RESUMEN
Recently, integrated and sustainable methods for extracting active substances from plant materials using green solvents, i.e., ionic liquids, have gained increasing attention. Ionic liquids showsuperiority over conventional organic solvents; however, they also exhibit negative factors and problems, such as high viscosity, poor water intermiscibility, intensive foaming and poor affinity for fat-soluble substances. The proposed method utilizes ultrasonic-enhanced surface-active ionic liquid-based extraction and defoaming (UESILED) to improve the extraction efficiency of ionic liquids. Single-factor experiments and a Box-Behnken design (BBD) were utilized to optimize the extraction procedure. The optimal conditions were as follows: extraction solvent, [C10MIM]Br; ultrasonic treatment time, 28 min; ultrasonic irradiation power, 437 W; liquid-solid ratio, 10 mL/g; particle size, 60 ~ 80 mesh; ultrasonication temperature, 313 K; and [C10MIM]Br solution concentration, 0.5 mol/L. In comparison with those of other reference extraction methods, the proposed method exhibited higher yields of two furocoumarins and operational feasibility. Moreover, the mechanism of UESILED was elaborated in terms of accelerating infiltration, dissolution and defoaming. The feasible and efficient ultrasonic-enhanced ionic liquid-based extraction established in this study strongly contributes to overcoming the limitations of ionic liquid solvents. The present research indicates that this improved process will be beneficial for the extraction of other fat-soluble substances and provides promising concepts and experimental data.
Asunto(s)
Ficusina/química , Furocumarinas/química , Líquidos Iónicos , Extracción Líquido-Líquido/métodos , Psoralea/química , Ultrasonido , Extractos Vegetales/química , Semillas/químicaRESUMEN
Psoralen or furocoumarin is a linear three ring heterocyclic compound. Psoralens are planar, tricyclic compounds, consisting of a furan ring fused to a coumarin moiety. Psoralen has been known for a wide spectrum of biological activities, spanning from cytotoxic, photosensitizing, insecticidal, antibacterial to antifungal effect. Thus, several structural changes were introduced to explore the role of specific positions with respect to the biological activity. Convenient approaches utilized for the synthesis of psoralen skeleton can be categorized into two parts: (i) the preparation of the tricyclic ring system from resorcinol, (ii) the exocyclic modification of the intact ring system. Furthermore, although psoralens have been used in diverse ways, we mainly focus in this work on their clinical utility for the treatment of psioraisis, vitiligo and skin-related disorder.
Asunto(s)
Ficusina , Furocumarinas/farmacología , Enfermedades de la Piel/tratamiento farmacológico , Disponibilidad Biológica , Fármacos Dermatológicos/farmacología , Ficusina/química , Ficusina/farmacología , Humanos , Fármacos Fotosensibilizantes/farmacología , Plantas MedicinalesRESUMEN
Psoralen (P) and isopsoralen (IP) are the main active ingredients in the dried fruit of Psoralen corylifolia L. (PC), with a wide range of pharmacology activities. The intestinal bacteria biotransformation plays a central role in the metabolism of the complex ingredients in traditional Chinese medicine (TCM). Our study aimed to investigated the metabolic profile of P and IP in the intestinal condition, co-cultured with human fecal bacteria anaerobically. Four bio-transforming products were obtained, including 6,7-furano-hydrocoumaric acid (P-1) and 6,7-furano-hydro- coumaric acid methyl ester (P-2), which transformed from P, and 5,6-furano-hydrocoumaric acid (IP-1) and 5,6-furano-hydrocoumaric acid methyl ester (IP-2), which were transformed from IP. It is worth mentioning that IP-2 is a new compound that has not been published. Their structures were analyzed based on their spectroscopic data. Moreover, a highly sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was used to characterize the metabolic pathways of P, IP, and their bio-transforming products in the reaction samples. In addition, the dampening effects against the oxidative stress of P, IP, and their bio-transforming products by human intestinal flora were estimated in vitro via the human colorectal cells (HCT116) and heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2) cell lines. The results showed that the metabolites have stronger activity than P and IP, which possibly provides a basis for elucidating the treating mechanisms of PC extract against inflammatory bowel disease.
Asunto(s)
Biotransformación , Ficusina/metabolismo , Furocumarinas/metabolismo , Microbioma Gastrointestinal , Cromatografía Líquida de Alta Presión , Ficusina/química , Furocumarinas/química , Humanos , Límite de Detección , Metabolómica/métodos , Estructura Molecular , Estrés Oxidativo , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
Furocoumarins are known for their phototoxic and potential carcinogenic effects. These types of compounds have previously been reported from fennel (Foeniculum vulgare Mill.), a widely used medicinal plant and spice; however, no reliable quantitative data are available on the occurrence of these compounds in fennel fruits. For the first time, we report a comprehensive analysis of fennel fruit samples of different origins, representing a wide range of accessions for their furocoumarin content. Psoralene, 5-methoxypsoralene (bergapten), and imperatorin contents of 33 fennel samples were analyzed using a sensitive liquid chromatography-mass spectrometry (LC-MS) method. When applied at the highest therapeutic dose described in the monograph issued by the European Medicines Agency, the furocoumarin content of the fruits ranged up to 1.22 µg/d, which is below the most restrictive recommendations. Based on our findings, fennel consumption can be considered as safe, at least based on its low furocoumarin content.
Asunto(s)
Foeniculum/química , Furocumarinas/farmacología , Extractos Vegetales/farmacología , Ficusina/química , Ficusina/farmacología , Frutas/química , Furocumarinas/química , Cromatografía de Gases y Espectrometría de Masas , Extractos Vegetales/química , SolventesRESUMEN
BACKGROUND: Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. RESULTS: Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn't inhibit the psoralen-induced ER stress in SMMC7721 cells. CONCLUSIONS: Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ficusina/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Chaperón BiP del Retículo Endoplásmico , Ficusina/química , Ficusina/uso terapéutico , Humanos , Neoplasias Hepáticas/patología , Proteínas Serina-Treonina Quinasas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. RESULTS: Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn't inhibit the psoralen-induced ER stress in SMMC7721 cells. CONCLUSIONS: Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.
Asunto(s)
Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ficusina/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Antineoplásicos Fitogénicos/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Ficusina/uso terapéutico , Ficusina/química , Neoplasias Hepáticas/patologíaRESUMEN
Psoralen and angelicin are two effective compounds isolated from psoraleae, a traditional Chinese medicine. They have a wide range of applications for bone disease treatment and immune modulation. In this study, we explored their new applications for the treatment of periodontal diseases. This study aimed to investigate the effects of psoralen and angelicin on Porphyromonas gingivalis growth and P. gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation, and further to evaluate their effects on osteogenesis. Finally, the effects of angelicin on a mouse model of periodontitis were also investigated. The results showed that psoralen and angelicin had beneficial dose-dependent effects regarding the inhibition of planktonic P. gingivalis and biofilms of P. gingivalis. There were no significant differences in the viability of monocyte-like THP-1 cells and human periodontal ligament cells (hPDLCs) treated with either psoralen or angelicin compared to the untreated control cells. Psoralen and angelicin also markedly decreased the mRNA expression and release of inflammatory cytokines (interleukin [IL]-1ß and IL-8) by THP-1 cells in a dose-dependent manner. They significantly enhanced the alkaline phosphatase (ALP) activity of hPDLCs and up-regulated the expression of osteogenic proteins (runt-related transcription factor 2 [RUNX2], distal-less homeobox 5 [DLX5], and osteopontin [OPN]). Angelicin significantly attenuated alveolar bone loss and inflammation response in the mice with periodontitis. In conclusion, our data demonstrated that psoralen and angelicin could inhibit the growth of planktonic P. gingivalis and P. gingivalis biofilm. It is also the first report on the anti-inflammatory effect of psoralen and angelicin against Pg-LPS. They also had an osteogenesis-potentiating effect on hPDLCs. The in vivo study also indicated the effect of angelicin regarding protection against periodontitis. Our study highlighted the potential ability of psoralen and angelicin to act as novel natural agents to prevent and treat periodontitis.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios/farmacología , Ficusina/farmacología , Furocumarinas/farmacología , Osteogénesis/efectos de los fármacos , Periodontitis/tratamiento farmacológico , Periodontitis/prevención & control , Fosfatasa Alcalina/metabolismo , Pérdida de Hueso Alveolar/diagnóstico por imagen , Pérdida de Hueso Alveolar/patología , Pérdida de Hueso Alveolar/prevención & control , Animales , Biopelículas/efectos de los fármacos , Proteínas Morfogenéticas Óseas/efectos de los fármacos , Proteínas Morfogenéticas Óseas/genética , Supervivencia Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Ficusina/química , Furocumarinas/química , Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Humanos , Inflamación , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Lipopolisacáridos/efectos adversos , Masculino , Medicina Tradicional China , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Osteopontina/metabolismo , Enfermedades Periodontales/tratamiento farmacológico , Ligamento Periodontal , Periodontitis/diagnóstico por imagen , Periodontitis/patología , Porphyromonas gingivalis/efectos de los fármacos , Porphyromonas gingivalis/crecimiento & desarrollo , ARN Mensajero/metabolismo , Células THP-1 , Factores de Transcripción/metabolismo , Regulación hacia ArribaRESUMEN
In the present study, a lipid-polymer hybrid drug carrier system was developed to encapsulate psoralen (PSO), a multidrug resistance reversal agent and traditional Chinese medicine. Emphasis was focused the parameters that influence physicochemical characteristics, and then the drug release profile, stability, cytotoxicity and drug resistance reversal effect of the lipid-polymer hybrid nanoparticles (LPNs) were investigated. It was found that various formulation parameters affected NP size, drug loading (DL) and release characteristics. Hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethylene glycol)2000 increased the ζ potential and thus the stability of the NPs, but also enlarged their diameter. The amount of PSO influenced their DL and encapsulation efficiency, but did not show any effect on drug release kinetics. Next, the stability of the LPNs in different media and their storage characteristics were assessed. Finally, the cytotoxicity and multidrug resistance reversal effect was studied in the K562 and HepG2 cell lines. The analysis of half maximal inhibitory concentration values demonstrated that combination therapy with doxorubicin (DOX) and PSO-loaded LPNs (P-LPNs) was 14- and 23-fold more effective than a single-dose DOX treatment in resistant K562 and HepG2 cells, respectively, and 2.2- and 2.1-fold more effective than a single-dose combination regimen of DOX and PSO in solution, respectively. These data indicate that the LPNs have superior properties compared with a combination therapy in solution.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Ficusina/química , Ficusina/farmacología , Lípidos/química , Nanopartículas/química , Polímeros/química , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Células Hep G2 , Humanos , Células K562 , Tamaño de la Partícula , Fosfatidiletanolaminas/química , Polietilenglicoles/químicaRESUMEN
Prostate cancer is the most common male reproductive system cancer. The prevalence of prostate cancer in Europe and the United States is higher than that in the Asian region. However, the treatment of prostate cancer remains unsatisfactory. Psoralea corylifolia has been used to cure this disease as Chinese medicine in the Asian region. In this study, we analyzed the components of ethanol extraction of unprepared and prepared P. corylifolia by HPLC. Psoralen and isopsoralen content from the prepared P. corylifolia is twofold higher than that from unprepared, so we use the prepared extraction in this study. However, the effects of the ethanol extraction of P. corylifolia (PCE) on PC-3 human prostate cancer cells remain unclear. PC-3 cells were treated with PCE for different time periods and cells were examined for cell morphological change and total viable cells by using contrast phase microscopy and flow cytometer, respectively. Results indicated that PCE induced cell morphological changes and cytotoxic effect in PC-3 cells in dose-dependent manners. PCE induced chromatin condensation of PC-3 cells dose-dependently. PCE also induced apoptosis and autophagy in PC-3 by western blotting and acridine orange (AO) staining, respectively. Furthermore, a complementary DNA microarray analysis demonstrated that PCE treatment led to 944 genes upregulation and 872 genes downregulation. For example, the DNA damage-associated gene DNA-damage-inducible transcript 3 (DDIT 3) had a 62.1-fold upregulation and CDK1 2.68-fold downregulation. The differential genes were classified according to the Gene Ontology. Furthermore, GeneGo software was used for the key genes involved and their possible interaction pathways. Those genes were affected by P. corylifolia, which provided information for the understanding of the antiprostate cancer mechanism at the genetic level and provide additional targets for the treatments of human prostate cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Extractos Vegetales/farmacología , Psoralea/química , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Etanol/química , Ficusina/química , Ficusina/aislamiento & purificación , Ficusina/farmacología , Furocumarinas/química , Furocumarinas/aislamiento & purificación , Furocumarinas/farmacología , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Extractos Vegetales/química , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Psoralea/metabolismo , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
As an active compound, psoralen is present in various Chinese herbal medicines and has exhibited significant activity in skin disease treatment. Its derivative 8-methoxypsoralan (8-MOP) is the most commonly used drug to induce repigmentation of vitiligo. In our previous screening assays, 4-methyl-6-phenyl-2H-furo[3,2-g]chromen-2-one (MPFC), a psoralen derivative, was identified as more effective tyrosinase and melanin activator than the positive control 8-MOP in consideration of low doses, as well as low toxicity. The overall purpose of this study was to characterize the melanogenic effect and mechanisms of MPFC in B16 cells. The melanin biosynthesis effects of MPFC were determined by examination of cellular melanin contents, tyrosinase activity assay, cyclic adenosinemonophosphate (cAMP) assay, and western blotting of MPFC-stimulated B16 mouse melanoma cells. Our results showed that MPFC enhanced both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly activated the expression of melanogenic proteins such as tyrosinase, tyrosinase-related protein-1 and tyrosinase-related protein-2. Western blot analysis showed that MPFC increased the phosphorylation of p38 mitogen-activated protein kinase and cAMP response element-binding protein (CREB) as well as the expression of microphthalmia-associated transcription factor (MITF). Moreover, MPFC stimulated intracellular cAMP levels and induced tyrosinase activity and melanin synthesis were attenuated by H89, a protein kinase A inhibitor. These results indicated that MPFC-mediated activation of the p38 MAPK and the protein kinase A (PKA) pathway may shed light on a novel approach for an effective therapy for vitiligo.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ficusina/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Melaninas/metabolismo , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
The leaves of fig (Ficus carica L.) have been used for traditional and Chinese medicine. We determined the composition of phenylpropanoids (polyphenols and furanocoumarins) as a functional agent in the leaves of 37 cultivars of fig. The most abundant polyphenol was caffeoylmalic acid (12.0-26.6 mg/g dry weight), followed by rutin (4.7-14.6 mg/g dry weight) and isoschaftoside (2.5-6.4 mg/g dry weight). Psoralen (3.8-23.0 mg/g dry weight) was dominant in the furanocoumarins. In molar amounts, psoralic acid glucoside (PAG), a precursor of psoralen, was equivalent to psoralen. Furanocoumarins and PAG were not detected in the leaves of only one cultivar, Grise de Tarascon. Fig leaves are potentially an excellent source of polyphenols such as caffeoylmalic acid and rutin. From the result of cluster analysis, some cultivars that contained large amount of polyphenols, and a small amount (e.g., Grise de Saint Jean) or no (Grise de Tarascon) furanocoumarins, were found. These cultivars are considered suitable for functional foods or medicinal products.
Asunto(s)
Ficus/química , Ficusina/química , Furocumarinas/química , Hojas de la Planta/química , Polifenoles/químicaRESUMEN
The first phytochemical investigation of the aerial parts of Bituminaria basaltica, an endemic species from the Aeolian Islands, led to the isolation and identification of eight compounds including plicatin B (3), two furanocoumarins: angelicin (1), psoralen (2), three pterocarpans: erybraedin C (4), 3,9-dihydroxy-4-isoprenyl-pterocarpan (5), bitucarpin A (8) and two flavonoid glycosides: isoorientin (6), daidzin (7). Their structures were elucidated by spectroscospic techniques and compared with data reported in the literature. Sesquiterpenes characterised the essential oil composition of the title plant where ß-caryophyllene and germacrene D were the main constituents.
Asunto(s)
Fabaceae/química , Fitoquímicos/química , Componentes Aéreos de las Plantas/química , Ficusina/química , Ficusina/aislamiento & purificación , Flavonoides/química , Flavonoides/aislamiento & purificación , Furocumarinas/química , Furocumarinas/aislamiento & purificación , Glicósidos/química , Glicósidos/aislamiento & purificación , Italia , Estructura Molecular , Aceites Volátiles/química , Fitoquímicos/aislamiento & purificación , Aceites de Plantas/química , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Psoralen in combination with ultraviolet A radiation (PUVA) is an FDA recommended therapy for clinical application in the management of severe recalcitrant psoriasis. Psoralen acts by intercalation of DNA and upon exposure to UV-A, it forms monoadducts which in turn induce apoptosis. Poor skin deposition, weak percutaneous permeability of psoralen and adverse effects of severe burning, blisters, pigmentation associated with conventional topical psoralen vehicles hinders the therapeutic efficacy and safety of topical PUVA. The aim of the present study is to formulate psoralen loaded liposomal nanocarriers for enhanced skin penetration, safety and efficacy of topical PUVA in psoriasis. Two different liposomal compositions i.e., cationic liposomes composed of DC-Chol, cholesterol and anionic liposomes composed of egg lecithin, cholesterol, tetramyristoyl cardiolipin were prepared for the topical delivery of psoralen. Liposomal carriers were characterized with respect to size, zeta potential, entrapment efficiency, stability, in vitro drug release and in vivo studies. Both liposomes were prepared with particle size of nearly 100nm. Zeta potential and entrapment efficiency of cationic liposomes were +25.8mV, 75.12% and anionic liposomes were -28.5mV, 60.08% respectively. Liposomal dermal distribution demonstrated higher penetration of both liposomal carriers over solution. Similarly, skin permeation study indicated 5 fold increase in permeation of psoralen with liposomal carriers. Topical application of psoralen liposomal gels on imiquimod induced psoriatic plaque model reduced the symptoms of psoriasis and levels of key psoriatic cytokines such as tumor necrosis factor-α, IL-17 and IL-22. In conclusion, the developed liposomal carriers of psoralen were found to be promising and can find application for optimal safety and efficacy of topical PUVA in psoriasis.
Asunto(s)
Portadores de Fármacos/administración & dosificación , Ficusina/administración & dosificación , Nanopartículas/administración & dosificación , Terapia PUVA/métodos , Psoriasis/tratamiento farmacológico , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Ficusina/química , Ficusina/metabolismo , Humanos , Liposomas , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/metabolismo , Tamaño de la Partícula , Psoriasis/metabolismo , Psoriasis/patología , Absorción Cutánea/fisiología , Resultado del TratamientoRESUMEN
A sensitive, specific and rapid ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method has been developed to investigate pharmacokinetic properties of psoralen and isopsoralen, two compounds isolated from raw/salt-processed fruit of Psoralea corylifolia L. UHPLC-MS/MS was used with positive ion electrospray. The mobile phase was composed of acetonitrile and 0.1% formic acid aqueous solution and a gradient elution program at flow rate of 0.3 mL/min was applied. Multiple reaction monitoring mode was used for the quantification of psoralen, isopsoralen ([M + H](+) m/z 187.0 â m/z 131.0) and scoparone (m/z 207.0 â m/z 151.1). Scoparone served as an internal standard. The method was fully validated for its sensitivity, selectivity, stability, matrix effect and extraction recovery. The obtained results showed that salt-processed Buguzhi significantly promoted the absorption of psoralen and isopsoralen, and increased the bioavailability of these compounds.
Asunto(s)
Medicamentos Herbarios Chinos/farmacocinética , Ficusina/farmacocinética , Furocumarinas/farmacocinética , Psoralea/química , Administración Oral , Animales , Antiinfecciosos/sangre , Antiinfecciosos/química , Antiinfecciosos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Ficusina/sangre , Ficusina/química , Frutas/química , Furocumarinas/sangre , Furocumarinas/química , Límite de Detección , Masculino , Ratas Sprague-Dawley , Sales (Química)/química , Espectrometría de Masas en Tándem/métodosRESUMEN
High-performance liquid chromatography with diode array detection (HPLC-DAD), time-of-flight mass spectrometry (HPLC-TOFMS) and quadrupole ion trap mass spectrometry (HPLC-QITMS) were used for separation and identification of multi-components in Psoralea corylifolia. Benefiting from combining the accurate mass measurement of HPLC-TOFMS to generate elemental compositions, the complementary multilevel structural information provided by HPLC-QITMS and the characteristic UV spectra obtained from HPLC-DAD, 24 components in P. corylifolia were identified. The five groups of isomers were differentiated based on the fragmentation behaviors in QITMS and UV spectra. It can be concluded that an effective method based on the combination of HPLC-DAD, HPLC-TOFMS and HPLC-QITMS for identification of chemical components in P. corylifolia was established. The results provide essential data for further pharmacological and clinical studies of P. corylifolia and facilitate the rapid quality control of the crude drug.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Frutas/química , Espectrometría de Masas/métodos , Extractos Vegetales/química , Psoralea/química , Benzofuranos/análisis , Benzofuranos/química , Chalconas/análisis , Chalconas/química , Ficusina/análisis , Ficusina/química , Glicósidos/análisis , Glicósidos/químicaRESUMEN
Photo-activation of psoralen with UVA irradiation, referred to as PUVA, is used in the treatment of proliferative skin disorders. The anti-proliferative effects of PUVA have been largely attributed to psoralen intercalation of DNA, which upon UV treatment, triggers the formation of interstrand DNA crosslinks (ICL) that inhibit transcription and DNA replication. Here, we show that PUVA exerts antitumor effects in models of human breast cancer that overexpress the ErbB2 receptor tyrosine kinase oncogene, through a new mechanism. Independent of ICL formation, the antitumor effects of PUVA in ErbB2+ breast cancer models can instead be mediated through inhibition of ErbB2 activation and signaling. Using a mass spectroscopy-based approach, we show for the first time that photo-activated 8MOP (8-methoxypsoralen) interacts with the ErbB2 catalytic autokinase domain. Furthermore, PUVA can reverse therapeutic resistance to lapatinib and other ErbB2 targeted therapies, including resistance mediated via expression of a phosphorylated, truncated form of ErbB2 (p85(ErbB2)) that is preferentially expressed in tumor cell nuclei. Current ErbB2 targeted therapies, small molecule kinase inhibitors or antibodies, do not block the phosphorylated, activated state of p85(ErbB2). Here we show that PUVA reduced p85(ErbB2) phosphorylation leading to tumor cell apoptosis. Thus, in addition to its effects on DNA and the formation of ICL, PUVA represents a novel ErbB2 targeted therapy for the treatment of ErbB2+ breast cancers, including those that have developed resistance to other ErbB2 targeted therapies.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Dominio Catalítico , Ficusina/farmacología , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacos , Rayos Ultravioleta , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de la radiación , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efectos de la radiación , Reactivos de Enlaces Cruzados/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Ficusina/química , Ficusina/uso terapéutico , Humanos , Lapatinib , Terapia Molecular Dirigida , Terapia PUVA , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Transducción de Señal/efectos de la radiaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruit of Psoralea corylifolia L. has been used to prevent and treat vitiligo, osteoporosis, arthralgia and asthma in Traditional Chinese Medicine for some 1600 years. Psoralen (P), isopsoralen (IP), psoralenoside (PO) and isopsoralenoside (IPO) are the major coumarins and coumarin-related benzofuran glycosides in Psoraleae Fructus, which have been reported to show estrogen-like activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. The first aim of this study is to develop a rapid, sensitive and selective ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach for simultaneous determination of PO, IPO, P and IP in rat plasma and samples collected from in vitro incubation experiments. The second aim is to investigate the pharmacokinetic properties of PO, IPO, P and IP after oral administration of Psoralea corylifolia extract (PCE) to rats. The third aim is to confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. MATERIALS AND METHODS: A UPLC-MS/MS method with a C18 column and a mobile phase of methanol-0.1% aqueous formic acid was validated according to the criteria in FDA guidelines about bioanalytical method, which was developed to investigate the pharmacokinetic behavior of PO, IPO, P and IP from PCE and the metabolic pathways of PO to P or IPO to IP. RESULTS: The criteria for establishment of a new UPLC-MS/MS method including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect and stability were validated. This method was successfully applied to the quantitative determination of PO, IPO, P and IP in biological samples collected from both in vitro incubations and in vivo rat experiments. After oral administration of PCE to rat, pharmacokinetic parameters of these four compounds indicated that in vivo biotransformation may occur between PO and P or IPO and IP. Purified benzofuran glycosides fraction (PBGF), containing only PO and IPO, was orally administered to rats to further confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. An in vitro incubation study elucidated that PO and IPO were metabolized to P and IP by intestinal microflora through de-glucosylation. CONCLUSIONS: This paper developed a rapid, sensitive and selective UPLC-MS/MS method for simultaneous determination of PO, IPO, P and IP from PCE in biological samples, and investigated on their comprehensive in vivo and in vitro pharmacokinetic studies. These obtained results showed that the metabolism by intestinal bacteria plays an important role in pharmacological effects of orally administered PCE.
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Benzofuranos/química , Benzofuranos/farmacocinética , Glicósidos/química , Glicósidos/farmacocinética , Extractos Vegetales/química , Psoralea/química , Animales , Benzofuranos/sangre , Cromatografía Liquida , Ficusina/sangre , Ficusina/química , Ficusina/farmacocinética , Frutas/química , Furocumarinas/sangre , Furocumarinas/química , Furocumarinas/farmacocinética , Glicósidos/sangre , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
A rapid and sensitive bioassay based on liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed and validated for the simultaneous determination of eight coumarins in rat plasma. The liquid-liquid extraction method with ethyl acetate was used to prepare the plasma samples after addition of warfarin as an internal standard (IS). Chromatographic separation was performed on an Eclipse plus C18 column (100mm×4.6mm, 1.8µm) using gradient elution when 1mM ammonium acetate aqueous solution - acetonitrile was used as the mobile phase. The lower limit of quantitation (LLOQ) of each coumarin was lower than 2.16ngmL(-1). Intra-day and inter-day precisions were less than 15%. The accuracies were in the range of 88.9-117%. The mean recoveries of coumarins and IS were higher than 84%. The method was successfully applied to a pharmacokinetic study of eight coumarins in rats after oral administration of radix angelicae pubescentis.
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Cumarinas/sangre , Ficusina/sangre , Furocumarinas/sangre , Metoxaleno/análogos & derivados , Metoxaleno/sangre , Escopoletina/sangre , 5-Metoxipsoraleno , Acetatos/química , Administración Oral , Animales , Cromatografía Liquida/métodos , Cumarinas/química , Cumarinas/farmacocinética , Medicamentos Herbarios Chinos/química , Ficusina/química , Ficusina/farmacocinética , Furocumarinas/química , Furocumarinas/farmacocinética , Extracción Líquido-Líquido/métodos , Masculino , Metoxaleno/química , Metoxaleno/farmacocinética , Extractos Vegetales/química , Raíces de Plantas/química , Ratas , Ratas Sprague-Dawley , Escopoletina/química , Escopoletina/farmacocinética , Espectrometría de Masas en Tándem/métodosRESUMEN
In this study, products of psoralen pyrolysis were detected using a solid pyrolysis apparatus and synchrotron radiation vacuum ultraviolet photoionization mass spectrum (SVUV-PIMS). The pyrolytic kinetics of psoralen was also studied by calculating its initial pyrolytic route in quantum chemistry. According to the findings with SVUV-PIMS, three pyrolytic products were observed, CO, C9H6O and C10H6O2. Theoretically, three fragment pathways were calculated for psoralen, in which the major primary decomposition route was de-CO, and the major secondary decomposition reaction was de-CO reaction of de-CO products.
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Ficusina/química , Calor , Espectrometría de Masas/métodos , Monóxido de Carbono/química , Cinética , Espectrometría de Masas/instrumentación , Modelos Químicos , Estructura Molecular , Compuestos Orgánicos/química , Sincrotrones , Rayos Ultravioleta , VacioRESUMEN
OBJECTIVE: To study the chemical constituents of the aerial part of Ligusticum jeholense. METHODS: The constituents were isolated by sillica gel column chromatography, Sephadex LH-20 column chromatography and their structures were elucidated by spectral analysis. RESULTS: Seven compounds were separated from the EtOH extracts. Their structures were identified as psoralen (1), beta-sitosterol (2), daucosterol (3), kaempferol-3-O-(2",4"-di-E-p-coumaroyl)-alpha-L-rhamnoside (4), kaempferol-3-O-beta-D-galactoside (5), quercetin-3-O-beta-D-galactoside (6), sucrose (7). CONCLUSION: Compounds 1, 4, 5 and 6 are isolated from the genus for the first time. Compounds 2, 3 and 7 are isolated from the aerial part of the plant for the first time.