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1.
Glycoconj J ; 41(2): 163-174, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38642280

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide COVID-19 pandemic, leading to 6.8 million deaths. Numerous variants have emerged since its outbreak, resulting in its significantly enhanced ability to spread among humans. As with many other viruses, SARS­CoV­2 utilizes heparan sulfate (HS) glycosaminoglycan (GAG) on the surface of host cells to facilitate viral attachment and initiate cellular entry through the ACE2 receptor. Therefore, interfering with virion-HS interactions represents a promising target to develop broad-spectrum antiviral therapeutics. Sulfated glycans derived from marine organisms have been proven to be exceptional reservoirs of naturally existing HS mimetics, which exhibit remarkable therapeutic properties encompassing antiviral/microbial, antitumor, anticoagulant, and anti-inflammatory activities. In the current study, the interactions between the receptor-binding domain (RBD) of S-protein of SARS-CoV-2 (both WT and XBB.1.5 variants) and heparin were applied to assess the inhibitory activity of 10 marine-sourced glycans including three sulfated fucans, three fucosylated chondroitin sulfates and two fucoidans derived from sea cucumbers, sea urchin and seaweed Saccharina japonica, respectively. The inhibitory activity of these marine derived sulfated glycans on the interactions between RBD of S-protein and heparin was evaluated using Surface Plasmon Resonance (SPR). The RBDs of S-proteins from both Omicrion XBB.1.5 and wild-type (WT) were found to bind to heparin, which is a highly sulfated form of HS. All the tested marine-sourced sulfated glycans exhibited strong inhibition of WT and XBB.1.5 S-protein binding to heparin. We believe the study on the molecular interactions between S-proteins and host cell glycosaminoglycans provides valuable insight for the development of marine-sourced, glycan-based inhibitors as potential anti-SARS-CoV-2 agents.


Asunto(s)
Heparina , Polisacáridos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , Heparina/farmacología , Heparina/química , Heparina/metabolismo , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/metabolismo , Humanos , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , COVID-19/virología , COVID-19/metabolismo , Unión Proteica , Animales , Antivirales/farmacología , Antivirales/química , Heparitina Sulfato/metabolismo , Heparitina Sulfato/química
2.
J Biol Chem ; 298(5): 101856, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35337800

RESUMEN

Sulfation pattern and molecular weight (MW) play a key role in the biological actions of sulfated glycans. Besides anticoagulant effects, certain sulfated glycans can also exhibit anti-SARS-CoV-2 properties. To develop a more selective antiviral carbohydrate, an efficient strategy to separate these two actions is required. In this work, low MW fractions derived from the red alga Botryocladia occidentalis sulfated galactan (BoSG) were generated, structurally characterized, and tested for activity against SARS-CoV-2 and blood coagulation. The lowest MW fraction was found to be primarily composed of octasaccharides of monosulfated monosaccharides. Unlike heparin or native BoSG, we found that hydrolyzed BoSG products had weak anticoagulant activities as seen by aPTT and inhibitory assays using purified cofactors. In contrast, lower MW BoSG-derivatives retained anti-SARS-CoV-2 activity using SARS-CoV-2 spike (S)-protein pseudotyped lentivirus vector in HEK-293T-hACE2 cells monitored by GFP. Surface plasmon resonance confirmed that longer chains are necessary for BoSG to interact with coagulation cofactors but is not required for interactions with certain S-protein variants. We observed distinct affinities of BoSG derivatives for the S-proteins of different SARS-CoV-2 strains, including WT, N501Y (Alpha), K417T/E484K/N501Y (Gamma), and L542R (Delta) mutants, and stronger affinity for the N501Y-containing variants. Docking of the four possible monosulfated BoSG disaccharides in interactions with the N501Y mutant S-protein predicted potential binding poses of the BoSG constructs and favorable binding in close proximity to the 501Y residue. Our results demonstrate that depolymerization and fractionation of BoSG are an effective strategy to segregate its anticoagulant property from its anti-SARS-CoV-2 action.


Asunto(s)
Anticoagulantes , Antivirales , Galactanos , Rhodophyta , SARS-CoV-2 , Anticoagulantes/química , Anticoagulantes/farmacología , Antivirales/química , Antivirales/farmacología , COVID-19 , Galactanos/química , Galactanos/farmacología , Células HEK293 , Humanos , Rhodophyta/química , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Sulfatos/química
3.
J Neurochem ; 165(6): 791-808, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36660878

RESUMEN

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.


Asunto(s)
Sistema de Señalización de MAP Quinasas , Memoria Espacial , Ratones , Animales , Transducción de Señal , Neuronas/metabolismo , Hipocampo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptor trkB/metabolismo , Células Cultivadas
4.
Mar Drugs ; 21(5)2023 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-37233458

RESUMEN

Sulfated glycans from marine organisms are excellent sources of naturally occurring glycosaminoglycan (GAG) mimetics that demonstrate therapeutic activities, such as antiviral/microbial infection, anticoagulant, anticancer, and anti-inflammation activities. Many viruses use the heparan sulfate (HS) GAG on the surface of host cells as co-receptors for attachment and initiating cell entry. Therefore, virion-HS interactions have been targeted to develop broad-spectrum antiviral therapeutics. Here we report the potential anti-monkeypox virus (MPXV) activities of eight defined marine sulfated glycans, three fucosylated chondroitin sulfates, and three sulfated fucans extracted from the sea cucumber species Isostichopus badionotus, Holothuria floridana, and Pentacta pygmaea, and the sea urchin Lytechinus variegatus, as well as two chemically desulfated derivatives. The inhibitions of these marine sulfated glycans on MPXV A29 and A35 protein-heparin interactions were evaluated using surface plasmon resonance (SPR). These results demonstrated that the viral surface proteins of MPXV A29 and A35 bound to heparin, which is a highly sulfated HS, and sulfated glycans from sea cucumbers showed strong inhibition of MPXV A29 and A35 interactions. The study of molecular interactions between viral proteins and host cell GAGs is important in developing therapeutics for the prevention and treatment of MPXV.


Asunto(s)
Glicosaminoglicanos , Pepinos de Mar , Animales , Glicosaminoglicanos/química , Resonancia por Plasmón de Superficie , Sulfatos/farmacología , Sulfatos/química , Heparitina Sulfato/farmacología , Sulfatos de Condroitina , Heparina/farmacología , Pepinos de Mar/química , Antivirales/farmacología
5.
J Biol Chem ; 297(4): 101207, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34537241

RESUMEN

Certain sulfated glycans, including those from marine sources, can show potential effects against SARS-CoV-2. Here, a new fucosylated chondroitin sulfate (FucCS) from the sea cucumber Pentacta pygmaea (PpFucCS) (MW ∼10-60 kDa) was isolated and structurally characterized by NMR. PpFucCS is composed of {→3)-ß-GalNAcX-(1→4)-ß-GlcA-[(3→1)Y]-(1→}, where X = 4S (80%), 6S (10%) or nonsulfated (10%), Y = α-Fuc2,4S (40%), α-Fuc2,4S-(1→4)-α-Fuc (30%), or α-Fuc4S (30%), and S = SO3-. The anti-SARS-CoV-2 activity of PpFucCS and those of the FucCS and sulfated fucan isolated from Isostichopus badionotus (IbFucCS and IbSF) were compared with that of heparin. IC50 values demonstrated the activity of the three holothurian sulfated glycans to be ∼12 times more efficient than heparin, with no cytotoxic effects. The dissociation constant (KD) values obtained by surface plasmon resonance of the wildtype SARS-CoV-2 spike (S)-protein receptor-binding domain (RBD) and N501Y mutant RBD in interactions with the heparin-immobilized sensor chip were 94 and 1.8 × 103 nM, respectively. Competitive surface plasmon resonance inhibition analysis of PpFucCS, IbFucCS, and IbSF against heparin binding to wildtype S-protein showed IC50 values (in the nanomolar range) 6, 25, and 6 times more efficient than heparin, respectively. Data from computational simulations suggest an influence of the sulfation patterns of the Fuc units on hydrogen bonding with GlcA and that conformational change of some of the oligosaccharide structures occurs upon S-protein RBD binding. Compared with heparin, negligible anticoagulant action was observed for IbSF. Our results suggest that IbSF may represent a promising molecule for future investigations against SARS-CoV-2.


Asunto(s)
Polisacáridos/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sulfatos/química , Animales , Sitios de Unión , COVID-19/patología , COVID-19/virología , Sulfatos de Condroitina/química , Sulfatos de Condroitina/metabolismo , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Tiempo de Tromboplastina Parcial , Polisacáridos/química , Unión Proteica , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Pepinos de Mar/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Resonancia por Plasmón de Superficie
6.
Glycobiology ; 32(10): 849-854, 2022 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-35788318

RESUMEN

The Coronavirus disease pandemic has steered the global therapeutic research efforts toward the discovery of potential anti-severe acute respiratory syndrome coronavirus (SARS-CoV-2) molecules. The role of the viral spike glycoprotein (S-protein) has been clearly established in SARS-CoV-2 infection through its capacity to bind to the host cell surface heparan sulfate proteoglycan (HSPG) and angiotensin-converting enzyme-2. The antiviral strategies targeting these 2 virus receptors are currently under intense investigation. However, the rapid evolution of the SARS-CoV-2 genome has resulted in numerous mutations in the S-protein posing a significant challenge for the design of S-protein-targeted inhibitors. As an example, the 2 key mutations in the S-protein receptor-binding domain (RBD), L452R, and T478K in the SARS-CoV-2 Delta variant (B.1.617.2) confer tighter binding to the host epithelial cells. Marine sulfated glycans (MSGs) demonstrate excellent inhibitory activity against SARS-CoV-2 via competitive disruption of the S-protein RBD-HSPG interactions and thus have the potential to be developed into effective prophylactic and therapeutic molecules. In this study, 7 different MSGs were evaluated for their anti-SARS-CoV-2 activity in a virus entry assay utilizing a SARS-CoV-2 pseudovirus coated with S-protein of the wild-type (Wuhan-Hu-1) or the Delta (B.1.617.2) strain. Although all tested MSGs showed strong inhibitory activity against both strains, no correlations between MSG structural features and virus inhibition could be drawn. Nevertheless, the current study provides evidence for the maintenance of inhibitory activity of MSGs against evolving SARS-CoV-2 strains.


Asunto(s)
Antivirales , Polisacáridos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Sulfatos , Internalización del Virus , Antivirales/farmacología , Proteoglicanos de Heparán Sulfato/metabolismo , Humanos , Polisacáridos/farmacología , Receptores Virales/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Sulfatos/farmacología , Internalización del Virus/efectos de los fármacos
7.
J Nat Prod ; 84(3): 846-856, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33710886

RESUMEN

Curcuma longa (turmeric) has an extensive history of ethnomedical use for common ailments, and "curcumin"-containing dietary supplements (CDS) are a highly visible portion of today's self-medication market. Owing to raw material cost pressure, CDS products are affected by economically motivated, nefarious adulteration with synthetic curcumin ("syncumin"), possibly leading to unexpected toxicological issues due to "residual" impurities. Using a combination of targeted and untargeted (phyto)chemical analysis, this study investigated the botanical integrity of two commercial "turmeric" CDS with vitamin and other additives that were associated with reported clinical cases of hepatotoxicity. Analyzing multisolvent extracts of the CDS by 100% quantitative 1H NMR (qHNMR), alone and in combination with countercurrent separation (CCS), provided chemical fingerprints that allowed both the targeted identification and quantification of declared components and the untargeted recognition of adulteration. While confirming the presence of curcumin as a major constituent, the universal detection capability of NMR spectroscopy identification of significant residual impurities, including potentially toxic components. While the loss-free nature of CCS captured a wide polarity range of declared and unwanted chemical components, and also increased the dynamic range of the analysis, (q)HNMR determined their mass proportions and chemical constitutions. The results demonstrate that NMR spectroscopy can recognize undeclared constituents even if they represent only a fraction of the mass balance of a dietary supplement product. The chemical information associated with the missing 4.8% and 7.4% (m/m) in the two commercial samples, exhibiting an otherwise adequate curcumin content of 95.2% and 92.6%, respectively, pointed to a product integrity issue and adulteration with undeclared synthetic curcumin. Impurities from synthesis are most plausibly the cause of the observed adverse clinical effects. The study exemplifies how the simultaneously targeted and untargeted analytical principle of the 100% qHNMR method, performed with entry-level high-field instrumentation (400 MHz), can enhance the safety of dietary supplements by identifying adulterated, non-natural "natural" products.


Asunto(s)
Curcuma/química , Contaminación de Medicamentos , Extractos Vegetales/análisis , Distribución en Contracorriente , Curcumina/análisis , Suplementos Dietéticos/análisis , Espectroscopía de Resonancia Magnética , Extractos Vegetales/normas
8.
J Nat Prod ; 83(6): 1846-1858, 2020 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-32426979

RESUMEN

Chlorophylls are present in all extracts from the aerial parts of green plant materials. Chlorophylls may act as in vitro bioassay nuisance compounds, possibly preventing the reproducibility and accurate measurement of readouts due to their UV/vis absorbance, fluorescence properties, and tendency to precipitate in aqueous media. Despite the diversity of methods used traditionally to remove chlorophylls, details about their mode of operation, specificity, and reproducibility are scarce. Herein, we report a selective and efficient 45 min liquid-liquid/countercurrent chlorophyll cleanup method using Centrifugal Partition Chromatography (CPC) with a solvent system composed of hexanes-EtOAc-MeOH-water (5:5:5:5, v/v) in elution-extrusion mode. The broader utility of the method was assessed with four different extracts prepared from three well-characterized plant materials: Epimedium sagittatum (leaves), Senna alexandrina (leaves), and Trifolium pratense (aerial parts). The reproducibility of the method, the selectivity of the chlorophyll removal, as well as the preservation of the phytochemical integrity of the resulting chlorophyll-free ("degreened") extracts were evaluated using HPTLC, UHPLC-UV, 1H NMR spectroscopy, and LC-MS as orthogonal phytochemical methods. The cleanup process adequately preserves the metabolomic diversity as well as the integrity of the original extracts. This method was found to be sufficiently rapid for the "degreening" of botanical extracts in higher-throughput sample preparation for further biological screening.


Asunto(s)
Clorofila/aislamiento & purificación , Extractos Vegetales/química , Clorofila/química , Cromatografía , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Espectroscopía de Resonancia Magnética , Componentes Aéreos de las Plantas/química , Hojas de la Planta/química , Reproducibilidad de los Resultados , Solventes , Espectrofotometría Ultravioleta
9.
Bioorg Chem ; 92: 103234, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31479985

RESUMEN

Nine new xanthones, cudracuspixanthones I - Q (12-14, 25, 32-36), and 30 known xanthones (1-11, 15-24, 26-31, 37-39) were isolated from the stems of Cudrania tricuspidata (Moraceae). The structures of isolated compounds were established by using 1D and 2D NMR in combination with HR-TOF-MS. Xanthones from the stems of C. tricuspidata exerted pancreatic lipase inhibitory activity. In addition, cudracuspixanthone P (35), a new xanthone, reduced the fat accumulation in liver cells stimulated with fatty acids. Therefore, these compounds might be beneficial in the treatment of metabolic diseases.


Asunto(s)
Lipasa/antagonistas & inhibidores , Metabolismo de los Lípidos/efectos de los fármacos , Moraceae/química , Páncreas/efectos de los fármacos , Tallos de la Planta/química , Xantonas/farmacología , Células Hep G2 , Humanos , Estructura Molecular , Páncreas/embriología , Extractos Vegetales/química , Triglicéridos/metabolismo , Xantonas/química , Xantonas/aislamiento & purificación
10.
Bioorg Chem ; 81: 127-133, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30118984

RESUMEN

Eighteen constituents, including nine new compounds, were isolated from the bee pollen of Quercus mongolica. The structures of the new compounds were established on the basis of combined spectroscopic analysis. Structurally, the nine new compounds are polyamine derivatives with phenolic moieties which were assigned as one putrescine derivative, mogolicine A (2), seven spermidine derivatives, mongolidines A-G (3-5, 8, 12, 14, 17) and one spermine derivative, mogoline A (18). Evaluation of the biological activity of isolated compounds revealed that the polyamine derivatives with coumaroyl and caffeoyl moieties showed tyrosinase inhibition with IC50 values of 19.5-85.8 µM; however, the addition of a methoxy group to phenolic derivatives reduced the inhibitory activity.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Polen/química , Poliaminas/farmacología , Quercus/química , Animales , Abejas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Poliaminas/química , Poliaminas/aislamiento & purificación , Relación Estructura-Actividad
11.
Biosci Biotechnol Biochem ; 81(10): 1973-1977, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28828930

RESUMEN

Efficient preparation of loganin from Cornus officinalis fruits was investigated. First, effect of extraction conditions on loganin yield was measured. The loganin content in C. officinalis extract was greatly affected by ethanol concentration and extraction time whereas extraction temperature exerted relatively little effect. Response surface methodology with Box-Behnken design suggested optimized extraction condition for maximum loganin yield as ethanol concentration, 32.0%; temperature 46.2 °C and extraction time, 46.7 min, which yielded 10.4 µg loganin/mg dried fruit. Next, the effect of maturation stage of C. officinalis fruits on loganin content was investigated. The loganin content in the extract of C. officinalis fruits was decreased as the maturation process. The loganin content in the unripe fruits was 18.0 µg/mg extract whereas reduced to 13.3 µg/mg extract for ripe fruits. Taken together, our present study suggested the importance of extraction condition and maturation stages for efficient preparation of loganin from C. officinalis fruits.


Asunto(s)
Fraccionamiento Químico/métodos , Cornus/metabolismo , Frutas/crecimiento & desarrollo , Frutas/metabolismo , Iridoides/aislamiento & purificación , Iridoides/metabolismo , Cornus/crecimiento & desarrollo
12.
Arch Pharm (Weinheim) ; 350(1)2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27902844

RESUMEN

Investigation of the CH2 Cl2 and EtOAc-soluble fractions of the roots of Cudrania tricuspidata afforded 31 compounds. The structures of the isolated compounds were determined on the basis of spectroscopic data interpretation such as 1D and 2D NMR analysis and elucidated as xanthones with prenyl moieties including four simple xanthones (1-4), five prenylated xanthones with one prenyl moiety (5-7, 20, and 21), and 22 prenylated xanthones with two prenyl moieties (8-19 and 22-31). Among them, three diprenylated xanthones named cudracuspixanthones E-G (16, 29, and 31) were first isolated in nature. Xanthones 2, 5, 6, 12, 19, 21, 22, 25, 27, and 28 showed moderate inhibition of lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 cells, with IC50 values ranging from 16.1 to 24.8 µM.


Asunto(s)
Lipopolisacáridos/antagonistas & inhibidores , Moraceae/química , Óxido Nítrico/biosíntesis , Raíces de Plantas/química , Xantonas/aislamiento & purificación , Xantonas/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Prenilación , Células RAW 264.7/metabolismo , Relación Estructura-Actividad , Xantonas/química
13.
Molecules ; 22(8)2017 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-28805750

RESUMEN

In this study, the characterization of chemical constituents and biological activity of the roots of Taraxacum coreanum (Asteraceae) was attempted. Phytochemical investigation of the roots of T. coreanum led to the isolation of two new inositol derivatives, taraxinositols A (1) and B (2), and a new phenolic compound, taraxinol (16), together with twenty known compounds including four inositol derivatives, neo-inositol-1,4-bis (4-hydroxybenzeneacetate) (3), chiro-inositol-1,5-bis(4- hydroxybenzeneacetate) (4), chiro-inositol-2,3-bis (4-hydroxybenzeneacetate) (5) and chiro-inositol- 1,2,3-tris (4-hydroxybenzeneacetate) (6), nine phenolic compounds: p-hydroxybenzaldehyde (7), vanillin (8), syringaldehyde (9), vanillic acid (10), 4-methoxyphenylacetic acid (11), 4-hydroxy- phenylacetic acid methyl ester (12), optivanin (13), isoferulic acid (14) and dihydroconiferyl alcohol (15), four coumarins: nodakenetin (17), decursinol (18), prangol (19) and isobyakangelicin (20), and three lignans: syringaresinol-4'-O-ß-d-glucoside (21), syringaresinol (22), and pinoresinol (23). The structures of isolated compounds were determined on the basis of spectroscopic analysis. Among the isolated compounds, vanillic acid, isoferulic acid and syringaresinol showed radical scavenging activity with IC50 values ranging from 30.4 to 75.2 µM.


Asunto(s)
Inositol/química , Fenol/química , Extractos Vegetales/química , Raíces de Plantas/química , Taraxacum/química , Antioxidantes/química , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión/métodos , Cumarinas/química , Furanos/química , Glucósidos/química , Humanos , Concentración 50 Inhibidora , Inositol/aislamiento & purificación , Lignanos/química , Espectroscopía de Resonancia Magnética/métodos , Fenol/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Receptores Depuradores/química , Receptores Depuradores/metabolismo
14.
Bioorg Med Chem Lett ; 26(20): 4950-4954, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27634197

RESUMEN

Seven new sesquiterpenes, linderolides N-T (1-7), along with nine known compounds, were isolated from roots of Lindera strychnifolia (Lauraceae). Their structures were established by extensive spectroscopic analysis. The relative and absolute configurations were determined by NOESY and CD analysis, respectively. Among the isolated compounds, two new compounds, linderolide O (2) and linderolide P (3) inhibited lipopolysaccharide-stimulated nitric oxide production in murine RAW 264.7 macrophage cells, with IC50 values of 6.3 and 9.6µM, respectively.


Asunto(s)
Lindera/química , Óxido Nítrico/antagonistas & inhibidores , Raíces de Plantas/química , Sesquiterpenos/aislamiento & purificación , Animales , Línea Celular , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Óxido Nítrico/biosíntesis , Espectrometría de Masa por Ionización de Electrospray
15.
Bioorg Med Chem Lett ; 25(17): 3455-7, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26227773

RESUMEN

A new benzylated and prenylated flavonone, cudracuspiflavanone A (17) were isolated from the roots of Cudrania tricuspidata (Moraceae), together with two chromones (1-2) and fourteen flavonoids (3-16). The structures of isolated compounds were determined on the basis of spectroscopic analysis. The absolute configuration was also defined by CD analysis. Among the isolated compounds, compounds 14 and 15 inhibited pancreatic lipase activity with an IC50 value of 9.0 and 6.5 µM, respectively.


Asunto(s)
Flavonoides/química , Lipasa/química , Moraceae/química , Obesidad/tratamiento farmacológico , Páncreas/efectos de los fármacos , Extractos Vegetales/química , Productos Biológicos , Estructura Molecular
16.
Bioorg Med Chem Lett ; 25(11): 2269-74, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25935644

RESUMEN

The leaves of Morus alba (Moraceae) have been traditionally used for the treatment of metabolic diseases including diabetes and hyperlipidemia. Thus, inhibitory effect of M. alba leaves on pancreatic lipase and their active constituents were investigated in this study. Twenty phenolic compounds including ten flavonoids, eight benzofurans, one stilbene and one chalcones were isolated from the leaves of M. alba. Among the isolated compounds, morachalcone A (20) exerted strong pancreatic lipase inhibition with IC50 value of 6.2 µM. Other phenolic compounds containing a prenyl group showed moderate pancreatic lipase inhibition with IC50 value of <50 µM. Next, extraction conditions with maximum pancreatic lipase inhibition and phenolic content were optimized using response surface methodology with three-level-three-factor Box-Behnken design. Our results suggested the optimized extraction condition for maximum pancreatic lipase inhibition and phenolic content as ethanol concentration of 74.9%; temperature 57.4 °C and sample/solvent ratio, 1/10. The pancreatic lipase inhibition and total phenolic content under optimized condition were found to be 58.5% and 26.2 µg GAE (gallic acid equivalent)/mg extract, respectively, which were well matched with the predicted value.


Asunto(s)
Lipasa/antagonistas & inhibidores , Morus/química , Páncreas/enzimología , Extractos Vegetales/farmacología , Hojas de la Planta/química , Fraccionamiento Químico/métodos , Lipasa/metabolismo , Estructura Molecular , Extractos Vegetales/química
17.
Int J Mol Sci ; 16(10): 24139-58, 2015 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-26473845

RESUMEN

Morus alba L. fruits have long been used in traditional medicine by many cultures. Their medicinal attributes include cardiovascular, hepatoprotective, neuroprotective and immunomodulatory actions. However, their mechanism of macrophage activation and anti-cancer effects remain unclear. The present study investigated the molecular mechanisms of immune stimulation and improved chemotherapeutic effect of M. alba L. fruit extract (MFE). MFE stimulated the production of cytokines, nitric oxide (NO) and tumor necrosis factor-α (TNF-α) and tumoricidal properties of macrophages. MFE activated macrophages through the mitogen-activated protein kinase (MAPKinase) and nuclear factor-κB (NF-κB) signaling pathways downstream from toll-like receptor (TLR) 4. MFE was shown to exhibit cytotoxicity of CT26 cells via the activated macrophages, even though MFE did not directly affect CT26 cells. In a xenograft mouse model, MFE significantly enhanced anti-cancer activity combined with 5-fluorouracil and markedly promoted splenocyte proliferation, natural killer (NK) cell activity, cytotoxic T lymphocyte (CTL) activity and IFN-γ production. Immunoglobulin G (IgG) antibody levels were significantly increased. These results indicate the indirect anti-cancer activity of MFE through improved immune response mediated by TLR4 signaling. M. alba L. fruit extract might be a potential anti-tumor immunomodulatory candidate chemotherapy agent.


Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Fluorouracilo/farmacología , Macrófagos/inmunología , Morus/metabolismo , Neoplasias/inmunología , Extractos Vegetales/farmacología , Linfocitos T Citotóxicos/inmunología , Receptor Toll-Like 4/inmunología , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Frutas/metabolismo , Células Asesinas Naturales/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas Activadas por Mitógenos/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , FN-kappa B/inmunología , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Óxido Nítrico/biosíntesis , Óxido Nítrico/inmunología , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/genética , Trasplante Heterólogo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología
18.
Molecules ; 20(9): 16933-45, 2015 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-26393543

RESUMEN

Resveratrol (1), a naturally occurring stilbene compound, has been suggested as a potential whitening agent with strong inhibitory activity on melanin synthesis. However, the use of resveratrol in cosmetics has been limited due to its chemical instability and poor bioavailability. Therefore, resveratrol derivatives were prepared to improve bioavailability and anti-melanogenesis activity. Nine resveratrol derivatives including five alkyl ether derivatives with C2H5, C4H9, C5H11, C6H13, and C8H17 (2a-2e) and four ester derivatives with CH3, CH=C(CH3)2, CH(C2H5)C4H9, C7H15 (3a-3d) were newly synthesized and their effect on melanin synthesis were assessed. All the synthetic derivatives efficiently reduced the melanin content in α-MSH stimulated B16F10 melanoma cells. Further investigation showed that the inhibitory effect of 2a on melanin synthesis was achieved not by the inhibition of tyrosinase activity but by the inhibition of melanogenic enzyme expressions such as tyrosinase and tyrosinase-related protein (TRP)-1. Our synthetic resveratrol derivatives have more lipophilic properties than resveratrol by the addition of alkyl or acyl chains to free hydroxyl moiety of resveratrol; thus, they are expected to show better bioavailability in skin application. Therefore, we suggest that our synthetic resveratrol derivatives might be promising candidates for better practical application to skin-whitening cosmetics.


Asunto(s)
Melaninas/metabolismo , Estilbenos/síntesis química , Estilbenos/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Ratones , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Oxidorreductasas/metabolismo , Resveratrol , Preparaciones para Aclaramiento de la Piel/síntesis química , Preparaciones para Aclaramiento de la Piel/farmacocinética , Preparaciones para Aclaramiento de la Piel/farmacología , Estilbenos/agonistas , Estilbenos/química , Estilbenos/farmacocinética , alfa-MSH/farmacología
19.
Molecules ; 20(11): 19764-74, 2015 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-26540033

RESUMEN

Bee pollen is flower pollen with nectar and salivary substances of bees and rich in essential components. Bee pollen showed antioxidant and tyrosinase inhibitory activity in our assay system. To maximize the antioxidant and tyrosinase inhibitory activity of bee pollen, extraction conditions, such as extraction solvent, extraction time, and extraction temperature, were optimized using response surface methodology. Regression analysis showed a good fit of this model and yielded the second-order polynomial regression for tyrosinase inhibition and antioxidant activity. Among the extraction variables, extraction solvent greatly affected the activity. The optimal condition was determined as EtOAc concentration in MeOH, 69.6%; temperature, 10.0 °C; and extraction time, 24.2 h, and the tyrosinase inhibitory and antioxidant activity under optimal condition were found to be 57.9% and 49.3%, respectively. Further analysis showed the close correlation between activities and phenolic content, which suggested phenolic compounds are active constituents of bee pollen for tyrosinase inhibition and antioxidant activity. Taken together, these results provide useful information about bee pollen as cosmetic therapeutics to reduce oxidative stress and hyperpigmentation.


Asunto(s)
Abejas , Extractos Vegetales/química , Polen/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Modelos Teóricos , Monofenol Monooxigenasa/antagonistas & inhibidores , Fenoles/química , Fenoles/farmacología , Extractos Vegetales/farmacología
20.
Molecules ; 20(5): 8730-41, 2015 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-26007176

RESUMEN

Melanin is a natural pigment that plays an important role in the protection of skin, however, hyperpigmentation cause by excessive levels of melatonin is associated with several problems. Therefore, melanogenesis inhibitory natural products have been developed by the cosmetic industry as skin medications. The leaves of Morus alba (Moraceae) have been reported to inhibit melanogenesis, therefore, characterization of the melanogenesis inhibitory constituents of M. alba leaves was attempted in this study. Twenty compounds including eight benzofurans, 10 flavonoids, one stilbenoid and one chalcone were isolated from M. alba leaves and these phenolic constituents were shown to significantly inhibit tyrosinase activity and melanin content in B6F10 melanoma cells. To maximize the melanogenesis inhibitory activity and active phenolic contents, optimized M. alba leave extraction conditions were predicted using response surface methodology as a methanol concentration of 85.2%; an extraction temperature of 53.2 °C and an extraction time of 2 h. The tyrosinase inhibition and total phenolic content under optimal conditions were found to be 74.8% inhibition and 24.8 µg GAE/mg extract, which were well-matched with the predicted values of 75.0% inhibition and 23.8 µg GAE/mg extract. These results shall provide useful information about melanogenesis inhibitory constituents and optimized extracts from M. alba leaves as cosmetic therapeutics to reduce skin hyperpigmentation.


Asunto(s)
Hiperpigmentación/tratamiento farmacológico , Melaninas/biosíntesis , Monofenol Monooxigenasa/antagonistas & inhibidores , Morus/metabolismo , Extractos Vegetales/farmacología , Benzofuranos/farmacología , Línea Celular Tumoral , Chalcona/farmacología , Flavonoides/farmacología , Humanos , Hiperpigmentación/metabolismo , Melaninas/metabolismo , Melanoma/metabolismo , Melanoma/patología , Fenoles/química , Hojas de la Planta/metabolismo , Estilbenos/farmacología
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