RESUMEN
Phytochemical reinvestigation on the whole plants of Derris laxiflora Benth. afforded two new diprenylated flavanones, derriflavanones B and C (1-2), together with thirty-two known compounds, including sixteen flavonoids (3-18), eleven aromatic compounds (19-29), and five chlorophylls (30-34). All known compounds were first isolated from this plant. The structures of these compounds were determined by analysis of the NMR spectroscopy, mass data, IR spectra, UV spectra, optical rotation and by comparison with literature data.
Asunto(s)
Derris/química , Flavanonas/química , Flavanonas/aislamiento & purificación , Flavonoides/química , Flavonoides/aislamiento & purificación , Extractos Vegetales/química , Prenilación , Análisis EspectralRESUMEN
Six compounds were isolated from Derris laxiflora Benth., including two new pterocarpans, 7,6'-dihydroxy-3'-methoxypterocarpan (1) and derrispisatin (2), as well as four known ones, lespedezol D, (3), secundiflorol 1 (4), 6a-hydroxymaackiain (5) and pisatin (6). The structures of these compounds were determined by analysis of their spectroscopic data.
Asunto(s)
Derris/química , Pterocarpanos/química , Estructura MolecularRESUMEN
BACKGROUND: The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells. CONCLUSIONS: CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.
Asunto(s)
Antineoplásicos/farmacología , Ácidos Cafeicos/farmacología , Neoplasias del Colon/enzimología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Células HCT116 , Humanos , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacologíaRESUMEN
BACKGROUND: Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. METHODS: Type 1 diabetes mellitus was induced in Sprague-Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats. RESULTS: Compared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (L-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals. CONCLUSIONS: CAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals.
Asunto(s)
Ácidos Cafeicos/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Animales , Diabetes Mellitus Experimental/patología , Masculino , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Glucose intolerance and cardiovascular complications are major symptoms in patients with diabetes. Many therapies have proven beneficial in treating diabetes in animals by protecting the cardiovascular system and increasing glucose utilization. In this study, we evaluated the effects of caffeic acid phenethyl amide (CAPA) on glucose homeostasis and vascular function in streptozotocin (STZ)-induced type 1 diabetic rats. METHODS: Diabetes (blood glucose levels > 350 mg/dL), was induced in Wistar rats by a single intravenous injection of 60 mg/kg STZ. Hypoglycemic effects were then assessed in normal and type 1 diabetic rats. In addition, coronary blood flow in Langendorff-perfused hearts was evaluated in the presence or absence of nitric oxide synthase (NOS) inhibitor. The thoracic aorta was used to measure vascular response to phenylephrine. Finally, the effect of chronic treatment of CAPA and insulin on coronary artery flow and vascular response to phenylephrine were analyzed in diabetic rats. RESULTS: Oral administration of 0.1 mg/kg CAPA decreased plasma glucose in normal (32.9 ± 2.3% decrease, P < 0.05) and diabetic rats (11.8 ± 5.5% decrease, P < 0.05). In normal and diabetic rat hearts, 1-10 µM CAPA increased coronary flow rate, and this increase was abolished by 10 µM NOS inhibitor. In the thoracic aorta, the concentration/response curve of phenylephrine was right-shifted by administration of 100 µM CAPA. Coronary flow rate was reduced to 7.2 ± 0.2 mL/min at 8 weeks after STZ-induction. However, 4 weeks of treatment with CAPA (3 mg/kg, intraperitoneal, twice daily) started at 4 weeks after STZ induction increased flow rate to 11.2 ± 0.5 mL/min (P < 0.05). In addition, the contractile response induced by 1 µM phenylephrine increased from 6.8 ± 0.6 mN to 11.4 ± 0.4 mN (P < 0.05) and 14.9 ± 1.4 mN (P < 0.05) by insulin (1 IU/kg, intraperitoneal) or CAPA treatment, respectively. CONCLUSIONS: CAPA induced hypoglycemic activity, increased coronary blood flow and vascular response to phenylephrine in type 1 diabetic rats. The increase in coronary blood flow may result from endothelial NOS activation. However, the detailed cellular mechanisms need to be further evaluated.
Asunto(s)
Aorta/efectos de los fármacos , Glucemia/efectos de los fármacos , Ácidos Cafeicos/farmacología , Circulación Coronaria/efectos de los fármacos , Diabetes Mellitus Experimental , Hipoglucemiantes/farmacología , Animales , Ácidos Cafeicos/síntesis química , Estudios de Casos y Controles , Insulina/metabolismo , Secreción de Insulina , Masculino , Alcohol Feniletílico/análogos & derivados , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
Caffeic acid phenyl ester is distributed wildly in nature and has antidiabetic and cardiovascular protective effects. However, rapid decomposition by esterase leads to its low bioavailability in vivo. In this study, chronic metabolic and cardiovascular effects of oral caffeic acid phenylethyl amide, whose structure is similar to caffeic acid phenyl ester and resveratrol, were investigated in ICR mice. We found that caffeic acid phenylethyl amide protected against diet or streptozocin-induced metabolic changes increased coronary flow and decreased infarct size after global ischemia-reperfusion in Langendorff perfused heart. Further study indicated that at least two pathways might be involved in such beneficial effects: the induction of the antioxidant protein MnSOD and the decrease of the proinflammatory cytokine TNFα and NFκB in the liver. However, the detailed mechanisms of caffeic acid phenylethyl amide need further studies. In summary, this study demonstrated the protective potential of chronic treatment of caffeic acid phenylethyl amide against the metabolic consequences in diabetes mellitus.
RESUMEN
Cardiac hypertrophy is an important compensatory mechanism in response to a pressure overload, but a sustained excessive cardiac workload may deteriorate to maladaptive hypertrophy and to increased risk of heart failure. In this study, we evaluated the effects of KS370G on left ventricular hypertrophy and function. Abdominal aortic banding was performed by constricting the abdominal aorta. Hypertrophied heart was studied at 8 weeks after the operation. After the operation, KS370G 1mg/kg (K1 group) was administered by oral gavage once a day. Left ventricular function was measured by a 1.2F pressure-volume catheter (Scisense, Canada). The levels of protein for α-SMA (smooth muscle actin), p-AKT (protein kinase B), p-GSK3ß (glycogen synthase kinase 3ß) and p-ERKs (extracellular signal-regulated kinases) in myocardium were analyzed by Western blot. Plasma levels of angiotensin II, atrial natriuretic peptide and lactate dehydrogenase were analyzed by commercial kits. H.E. staining and M.T. staining methods were also used to observe diameter of cardiomyocytes and collagen accumulation. Chronic oral treatment with 1mg/kg KS370G inhibited cardiac hypertrophy and improved cardiac function induced by pressure overload. KS370G also decreased the plasma levels of atrial natriuretic peptide and lactate dehydrogenase. Besides, pressure overload-induced increase of α-SMA and phosphorylation of ERK, AKT and GSK3ß were significantly reduced by chronic oral treatment with KS370G. We also found that chronic oral treatment with KS370G reduced cardiac collagen accumulation. KS370G improved left ventricular function and inhibited cardiac hypertrophy through the decrease of the phosphorylation of ERK, AKT and GSK3ß in pressure-overload mice heart.
Asunto(s)
Ácidos Cafeicos/farmacología , Cardiotónicos/farmacología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Presión/efectos adversos , Actinas/metabolismo , Angiotensina II/sangre , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Factor Natriurético Atrial/sangre , Ácidos Cafeicos/uso terapéutico , Cardiotónicos/uso terapéutico , Colágeno/metabolismo , Constricción , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Ventrículos Cardíacos/efectos de los fármacos , Hipertrofia/tratamiento farmacológico , Hipertrofia/etiología , Hipertrofia/metabolismo , Hipertrofia/fisiopatología , L-Lactato Deshidrogenasa/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de TiempoRESUMEN
Four new lactone chlorins, ficuschlorins A - D (1-4, resp.), and six known pheophytins were isolated from the leaves of Ficus microcarpa. The structures of these compounds were determined by 1D- and 2D-NMR spectroscopy, and other techniques. New natural pheophytins were rarely obtained. In the past ten years, only three new pheophytins were isolated from natural sources.
Asunto(s)
Ficus/química , Lactonas/química , Porfirinas/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Hojas de la Planta/química , Porfirinas/aislamiento & purificaciónRESUMEN
Two new methoxy lactone chlorins ficusmicrochlorin A (1) and ficusmicrochlorin B (2), and one new anhydride chlorin ficusmicrochlorin C (3), along with eight known pheophytins were isolated from the leaves of Ficus microcarpa. Their structures were determined by the extensive 1D- and 2D-NMR techniques. New pheophytin compound was rarely obtained from natural sources. In the past ten years, only three new natural pheophytins were characterized.
Asunto(s)
Ficus/química , Lactonas/química , Porfirinas/química , Lactonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Conformación Molecular , Hojas de la Planta/química , Porfirinas/aislamiento & purificaciónRESUMEN
The antihyperglycemic actions of caffeamide derivatives, especially KS370G, in normal ICR, streptozotocin-induced diabetic (T1DM) and diet-induced diabetic (T2DM) mice were investigated in this study. Oral administration of the compound decreased the plasma glucose levels in both normal and diabetic mice, and appeared to be in a dose-dependent manner in normal and diet-induced type 2 diabetic mice. It was found that KS370G could stimulate the release of insulin in both normal and T2DM mice, and a dose of 1 mg per kg KS370G could significantly attenuate the increase of plasma glucose induced by an intraperitoneal glucose challenge test in normal and diabetic mice. Similar treatment with KS370G significantly increased glycogen content in both liver and skeletal muscle. Hence, the hypoglycemic effect of KS370G in normal and diabetic mice could be attributed to the stimulation of insulin release and the increase of glucose utilization.
Asunto(s)
Ácidos Cafeicos/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Animales , Glucemia/análisis , Ácidos Cafeicos/síntesis química , Ácidos Cafeicos/química , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
A new phenolic, bis(6-hydroxy-2,3,4-trimethoxylphen-1-yl)methane (1) and a new butanedioate, butylmethyl succinate (2), along with twenty-nine known compounds including one naphthoquinone derivative, two chromanones, eight benzenoids, one lignan, one tocopherol, and sixteen triterpenoids were isolated from the stems of Diospyros maritima. epi-Isoshinanolone (3) was isolated in pure form for the first time. In addition, 5,7-dihydroxy-2-methylchomanone (4) was isolated from a natural source for the first time. Their structures were established on the basis of spectroscopic data as well as direct comparison with authentic samples.
Asunto(s)
Diospyros/química , Tallos de la Planta/química , Cromatografía Líquida de Alta Presión , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Seven new compounds, O-trans-cinnamoylglutinol (1), 22ß-hydroxy-12-oleanen-3-one (2), 15α,16α-epoxy-12-oleanen-3-one (3), 29-hydroxy-12-oleanene-3,22-dione (4), 22ß,29-dihyroxy-12-oleanen-3-one (5), 2,3-(methylenedioxy)-4-methoxy-5-methylphenol (8), and 2,3,6-trimethoxy-5-methylphenol (9), as well as two first isolated from natural sources, 25-cycloartene-3,24-dione (6) and 24ξ-hydroxy-25-cycloarten-3-one (7), were characterized from Derris laxiflora. The structures of these compounds were determined by analysis of their spectroscopic data.
Asunto(s)
Derris/química , Hidrocarburos Aromáticos/aislamiento & purificación , Triterpenos/aislamiento & purificación , Hidrocarburos Aromáticos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Taiwán , Triterpenos/químicaRESUMEN
One new compound, 10-hydroxy-gamma-dodecalactone (1) and three natural new compounds, 11-hydroxy-gamma-dodecalactone (2), 2-(2-hydroxyethyl)phenol (3) and 12-hydroxydodecanoic acid methyl ester (4), together with eight known compounds, ergostatrien-3beta-ol, ergosterol peroxide, methyl (4-hydroxyphenyl)acetate, vanillin, 4-hydroxybenzaldehyde, hexadecanoic acid, 5-methoxymethylfuran-2-carbaldehyde and 5-hydroxymethylfuran-2-carbaldehyde, all were isolated from the submerged whole broth of Antrodia camphorata. The structures of 1 and 2 were principally elucidated by spectral evidence and the absolute configuration was elucidated by the modified Mosher's method.
Asunto(s)
Antrodia/química , Cuerpos Fructíferos de los Hongos/química , Lactonas/química , Fenol/química , Medios de Cultivo Condicionados/química , Lactonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Medicina Tradicional China , Estructura Molecular , Fenol/aislamiento & purificaciónRESUMEN
Seven nor- and podocarpane-type diterpenes were isolated from the bark of Taiwania cryptomerioides Hayata, including three 18-nor-podocarpanes: 18-nor-1beta,4alpha,14-trihydroxy-13-methoxy-8,11,13-podocarpatriene (1), 18-nor-1beta,4alpha,13,14-tetrahydroxy-8,11,13-podocarpatrien-7-one (2), 18-nor-1beta,4alpha,14-trihydroxy-13-methoxy-8,11,13-podocarpatrien-7-one (3), 1beta,14,19-trihydroxy-13-methoxy-8,11,13-podocarpatrien-7-one (4), 1beta,13,14,18-tetrahydroxy-8,11,13-podocarpatrien-7-one (5), 18-acetoxy-1beta,13,14-trihydroxy-8,11,13-podocarpatrien-7-one (6), and 1beta,14,18-trihydroxy-13-methoxy-8,11,13-podocarpatrien-7-one (7). Their structures were determined by application of 1D and 2D NMR spectroscopy and other techniques. Podocarpane-type diterpenes do not occur extensively in nature, and the presumed oxidative enzyme in this plant will be of interest to identify.