Natural Phenolic Compounds with Neuroprotective Effects.

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases are three of the major neurodegenerative diseases. To date, researchers have found various natural phytochemicals that could potentially be used to treat neurodegenerative diseases. Particularly, the application of natural phenolic compounds has gained significant traction in recent years, driven by their various biological activities and therapeutic efficacy in human health. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and can neutralize the effects of oxidative stress, inflammation, and apoptosis in animal models. This review focuses on the current state of knowledge on phenolic compounds, including phenolic acids, flavonoids, stilbenes, and coumarins, as well as their beneficial effects on human health. We further provide an overview of the therapeutic potential and mechanisms of action of natural dietary phenolics in curing neurodegenerative diseases in animal models.

Novel insights into enzymes inhibitory responses and metabolomic profile of supercritical fluid extract from chestnut shells upon intestinal permeability.

The health benefits of chestnut (Castanea sativa) shells (CSs) have been ascribed to phytochemicals, mainly phenolic compounds. Nevertheless, an exhaustive assessment of their intestinal absorption is vital considering a possible nutraceutical application. This study evaluated the bioactivity of CSs extract prepared by Supercritical Fluid Extraction and untargeted metabolomic profile upon in-vitro intestinal permeation across a Caco-2/HT29-MTX co-culture model. The results demonstrated the neuroprotective, hypoglycemic, and hypolipidemic properties of CSs extract by inhibition of acetylcholinesterase, α-amylase, and lipase activities. The untargeted metabolic profiling by LC-ESI-LTQ-Orbitrap-MS unveiled almost 60 % of lipids and 30 % of phenolic compounds, with 29 metabolic pathways indicated by enrichment analysis. Among phenolics, mostly phenolic acids, flavonoids, and coumarins permeated the intestinal barrier with most metabolites arising from phase I reactions (reduction, hydrolysis, and hydrogenation) and a minor fraction from phase II reactions (methylation). The permeation rates enhanced in the following order: ellagic acid < o-coumaric acid < p-coumaric acid < ferulaldehyde ≤ hydroxyferulic acid ≤ dihydroferulic acid < ferulic acid < trans-caffeic acid < trans-cinnamic acid < dihydrocaffeic acid, with better outcomes for 1000 µg/mL of extract concentration and after 4 h of permeation. Taken together, these findings sustained a considerable in-vitro intestinal absorption of phenolic compounds from CSs extract, enabling them to reach target sites and exert their biological effects.

Design and in vitro effectiveness evaluation of Echium amoenum extract loaded in bioadhesive phospholipid vesicles tailored for mucosal delivery.

The Echium amoenum Fisch. and C.A. Mey. (E. amoenum) is an herb native from Iranian shrub, and its blue-violet flowers are traditionally used as medical plants. In the present study, an antioxidant phytocomplex was extracted from the flowers of E. amoenum by ultrasounds-assisted hydroalcoholic maceration. The main components, contained in the extract, have been detected using HPLC-DAD, and rosmarinic acid was found to be the most abundant. The antioxidant power of the extract along with the phenolic content were measured using colorimetric assays. The extract was loaded in liposomes, which were enriched adding different bioadhesive polymers (i.e., mucin, xanthan gum and carboxymethyl cellulose sodium salt) individually or in combination. The main physico-chemical properties (i.e. size, size distribution, surface charge) of the prepared vesicles were measured as well as their stability on storage. The viscosity of dispersion and the ability of vesicles to interact with mucus were evaluated measuring their stability in a mucin dispersion and mobility in a mucin film. The biocompatibility and the ability of the formulations to protect keratinocytes from damages caused by hydrogen peroxide and to promote the cell migration were measured in vitro.

Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia.

A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3's downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3Y367C/+) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH.

Therapeutic Targets for Phenolic Compounds from Agro-industrial By-products against Obesity.

BACKGROUND: Obesity is considered a global epidemic. This disorder is associated with several health effects, such as metabolic disturbances that need both prevention and treatment actions. In this sense, bioactive secondary metabolites can be obtained from cheap sources such as agro-industrial waste, providing a sustainable alternative against obesity. Among these secondary metabolites, phenolic compounds present a common chemical structure core with different substitutions that provide them with biological properties such as antioxidant, inflammatory, and anti-aging capacities. OBJECTIVE: The aim of this review is to compile anti-obesity therapeutic targets for phenolic compounds from agro-industrial by-products. METHOD: Scientific information has been obtained from different databases, such as Scopus, PubMed and Google Scholar, in order to select the available full-text studies conducted in the last few years. RESULTS: This review shows that peel, seed, pomace and other by-products from agro-industry have different effects inhibiting enzymes related to lipid or glucose metabolism and modulating biomarkers, genes and gut microbiota in animal models. CONCLUSION: Revalorizing actions of agro-industrial byproducts in the prevention or treatment of obesity or associated disorders can be considered to develop new high value products that act on lipid, glucose and energy metabolisms, oxidative stress, inflammation, adipose tissue or gut microbiota. However, further human studies are needed in order to establish the optimal administration parameters.

A Prospective of Multiple Biopharmaceutical Activities of Procyanidins-Rich Uapaca togoensis Pax Extracts: HPLC-ESI-TOF-MS Coupled with Bioinformatics Analysis.

The article reports the chemical composition, antioxidant, six key enzymes inhibitory and antimicrobial activities of two solvent extracts (water and methanol) of leaves and stem bark of Uapaca togoensis. For chemical composition, methanol extract of stem bark exhibited significant higher total phenolic (129.86 mg GAE/g) and flavanol (10.44 mg CE/g) contents. Methanol extract of leaves and water extract of stem bark showed high flavonoids (20.94 mg RE/g) and phenolic acid (90.40 mg CAE/g) content, respectively. In addition, HPLC-ESI-TOF-MS analysis revealed that U. togoensis was rich in procyanidins. The methanol and water extracts of stem bark had overall superior antioxidant activity; however, only methanol extract of stem bark showed higher inhibition of cholinesterase (AChE: 2.57 mg GALAE/g; BChE: 4.69 mg GALAE/g), tyrosinase (69.53 mg KAE/g) and elastase (2.73 mmol CE/g). Potent metal chelating ability was showed by water extract of leaves (18.94 mg EDTAE/g), higher inhibition of amylase was detected for water extracts of leaves (0.94 mmol ACAE/g) and stem bark (0.92 mmol ACAE/g). The tested extracts have shown wide-spectrum antibacterial properties and these effects have shown to be more effective against Aspergillus ochraceus, Penicillium funiculosum, Trichoderma viride, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa. The results revealed that the antioxidant, enzyme inhibitory and antimicrobial activities depended on the extraction solvents and the parts of plant. Bioinformatics analysis on the 17 major compounds showed modulation of pathway associated with cancer. In brief, U. togoensis might be valuable as potential source of natural agents for therapeutic application.

The Role of High-Resolution Analytical Techniques in the Development of Functional Foods.

The approaches based on high-resolution analytical techniques, such as nuclear magnetic resonance or mass spectrometry coupled to chromatographic techniques, have a determining role in several of the stages necessary for the development of functional foods. The analyses of botanical extracts rich in bioactive compounds is one of the fundamental steps in order to identify and quantify their phytochemical composition. However, the compounds characterized in the extracts are not always responsible for the bioactive properties because they generally undergo metabolic reactions before reaching the therapeutic targets. For this reason, analytical techniques are also applied to analyze biological samples to know the bioavailability, pharmacokinetics and/or metabolism of the compounds ingested by animal or human models in nutritional intervention studies. In addition, these studies have also been applied to determine changes of endogenous metabolites caused by prolonged intake of compounds with bioactive potential. This review aims to describe the main types and modes of application of high-resolution analytical techniques in all these steps for functional food development.

Bioactivity assays, chemical characterization, ADMET predictions and network analysis of Khaya senegalensis A. Juss (Meliaceae) extracts.

Khaya senegalensis A. Juss (Meliaceae) is a popular medicinal plant, widely used in the management of various ailments in the African traditional medicine. This study attempts to investigate into the different extraction methods (homogenizer-assisted extraction (HAE), maceration (MAC), infusion and Soxhlet (SE) extraction) on the pharmacological properties and chemical profiles of K. senegalensis. Antioxidant properties and inhibitory potential against key enzymes were assessed and bioinformatics analysis was conducted on selected limonoids to predict putative pharmacokinetics and protein targets underlying the pharmacological effects. Overall, the leaf extracts showed notable flavonoid (20.59-104.43 mg RE/g) content and the stem barks extracts displayed the highest total phenolic (87.69-46.28 mg GAE/g), phenolic acid (62.96-107.22 mg CE/g), flavanol (3.60-135.40 mg CAE/g) contents. All extracts showed remarkable antioxidant activities, with the MAC-Water leaf extract being most active in all the assays. Regarding stem bark, the MAC-MeOH extract exerted the highest free radical scavenging abilities, while HAE and MAC extracts were better sources of reducing agent and metal chelators. The HAE-MeOH, MAC-Water, and SE extracts showed noteworthy inhibitory activity against AChE, BChE (only stem barks), tyrosinase and α-glucosidase (only stem barks). All extracts displayed moderate inhibitory activities against α-amylase. The bioinformatics approach showed that khayanoside A and C interacted with multiple isoforms of metalloproteinase, while humilin B and khayanone interacted with opioid receptors. To sum up, the chemical profiles and biological activities of K. senegalensis were closely dependent on the extraction methods. Results amassed from this study showed that K. senegalensis is a potent source of bioactive compounds which could be explored as a functional food.

Areca catechu-From farm to food and biomedical applications.

The family Arecaceae includes 181 genera and 2,600 species with a high diversity in physical characteristics. Areca plants, commonly palms, which are able to grow in nearly every type of habitat, prefer tropical and subtropical climates. The most studied species Areca catechu L. contains phytochemicals as phenolics and alkaloids with biological properties. The phenolics are mainly distributed in roots followed by fresh unripe fruits, leaves, spikes, and veins, while the contents of alkaloids are in the order of roots, fresh unripe fruits, spikes, leaves, and veins. This species has been reputed to provide health effects on the cardiovascular, respiratory, nervous, metabolic, gastrointestinal, and reproductive systems. However, in many developing countries, quid from this species has been associated with side effects, which include the destruction of the teeth, impairment of oral hygiene, bronchial asthma, or oral cancer. Despite these side effects, which are also mentioned in this work, the present review collects the main results of biological properties of the phytochemicals in A. catechu. This study emphasizes the in vitro and in vivo antioxidant, antimicrobial, anticancer, and clinical effectiveness in humans. In this sense, A. catechu have demonstrated effectiveness in several reports through in vitro and in vivo experiments on disorders such as antimicrobial, antioxidant, or anticancer. Moreover, our findings demonstrate that this species presents clinical effectiveness on neurological disorders. Hence, A. catechu extracts could be used as a bioactive ingredient for functional food, nutraceuticals, or cosmeceuticals. However, further studies, especially extensive and comprehensive clinical trials, are recommended for the use of Areca in the treatment of diseases.

The Potential Synergistic Modulation of AMPK by Lippia citriodora Compounds as a Target in Metabolic Disorders.

Lippia citriodora (LC) represents a complex plant-derived source of polyphenols and iridoids that has shown beneficial properties against obesity-related metabolic disorders. The complete extract and its major compound, verbascoside, have shown AMPK-activating capacity in cell and animal models. In this work, we aimed to elucidate the contribution of the different compounds present in the LC extract on the AMPK activation capacity of the whole extract. Semipreparative reversed-phase high-performance liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (RP-HPLC-ESI-TOF-MS) was used to identify the major compounds with bioassay-guided fractionation in an adipocyte cell model for the measurement of AMPK activity. Twenty-two compounds were identified and purified almost to homogeneity in 16 fractions, and three compounds, namely verbascoside, luteolin-7-diglucuronide and loganic acid, showed the highest AMPK-activating capacity. The synergy study using the checkerboard and fractional inhibitory concentration index (FICI) methods exhibited synergistic behavior between loganic acid and luteolin-7-diglucuronide. Molecular docking experiments revealed that these three compounds might act as direct agonists of AMPK, binding to the AMP binding sites of the gamma subunit and/or the different sites of the interaction zones between the gamma and beta subunits. Although our findings conclude that the bioactivity of the extract is mainly due to verbascoside, the synergy found between loganic acid and luteolin-7-diglucuronide deserves further research aimed to develop optimized combinations of polyphenols as a new nutritional strategy against obesity-related metabolic disorders.

Berberis Plants-Drifting from Farm to Food Applications, Phytotherapy, and Phytopharmacology.

The genus Berberis includes about 500 different species and commonly grown in Europe, the United States, South Asia, and some northern areas of Iran and Pakistan. Leaves and fruits can be prepared as food flavorings, juices, and teas. Phytochemical analysis of these species has reported alkaloids, tannins, phenolic compounds and oleanolic acid, among others. Moreover, p-cymene, limonene and ocimene as major compounds in essential oils were found by gas chromatography. Berberis is an important group of the plants having enormous potential in the food and pharmaceutical industry, since they possess several properties, including antioxidant, antimicrobial, anticancer activities. Here we would like to review the biological properties of the phytoconstituents of this genus. We emphasize the cultivation control in order to obtain the main bioactive compounds, the antioxidant and antimicrobial properties in order to apply them for food preservation and for treating several diseases, such as cancer, diabetes or Alzheimer. However, further study is needed to confirm the biological efficacy as well as, the toxicity.

Innovative perspectives on Pulicaria dysenterica extracts: phyto-pharmaceutical properties, chemical characterization and multivariate analysis.

BACKGROUND: In this study, we aimed to evaluate the influence of different extraction procedures [decoction, homogenizer-assisted extraction (HAE), infusion, maceration, Soxhlet and ultrasound-assisted extraction (UAE)] on the chemical profiling and biological properties of methanol and water extracts of Pulicaria dysenterica (L.) Bernh. The chemical profiles of the extracts were evaluated by high-performance liquid chromatography coupled to electrospray ionization and time-of-flight mass spectrometry (HPLC-ESI-TOF-MS). The antioxidant properties and enzymes (lipase, α-amylase, α-glucosidase, tyrosinase and cholinesterases) inhibitory potential of the extracts were evaluated. RESULTS: The chemical profiles were dependent on the type of extraction methods as well as on the type of solvent. The methanolic extracts showed higher levels of total phenolic, flavonoid, and phenolic acid content, while the highest total flavonol content was observed in the HAE-water extract. Forty different compounds were identified from P. dysenterica. In relation to the potential in vitro anti-diabetic effects, the highest activity against the studied key enzymes was observed for the macerated extract (α-amylase: 0.58 ± 0.03 and α- glucosidase: 1.65 ± 0.03 mmol ACAE g-1 ). The HAE-methanol extract was the most potent inhibitor of cholisterases, whereas the highest activities against tyrosinase were observed for UAE-methanol extract, followed by macerated and Soxhlet. The inhibitory activity of the studied extracts against lipase were in the order: soxhlet > macerated> HAE-methanol > UAE-methanol. CONCLUSION: This study has established scientific baseline data on the therapeutic properties of P. dysentrica, thereby advocating the need for further investigations in an endeavour to develop novel pharmaceuticals from this plant. © 2019 Society of Chemical Industry.

Different behavior of polyphenols in energy metabolism of lipopolysaccharide-stimulated cells.

Energy metabolism is one of the main sources of reactive oxygen species leading to oxidation and inflammation in pathophysiological processes. Lipopolysaccharide (LPS)-activated mouse embryonic fibroblast (MEF) cell lines from knock-out mice for paraoxonase-1 and from transgenic mice overexpressing monocyte chemoattractant protein-1 were obtained as model of pro-oxidant and pro-inflammatory scenarios. Theobroma cacao and Lippia citriodora (worldwide consumed and common ingredient of many food products) were tested in these cell models to assess the action of polyphenols in the energy management. Our metabolomics experiments show a different behavior of polyphenols: T. cacao extract partially reverts the effect of LPS in a pro-oxidant scenario through the antioxidant properties of theobromine, flavonols and procyanidins, while L. citriodora seems to act mainly in a pro-inflammatory cell model through the action of verbascoside decreasing the production of pro-inflammatory cytokines and MCP-1. Nevertheless, the action of polyphenols cannot be attributed only to a mechanism of action but the sum of different modulations in biological pathways. The capacity of both plant extracts to decrease α-ketoglutarate levels merits special attention due to the implications in future medicine. The action of polyphenols modulating oxidative stress, cytokine production and epigenetic changes make an interesting source of bioactive compounds for nutraceutical or functional food purposes.

Bioactive Compounds from Theobroma cacao: Effect of Isolation and Safety Evaluation.

Plants, including most food and feed plants, produce a broad range of bioactive chemical compounds. Among these compounds, polyphenols are reported to provide beneficial effects as anti-carcinogenic, anti-atherogenic, anti-inflammatory, immune modulating, anti-microbial, vasodilatory and analgesic. Cocoa (Theobroma cacao), a major, economically important, international crop, has been related to several nutritional benefits, which have been associated with the phenolic fraction. The main subclass of flavonoids found in cocoa is flavanols, particularly (epi)catechins monomers, and their oligomers, also known as procyanidins. In this study, these compounds were isolated by different methodologies as solid phase extraction (SPE), semi-preparative high-performance liquid chromatography (HPLC) and membrane technologies to obtain different polyphenolic profiles by HPLC coupled to electrospray time-of-flight mass spectrometry (ESI-TOF-MS) and to test their cytotoxicity. Finally, different polyphenolic profiles were collected, where the combination of both semi-preparative HPLC and SPE technologies provided the most purified fractions. Filtration with membranes and SPE provide extracts with different composition depending on the pore size of membranes and on the solvent, respectively. In addition, the results of toxicity assay indicated low levels in all fractions.

The impact of polyphenols on chondrocyte growth and survival: a preliminary report.

BACKGROUND: Imbalances in the functional binding of fibroblast growth factors (FGFs) to their receptors (FGFRs) have consequences for cell proliferation and differentiation that in chondrocytes may lead to degraded cartilage. The toxic, proinflammatory, and oxidative response of cytokines and FGFs can be mitigated by dietary polyphenols. OBJECTIVE: We explored the possible effects of polyphenols in the management of osteoarticular diseases using a model based on the transduction of a mutated human FGFR3 (G380R) in murine chondrocytes. This mutation is present in most cases of skeletal dysplasia and is responsible for the overexpression of FGFR3 that, in the presence of its ligand, FGF9, results in toxic effects leading to altered cellular growth. DESIGN: Different combinations of dietary polyphenols derived from plant extracts were assayed in FGFR3 (G380R) mutated murine chondrocytes, exploring cell survival, chloride efflux, extracellular matrix (ECM) generation, and grade of activation of mitogen-activated protein kinases. RESULTS: Bioactive compounds from Hibiscus sabdariffa reversed the toxic effects of FGF9 and restored normal growth, suggesting a probable translation to clinical requests in humans. Indeed, these compounds activated the intracellular chloride efflux, increased ECM generation, and stimulated cell proliferation. The inhibition of mitogen-activated protein kinase phosphorylation was interpreted as the main mechanism governing these beneficial effects. CONCLUSIONS: These findings support the rationale behind the encouragement of the development of drugs that repress the overexpression of FGFRs and suggest the dietary incorporation of supplementary nutrients in the management of degraded cartilage.

Pine bark and green tea concentrated extracts: antioxidant activity and comprehensive characterization of bioactive compounds by HPLC-ESI-QTOF-MS.

The consumption of polyphenols has frequently been associated with low incidence of degenerative diseases. Most of these natural antioxidants come from fruits, vegetables, spices, grains and herbs. For this reason, there has been increasing interest in identifying plant extract compounds. Polymeric tannins and monomeric flavonoids, such as catechin and epicatechin, in pine bark and green tea extracts could be responsible for the higher antioxidant activities of these extracts. The aim of the present study was to characterize the phenolic compounds in pine bark and green tea concentrated extracts using high-performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC-ESI-QTOF-MS). A total of 37 and 35 compounds from pine bark and green tea extracts, respectively, were identified as belonging to various structural classes, mainly flavan-3-ol and its derivatives (including procyanidins). The antioxidant capacity of both extracts was evaluated by three complementary antioxidant activity methods: Trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC). Higher antioxidant activity values by each method were obtained. In addition, total polyphenol and flavan-3-ol contents, which were determined by Folin-Ciocalteu and vanillin assays, respectively, exhibited higher amounts of gallic acid and (+)-catechin equivalents.