RESUMEN
The response of porcine pancreatic elastase (PPE) to propanol was examined by various techniques including UV-vis spectrophotometry, spectrofluorometry and circular dichroism, as well as molecular docking and molecular simulation. These techniques were used to investigate the structural changes and elastase activity in the presence of propanol. This work was performed at three temperatures of 303, 313 and 323 K, with the pH value of 8.5 (Tris buffer). The results of the UV-vis spectrophotometry indicated the transfer of tryptophan to an environment with low hydrophobicity. Fluorescence measurements also revealed the quenching of fluorescence intensity was induced by propanol, and dynamic quenching was the proposed quenching mechanism. Kinetic studies also suggested the inhibitory effect (noncompetitive) of propanol on elastase. Further, Circular Dichroism (CD) spectra showed that propanol caused slight alterations in the secondary structures of PPE (0.3% increase for the α-helix and 0.5% decrease for the ß-sheet). Addition of propanol decreased the Tm (Melting Temperature) parameter from 332.8 K to 330.1 K.
Asunto(s)
1-Propanol/química , 1-Propanol/farmacología , Simulación del Acoplamiento Molecular/métodos , Elastasa Pancreática/química , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Animales , Fenómenos Químicos , Dicroismo Circular , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Desnaturalización Proteica/efectos de los fármacos , Estructura Secundaria de Proteína/efectos de los fármacos , Espectrometría de Fluorescencia , Porcinos , Temperatura , Triptófano/metabolismoRESUMEN
Fifty-seven compounds were purified from the stems of Tinospora sinensis, including three new compounds characterized as a lignan (1), a pyrrole alkaloid (11), and a benzenoid (17), respectively. Their structures were elucidated and established by various spectroscopic and spectrometric analytical methods. Among the isolates, fifteen compounds were examined for their anti-inflammatory potential in vitro. The results showed that several compounds displayed moderate inhibition of N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release.
Asunto(s)
Alcaloides/farmacología , Lignanos/farmacología , Elastasa Pancreática/metabolismo , Pirroles/farmacología , Alcaloides/química , Citocalasina B/antagonistas & inhibidores , Citocalasina B/toxicidad , Humanos , Lignanos/química , Estructura Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Elastasa Pancreática/biosíntesis , Elastasa Pancreática/efectos de los fármacos , Tallos de la Planta/química , Pirroles/química , Superóxidos/antagonistas & inhibidores , Superóxidos/toxicidad , Tinospora/químicaRESUMEN
A continuing chemical investigation of the ethyl acetate (EtOAc) extract of a reef soft coral Sinularia brassica, which was cultured in a tank, afforded four new steroids with methyl ester groups, sinubrasones A-D (1-4) for the first time. In particular, 1 possesses a ß-D-xylopyranose. The structures of the new compounds were elucidated on the basis of spectroscopic analyses. The cytotoxicities of compounds 1-4 against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of these new compounds 1-4 were also evaluated by measuring their ability to suppress superoxide anion generation and elastase release in N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced human neutrophils. Compounds 2 and 3 were shown to exhibit significant cytotoxicity, and compounds 3 and 4 were also found to display attracting anti-inflammatory activities.
Asunto(s)
Antozoos/química , Esteroides , Acetatos/química , Animales , Antiinflamatorios no Esteroideos/farmacología , Humanos , N-Formilmetionina Leucil-Fenilalanina/química , Neutrófilos/efectos de los fármacos , Elastasa Pancreática/efectos de los fármacos , Esteroides/química , Esteroides/aislamiento & purificación , Esteroides/farmacología , Superóxidos/metabolismo , Xilosa/análogos & derivados , Xilosa/químicaRESUMEN
Clitocybin A, an isoindolinone from Clitocybe aurantiaca, was investigated to assess its anti-wrinkle properties, through reactive oxygen species (ROS)-scavenging and elastase inhibitory activities, procollagen synthesis, and matrix metalloproteinase-1 (MMP-1) expression, in human primary dermal fibroblast-neonatal (HDF-N) cells. Clitocybin A exhibited no significant cytotoxicity up to 10 ppm in HDF-N cells, with cell viability and cell proliferation activity greater than 94.6% and 91.9%, respectively. Strong and concentration-dependent ROS radical scavenging activities of clitocybin A were observed following irradiation with UVB at 30 mJ/cm2. Furthermore, clitocybin A treatment of cells at 0.1, 1, and 10 ppm exhibited decreased elastase activity, in a concentration-dependent manner, by 1.97%, 6.6%, and 8.31%, respectively, versus the control group. The effects of clitocybin A on procollagen synthesis and MMP-1 expression were investigated. Clitocybin A treatment of cells at 1, 5, and 10 ppm increased procollagen synthesis, by 67.9%, 74.4%, and 112.9%, respectively, versus the control group. At these concentrations, MMP-1 expression decreased significantly following UV irradiation. Together, these findings suggest that clitocybin A may be an effective ingredient for use in anti-wrinkle cosmetic products.
Asunto(s)
Agaricales/química , Depuradores de Radicales Libres/farmacología , Isoindoles/antagonistas & inhibidores , Micelio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular/efectos de los fármacos , Línea Celular/metabolismo , Línea Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Humanos , Isoindoles/administración & dosificación , Isoindoles/química , Metaloproteinasa 1 de la Matriz/biosíntesis , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/efectos de la radiación , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Procolágeno/antagonistas & inhibidores , Procolágeno/biosíntesis , Procolágeno/efectos de la radiación , Especies Reactivas de Oxígeno/efectos de la radiación , Dispersión de Radiación , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Rayos UltravioletaRESUMEN
Fifty compounds were isolated from the fruits of Forsythia suspensa, including 13 new compounds characterized as eight new diterpenoids (1-8), three new lignans (9-11), a new iridoid (12), and a new triterpenoid (13). Their structures were established on the basis of spectroscopic and spectrometric analysis. Most of the isolated compounds were examined for their anti-inflammatory activity in vitro. The results showed that several compounds displayed significant inhibition of fMLP/CB-induced superoxide anion generation and elastase release, with IC50 values ranging from 0.6 ± 0.1 to 8.6 ± 0.8 µg/mL and from 0.8 ± 0.3 to 7.3 ± 1.1 µg/mL, respectively.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Forsythia/química , Frutas/química , Lignanos/aislamiento & purificación , Lignanos/farmacología , Antiinflamatorios/química , Diterpenos/química , Humanos , Lignanos/química , Estructura Molecular , Neutrófilos/efectos de los fármacos , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Superóxidos/metabolismo , TaiwánRESUMEN
Zoanthus kuroshio is a colorful zoanthid with a fluorescent pink oral disc and brown tentacles, which dominates certain parts of the Taiwanese and Japanese coasts. This sea anemone is a rich source of biologically active alkaloids. In the current investigation, two novel halogenated zoanthamines [5α-iodozoanthenamine (1) and 11ß-chloro-11-deoxykuroshine A (2)], along with four new zoanthamines [18-epi-kuroshine A (3), 7α-hydroxykuroshine E (4), 5α-methoxykuroshine E (5), and 18-epi-kuroshine E (6)], and six known compounds were isolated from Z. kuroshio. Compounds 1 and 2 are the first examples of halogenated zoanthamine-type alkaloids isolated from nature. Compounds 3 and 6 are the first zoanthamine stereoisomers with a cis-junction of the A/B rings. All isolated compounds were evaluated for their anti-inflammatory activities by measuring their effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP.
Asunto(s)
Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Antiinflamatorios/aislamiento & purificación , Azepinas/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Hidrocarburos Halogenados/aislamiento & purificación , Quinolinas/química , Anémonas de Mar/química , Alcaloides/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Humanos , Hidrocarburos Halogenados/química , Hidrocarburos Halogenados/farmacología , Japón , Estructura Molecular , Neutrófilos/metabolismo , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Estereoisomerismo , Superóxidos/química , TaiwánRESUMEN
Nine new phenanthrenes (1-9) and a new benzyl glycoside (10) together with 45 known compounds were isolated from the rhizomes of Bletilla formosana. The structures of 1-10 were elucidated primarily on the basis of their 1D and 2D NMR spectroscopic data. Most of the isolated compounds were evaluated for their anti-inflammatory activities. The results showed that IC50 values for the inhibition of superoxide anion generation and elastase release ranged from 0.2 to 6.5 µM and 0.3 to 5.7 µM, respectively. Structure-activity relationships of the isolated compounds were also investigated. The inhibitory potencies were determined as phenanthrenes > bibenzyls > biphenanthrenes.
Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Bibencilos , Orchidaceae/química , Fenantrenos/aislamiento & purificación , Fenantrenos/farmacología , Rizoma/química , Antiinflamatorios no Esteroideos/química , Bibencilos/química , Bibencilos/aislamiento & purificación , Bibencilos/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Fenantrenos/química , Relación Estructura-Actividad , Superóxidos/química , TaiwánRESUMEN
A chemical investigation of the fruiting bodies of Hexagonia apiaria resulted in the identification of nine compounds including five new triterpenoids, hexagonins A-E (1-5), along with four known compounds. The purified constituents were examined for their anti-inflammatory activity. Among the tested compounds, hexatenuin A displayed the most significant inhibition of superoxide anion generation and elastase release. These triterpenoids may have potentials as anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Cuerpos Fructíferos de los Hongos/química , Polyporaceae/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antiinflamatorios/sangre , Antiinflamatorios/química , Antiinflamatorios/farmacología , Humanos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Superóxidos/metabolismo , Triterpenos/sangre , Triterpenos/químicaRESUMEN
RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown. OBJECTIVES: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism. METHODS: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling. MEASUREMENTS AND MAIN RESULTS: In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1. CONCLUSIONS: Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo II/efectos de los fármacos , Caveolina 1/efectos de los fármacos , Elafina/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Elastasa Pancreática/efectos de los fármacos , RatasRESUMEN
Isoflavones are phytoestrogens known by their anti-inflammatory, antioxidant and immunomodulatory properties. Presently, there is no information on whether afrormosin, an isoflavone from Amburana cearensis A.C. Smith (Fabaceae), has some effect on the inflammatory response from stimulated human neutrophils. Thus, the aim of this study was to evaluate the anti-inflammatory and antioxidant potentials of afrormosin on human neutrophils. Neutrophils (2.5 × 10(6) cells/mL) were incubated with afrormosin (3.35-335.2 µM) prepared from a product isolated from Amburana cearensis A.C. Smith with a 78.5% degree of purity and stimulated by the addition of cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol 12-myristate-13-acetate (PMA). Afrormosin inhibited the neutrophil degranulation induced by fMLP (10.47-335.2 µM) or PMA (0.33-167.6 µM), myeloperoxidase activity (3.3-335.2 µM), TNF-α secretion (16.7-335.2 µM) and the reactive oxygen species (ROS) generation (16.7-335.2 µM). On the other hand, afrormosin did not show any effect either on elastase or as a free radical scavenger. These data suggest that afrormosin modulates intermediary steps of the neutrophil ROS generation process. In addition, the modulatory effect of afrormosin on human neutrophil degranulation seems to be directed towards PMA-induced activation, indicating a potent inhibition of the protein kinase C activity. This study provided evidence, for the first time, to support the anti-inflammatory and antioxidant activities of afrormosin, creating novel insights into the pharmacological actions of this natural isoflavone.
Asunto(s)
Fabaceae/química , Mediadores de Inflamación/farmacología , Inflamación/tratamiento farmacológico , Isoflavonas/farmacología , Neutrófilos/efectos de los fármacos , Adulto , Antioxidantes/farmacología , Degranulación de la Célula/efectos de los fármacos , Humanos , Isoflavonas/aislamiento & purificación , Neutrófilos/química , Elastasa Pancreática/efectos de los fármacos , Peroxidasa/efectos de los fármacos , Especies Reactivas de Oxígeno/análisis , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Three new cembrane-type diterpenoids, flexibilins A-C (1-3), along with a known cembrane, (-)-sandensolide (4), were isolated from the soft coral, Sinularia flexibilis. The structures of cembranes 1-4 were elucidated by spectroscopic methods. The structure of 4, including its absolute stereochemistry, was further confirmed by single-crystal X-ray diffraction analysis. Cembrane 2 displayed a moderate inhibitory effect on the release of elastase by human neutrophils.
Asunto(s)
Antozoos/química , Diterpenos/farmacología , Neutrófilos/efectos de los fármacos , Elastasa Pancreática/efectos de los fármacos , Animales , Diterpenos/química , Diterpenos/aislamiento & purificación , Humanos , Neutrófilos/metabolismo , Elastasa Pancreática/metabolismo , Análisis Espectral , Taiwán , Difracción de Rayos XRESUMEN
Phytochemical investigation of the methanolic extract of Croton tonkinensis afforded two known kauranes (1, 2), eight new ent-kauranes (3-10), and 16 known ent-kaurane-type diterpenoids (12-27). In addition, 30 known compounds were identified by comparison of their physical and spectroscopic data with reported data. Among the isolated compounds, ent-18-acetoxykaur-16-en-15-one (20) displayed the most significant inhibition of superoxide anion generation and elastase release.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Diterpenos de Tipo Kaurano/aislamiento & purificación , Diterpenos de Tipo Kaurano/farmacología , Antiinflamatorios/química , Croton/química , Diterpenos de Tipo Kaurano/química , Estructura Molecular , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , VietnamRESUMEN
A new bioactive sterol glycoside, 3beta-O-(3',4'-di-O-acetyl-beta-D-arabinopyranosyl)-25xi-cholestane-3beta,5alpha,6beta,26-tetrol-26-acetate) (carijoside A, 1), was isolated from an octocoral identified as Carijoa sp. The structure of glycoside 1 was established by spectroscopic methods and by comparison with spectral data for the other known glycosides. Carijoside A (1) displayed significant inhibitory effects on superoxide anion generation and elastase release by human neutrophils and this compound exhibited moderate cytotoxicity toward DLD-1, P388D1, HL-60, and CCRF-CEM tumor cells.
Asunto(s)
Antozoos/química , Glicósidos/farmacología , Saponinas/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Glicósidos/aislamiento & purificación , Humanos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Saponinas/aislamiento & purificación , Análisis Espectral , Esteroles/aislamiento & purificación , Esteroles/farmacología , Superóxidos/metabolismoRESUMEN
Six new xenicane-type diterpenoids, designated as asterolaurins A-F (1-6), have been isolated from the organic extract of the soft coral Asterospicularia laurae, collected in southern Taiwan. Compounds 1-4 possess a xenicin skeleton with a 2-oxabicyclo[7.4.0]tridecane ring system, while 5 and 6 are xeniolide A-type compounds. The structures of the new secondary metabolites, including their configurations, were established on the basis of an extensive spectroscopic analysis, including 1D and 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY), and by comparison of their NMR data with those of the related compounds. The structure of asterolaurin A (1) was confirmed by X-ray diffraction analysis, and its absolute configuration was determined using the modified Mosher's method. Asterolaurin A (1) exhibited moderate cytotoxicity against HepG2 cells with an IC50 of 8.9 microM, while asterolaurin D (4) showed potent inhibition of elastase release and superoxide anion generation in vitro.
Asunto(s)
Antozoos/química , Antineoplásicos/aislamiento & purificación , Diterpenos/aislamiento & purificación , Elastasa Pancreática/efectos de los fármacos , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Diterpenos/química , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Elastasa Pancreática/metabolismo , TaiwánRESUMEN
Two new briarane-related diterpenoids, designated as excavatoids E (1) and F (2), were isolated from the cultured octocoral Briareum excavatum. The structures of compounds 1 and 2 were established on the basis of extensive spectral data analysis. Briaranes 1 and 2 were found to exhibit moderate inhibitory effects on elastase release by human neutrophils.
Asunto(s)
Antozoos/química , Diterpenos/farmacología , Animales , Diterpenos/aislamiento & purificación , Humanos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Análisis Espectral , TaiwánRESUMEN
Five new benzophenone derivatives, 13,14-didehydoxyisogarcinol (1), garcimultiflorone A (2), garcimultiflorone B (3), 13-hydroxygarcimultiflorone B (4), and garcimultiflorone C (5), have been isolated from the fruits of Garcinia multiflora, together with seven known compounds (6-12). The structures of these new compounds were determined through spectroscopic and MS analyses. 13,14-Didehydoxyisogarcinol (1), garcimultiflorone A (2), garcimultiflorone B (3), and 13-hydroxygarcimultiflorone B (4) exhibited inhibition with an IC(50) range of 0.11-5.58 microM on superoxide anion generation and elastase release by human neutrophils in response to fMet-Leu-Phe/cytochalasin B (fMLP/CB).
Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Benzofenonas/aislamiento & purificación , Benzofenonas/farmacología , Garcinia/química , Elastasa Pancreática/efectos de los fármacos , Plantas Medicinales/química , Antiinflamatorios no Esteroideos/química , Benzofenonas/química , Citocalasina B/farmacología , Frutas/química , Humanos , Estructura Molecular , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Resonancia Magnética Nuclear Biomolecular , Elastasa Pancreática/antagonistas & inhibidores , Superóxidos/análisisRESUMEN
BACKGROUND: Desmosine and Isodesmosine (D/I) are cross-linking amino acids which are present only in mature elastin. Changes in their concentration in body fluids indicate changes in elastin degradation and can be a reflection of tissue elastase activity. This study was undertaken to determine whether continuous therapy with the long-acting bronchodilator Tiotropium bromide (TTP) could result in reductions in D/I as measured by mass spectrometry in plasma, urine and sputum. METHODS: Twelve not currently smoking patients with chronic obstructive pulmonary disease (COPD), never on TTP, were selected for study. Levels of D/I, along with measurements of FVC, FEV1 and FEV1/FVC. were determined before starting TTP daily, and then one and two months after. RESULTS: D/I decreased in plasma (10 of 12 patients), in sputum all (12 of 12), and in the percentage of free D/I in urine (10 of 12). Most patients showed slight increases in FVC and FEV1 percent predicted over two months. CONCLUSION: The results are consistent with an effect of prolonged bronchodilitation by anti-cholinergic blockade to also result in reduced lung elastin degradation.
Asunto(s)
Broncodilatadores/uso terapéutico , Elastina/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Derivados de Escopolamina/uso terapéutico , Desmosina/sangre , Desmosina/metabolismo , Desmosina/orina , Volumen Espiratorio Forzado , Humanos , Isodesmosina/sangre , Isodesmosina/metabolismo , Isodesmosina/orina , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Cese del Hábito de Fumar , Bromuro de Tiotropio , Capacidad VitalRESUMEN
Pulmonary arterial hypertension is a progressive, fatal disease. Current treatments including prostanoids, endothelin-1 (ET-1) antagonists, and phosphodiesterase (PDE) inhibitors, have sought to address the pulmonary vascular endothelial dysfunction and vasoconstriction associated with the condition. These treatments may slow the progression of the disease but do not afford a cure. Future treatments must target more directly the structural vascular changes that impair blood flow through the pulmonary circulation. Several novel therapeutic targets have been proposed and are under active investigation, including soluble guanylyl cyclase, phosphodiesterases, tetrahydrobiopterin, 5-HT2B receptors, vasoactive intestinal peptide, receptor tyrosine kinases, adrenomedullin, Rho kinase, elastases, endogenous steroids, endothelial progenitor cells, immune cells, bone morphogenetic protein and its receptors, potassium channels, metabolic pathways, and nuclear factor of activated T cells. Tyrosine kinase inhibitors, statins, 5-HT2B receptor antagonists, EPCs and soluble guanylyl cyclase activators are among the most advanced, having produced encouraging results in animal models, and human trials are underway. This review summarises the current research in this area and speculates on their likely success.
Asunto(s)
GMP Cíclico/farmacología , GMP Cíclico/fisiología , Descubrimiento de Drogas , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Adrenomedulina/farmacología , Adrenomedulina/uso terapéutico , Animales , Receptores de Proteínas Morfogenéticas Óseas/efectos de los fármacos , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , GMP Cíclico/metabolismo , Ácido Dicloroacético/farmacología , Ácido Dicloroacético/uso terapéutico , Células Endoteliales , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Factores de Transcripción NFATC/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Elastasa Pancreática/antagonistas & inhibidores , Elastasa Pancreática/efectos de los fármacos , Neumonía/tratamiento farmacológico , Neumonía/fisiopatología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Tirosina Quinasas Receptoras/fisiología , Serotonina/farmacología , Serotonina/fisiología , Células Madre/metabolismo , Péptido Intestinal Vasoactivo/farmacología , Péptido Intestinal Vasoactivo/uso terapéutico , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Twenty-four new dipeptide analogs (1-24) of aurantiamide acetate were designed, synthesized, and assayed for effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, seven N-(fluorenyl-9-methoxycarbonyl) (Fmoc)-dipeptides (6, 9, 12, 14, 17, 18 and 20) showed potent inhibitory effects. Compounds 9 and 18 showed the most selective effects against human neutrophil elastase release, with IC(50) values of 0.8+/-0.1 and 1.7+/-0.6muM, respectively, and were 130-fold more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in this anti-inflammatory assay. These two compounds could be developed as new lead anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/síntesis química , Dipéptidos/síntesis química , Antiinflamatorios/farmacología , Dipéptidos/farmacología , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Elastasa Pancreática/efectos de los fármacos , Elastasa Pancreática/metabolismo , Superóxidos/metabolismoRESUMEN
Chemical investigation of the gorgonian octocoral Junceella fragilis, collected in Taiwan, resulted in the isolation of seven new briarane-type diterpenes, frajunolides E-K (1-7), in addition to 14 known briaranes, praelolide, junceellin, junceellolides A-E, and K, 11a,20a-epoxy-4-deacetoxyjunceelolide D, umbraculolide A, junceellonoid A, and juncins Y, Z, and ZI, as well as ergosterol peroxide. The structures of 1-7 were determined by analysis of HRESIMS and 2D NMR spectroscopic data. Cytotoxicity and in vitro anti-inflammatory activities of compounds 1-7 were also evaluated.