Grayanane diterpenoids from Craibiodendron yunnanense with anti-inflammatory and antinociceptive activities.

Twenty-five grayanane diterpenoids including six undescribed compounds (craibiodenoside A-F), were isolated from the leaves of Craibiodendron yunnanense W. W. Smith. The structures of the isolated compounds were determined by 1D-NMR, 2D-NMR, and HR-ESI-MS spectrometric analyses. All compounds were evaluated for their anti-inflammatory activities by inhibiting the release of interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 cells. The results demonstrated that three undescribed compounds craibiodenoside A, B, F, and three known compounds could inhibit the release of IL-6 significantly. In addition, the antinociceptive activities of compounds were assessed using acetic acid-induced writhing test. Craibiodenoside D, grayanoside D, and rhodojaponins VI exhibited notable antinociceptive activities. Specifically, rhodojaponins VI exhibited antinociceptive activity with the inhibition percentage of 87.6%.

Vaccinium Species (Ericaceae): Phytochemistry and Biological Properties of Medicinal Plants.

The Vaccinium L. (Ericaceae) genus consists of a globally widespread and diverse genus of around 4250 species, of which the most valuable is the Vaccinioidae subfamily. The current review focuses on the distribution, history, bioactive compounds, and health-related effects of three species: cranberry, blueberry, and huckleberry. Several studies highlight that the consumption of Vaccinium spp. presents numerous beneficial health-related outcomes, including antioxidant, antimicrobial, anti-inflammatory, and protective effects against diabetes, obesity, cancer, neurodegenerative diseases and cardiovascular disorders. These plants' prevalence and commercial value have enhanced in the past several years; thus, the generated by-products have also increased. Consequently, the identified phenolic compounds found in the discarded leaves of these plants are also presented, and their impact on health and economic value is discussed. The main bioactive compounds identified in this genus belong to anthocyanins (cyanidin, malvidin, and delphinidin), flavonoids (quercetin, isoquercetin, and astragalin), phenolic acids (gallic, p-Coumaric, cinnamic, syringic, ferulic, and caffeic acids), and iridoids.

Minor terpenoids from the leaves of Craibiodendron yunnanense.

One new taraxastane-type triterpenoid, three new grayanane-type diterpenoids (2 - 4), and 12 known compounds (5 - 16) were isolated from the leaves of Craiobiodendron yunnanens W. W. Smith. The structures of these compounds were elucidated on the basis of their spectroscopic data and chemical evidence. Compounds 1 and 8 exhibited partly anti-inflammatory activity based on the inhibition of NF-κB activity in SW480 cells at 10 µM with inhibition ratios of 60.53 and 59.20%, respectively. Compounds 10 and 13 showed excellent cytotoxicity against human leukemia cell (MV4-11) at 10 µM with inhibition ratios of 43.02 and 49.11%, respectively.

Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility.

BACKGROUND: Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential. METHODS: In vitro assays were used to investigate heather's anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition. RESULTS: Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage. CONCLUSIONS: Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe.

Determination of the Phenolic Profile by Liquid Chromatography, Evaluation of Antioxidant Activity and Toxicity of Moroccan Erica multiflora, Erica scoparia, and Calluna vulgaris (Ericaceae).

This study aimed to investigate the phenolic profile and selected biological activities of the leaf and aerial extracts of three Ericaceae species, namely Erica multiflora, Erica scoparia, and Calluna vulgaris, collected from three different places in the north of Morocco. The phenolic composition of all extracts was determined by LC coupled with photodiode array and mass spectrometry detection. Among the investigated extracts, that of E. scoparia aerial parts was the richest one, with a total amount of polyphenols of 9528.93 mg/kg. Up to 59 phenolic compounds were detected: 52 were positively identified and 49 quantified-11 in C. vulgaris, 14 in E. multiflora, and 24 in E. scoparia. In terms of chemical classes, nine were phenolic acids and 43 were flavonoids, and among them, the majority belonged to the class of flavonols. The antioxidant activity of all extracts was investigated by three different in vitro methods, namely DPPH, reducing power, and Fe2+ chelating assays; E. scoparia aerial part extract was the most active, with an IC50 of 0.142 ± 0.014 mg/mL (DPPH test) and 1.898 ± 0.056 ASE/mL (reducing power assay). Further, all extracts were non-toxic against Artemia salina, thus indicating their potential safety. The findings attained in this work for such Moroccan Ericaceae species, never investigated so far, bring novelty to the field and show them to be valuable sources of phenolic compounds with interesting primary antioxidant properties.

Cytotoxic activity of strawberry tree (Arbutus unedo L.) honey, its extract, and homogentisic acid on CAL 27, HepG2, and Caco-2 cell lines.

Strawberry tree (Arbutus unedo L.) honey (STH), also known as "bitter honey", is a traditional medicine widely used in the Mediterranean area. Regardless of geographical origin, it usually has a very high content of phenolic compounds and strong antioxidant capacity. Yet, little is still known about the effects of STH, its phenolic extract (STHE), and its main bioactive compound - homogentisic acid (HGA) - at the cell level. The aim of this study was to estimate total phenolic content, DPPH radical scavenging activity, and ferric reducing antioxidant power of STH made in Croatia and investigate cytotoxic and pro-oxidative effects of STH, STHE and HGA on three human cell lines: tongue squamous cell carcinoma (CAL 27), hepatocellular carcinoma (HepG2), and epithelial colorectal adenocarcinoma cells (Caco-2) cells. These substances were tested at four concentrations (0.5-5× average human daily intake of STH) and over 30 min and 1 and 2 h. Croatian STH had a total phenolic content of 1.67 g gallic acid equivalents (GAE) per kg of honey, DPPH radical scavenging activity of 2.96 mmol Trolox equivalents (TE) per kg of honey, and ferric reducing antioxidant power (FRAP) of 13.5 mmol Fe2+ per kg of honey. Our results show no clear and consistent time- or concentration-dependent cytotoxicity in any of the cell lines. ROS levels in all the three cell types at almost all exposure times were not significantly higher than control. The most important observation is that the tested substances have low cytotoxicity and high biocompatibility, regardless of concentration, which is a good starting point for further research of their biological effects in other models.

Optimization of an Ultrasound-Assisted Extraction Method for the Analysis of Major Anthocyanin Content in Erica australis Flowers.

Erica australis plants have been used in infusions and folk medicine for years for its diuretic and antiseptic properties and even for the treatment of infections. In addition, a recently published thorough study on this species has demonstrated its antioxidant, antibiotic, anti-inflammatory, anticarcinogenic and even antitumoral activities. These properties have been associated with the high content of anthocyanins in E. australis leaves and flowers. The aim of the present research is to optimize an ultrasound-assisted extraction methodology for the recovery of the anthocyanins present in E. australis flowers. For that purpose, a Box Behnken design with response surface methodology was employed, and the influence of four variables at different values was determined: namely, the composition of the extraction solvents (0-50% MeOH in water), the pH level of those solvents (3-7), the extraction temperature (10-70 °C), and the sample:solvent ratio (0.5 g:10 mL-0.5 g:20 mL). UHPLC-UV-vis has been employed to quantify the two major anthocyanins detected in the samples. The extraction optimum conditions for 0.5 g samples were: 20 mL of solvent (50% MeOH:H2O) at 5 pH, with a 15 min extraction time at 70 °C. A precision study was performed and the intra-day and inter-day relative standard deviations (RSDs) obtained were 3.31% and 3.52%, respectively. The developed methodology has been successfully applied to other Erica species to validate the suitability of the method for anthocyanin extraction.

Oxygenated pentacyclic triterpenoids from the stems and branches of Enkianthus chinensis.

Thirty new pentacyclic triterpenoids, including five oleanane-type (1-5), twenty-three ursane-type (9-23, 26-33) and two taraxerane-type (24 and 25), along with fourteen known triterpenoids, were isolated from the stems and branches of Enkianthus chinensis. Their structures were elucidated by extensive spectroscopic analyses, X-ray crystallographic data and electronic circular dichroism (ECD) techniques. Sixteen compounds (1-5, 9-13, 20, 22, 32, 34-36) bearing a gem-hydroxymethyl group at C-4 represent rare examples of pentacyclic triterpenoids. In the in vitro biological activity evaluation, compounds 8, 9, 12-14, 17, 24, and 44 exhibited potent hepatoprotective effects at 10 µM. Moreover, compound 25 showed latent activity against HSV-1 with an IC50 value of 6.4 µM.

In-vivo anti-inflammatory activity and safety assessment of the aqueous extract of Algerian Erica arborea L. (Ericaceae) aerial parts.

ETHNOPHARMACOLOGICAL RELEVANCE: Erica arborea known as Khlenj in Algeria is a small shrub belonging to Ericaceae family. E. arborea Aqueous extract (EAAE) is used in traditional medicine for anti-inflammatory, diuretic, antimicrobial, and antiulcer purposes. AIM OF THE STUDY: To our knowledge, no data reveal the combination between in-vivo anti-inflammatory and toxicological studies of EAAE. For this purpose, the aim of this study is to evaluate the biological activity cited above and assess its safety. MATERIAL AND METHODS: Anti-inflammatory activity was undergone using carrageenan-induced paw edema and croton oil-induced ear edema. The acute and sub-acute toxicity were conducted following the OECD guidelines 423 and 407, respectively. Phytochemical identification was carried out using HPLC-DAD-MS. Quantitative evaluation of polyphenols; flavonoids and antioxidant activity of EAAE were also determined. RESULTS: Oral administration of EAAE (250 and 500 mg/kg) significantly (p < 0.05) reduced the edema induced by carrageenan. Administration of EAAE dosed at 250 and 500 mg/kg exhibited efficacy in reducing edema induced by croton oil. The acute administration of EAAE at doses of 2000 and 5000 mg/kg did not cause any mortality or adverse effects indicating that the LD50 is above 5000 mg/kg. The prolonged administration of EAAE (500 and 1000 mg/kg) showed a significant reduction in triglycerides levels in male and female rats whereas no significant changes in other biochemical and hematological parameters were observed. Histopathological damages were recorded in both liver and kidney animal's tissues of both sexes treated with medium and maximum doses of EAAE. Phytochemical characterization of EAAE revealed a high amount of phenolic compounds, HPLC-DAD-MS analysis led to the identification of chlorogenic acid and five flavonol glycosides: myricetin pentoside, quercetin-3-O-glucoside, myricetin-3-O-rhamnoside, quercetin-3-O-pentoside, and quercetin-3-O-rhamnoside. CONCLUSION: In the light of the results obtained in this study, EAAE corroborates the popular use to treat the anti-inflammatory impairments. EAAE can be considered as non-toxic in acute administration and exhibited a moderate toxicity in sub-acute administration. High phenolic content and in-vitro antioxidant activity observed indicate that EAAE may reduce oxidative stress markers in-vivo.

Phenolic Compounds in Poorly Represented Mediterranean Plants in Istria: Health Impacts and Food Authentication.

Phenolic compounds are well-known bioactive compounds in plants that can have a protective role against cancers, cardiovascular diseases and many other diseases. To promote local food development, a comprehensive overview of the phenolic compounds' composition and their impact on human health from typical Mediterranean plants such as Punica granatum L., Ziziphus jujuba Mill., Arbutus unedo L., Celtis australis L., Ficus carica L., Cynara cardunculus var. Scolymus L. is provided. Moreover, the potential use of these data for authenticity determination is discussed. Some of the plants' phenolic compounds and their impact to human health are very well determined, while for others, the data are scarce. However, in all cases, more data should be available about the content, profile and health impacts due to a high variation of phenolic compounds depending on genetic and environmental factors. Quantifying variation in phenolic compounds in plants relative to genetic and environmental factors could be a useful tool in food authentication control. More comprehensive studies should be conducted to better understand the importance of phenolic compounds on human health and their variation in certain plants.

Stability assessment of extracts obtained from Arbutus unedo L. fruits in powder and solution systems using machine-learning methodologies.

Arbutus unedo L. (strawberry tree) has showed considerable content in phenolic compounds, especially flavan-3-ols (catechin, gallocatechin, among others). The interest of flavan-3-ols has increased due their bioactive actions, namely antioxidant and antimicrobial activities, and by association of their consumption to diverse health benefits including the prevention of obesity, cardiovascular diseases or cancer. These compounds, mainly catechin, have been showed potential for use as natural preservative in foodstuffs; however, their degradation is increased by pH and temperature of processing and storage, which can limit their use by food industry. To model the degradation kinetics of these compounds under different conditions of storage, three kinds of machine learning models were developed: i) random forest, ii) support vector machine and iii) artificial neural network. The selected models can be used to track the kinetics of the different compounds and properties under study without the prior knowledge requirement of the reaction system.

Lanostane triterpene glycosides from the flowers of Lyonia ovalifolia var. hebecarpa and their antiproliferative activities.

Sixteen lanostane-type triterpene glycosides including eight new ones, named lyonicarposides A-H (1-8), were isolated from the flowers of Lyonia ovalifolia var. hebecarpa (Franch. ex F.B. Forbes & Hemsl.) Chun (Ericaceae). The chemical structures of the new compounds were elucidated by the comprehensive spectroscopic techniques and chemical methods. The Mo2(OAc)4-induced electronic circular dichroism method was used to determine the absolute configurations of C-24 in lyonicarposides A (1), C (3), and E (5). This is the first phytochemical study on the flowers of L. ovalifolia var. hebecarpa. All the isolates were evaluated for their antiproliferative activities against SMMC-7721, HL-60, SW480, MCF-7, and A-549 cell lines. Lyonicarposides A (1) and B (2) showed moderate antiproliferative activities against five cancer cell lines with IC50 values ranging from 12.39 to 28.71 µM. Lyonicarposides C (3) and G (7) and lyonifoloside M (12) selectively inhibited the proliferation of HL-60 and MCF-7 cell lines with IC50 values ranging from 13.03 to 17.71 µM. Interestingly, lyonifoloside L (13) selectively inhibited the proliferation of MCF-7 cell line with an IC50 value of 16.27 µM. Their structure-activity-relationships were discussed.

Grayanane diterpenoid glucosides as potent analgesics from Pieris japonica.

A total of fifteen grayanane diterpenoid glucosides including eight undescribed ones, pierisjaponosides A-H, were isolated from the leaves of Pieris japonica (Thunb.) D. Don ex G. Don (Ericaceae). Their structures were established by extensive spectros copic techniques including HRESIMS and NMR, as well as chemical methods. The absolute configurations of pierisjaponosides A, B, and D were finally established by single-crystal X-ray diffraction with Cu Kα radiation. This is the first time to report the crystal structure of a 5,9-epoxygrayanane diterpenoid glucoside. Pierisjaponoside E represents the first example of a 9ß-hydroxygrayan-1(10)-ene diterpenoid. All the isolated grayanane diterpenoid glucosides were evaluated for their analgesic activities in the acetic acid-induced writhing models in mice, and showed significant analgesic effects. Pierisjaponosides A and C-H, micranthanoside A, pieroside A, and craiobiosides A and B displayed significant analgesic effects with the writhe inhibition rates over 50% at a dose of 5.0 mg/kg. Pierisjaponoside E exhibited significant analgesic activities with the percentage inhibitions of 81.7%, 70.4%, and 52.1% at the doses of 5.0, 1.0, and 0.2 mg/kg, respectively. The preliminary structure-activity relationships of grayanane diterpenoid glucosides as potent analgesics were discussed, giving some clues to design novel analgesics.

Essential oil and fractions isolated of Laurel to control adults and larvae of cattle ticks.

This study, was to evaluate the acaricidal effect of the essential oil (EO) and fractions (FR) obtained from Laurus nobilis leaves on Rhipicephalus (Boophilus) microplus. Eight fractions were obtained, however FR1: sabinene (37.83%), ß-pinene (13.50%), 1,8-cineole (12.66%), α-pinene (12.56%) and FR8: α-terpineol (79.19%) were highlighted as to the larvicidal potential when submitted by Larval Packet Test. The EO was tested by the Adult Immersion Test, at concentrations of 200.00; 100.00 and 50.00 µL/mL caused mortality of engorged females, egg mass reduction and hatching inhibition. Two fractions are shown to be efficient in controlling larvae FR8 (LC50 = 0.13 µL/mL, LC99 = 0.51 µL/mL) and FR1 (LC50 = 0.20 µL/mL, LC99 = 0.56 µL/mL). The fractionation of EO was determinant to elucidate which compounds were responsible for the larvicidal potential. This study opens new perspectives to direct new bioassays with the compounds obtained in the fractionation, since they present high potential on cattle tick larvae.

α-Arbutin Protects Against Parkinson's Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.

Isolation, synthesis, and biological activities of a bibenzyl from Empetrum nigrum var. japonicum.

4-(2-Hydroxyphenethyl)-2,6-dimethoxyphenol, a bibenzyl, was isolated from the leaves of Empetrum nigrum var. japonicum, collected from Mount Tateyama. Japanese rock ptarmigans frequently eat the leaves and fruits of this plant. The structure of the bibenzyl was confirmed by NMR spectroscopic analysis and fully characterized. A synthesis of this compound was accomplished by coupling 2-hydroxyphenylacetic acid with syringaldehyde, decarboxylation of the resultant isoaurones, and hydrogenation of the double bond in the corresponding stilbene. This compound displayed cytotoxic activity against human cancer cells (HCT116 and Hela cells) and leukemia cells (HL-60 cells). The present study suggests that this plant serves as a source of biologically active natural products. Also, our findings provide information on the secondary metabolites in the diet of Japanese rock ptarmigans.

New Lectins from Mediterranean Flora. Activity against HT29 Colon Cancer Cells.

Experiments conducted in vitro and in vivo, as well as some preclinical trials for cancer therapeutics, support the antineoplastic properties of lectins. A screening of antitumoral activity on HT29 colon cancer cells, based on polypeptide characterization and specific lectin binding to HT29 cells membrane receptors, was performed in order to assess the bioactivities present in four Mediterranean plant species: Juniperus oxycedrus subsp. oxycedrus, Juniperus oxycedrus subsp. badia, Arbutus unedo and Corema album. Total leaf proteins from each species were evaluated with respect to cell viability and inhibitory activities on HT29 cells (cell migration, matrix metalloproteinase -MMP proteolytic activities). A discussion is presented on a possible mechanism justifying the specific binding of lectins to HT29 cell receptors. All species revealed the presence of proteins with affinity to HT29 cell glycosylated receptors, possibly explaining the differential antitumor activity exhibited by the two most promising species, Juniperus oxycedrus subsp. badia and Arbutus unedo.

Phenolic Compounds from Five Ericaceae Species Leaves and Their Related Bioavailability and Health Benefits.

Some species of the Ericaceae family have been intensively studied because of the beneficial health impact, known since ancient times, of their chemical components. Since most studies focus on the effects of fruit consumption, this review aims to highlight the phenolic components present in the leaves. For this purpose, five species from Ericaceae family (bilberry-Vaccinium myrtillus L., lingonberry-V. vitis-idaea L., bog bilberry-V. uliginosum L., blueberry-V. corymbosum L. and bearberry-Arctostapylos uva-ursi L.) were considered, four of which can be found in spontaneous flora. The chemical composition of the leaves revealed three major phenolic compounds: chlorogenic acid, quercetin and arbutin. The health promoting functions of these compounds, such as antioxidant and anti-inflammatory properties that could have preventive effects for cardiovascular disease, neurodegenerative disorders, cancer, and obesity, have been exemplified by both in vitro and in vivo studies in this review. Furthermore, the importance of bioaccessibility and bioavailability of the phenolic compounds have been summarized. The findings highlight the fact that leaves of some Ericaceae species deserve increased attention and should be studied more profoundly for their biological activities, especially those from spontaneous flora.

An overview of grayanane diterpenoids and their biological activities from the Ericaceae family in the last seven years.

Grayanane diterpenoids, possessing a unique 5/7/6/5 tetracyclic system, exist exclusively in plants of the Ericaceae family. Owing to their various skeletons, complex structures, and diverse bioactivities, grayanoids have been the topic of research in many phytochemical and pharmacological laboratories, offering opportunities for the development of new drugs with analgesic, anti-inflammatory, and protein tyrosine phosphatase 1B (PTP1B) properties. Recently, a number of new grayanane diterpenoids with unprecedented carbon skeletons have been obtained from plants of the Ericaceae family, and they exhibit diverse biological properties, such as agalgesic, antinociceptive, anticancer, antiviral, antifeedant, insecticidal, toxicity, and PTP1B. In this review, 162 new grayanoids with 14 carbon skeletons from the Ericaceae family over the past seven years (2012-October 2018) are discussed, including their occurrence and distribution, skeleton types, structural features, biological activities, and structure-activity relationships (SARs). Also, strategies for the structural elucidation are summarized to provide useful information for medicinal chemists in developing potent anticancer, antiviral, analgesic, anti-inflammatory, and novel PTP1B agents.

Bioactive megastigmane glucosides and monoterpenes from Lyonia ovalifolia.

Three new megastigmane glucosides (1-3) and two new monoterpenes (4-5), together with 14 related known compounds (6-19) were isolated from the twigs and leaves of Lyonia ovalifolia. The structures of the new compounds were determined by extensive MS, NMR, CD experiments and chemical methods. Compounds 2, 6, and 18 displayed potent antiviral activity against Coxsackie B3, with IC50 values between 6.4 and 14.6 µM. Additionally, compounds 6, 10, and 11 exhibited noteworthy anti-inflammatory activities, with inhibition rates ranging from 54.55% to 83.33% under the concentration of 10-5 M.