RESUMEN
In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (Solanum lycopersicum) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production.
Asunto(s)
Diinos/metabolismo , Ácidos Grasos/biosíntesis , Alcoholes Grasos/metabolismo , Solanum lycopersicum/genética , Resistencia a la Enfermedad/genética , Diinos/química , Ácidos Grasos/metabolismo , Alcoholes Grasos/química , Regulación de la Expresión Génica de las Plantas/genética , Metabolómica , Familia de Multigenes/genética , Enfermedades de las Plantas/microbiología , Hojas de la Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente , Estrés Fisiológico/genéticaRESUMEN
Tyrosinase is the rate-limiting enzyme critical for melanin synthesis and controls pigmentation in the skin. The inhibition of tyrosinase is currently the most common approach for the development of skin-whitening cosmetics. Gagunin D (GD), a highly oxygenated diterpenoid isolated from the marine sponge Phorbas sp., has exhibited cytotoxicity toward human leukemia cells. However, the effect of GD on normal cells and the molecular mechanisms remain to be elucidated. In the present study, we identified for the first time the anti-melanogenic activity of GD and its precise underlying mechanisms in mouse melan-a cells. GD significantly inhibited melanin synthesis in the melan-a cells and a reconstructed human skin model. Further analysis revealed that GD suppressed the expression of tyrosinase and increased the rate of tyrosinase degradation. GD also inhibited tyrosinase enzymatic activity. In addition, GD effectively suppressed the expression of proteins associated with melanosome transfer. These findings suggest that GD is a potential candidate for cosmetic formulations due to its multi-functional properties.
Asunto(s)
Diterpenos/farmacología , Indoles/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Pigmentación/efectos de los fármacos , Poríferos/química , Animales , Línea Celular Tumoral , Humanos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Melaninas/antagonistas & inhibidores , Ratones , Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/metabolismoRESUMEN
Two new peptides, chujamides A (1) and B (2), were isolated from the marine sponge Suberites waedoensis, which was collected from Korean waters. Based upon the results of the combined spectroscopic analyses, the structures of these compounds were determined to be proline-riched and cyclic cystine bridged dodeca- and undecapeptides. The absolute configurations of all amino acid residues were determined to be l by advanced Marfey's analysis. The new compounds exhibited weak cytotoxicities against A549 and K562 cell-lines, and compound 2 also demonstrated moderate inhibitory activity against Naâº/Kâº-ATPase.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/química , Cisteína/química , Péptidos Cíclicos/química , Poríferos/química , Aminoácidos/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Hidrocarburos Aromáticos con Puentes/aislamiento & purificación , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Péptidos Cíclicos/aislamiento & purificación , Péptidos Cíclicos/farmacología , Prolina/química , República de Corea , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidoresRESUMEN
A new peptide, gombamide A (1), was isolated from the marine sponge Clathria gombawuiensis, collected from Korean waters. On the basis of the results of combined spectroscopic analyses, the structure of this compound was determined to be a cyclic C-terminally modified thiohexapeptide containing the unusual amino acid residues para-hydroxystyrylamide (pHSA) and pyroglutamic acid (pyroGlu). The absolute configurations of all amino acid residues were determined to be l by advanced Marfey's analysis. The new compound exhibited weak cytotoxicity against A549 and K562 cell lines as well as moderate inhibitory activity against Na(+)/K(+)-ATPase.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Péptidos Cíclicos/aislamiento & purificación , Poríferos/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , República de Corea , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidoresRESUMEN
Four new cytotoxic diterpenoid pseudodimers (2-5), along with a previously reported one, gukulenin A (1), were isolated from the marine sponge Phorbas gukhulensis collected off the coast of Gagu-do, Korea. These novel compounds, designated gukulenins C-F (2-5), were determined by extensive spectroscopic analyses to be pseudodimers of the gagunins, like gukulenin A. The termini of the tropolone-containing side chains in gukulenins C-E (2-4) were found to have diverse modifications involving acetamides or taurine, whereas gukulenin F (5) was formed from 1 by the ring-opening of a cyclic hemiketal. The relative and absolute configurations were assigned by Murata's and modified Snatzke's methods using a HETLOC experiment and a CD measurement of a dimolybdenum complex, respectively. All of these compounds exhibited significant cytotoxicity against the K562 and A549 cell lines.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Poríferos/química , Animales , Antineoplásicos/química , Diterpenos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , República de Corea , Taurina/química , Terpenos/química , Terpenos/farmacologíaRESUMEN
Phorbasin H is a diterpene acid of a bisabolane-related skeletal class isolated from the marine sponge Phorbas sp. In this study, we examined whether phorbasin H acted as a yeast-to-hypha transition inhibitor of Candida albicans. Growth experiments suggest that this compound does not inhibit yeast cell growth but inhibits filamentous growth in C. albicans. Northern blot analysis of signaling pathway components indicated that phorbasin H inhibited the expression of mRNAs related to cAMP-Efg1 pathway. The exogenous addition of db-cAMP to C. albicans cells had no influence on the frequency of hyphal formation. The expression of hypha-specific HWP1 and ALS3 mRNAs, both of which are positively regulated by the important regulator of cell wall dynamics Efg1, was significantly inhibited by the addition of phorbasin H. This compound also reduced the ability of C. albicans cells to adhere in a dose-dependent manner. Our findings suggest that phorbasin H impacts the activity of the cAMP-Efg1 pathway, thus leading to an alteration of C. albicans morphology.
Asunto(s)
Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Diterpenos/farmacología , Inhibidores de Crecimiento/farmacología , Hifa/efectos de los fármacos , Hifa/crecimiento & desarrollo , Candida albicans/citología , Proteínas Fúngicas/biosíntesis , Expresión Génica , Hifa/citología , Glicoproteínas de Membrana/biosíntesis , ARN Mensajero/biosíntesis , Transducción de Señal/efectos de los fármacosRESUMEN
Halichondramide (HCA), a trisoxazole-containing macrolide isolated from the marine sponge Chondrosia corticata has been shown to exhibit cytotoxicity and antifungal activities. In our previous study, HCA was also found to exhibit antiproliferative activity against a variety of cancer cells. However, the precise mechanism of action of HCA in the antitumor activity remains to be elucidated. In the present study, we identified the antimetastatic activity of HCA in the highly metastatic PC3 human prostate cancer cells. HCA showed potent growth inhibitory activity of the PC3 cells with an IC50 value of 0.81 µM. Further analysis revealed that HCA suppressed the expression of a potential metastatic biomarker, phosphatase of regenerating liver-3 (PRL-3), in PC3 cells. The suppression of PRL-3 by HCA sequentially down-regulates the expression of phosphoinositide 3-kinase (PI3K) subunits p85 and p110. The antimetastatic effect of HCA was also correlated with the down-regulation of matrix metalloproteases (MMPs) and the modulation of cadherin switches N-cadherin and E-cadherin. In addition, HCA also effectively suppressed the migration and invasion of PC3 cells. These findings suggest that halichondramide might serve as a potential inhibitor of tumor cell metastasis with the modulation of PRL-3.
Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Poríferos/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Invasividad Neoplásica/genética , Invasividad Neoplásica/prevención & control , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismoRESUMEN
Six ß-carboline alkaloids (1-6) of the eudistomin Y class were isolated from the Korean ascidian Synoicum sp. These compounds were chemically converted to a known compound, eudistomin Y(1) (7) and six new derivatives, designated eudistomins Y(8)-Y(13) (8-13). Several of these natural and synthetic compounds exhibited moderate to significant antimicrobial activity, weak cytotoxic activity, and inhibitory activities toward sortase A, isocitrate lyase, and Na(+)/K(+)-ATPase. Structure-activity relationships were also deduced.
Asunto(s)
Alcaloides/química , Antiinfecciosos/química , Carbolinas/química , Urocordados/química , Alcaloides/farmacología , Alcaloides/toxicidad , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/metabolismo , Animales , Antiinfecciosos/farmacología , Antiinfecciosos/toxicidad , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Carbolinas/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisteína Endopeptidasas/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Isocitratoliasa/antagonistas & inhibidores , Isocitratoliasa/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-ActividadRESUMEN
Nine new compounds, tris-aromatic furanones (1, 2, 3a, 3b, and 4) and related bis-aromatic diesters (5a, 5b, 6a, and 6b), are described from the ascidian Synoicum sp. collected off the coast of Chuja-do, Korea. The structures of these compounds, designated as cadiolides E and G-I (1-4) and synoilides A and B (5 and 6), were determined by extensive spectroscopic analyses. The absolute configuration at the asymmetric center of cadiolide G (2) was assigned by ECD analysis. Of these new compounds, cadiolide I and the synoilides possess unprecedented carbon skeletons. Several of these compounds exhibited significant inhibition against diverse bacterial strains as well as moderate inhibition against the enzymes sortase A, isocitrate lyase, and Na(+)/K(+)-ATPase.
Asunto(s)
Furanos/aislamiento & purificación , Hidrocarburos Bromados/aislamiento & purificación , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Proteínas Bacterianas/antagonistas & inhibidores , Cisteína Endopeptidasas , Ensayos de Selección de Medicamentos Antitumorales , Ésteres , Furanos/química , Furanos/farmacología , Hidrocarburos Bromados/química , Hidrocarburos Bromados/farmacología , Isocitratoliasa/antagonistas & inhibidores , Pruebas de Sensibilidad Microbiana , Estructura Molecular , República de Corea , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Staphylococcus aureus/efectos de los fármacos , Urocordados/químicaRESUMEN
Five new nortriterpene glycosides, along with eight known compounds of the sarasinoside class, were isolated from the tropical sponge Lipastrotethya sp. collected from Chuuk, Micronesia. The structures of these new compounds, designated as sarasinosides N-R (9-13), were determined by combined spectroscopic and chemical methods. The aglycone portions of 10-13 were found to be unprecedented among nortriterpeneoids on the basis of extensive NMR analyses. Several of these compounds exhibited cytotoxicity against A549 and K562 cell lines as well as weak inhibitory activity against Na(+)/K(+)-ATPase.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Triterpenos/aislamiento & purificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Glicósidos/química , Glicósidos/farmacología , Humanos , Células K562 , Micronesia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Poríferos/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Eight novel cyclic bis-1,3-dialkylpyridiniums, as well as two known compounds from the cyclostellettamine class, were isolated from the sponge Haliclona sp. from Korea. Structures of these novel compounds were determined using combined NMR and FAB-MS/MS analyses. Several of these compounds exhibited moderate cytotoxic and antibacterial activities against A549 cell-line and Gram-positive strains, respectively. The structure-activity relationships of cyclostellettamines are discussed based on their bioactivities.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Haliclona/química , Poríferos/química , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Corea (Geográfico) , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Relación Estructura-ActividadRESUMEN
Oxazole-containing macrolides (1-5) isolated from the marine sponge Chondrosia corticata were evaluated for their actin depolymerizing activities by monitoring fluorescent intensity of pyrene F-actin. These studies led to the identification of (19Z)-halichondramide (5) as a new actin depolymerizing agent. The actin depolymerizing activity by (19Z)-halichondramide (5) was four times more potent than that of halichondramide (1). Compounds 1 and 5 also have potent antifungal activity. The preliminary structure-activity relationship of these compounds is described to elucidate the essential structural requirements.
Asunto(s)
Macrólidos/química , Oxazoles/química , Poríferos/química , Animales , Antifúngicos/química , Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Fluorescencia , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazoles/farmacología , Polimerizacion/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Five new sesterterpenes (7-11) along with six known compounds (1-6) were isolated from the sponge Hyatella sp., collected off the coast of Soheuksan-do, Korea. Spectroscopic analyses revealed these compounds as scalarane sesterterpenes with oxidized furan moieties (7-10) and a corresponding lactam (11). The compounds exhibited moderate cytotoxicity, antibacterial activity, and weak inhibitory activity against isocitrate lyase.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antineoplásicos/aislamiento & purificación , Poríferos/química , Sesterterpenos/aislamiento & purificación , Animales , Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Bacillus subtilis/efectos de los fármacos , República Popular Democrática de Corea , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli/efectos de los fármacos , Isocitratoliasa/antagonistas & inhibidores , Pruebas de Sensibilidad Microbiana , Micrococcus/efectos de los fármacos , Estructura Molecular , Proteus vulgaris/efectos de los fármacos , Salmonella typhimurium/efectos de los fármacos , Sesterterpenos/química , Sesterterpenos/farmacología , Staphylococcus aureus/efectos de los fármacosRESUMEN
Eight new sesterterpenes (2, 5, and 10-15), including structurally related pentaprenyl hydroquinones (2 and 5), and seven known ones of the same structural classes were isolated from the sponge Coscinoderma sp., collected from Chuuk Island, Micronesia. On the basis of the results of combined spectroscopic analyses, the new compounds were determined to be derivatives of the halisulfates and suvanine. These compounds exhibited moderate cytotoxicity against the K562 cell line and inhibitory activities against isocitrate lyase, sortase A, and Na+/K+-ATPase; significant structure-activity relationships were evident.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Poríferos/química , Sesterterpenos/aislamiento & purificación , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Cisteína Endopeptidasas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isocitratoliasa/antagonistas & inhibidores , Células K562 , Micronesia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Sesterterpenos/química , Sesterterpenos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Pd-catalyzed C-H alkenylations targeting the least hindered position of N-alkyl pyrroles and 3-substituted thiophenes, as opposed to electronically controlled approaches, are developed. The steric demand and stable bidentate binding mode of the pyrazolonaphthyridine ligand are key to the success of these sterically controlled alkenylations using oxygen as an oxidant.
RESUMEN
Psammocindoles A-C (1-3), a new class of indole alkaloids, were isolated from a Psammocinia vermis sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (4), and the N-lactam isomers isopsammocindoles A-D (5-8) were also synthesized. These natural products and synthetic analogues were found to significantly stimulate adiponectin secretion in human bone marrow mesenchymal stem cells.
Asunto(s)
Alcaloides Indólicos/química , Lactamas/química , Células Madre Mesenquimatosas/efectos de los fármacos , Poríferos/química , Animales , Productos Biológicos , Humanos , Alcaloides Indólicos/aislamiento & purificación , Lactamas/aislamiento & purificación , Células Madre Mesenquimatosas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Two new pyrroloiminoquinone alkaloids of the discorhabdin class, along with 12 compounds including one previously described synthetic derivative of the same and related skeletal classes, were isolated from the sponge Sceptrella sp., collected from Gageodo, Korea. The structures of these new compounds, designated as (-)-3-dihydrodiscorhabdin D (11) and (-)-discorhabdin Z (12), were determined by combined spectroscopic analyses. Compound 12 possesses an unusual hemiaminal group among the discorhabdin alkaloids. These compounds exhibited moderate to significant cytotoxicity, antibacterial activity, and inhibitory activity against sortase A.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Poríferos/química , Quinonas/aislamiento & purificación , Quinonas/farmacología , Alcaloides/química , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Antibacterianos/química , Antineoplásicos/química , Bacillus subtilis/efectos de los fármacos , Proteínas Bacterianas/antagonistas & inhibidores , Cisteína Endopeptidasas , Ensayos de Selección de Medicamentos Antitumorales , Escherichia coli/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Células K562 , Biología Marina , Micrococcus luteus/efectos de los fármacos , Resonancia Magnética Nuclear Biomolecular , Proteus vulgaris/efectos de los fármacos , Quinonas/química , Salmonella typhimurium/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , EstereoisomerismoRESUMEN
Ten new polyoxygenated diterpenes (7-16) along with six known gagunin compounds (1-6) were isolated from the sponge Phorbas sp. collected in the Korean Sea. On the basis of a combination of NMR and mass spectroscopic analyses, the molecular structures of these diterpenes, designated as gagunins H-Q, were determined to be penta- or hexa-oxygenated diterpenes of the 10,13-bis-epi-homoverrucosane class. A new diterpene acid (17) of a bisabolane-related skeletal class was also isolated and structurally defined by the spectroscopic analyses. These compounds exhibited moderate to significant cytotoxicity against the K-562 cell line as well as weak inhibitory activity against isocitrate lyase (ICL).
Asunto(s)
Diterpenos/aislamiento & purificación , Oxígeno/química , Poríferos/química , Animales , Diterpenos/química , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isocitratoliasa/antagonistas & inhibidores , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
Inflammation is a part of the complex biological responses of a tissue to injury that protect the organ by removing injurious stimuli and initiating the healing process, and is considered as a mechanism of innate immunity. To identify biologically active compounds against pathogenic inflammatory and immune responses, we fractionated water, aqueous methanol and n-hexane layers from nine kinds of leguminosae and examined anti-inflammatory activity of the fractions in human keratinocytes and mouse skin. Among the fractions, rf3 and rf4, isolated from the aqueous methanol layer of Astragalus sinicus L., exhibited the strongest reactive oxygen species (ROS)-scavenging and anti-inflammatory activities as measured by inhibition of the intracellular ROS production, nuclear factor-kappaB (NF-κB), janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphatidylinositol 3-kinase/Akt signaling in cytokine-stimulated human keratinocytes, as well as by effects on T-cell differentiation in mouse CD4(+) T cells. In addition, topical application of rf3 and rf4 suppressed the progression of psoriasis-like dermatitis and expression of pro-inflammatory mediators in interleukin (IL)-23-injected mouse ears. Our results suggest that Astragalus sinicus L. may ameliorate chronic inflammatory skin diseases due to its antioxidant and anti-inflammatory activities via regulation of the intracellular ROS production, NF-κB, JAK/STAT and PI3/Akt signaling cascades as well as immune responses, and these results are the first report that Astragalus sinicus L. exhibits pharmacological activity.
Asunto(s)
Antiinflamatorios/farmacología , Planta del Astrágalo/química , Queratinocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Piel/efectos de los fármacos , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Línea Celular , Dermatitis/tratamiento farmacológico , Humanos , Interleucina-23/farmacología , Quinasas Janus/metabolismo , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción STAT/metabolismo , Piel/metabolismoRESUMEN
Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines. (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges. Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells. (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45α and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C. In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K. The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK. These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways.