RESUMEN
Tetrahexyldecyl Ascorbate (THDC) is an L-ascorbic acid precursor with improved stability and ability to penetrate the epidermis. The stability and transdermal penetration of THDC, however, may be compromised by the oxidant-rich environment of human skin. In this study, we show that THDC is a poor antioxidant that degrades rapidly when exposed to singlet oxygen. This degradation, however, was prevented by combination with acetyl zingerone (AZ) as a stabilizing antioxidant. As a standalone ingredient, THDC led to unexpected activation of type I interferon signaling, but this pro-inflammatory effect was blunted in the presence of AZ. Moreover, the combination of THDC and AZ increased expression of genes associated with phospholipid homeostasis and keratinocyte differentiation, along with repression of MMP1 and MMP7 expression, inhibition of MMP enzyme activity, and increased production of collagen proteins by dermal fibroblasts. Lastly, whereas THDC alone reduced viability of keratinocytes exposed to oxidative stress, this effect was completely abrogated by the addition of AZ to THDC. These results show that AZ is an effective antioxidant stabilizer of THDC and that combination of these products may improve ascorbic acid delivery. This provides a step towards reaching the full potential of ascorbate as an active ingredient in topical preparations.
Asunto(s)
Antioxidantes , Ácido Ascórbico , Colágeno/biosíntesis , Fibroblastos/metabolismo , Guayacol/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/farmacología , Línea Celular , Guayacol/farmacocinética , Guayacol/farmacología , HumanosRESUMEN
RATIONALE: Gigantol (3',4-dihydroxy-3,5'-dimethoxybibenzyl) is a bibenzyl compound isolated from Dendrobii Caulis that has been widely used as a medicinal herb in China. To fully understand the mechanism of action of gigantol, it is necessary to determine its metabolic profile. METHODS: Gigantol at a concentration of 20 µM was incubated with hepatocytes (rat, dog, monkey, and human) at 37°C. After 120 min incubation, the samples were analyzed using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The structures of the metabolites were characterized by their molecular masses, product ions, and retention times. RESULTS: A total of 17 metabolites were detected and structurally identified. The metabolism involved the following pathways: (a) oxidation to form quinone-methide species and subsequently conjugation with glutathione (GSH); (b) demethylation to form demethylated gigantol, which was further conjugated with GSH; (c) hydroxylation to yield hydroxyl-gigantol followed by glucuronidation or GSH conjugation; and (d) glucuronidation to form glucuronide conjugates. Glucuronidation was the primary metabolic pathway in all tested species. CONCLUSIONS: Hydroxylation, demethylation, glucuronidation, and GSH conjugation were the major metabolic pathways of gigantol. This study provides new information on the metabolic profiles of gigantol and helps us understand the disposition of the compound.
Asunto(s)
Bibencilos , Cromatografía Líquida de Alta Presión/métodos , Guayacol/análogos & derivados , Hepatocitos/metabolismo , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Bibencilos/análisis , Bibencilos/química , Bibencilos/metabolismo , Bibencilos/farmacocinética , Células Cultivadas , Perros , Guayacol/análisis , Guayacol/química , Guayacol/metabolismo , Guayacol/farmacocinética , Haplorrinos , Humanos , Ratas , Espectrometría de Masas en Tándem/métodosRESUMEN
In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg-1· d-1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Bibencilos/uso terapéutico , Guayacol/análogos & derivados , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Bibencilos/administración & dosificación , Bibencilos/farmacocinética , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Complejo de Ataque a Membrana del Sistema Complemento/antagonistas & inhibidores , Guayacol/administración & dosificación , Guayacol/farmacocinética , Guayacol/uso terapéutico , Hepatocitos/efectos de los fármacos , Humanos , Inflamación/patología , Peroxidación de Lípido/efectos de los fármacos , Ácido Litocólico , Hígado/patología , Masculino , Ratones Endogámicos ICR , Fenantrenos/farmacología , Fenantrenos/uso terapéutico , Proteoma/metabolismo , Ratas Sprague-Dawley , Estilbenos/farmacología , Estilbenos/uso terapéuticoRESUMEN
The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosis. Here we estimate that the maximum tolerated dose in a mouse model is 40 mg/kg; the drug is well tolerated both in single dose and in repeated administration schedules. The drug displays a significant antitumor activity and a tumor growth delay when administered at the MTD both in single and fractionated i.v. administration in a mouse xenograft model of colorectal cancer. Arrest of tumor growth and relapse after drug suspension are parallel to modification in glucose demand as shown by PET studies with [(18)F] FDG. These data strongly support Compound (1) as a promising molecule for in vivo treatment of colorectal cancer.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos , Azetidinas , Neoplasias Colorrectales/tratamiento farmacológico , Glucosa/metabolismo , Guayacol/análogos & derivados , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Azetidinas/sangre , Azetidinas/farmacocinética , Azetidinas/farmacología , Azetidinas/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Guayacol/sangre , Guayacol/farmacocinética , Guayacol/farmacología , Guayacol/uso terapéutico , Humanos , Masculino , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We base this study on the concept of drug repositioning to reconstitute the natural product of zingerone as zingerone nanoparticles (zingerone NPs) through a one-pot synthesized process. The as-fabricated zingerone NPs were characterized; they possessed a particle size of 1.42 ± 0.67 nm and a reconstituted structure of zingerone nanotetramer. We further validate the effects of zingerone NPs on the antitumor activity and investigate the relative underlying mechanisms on the human hepatoma SK-Hep-1 and Huh7 cell lines. Our results demonstrated that zingerone NPs significantly inhibit Akt activity and NFκB expression as well as activate the caspases cascade signaling pathway which are involved in the antiproliferation, antitumorigenicity, disturbing cell cycle progression, and induction of DNA damage as well as cell apoptosis. These findings were promising to provide a "Nano-chemoprevention" strategy in future cancer therapeutics and medical and clinical applications.
Asunto(s)
Carcinoma Hepatocelular , Guayacol/análogos & derivados , Neoplasias Hepáticas , Nanopartículas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN , Guayacol/química , Guayacol/farmacocinética , Guayacol/farmacología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Nanopartículas/química , Nanopartículas/uso terapéutico , Proteínas de Neoplasias/metabolismoRESUMEN
Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, and thus, the in vivo imaging of plaques and tangles would be beneficial for the early diagnosis of AD. It has been suggested that 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (curcumin) may be responsible for low age-adjusted prevalence of AD in India. In the present study, eight novel derivatives of curcumin and 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (dehydrozingerone) were synthesized and their binding affinities for beta-amyloid (Abeta) aggregates were measured. Of these ligands, fluoropropyl-substituted curcumin (8) showed the highest binding affinity (Ki=0.07 nM), and therefore, 8 was radiolabeled and evaluated as a potential probe for Abeta plaque imaging. Partition coefficient measurement and biodistribution in normal mice demonstrated that [18F]8 has a suitable lipophilicity and reasonable initial brain uptake. Metabolism studies also indicated that [18F]8 is metabolically stable in the brain. These results suggest that [18F]8 is a suitable radioligand for Abeta plaque imaging.
Asunto(s)
Amiloide/metabolismo , Curcumina/análogos & derivados , Curcumina/síntesis química , Guayacol/análogos & derivados , Radiofármacos/síntesis química , Estirenos/síntesis química , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Curcumina/farmacocinética , Radioisótopos de Flúor , Guayacol/síntesis química , Guayacol/química , Guayacol/farmacocinética , Marcaje Isotópico , Ligandos , Masculino , Ratones , Ratones Endogámicos ICR , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/farmacocinética , Estirenos/farmacocinética , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The kinetics parameters of paradols with different acyl chain lengths have been evaluated to determine their antiobesity site of action. Rats were orally administered olive oil containing 0-, 6-, 8-, or 12-paradol, and blood samples were collected at different time points. The concentrations of the paradols in the plasma were analyzed both with and without ß-glucuronidase treatment. The area under the plasma concentration-time curve from 0 to 24 h (AUC(0-24h)) of the parent compounds decreased with increasing acyl chain length. Whereas 12-paradol showed the largest AUC(0-24h) with the longest time to reach its maximum plasma concentration of all of the compounds tested, the AUC(0-24h) values of the metabolites decreased with increasing acyl chain length. These results indicate that increasing acyl chain length leads to a decrease in the absorption of paradols via the intestinal tract, the wall of which was estimated to be their antiobesity site of action.
Asunto(s)
Cetonas/farmacocinética , Fenoles/farmacocinética , Animales , Fármacos Antiobesidad/administración & dosificación , Catecoles , Alcoholes Grasos , Guayacol/análogos & derivados , Guayacol/sangre , Guayacol/química , Guayacol/farmacocinética , Cetonas/sangre , Cetonas/química , Masculino , Fenoles/química , Ratas , Ratas Sprague-DawleyRESUMEN
meso-Dihydroguaiaretic acid (MDGA) is a major component of Myristica fragrans and Machilus thunbergii that is traditionally used as a spice and for medicinal purposes. Despite reports of various biological activities exerted by MDGA, there is no information regarding its metabolic properties. The purpose of this study was to determine the metabolic stability and cytochrome P450 (CYP) inhibitory potential of MDGA, using pooled human liver microsomes (HLMs) to characterize its metabolic properties. In addition, pharmacokinetic analysis was performed in mice treated intravenously (5 mg/kg) or orally (20 mg/kg) with MDGA for comparison with our in vitro results. The half-life of MDGA in HLMs and mouse liver microsomes incubated with NADPH, UDPGA or NADPH plus UDPGA was 25.41 and 22.74, 0.39 and 0.20 or 0.28 and 0.22 min, respectively. In our pharmacokinetic study, MDGA rapidly declined in plasma and had low bioavailability, which was attributable to extensive metabolism by UDP-glucuronosyltransferases and CYPs. Among CYP isoforms, CYP2E1 activity was selectively inhibited by MDGA through a competitive inhibitory mode, with an inhibitory constant (Ki) value of 13.1 µM. These results suggest that MDGA can be used as a selective CYP2E1 inhibitor in vitro, which warrants evaluation of the pharmacological significance of MDGA-induced CYP2E1 inhibition.
Asunto(s)
Guayacol/análogos & derivados , Lignanos/farmacocinética , Microsomas Hepáticos/efectos de los fármacos , Animales , Inhibidores del Citocromo P-450 CYP2E1/sangre , Inhibidores del Citocromo P-450 CYP2E1/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Glucuronosiltransferasa/metabolismo , Guayacol/sangre , Guayacol/farmacocinética , Semivida , Humanos , Lauraceae/química , Lignanos/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismoRESUMEN
Neuronal death induced by I6 displayed apoptotic characteristics but the precise mechanism has not been fully elucidated. In the present studies, I6 at 24 h after intraperitoneal administration significantly decreased the density of surviving neurons and increased caspase-3 activity in frontal cortex, suggesting that peripherally administered I6 may cross BBB to induce CNS toxicity. In rat embryonic primary cortical cells, I6-induced reduction of mitochondrial viability and neuronal apoptosis was inhibited by vitamin E. In addition, I6-induced reactive oxygen species (ROS) caused the disruption of mitochondria membrane potential (MMP), the release of cytochrome c, the activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP), resulting in activation of mitochondrial-mediated intrinsic death pathway. Pre-treatment with antioxidant vitamin E or N-acetylcysteine (NAC) completely abolished the I6-induced generation of ROS, loss of MMP, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. Carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), a mitochondrial uncoupler, significantly reduced I6-induced neuronal death as well as caspase-3 activation and PARP cleavage. These results suggest that I6 induces neuronal death by promoting intracellular ROS production to cause a loss of MMP that result in release of cytochrome c and activation of mitochondria-mediated intrinsic death pathway.
Asunto(s)
Apoptosis/efectos de los fármacos , Guayacol/análogos & derivados , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Antioxidantes/farmacología , Barrera Hematoencefálica , Western Blotting , Caspasa 3/metabolismo , Células Cultivadas , Activación Enzimática , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/enzimología , Guayacol/farmacocinética , Guayacol/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/fisiología , Neuronas/citología , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Freshwater mussels (Anodonta anatina L.) were exposed to [14C]pentachlorophenol (PCP) and [14C]3,4,5-trichloroguaiacol (CG-3) under laboratory conditions. Uptake and body distribution in mussels as well as total water-soluble metabolites of chlorophenolics in hemolymph and digestive gland were measured. The time course of chlorophenolic accumulation in the mussel soft tissue was followed by analyzing the decrease in the radioactivity in exposure water. The bioconcentration factors (BCFs, activity in animal per activity in water) were measured at steady state for the soft tissue homogenate and separate organs. Both chlorinated phenolics reached a steady-state concentration during the first 24 hr. BCFs in soft tissue ranged from 145 to 342 for PCP and 34 to 125 for CG-3. Accumulations by the digestive gland (hepatopancreas) and kidneys were 2 and 1.3 times greater, respectively, than the average accumulation by the whole soft tissue. The water-soluble fraction of PCP (1-8%) and CG-3 (0.4-2.9%) in separate organs implied only a minor metabolism of chlorophenolics in this animal.
Asunto(s)
Guayacol/análogos & derivados , Pentaclorofenol/farmacocinética , Contaminantes Químicos del Agua/farmacocinética , Animales , Bivalvos , Carga Corporal (Radioterapia) , Guayacol/farmacocinética , Distribución TisularRESUMEN
The absorption rates of 4-bromophenol, 2,4-dibromophenol, 3,4,5-trichloroguaiacol, and tetrachloroveratrol across fish gill epithelium have been measured in a perfused gill preparation from rainbow trout (Oncorhynchus mykiss). In additional experiments the absorption rate of tetrachloroveratrol was measured in free swimming fish. The absorption rates were perfusion limited in gills perfused with a saline containing 2% polyvinylpyrrolidone MW 40,000 (PVP-40) as a plasma protein substitute. Replacement of PVP-40 with 2% bovine serum albumin increased the absorption rates 5-10 times, and in this case rates were not perfusion limited. Furthermore, they were not ventilation limited at ventilatory water flow rates between 0.45 and 1.5 liter/(min 100 g). Our observations suggest that the absorption rates in the presence of albumin are limited by diffusion in the epithelial cell layers. The rates measured in the perfused gills are in close agreement with those measured in vivo. We conclude that the preparation is well suited to investigate the mechanisms behind the absorption of hydrophobic compounds across fish gills and how the absorption rate is related to the physicochemical properties of the compounds, as well as to environmental factors.
Asunto(s)
Anisoles/farmacocinética , Branquias/metabolismo , Guayacol/farmacocinética , Fenoles/farmacocinética , Trucha/metabolismo , Absorción , Animales , Perfusión , Albúmina Sérica BovinaRESUMEN
Wood creosote, principally a mixture of non-, alkyl- and/or alkoxy-substituted phenolic compounds, was orally administered to adult male volunteers to determine its metabolites and pharmacokinetic parameters. After a 133-mg single dose, its major constituents (i.e. phenol 15 mg, guaiacol 32 mg, p-cresol 18 mg and creosol 24 mg) were found in peripheral venous blood and urine, mostly as glucuronic acid and, except for creosol, as sulfate conjugates. Low concentrations of unconjugated phenols were also detected. The metabolites in the serum started to increase 15 min after the dose, and they reached their maximum concentrations 30 min after administration. The maximum concentrations of glucuronides were 0.18 +/- 0.07, 0.91 +/- 0.38, 0.33 +/- 0.18 and 0.47 +/- 0.23 mg/l; those of sulfates were 0.16 +/- 0.06, 0.22 +/- 0.09, 0.17 +/- 0.07 and < 0.04 mg/l for phenol, guaiacol, p-cresol and creosol, respectively. The 24-hour urinary recoveries of the sum of each compound and its metabolites were 75 +/- 35, 45 +/- 36, 103 +/- 51 and 74 +/- 36%, in the above order. The presence of guaiacol glucuronide in blood and urine was directly verified by its isolation and structure analyses.
Asunto(s)
Creosota/farmacocinética , Fenoles/farmacocinética , Madera , Adulto , Biotransformación , Cromatografía Líquida de Alta Presión , Cresoles/farmacocinética , Glucuronatos/metabolismo , Guayacol/farmacocinética , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Sulfatos/metabolismoRESUMEN
We recently reported that capsaicin, a pungent principle of hot red pepper, evokes catecholamine secretion from the rat adrenal medulla. In this study, the effects of some pungent principles of spices on adrenal catecholamine secretion were investigated as compared with that of capsaicin. An increase in catecholamine, especially epinephrine, secretion was observed not only on capsaicin infusion but also on piperine (a pungent principle of pepper) and zingerone (ginger) infusion. Even on infusion of the same amount (650 nmol/kg, i.v.), the order of potency as to catecholamine secretion was capsaicin much greater than piperine greater than or equal to zingerone. While, sulfur-containing and volatile pungent principles, allylisothiocyanate (mustard, etc.) and diallyldisulfide (garlic, etc.), did not even cause slight catecholamine secretion. Furthermore, these adrenergic secretagogues were readily transported via the gut into the body. These results indicate that some pungent principles of dietary spices can induce a warming action via adrenal catecholamine secretion.