Medrano, Casimiroa edulis Llave et Lex, and Casimiroa pubescens Ramirez. MATERIALS AND METHODS: The vascular effects of Casimiroa spp. extracts were investigated on rat caudal and aortic arteries. In addition, the extracts were characterized by HPLC using heraclenol, isopimpinellin, heraclenin and phellopterin as external standards. The methanolic extract of Casimiroa pubescens seeds (Cp12) was also studied by H-NMR and LC-MS (ESI-TOF) for the determination of casimiroin and zapotin. RESULTS: The hexanic and methanolic extracts of Casimiroa spp. (20 µg/ml) showed vasorelaxation in arterial tissues precontracted by phenylephrine (0.5 µM); the extracts from seeds always caused a greater relaxation in comparison to those from leaves. The most active were the methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12). To study the pharmacological mechanisms of vasodilatation we used various inhibitors selective to different receptor subtypes or intracellular enzymes. The vasorelaxant effect of Ce8 (20 µg/ml) remained unaffected by the pretreatment with pyrilamine (10 µM), an antagonist of histamine H(1) receptors, but was inhibited by atropine (0.1 µM), a muscarinic receptor antagonist. Therefore, to determine muscarinic receptor subtypes, we used pirenzepine (1 µM), a selective inhibitor of M(1) receptor, and 4-diphenylacetoxyl-N-methylpiperidine methiodide (DAMP, 0.01 µM), a selective inhibitor of M(3) receptor. Only the latter reduced the vasodilatation by Ce8 and Cp12. To investigate the role of the nitric oxide synthase (NOS), we used N(G)-nitro-l-arginine methyl ester (l-NAME, 10 µM), a selective NOS inhibitor, which decreased the dilatation induced by Ce8 and Cp12. Finally, we studied the action of (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 3 µM), a selective guanylyl cyclase inhibitor, which inhibited the dilatation by Casimiroa extracts. CONCLUSION: The data show that methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12) induce vasorelaxation by M(3) receptor through the activation of cGMP-dependent NO signaling. These results support the traditional use of Casimiroa decoctions for antihypertensive treatments in the Mexican ethnomedicine.

Aescin protection of human vascular endothelial cells exposed to cobalt chloride mimicked hypoxia and inflammatory stimuli.

Human vascular endothelial cells (HUVECs) were exposed to CoCl2 as an in vitro model of hypoxia. Expression of VCAM-1 (vascular cell adhesion molecule), reduction of PECAM-1 (platelet endothelial cell adhesion molecule) and cytoskeletal changes without alterations in cell viability were observed. HUVECs were also exposed to Escherichia coli lipopolysaccaride (LPS) as an in vitro model of inflammation: significant IL-6 release was measured. Pre-treatment of HUVECs with aescin prevented, in a concentration-dependent fashion (0.1-1 microM), the action of CoCl2 on VCAM-1 and PECAM-1, also preserving endothelial cell morphology. Furthermore, aescin pre-treatment reduced IL-6 release from LPS-activated vascular endothelium.

Gramine: a vasorelaxing alkaloid acting on 5-HT(2A) receptors.

The vascular effects of gramine on resistance vessels were evaluated, in particular as regards the 5-hydroxytryptamine (5-HT) system. We compared the action of gramine with that of ketanserin, a 5-HT (2A) antagonist; both compounds induced concentration-dependent relaxation in precontracted arterial rings. Also, the 5-HT concentration-effect curve shifted to the right in the presence of gramine, like ketanserin. These results suggest that gramine is a vasorelaxing agent acting mainly by antagonism at 5-HT (2A) receptors.