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1.
Mol Biol Rep ; 49(1): 279-291, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34709570

ABSTRACT

BACKGROUND: Angiogenesis is the formation of new blood vessels from an existing vasculature through a series of processes such as activation, proliferation, and directed migration of endothelial cells. Angiogenesis is instrumental in the metastatic spread of tumors. Isopimpinellin, a furanocoumarin group of phytochemicals, is an anticarcinogenic agent. However, no studies have proven its antiangiogenic effects. The current study thus aimed to screen the antiangiogenic effect of isopimpinellin. METHODS AND RESULTS: Human Umblical Vein Endothelial Cell (HUVEC) as an in vitro model and zebrafish embryos as an in vivo model was used in this study. The experimental results showed that isopimpinellin effectively inhibited HUVEC proliferation, invasion, migration, and tube formation, which are the key steps in angiogenesis by markedly suppressing the expression of pro-angiogenic genes VEGF, AKT, and HIF-1α. In addition, isopimpinellin exerts its anti-angiogenic effect through the regulation of miR-15b-5p and miR-542-3p. Furthermore, in zebrafish embryos, isopimpinellin inhibited the development of intersegmental vessels (ISVs) through the significant downregulation of all pro-angiogenic genes vegf, vegfr2, survivin, angpt-1, angpt-2, and tie-2. CONCLUSION: Collectively, these experimental findings offer novel insights into the antiangiogenic nature of isopimpinellin and open new avenues for therapeutic approaches.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Furocoumarins/administration & dosage , MicroRNAs/genetics , Up-Regulation , Zebrafish/embryology , Angiogenesis Inhibitors/pharmacology , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Furocoumarins/pharmacology , Gene Expression Regulation, Developmental/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Models, Animal , Proto-Oncogene Proteins c-akt/genetics , Vascular Endothelial Growth Factor A/genetics , Zebrafish/genetics
2.
Sci Rep ; 11(1): 8590, 2021 04 21.
Article in English | MEDLINE | ID: mdl-33883654

ABSTRACT

In view of the complicated pathophysiological process of vascular dementia (VD), drugs for the clinical treatment of VD mainly target related risk factors, while drugs with excellent efficacy in cognitive function are still relatively lacking. Imperatorin (IMP), an active constituent extracted from angelica dahuricae and notopterygium Notopterygii, which has anti-inflammatory, vasodilator, anticoagulant, block calcium channel, anticonvulsant, and anti oxygen free radical injury properties. Therefore,the present study examined its effects on VD rats and the underlying molecular mechanisms, in order to provide promising therapeutic methods. VD was established by modified ligation of perpetual two-vessel occlusion (2VO). After 2VO surgery, IMP (2.5, 5, and 10 mg/kg) was administered by intraperitoneal injection for 12 consecutive weeks to evaluate therapeutic effects. Cognitive function was verified by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin-Eosin staining. Real-Time PCR and Western blot were used for detecting pro- and antiapoptotic biomarkers, and the hippocampus synaptic damage was examined by Transmission electron microscope. We revealed that 2VO-induced cognitive impairment, hippocampus CA1 neuron damage, apoptosis and synaptic damage. IMP-treatment significantly improved 2VO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that IMP inhibited apoptosis through the down regulation of Bax, Caspase-3 and upregulation of Bcl-2. Meanwhile, IMP-treatment markedly improved synaptic ultrastructure morphology, increased the SAZ length, PSD thickness and up-regulated PSD-95 expression. Collectively, our findings demonstrated that IMP was effective in the treatment of 2VO-induced VD via inhibiting apoptosis of hippocampus neurons and reducing the synaptic plasticity destroy.


Subject(s)
Apoptosis/drug effects , Dementia, Vascular/drug therapy , Furocoumarins/therapeutic use , Neuronal Plasticity/drug effects , Neuroprotective Agents/therapeutic use , Animals , Blotting, Western , Furocoumarins/administration & dosage , Hippocampus/drug effects , Hippocampus/ultrastructure , Injections, Intraperitoneal , Male , Microscopy, Electron, Transmission , Morris Water Maze Test/drug effects , Neuroprotective Agents/administration & dosage , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction
3.
J Nutr ; 150(6): 1535-1544, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32221600

ABSTRACT

BACKGROUND: In prior studies, higher citrus consumption was associated with higher risk of cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furocoumarins, compounds with phototoxicity and photocarcinogenicity in citrus, may be responsible for the association. OBJECTIVES: The objective of the study was to investigate the association between furocoumarin intake and skin cancer risk. METHODS: A total of 47,453 men from the Health Professionals Follow-Up Study (HPFS) and 75,291 women from the Nurses' Health Study (NHS) with diet data collected every 2-4 y in the 2 prospective cohort studies were included. A furocoumarin food composition database for 7 common furocoumarins [bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6'7'-DHB), epoxybergamottin, and bergamottin] was developed and used to calculate participants' cumulative average and energy-adjusted furocoumarin intake. Multivariate HRs and 95% CIs of the associations between furocoumarin intake and skin cancer risk were estimated using Cox proportional hazards models. Analyses were performed separately in each cohort as well as pooled using a fixed-effects model. RESULTS: Throughout follow-up (1984-2012 in the NHS and 1986-2012 in the HPFS), we identified 1593 melanoma, 4066 SCC, and 28,630 BCC cases. Higher intake of total furocoumarins was associated with an increased risk of BCC; the pooled HR comparing the top with the bottom quintile was 1.16 (95% CI: 1.11, 1.21; P-trend = 0.002). Higher intakes of bergaptol, bergapten, 6'7'-DHB, and bergamottin were also significantly associated with increased BCC risk. No significant associations were found between intake of total furocoumarins and the risks of SCC or melanoma. CONCLUSIONS: Intakes of total furocoumarins as well as some individual furocoumarins were associated with an increased risk of skin cancer, especially BCC, in 2 cohorts of US health professionals.


Subject(s)
Citrus , Furocoumarins/administration & dosage , Skin Neoplasms/chemically induced , Adult , Female , Furocoumarins/adverse effects , Humans , Middle Aged , Proportional Hazards Models , Prospective Studies , Risk Factors , Skin Neoplasms/classification , Skin Neoplasms/epidemiology , United Kingdom , United States/epidemiology
4.
J Sep Sci ; 43(12): 2349-2362, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32222035

ABSTRACT

A combination of Angelicae Dahuricae Radix and Acori Tatarinowii Rhizoma has been widely used as the herb pair in traditional Chinese medicine to treat stroke, migraine, and epilepsy. However, the underlying synergistic mechanism of the herb pair remains unknown. This study was aimed at investigating the effects of Acori Tatarinowii Rhizoma volatile oil on the pharmacokinetic parameters of xanthotoxol, oxypeucedanin hydrate, and byakangelicin from Angelicae Dahuricae Radix in rat, and in vitro absorption behavior of the three compounds using rat everted gut sac, in situ single-pass intestinal perfusion, and Caco-2 cell monolayer models. The pharmacokinetic study exhibited clear changes in the key pharmacokinetic parameters of the three main coumarins through co-administering with Acori Tatarinowii Rhizoma volatile oil (50 mg/kg), the area under curve and the maximum plasma concentration of xanthotoxol increased 1.36 and 1.31 times; the area under curve, the maximum plasma concentration, mean residence time, half-life of elimination, and the time to reach peak concentration of oxypeucedanin hydrate increased by 1.35, 1.18, 1.24, 1.19 and 1.49 times, respectively; the area under curve, mean residence time, half-life of elimination, and time to reach peak concentration of byakangelicin climbed 1.29, 1.27, 1.37, and 1.28 times, respectively. The three coumarin components were absorbed well in the jejunum and ileum in the intestinal perfusion model, when co-administered with Acori Tatarinowii Rhizoma volatile oil (100 µg/mL). The in vivo and in vitro experiments showed good relevance and consistency. The results demonstrated that the three coumarin compounds from Angelicae Dahuricae Radix were absorbed through the active transportation, and Acori Tatarinowii Rhizoma volatile oil could promote the intestinal absorption and transport of these compounds by inhibiting P-glycoprotein (P-gp)-mediated efflux.


Subject(s)
Angelica/chemistry , Araceae/chemistry , Furocoumarins/pharmacokinetics , Oils, Volatile/pharmacokinetics , Administration, Oral , Animals , Caco-2 Cells , Furocoumarins/administration & dosage , Humans , Intestinal Absorption/drug effects , Male , Oils, Volatile/administration & dosage , Rats , Rats, Sprague-Dawley
5.
J Pharm Biomed Anal ; 177: 112836, 2020 Jan 05.
Article in English | MEDLINE | ID: mdl-31473481

ABSTRACT

Xian-Ling-Gu-Bao capsule (XLGB) is an effective traditional Chinese medicine prescription (TCMP) that is used for the prevention and treatment of osteoporosis in China. A rapid, simple, efficient and stable method based on UPLC-MS/MS technology was developed for simultaneous determination of multiple components of XLGB in rat plasma. Mass spectrometric detection was performed in multiple reaction monitoring (MRM) mode with electrospray ionization (ESI). For twenty-one selected quantitative prototypes, all calibration curves showed favourable linearity (r>0.9932) in linear ranges. The lower limits of quantification (LLOQs) were 2 ng/mL for psoralen (PL), 2.5 ng/mL for asperosaponin VI (AS), 1 ng/mL for isopsoralen (IPS) and sweroside (SW), 0.5 ng/mL for magnoflorine (MA), bavachinin (BVN), tanshinone IIA (TA), timosaponin BII (TBII) and icaritin (ICT), 0.1 ng/mL for epimedin B (EB) and epimedin C (EC), 0.05 ng/mL for icariin (IC), isobavachalcone (IBC), psoralidin (PD), bavachin (BV), bavachalcone (BC), epimedin A (EA) and isobavachin (IBV), 0.02 ng/mL for neobavaisoflavone (NEO) and icariside I (ICI) and 0.01 ng/mL for icariside II (ICII). The intra-day and inter-day (low, medium, high) precision (relative standard deviation) for all analytes was less than 8.63%, and the accuracies (as relative error) were in the range of -12.45% to 8.91%. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The validated method was successfully applied to the pharmacokinetics (PK) studies of the twenty-one prototypes at pharmacodynamic doses (0.3 and 1 g/kg/day). In addition, dynamic profiles of 28 metabolites (phase II conjugates: 23 glucuronide conjugates, 2 sulfate conjugates and 3 glucuronide or sulfate conjugates) were also monitored by their area/IS area-time curves. As a result, coumarins, prenylated flavonoids from Psoraleae Fructus, alkaloids and prenylated flavonol glycosides from Epimedii Herba, and iridoid glycosides, triterpenoid saponins from Dipsaci Asperoidis Radix were considered to be the key effective substances of XLGB due to their high exposure and appropriate pharmacokinetic features. This is the first report to reveal pharmacodynamic ingredients by a reversed pharmacodynamic (PD) - pharmacokinetics (PK) study.


Subject(s)
Drugs, Chinese Herbal/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Aporphines/administration & dosage , Aporphines/blood , Aporphines/pharmacokinetics , Capsules , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/analysis , Female , Ficusin/administration & dosage , Ficusin/blood , Ficusin/pharmacokinetics , Flavonoids/administration & dosage , Flavonoids/blood , Flavonoids/pharmacokinetics , Furocoumarins/administration & dosage , Furocoumarins/blood , Furocoumarins/pharmacokinetics , Iridoid Glucosides/administration & dosage , Iridoid Glucosides/blood , Iridoid Glucosides/pharmacokinetics , Models, Animal , Rats , Saponins/administration & dosage , Saponins/blood , Saponins/pharmacokinetics
6.
Med. clín (Ed. impr.) ; 152(12): 488-492, jun. 2019. graf, tab
Article in Spanish | IBECS | ID: ibc-183319

ABSTRACT

Introducción: Los trabajos que determinan la incidencia de cáncer cutáneo no melanoma (CCNM) en la población tratada con psoralenos orales+UVA son heterogéneos, dependen de la localización geográfica de la población estudiada y tienen períodos de seguimiento cortos. El objetivo del trabajo es determinar la seguridad a largo plazo de la PUVAterapia y en concreto determinar la incidencia de CCNM en los pacientes tratados con PUVAterapia oral en el área mediterránea. Material y método: Se ha realizado un estudio longitudinal de seguimiento retrospectivo, recogiendo 234 pacientes tratados con PUVA sistémico entre 1982 y 1996 con un seguimiento hasta mayo de 2017. Se ha calculado la densidad de incidencia de CCNM bruta y ajustada por edad mediante estandarización directa. Resultados: En 22 pacientes se diagnosticaron 50 neoplasias. La prevalencia de CCNM en pacientes tratados con fototerapia fue del 10,3%. El tiempo medio de seguimiento fue de 21 años. la densidad de incidencia bruta-ajustada de CCNM fue de 554,4-183,9 casos/100.000 pacientes tratados-año. La densidad de incidencia bruta-ajustada de carcinoma basocelular fue de 352,3-111,2 casos/100.000 pacientes y la de carcinoma epidermoide de 229-77,7 casos/100.000 pacientes. Conclusión: La incidencia de cáncer cutáneo en los pacientes tratados con PUVAterapia es superior a la descrita en la población mediterránea


Introduction: Studies reporting incidences of non-melanoma skin cancer (NMSC) are heterogeneous, depend on the geographic area of the studied population and are often short-term. The aim of this study is to determine the incidence of NMSC in patients treated with oral PUVA therapy in the Mediterranean area. Material and methods: A retrospective, observational study was carried out with a sample of 234 patients treated with systemic PUVA between 1982 and 1996, carrying out a historical follow-up until May 2017. The incidencedensity rate of CCNM (crude and adjusted) was calculated by direct standardisation. The incidence of CCNM was compared with that reported in the general population in a similar geographical area. Results: 50 neoplasms were diagnosed in 22 patients. The prevalence of CCNM in patients treated with phototherapy was 10.3%. The mean follow-up time was 21 years. The crude-adjusted incidence density rate of CCNM was 554.4-183.9 cases/100,000 treated patients per year. The crude-adjusted incidence density rate of basal cell carcinoma was 352.3-111.2 cases/100.000 patients and of squamous cell carcinoma was 229-77.7 cases /100,000 patients. Conclusion: PUVA therapy is associated with an increased risk of CCNM inthe Mediterranean population


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Skin Neoplasms/epidemiology , Melanoma/therapy , PUVA Therapy/methods , Carcinoma, Basal Cell/epidemiology , Furocoumarins/administration & dosage , Longitudinal Studies , Retrospective Studies
7.
Phytomedicine ; 62: 152963, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31128487

ABSTRACT

BACKGROUND: The elucidation of the biological roles of individual active compounds in terms of their in vivo bio-distribution and bioactivity could provide crucial information to understand how natural compounds work together as treatments for diseases. PURPOSE: We examined the functional roles of Byakangelicin (Byn) to improve the brain accumulation of active compounds, e.g., umbelliferone (Umb), curcumin (Cur), and doxorubicin (Dox), and consequently to enhance their biological activities. METHODS: Active compounds were administered intravenously to mice, with or without Byn, after which organs were isolated and visualized for their ex vivo fluorescence imaging to determine the bio-distribution of each active compound in vivo. For the in vivo bioactivity, Cur, either with or without Byn, was administered to a lipopolysaccharide (LPS)-induced neuro-inflammation model for 5 days, and its anti-inflammatory effects were examined by ELISA using a brain homogenate and serum. RESULTS: We successfully demonstrated that the levels of active compounds (Umb, Cur, and Dox) in the brain, lung, and pancreas were greatly elevated by the addition of Byn via direct ex vivo fluorescence monitoring. In addition, sufficient accumulation of the active compound, Cur, greatly reduced LPS-induced neuro-inflammation in vivo. CONCLUSION: Byn could serve as a modulator to allow improved brain accumulation of diverse active compounds (Umb, Cur, and Dox) and enhanced therapeutic effects.


Subject(s)
Curcumin/metabolism , Doxorubicin/metabolism , Furocoumarins/pharmacokinetics , Neurogenic Inflammation/drug therapy , Umbelliferones/metabolism , Administration, Intravenous , Animals , Brain/drug effects , Brain/metabolism , Curcumin/chemistry , Disease Models, Animal , Doxorubicin/blood , Doxorubicin/chemistry , Female , Furocoumarins/administration & dosage , Humans , Lipopolysaccharides/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Umbelliferones/blood , Umbelliferones/chemistry
8.
Regul Toxicol Pharmacol ; 103: 1-9, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30634019

ABSTRACT

Isopsoralen is a major active and quality-control component of Fructus Psoraleae, but lacks a full safety evaluation. We evaluated the oral toxicity of isopsoralen in Wistar rats treated for 3 months at doses of 0, 3.5, 7.0, and 14 mg/kg. Additionally, the plasma metabolomics of isopsoralen in male and female rats treated for 3 months at doses of 0 and 14 mg/kg were investigated by gas chromatography-mass spectrometry. Many abnormalities were observed in the isopsoralen-treated rats, including suppression of body weight gain, and changes in serum biochemical parameters and visceral coefficients. Histopathological changes in liver, pancreatic, and reproductive system tissues were also observed in the isopsoralen-treated rats. The metabolomic analyses showed alterations in many metabolites (19 in female rats; 28 in male rats) after isopsoralen administration. The significant changes in these metabolites revealed metabolomic alterations in the isopsoralen-treated rats, especially in amino acid metabolism regardless of sex, including phenylalanine, tyrosine, and tryptophan biosynthesis and glycine, serine, and threonine metabolism. Furthermore, fatty acid metabolism comprised the main affected pathways in female rats, while lipid metabolism and energy metabolism were the main affected pathways in male rats.


Subject(s)
Digestive System/drug effects , Digestive System/metabolism , Furocoumarins/toxicity , Sex Characteristics , Urogenital System/drug effects , Urogenital System/metabolism , Animals , Body Weight/drug effects , Digestive System/pathology , Dose-Response Relationship, Drug , Female , Furocoumarins/administration & dosage , Furocoumarins/metabolism , Gas Chromatography-Mass Spectrometry , Male , Rats , Rats, Wistar , Toxicity Tests , Urogenital System/pathology
9.
J Pharm Sci ; 108(4): 1619-1626, 2019 04.
Article in English | MEDLINE | ID: mdl-30528198

ABSTRACT

This study investigated the mechanism of transporting imperatorin across the inner blood-retinal barrier (iBRB). The carotid artery single injection method was used to calculate the retinal uptake index (RUI) of [3H]imperatorin in vivo, whereas the retinal capillary endothelial cell lines were used for the in vitro uptake and mRNA expression assays. RUI value of [3H]imperatorin was greater than that of the reference compound ([14C]n-butanol). [3H]Imperatorin significantly reduced the RUI in the presence of neuroprotective organic cationic drugs at 10 mM. However, tetraethylammonium and p-aminohippuric acid showed no significant effects. [3H]Imperatorin uptake by TR-iBRB2 cells was time-, pH-, energy-, and concentration-dependent with a Km value of 679 ± 130 µM. In addition, the uptake study showed insensitivity to sodium and membrane potential. Various organic cations including pyrilamine, nicotine, and clonidine significantly reduced the uptake of [3H]imperatorin, whereas organic anions and monocarboxylic acids did not. Furthermore, the mRNA expression level dropped markedly with rOCTN1, rOCTN2, rPMAT, and rMATE1 small interfering RNAs in the transfection study. Moreover, [3H]imperatorin uptake remained neutral with small interfering RNA transfections. Our results indicate that imperatorin transport across the iBRB involves carrier-mediated transporter system.


Subject(s)
Blood-Retinal Barrier/metabolism , Furocoumarins/pharmacokinetics , Solute Carrier Proteins/metabolism , Animals , Blood-Retinal Barrier/cytology , Cell Line , Endothelial Cells , Endothelium, Vascular/cytology , Furocoumarins/administration & dosage , Gene Expression Profiling , Humans , Injections, Intra-Arterial , Male , Permeability , RNA, Small Interfering/metabolism , Rats , Retinal Diseases/drug therapy , Retinal Vessels/cytology , Solute Carrier Proteins/genetics
10.
Am J Chin Med ; 46(3): 601-615, 2018.
Article in English | MEDLINE | ID: mdl-29614883

ABSTRACT

Obesity is a serious and increasing health problem worldwide, and the inhibition of adipogenesis is considered to be a potential therapeutic target for it. Bergamottin (BGM), a component of grapefruit juice, has been reported to regulate lipolysis. However, the physiological role of BGM in obesity has not been evaluated so far. In the present study, we investigated the effects of BGM on obesity in 3T3-L1 cells and in mice fed a high-fat diet (HFD). BGM inhibited adipogenic differentiation of 3T3-L1 cells along with a significant decrease in the lipid content by downregulating the expression of two critical adipogenic factors, CCAAT enhancer-binding protein-alpha (C/EBP[Formula: see text]) and peroxisome proliferator activated receptor-gamma (PPAR[Formula: see text]). The expressions of target proteins such as adipocyte fatty acid-binding protein (aP2), adiponectin, and resistin were also decreased by BGM. It activated AMP-activated protein kinase (AMPK) by increasing phosphorylation of AMPK and the downstream target acetyl-CoA carboxylase (ACC), indicating that BGM exerted its antiadipogenic effect through AMPK activation. In the HFD-induced obese mouse model, BGM administration significantly reduced the weight and sizes of white adipose tissue as well as the weight gain of mice fed HFD. Moreover, UCP1 and PGC1[Formula: see text] expressions, well-known as brown adipocyte marker genes, were higher in the BGM-treated HFD mice than that in the HFD-induced obese mice. This study suggests that BGM suppress adipogenesis by AMPK activation in vitro and reduces body weight in vivo.


Subject(s)
Adipogenesis/drug effects , Body Weight/drug effects , Diet, High-Fat/adverse effects , Furocoumarins/pharmacology , Obesity/etiology , Obesity/metabolism , Weight Gain/drug effects , 3T3-L1 Cells , AMP-Activated Protein Kinases/metabolism , Animals , CCAAT-Enhancer-Binding Protein-alpha/genetics , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cell Differentiation/drug effects , Citrus paradisi/chemistry , Depression, Chemical , Disease Models, Animal , Furocoumarins/administration & dosage , Furocoumarins/isolation & purification , Gene Expression/drug effects , Lipolysis/drug effects , Mice , Obesity/drug therapy , PPAR gamma/genetics , PPAR gamma/metabolism , Phytotherapy
11.
Int J Nanomedicine ; 13: 831-842, 2018.
Article in English | MEDLINE | ID: mdl-29467573

ABSTRACT

AIM: The aim of this work was to develop a novel vesicular carrier, ultradeformable liposomes (UDLs), to expand the applications of the Chinese herbal medicine, imperatorin (IMP), and increase its transdermal delivery. METHODS: In this study, we prepared IMP-loaded UDLs using the thin-film hydration method and evaluated their encapsulation efficiency, vesicle deformability, skin permeation, and the amounts accumulated in different depths of the skin in vitro. The influence of different charged surfactants on the properties of the UDLs was also investigated. RESULTS: The results showed that the UDLs containing cationic surfactants had high entrapment efficiency (60.32%±2.82%), an acceptable particle size (82.4±0.65 nm), high elasticity, and prolonged drug release. The penetration rate of IMP in cationic-UDLs was 3.45-fold greater than that of IMP suspension, which was the highest value among the vesicular carriers. UDLs modified with cationic surfactant also showed higher fluorescence intensity in deeper regions of the epidermis. CONCLUSION: The results of our study suggest that cationic surfactant-modified UDLs could increase the transdermal flux, prolong the release of the drug, and serve as an effective dermal delivery system for IMP.


Subject(s)
Furocoumarins/administration & dosage , Liposomes/administration & dosage , Liposomes/chemistry , Administration, Cutaneous , Animals , Drug Carriers/chemistry , Drug Carriers/pharmacology , Drug Delivery Systems/methods , Elasticity , Male , Microscopy, Electron, Transmission , Particle Size , Rats, Sprague-Dawley , Skin/drug effects , Skin/ultrastructure , Skin Absorption/drug effects , Spectroscopy, Fourier Transform Infrared , Surface-Active Agents/chemistry
12.
Oncol Rep ; 37(6): 3397-3404, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28440462

ABSTRACT

Inflammation contributes to development and progression in a variety of cancers, including cervical cancer, which is the second leading cause of cancer deaths in women worldwide. In this study, we examined the anti-inflammatory effects of imperatorin, a psoralen-type furanocoumarin from the fruits of Angelica dahurica, in tumor necrosis factor-α (TNF-α)-stimulated HeLa cells by investigating its impact on the production and expression of cytokines and the major signal-transduction pathways. We found this compound significantly inhibited the TNF-α-induced expression of NF-κB target genes, such as COX-2, cyclin  D1, MMP-9, VEGF, IL-6 and Bcl-xL in a concentration-dependent manner. Further analysis revealed that imperatorin was a potent inhibitor of NF-κB activation by the suppression of TNF-α-induced IKKα/ß phosphorylation, IκB phosphorylation and degradation, and NF-κB p65 nuclear translocation. We also demonstrated that imperatorin downregulated TNF-α-induced activation of PI3K/Akt. Furthermore, our findings show that imperatorin inhibits TNF-α-induced ROS generation. Taken together, imperatorin can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-κB pathway.


Subject(s)
Furocoumarins/administration & dosage , Inflammation/drug therapy , Tumor Necrosis Factor-alpha/genetics , Uterine Cervical Neoplasms/drug therapy , Angelica/chemistry , Female , Fruit/chemistry , Furocoumarins/chemistry , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Inflammation/genetics , Inflammation/pathology , NF-kappa B/genetics , Neoplasm Proteins/genetics , Phosphatidylinositol 3-Kinases/genetics , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology
13.
Neuroreport ; 28(8): 426-433, 2017 May 24.
Article in English | MEDLINE | ID: mdl-28383321

ABSTRACT

Adolescence is a time of continued brain maturation, particularly in limbic and cortical regions, which undoubtedly plays a role in the physiological and emotional changes. Prenatally stressed offspring rats were used to investigate the potential antidepressive-like effects of imperatorin (IMP) extracted from the root of radix angelica. After 4 weeks of treatment of IMP, behavioral tests (sucrose-preference test, forced-swimming test, and open-field test) were measured. 5-hydroxytryptamine (5-HT) concentration in the hippocampus and frontal cortex was measured using an enzyme-linked immunosorbent assay. Serotonin transporters (5-HTT) and 5-HT1A receptor (5-HT1AR) mRNA expression in the hippocampus and frontal cortex were also determined by real-time PCR. Administration with IMP (15 and 30 mg/kg/day, intragastrically) for 28 days markedly increased the percentage of sucrose (anhedonia), decreased the immobility time, and increased the number of total crossings, center crossings, rearing, and grooming in the male prenatally stressed offspring. Meanwhile, we found that 5-HT concentration in the hippocampus and frontal cortex was significantly increased in the IMP-treated group. Subsequently, we found significantly decreased 5-HTT and increased 5-HT1AR mRNA expressions in the hippocampus and frontal cortex after IMP treatment in the prenatally stressed male offspring. IMP showed antidepressive-like effects and increased 5-HT concentration in male prenatally stressed offspring, suggesting that IMP could be of therapeutic use in preventing depressive-like behavior in adolescence.


Subject(s)
Antidepressive Agents/administration & dosage , Depression/metabolism , Furocoumarins/administration & dosage , Prenatal Exposure Delayed Effects/metabolism , Prenatal Exposure Delayed Effects/psychology , Serotonin/metabolism , Stress, Psychological/complications , Angelica , Animals , Depression/etiology , Depression/prevention & control , Female , Frontal Lobe/metabolism , Hippocampus/metabolism , Male , Plant Extracts/administration & dosage , Pregnancy , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism
14.
Molecules ; 22(3)2017 Mar 07.
Article in English | MEDLINE | ID: mdl-28272365

ABSTRACT

In traditional oriental medicine, Angelica dahurica Radix (ADR) is used in the treatment of gastrointestinal, respiratory, neuromuscular, and dermal disorders. We evaluated the pharmacokinetic profiles of oxypeucedanin, imperatorin, and isoimperatorin, major active ingredients of ADR, in normal and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats. A rapid, sensitive, and validated UPLC/MS/MS method was established for evaluating the pharmacokinetics of three furanocoumarins. After oral administration of ADR (0.5 and 1.0 g/kg), blood samples were collected periodically from the tail vein. In colitis rats, the time to reach the peak concentration (Tmax) of imperatorin and isoimperatorin was significantly delayed (p < 0.05). Lower peak plasma concentrations (Cmax) and longer mean residence times for all furanocoumarins were also observed (p < 0.05) compared with normal rats. There was no significant difference in the area under the plasma concentration-time curve or elimination half-lives. Thus, the delayed Tmax and decreased Cmax, with no influence on the elimination half-life, could be colitis-related changes in the drug-absorption phase. Therefore, the prescription and use of ADR in colitis patients should receive more attention.


Subject(s)
Colitis/pathology , Furocoumarins/chemistry , Furocoumarins/pharmacokinetics , Angelica/chemistry , Animals , Chromatography, High Pressure Liquid , Colitis/drug therapy , Colitis/etiology , Disease Models, Animal , Drug Stability , Furocoumarins/administration & dosage , Male , Molecular Structure , Plant Extracts/administration & dosage , Plant Extracts/chemistry , Plant Extracts/pharmacokinetics , Rats , Reproducibility of Results , Tandem Mass Spectrometry
15.
J Clin Pharmacol ; 57(3): 305-311, 2017 03.
Article in English | MEDLINE | ID: mdl-27503364

ABSTRACT

The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, 3-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low-furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed "Hudson" grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107-140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80% to 125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. Although most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice.


Subject(s)
Citrus paradisi , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Fruit and Vegetable Juices , Furocoumarins/pharmacology , Midazolam/pharmacokinetics , Adult , Area Under Curve , Cross-Over Studies , Double-Blind Method , Female , Food-Drug Interactions , Furocoumarins/administration & dosage , Healthy Volunteers , Humans , Male , Prospective Studies
16.
Biomed Res Int ; 2016: 6869452, 2016.
Article in English | MEDLINE | ID: mdl-27239473

ABSTRACT

Osteoporosis is a systemic skeletal disease, which is characterized by a systemic destruction of bone mass and microarchitecture. With life standard improved, the treatment of osteoporosis attracted more attention. The aim of this study is to verify the osteoprotective effect of psoralen and isopsoralen in females and males. Female and male mice were divided into 7 groups in this study: control group (sham-operation), model group (by ovariectomy or orchidectomy), positive control group (females given estradiol valerate; males given alendronate sodium), psoralen groups (10 mg/kg and 20 mg/kg), and isopsoralen groups (10 mg/kg and 20 mg/kg). After administration of psoralen and isopsoralen for 8 weeks, osteoporosis was ameliorated with increasing bone strength and improving trabecular bone microstructure as indicated by CT scan and pathology. Serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRACP), osteocalcin (OC), and C-terminal cross-linking telopeptides of type I collagen (CTX-1) were examined. Decreased TRACP and increased ALP/TRACP suggested restoring from bone destruction. These results suggest that psoralen and isopsoralen may be used as good natural compounds for the treatment of osteoporosis in males, as well as females.


Subject(s)
Bone Density/drug effects , Ficusin/administration & dosage , Furocoumarins/administration & dosage , Osteoporosis/drug therapy , Osteoporosis/physiopathology , Tibia/physiopathology , Animals , Dose-Response Relationship, Drug , Female , Male , Mice , Mice, Inbred ICR , Orchiectomy , Osteoporosis/diagnosis , Ovariectomy , Tibia/drug effects , Tibia/pathology , Treatment Outcome
17.
Article in English | MEDLINE | ID: mdl-27070117

ABSTRACT

The detection of drug metabolites, particularly for minor metabolites, continues to be a challenge owing to the complexity of biological samples. Imperatorin is an active natural furocoumarin ingredient originating from many traditional Chinese herbal medicines. In the present study, the metabolites of imperatorin after oral administration were qualitatively investigated, and possible metabolic pathways of it were subsequently proposed. Bile samples were collected after oral administration and pretreated by the application of Waters Ostro. The QTOF-MS/MS data was acquired using ultra high performance liquid chromatography coupled to quadrupole time flight spectrometry (UPLC-QTOF-MS). Based on this analytical strategy, 32 metabolites (23 phase I and 9 phase II metabolites) were identified in rat bile. The results demonstrated that C5H8 could be easily eliminated from imperatorin forming the metabolite M1. It also indicated that imperatorin and M1 underwent extensive metabolic reactions including oxidation, hydrolysis, methylation, glucuronide conjugation, C2H5NO2S conjugation and C3H5NO2S conjugation. This is the first study of imperatorin metabolism in bile samples. The proposed metabolic pathways in this research will provide essential data for further pharmaceutical studies of other linear-type furocoumarins.


Subject(s)
Bile/chemistry , Chromatography, High Pressure Liquid/methods , Furocoumarins/analysis , Furocoumarins/pharmacokinetics , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Furocoumarins/administration & dosage , Furocoumarins/chemistry , Male , Rats , Rats, Sprague-Dawley
18.
Int J Parasitol Drugs Drug Resist ; 5(2): 58-64, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26042195

ABSTRACT

Ichthyophthirius multifiliis, an external fish parasite, often causes significant economic damage to the aquaculture industry. Since the use of malachite green was banned, the search of alternative substance to control I. multifiliis infections becomes stringent. In present study, in vitro and in vivo anti-ich efficacies of isopsoralen and psoralidin, two active compounds isolated from methanol extract of Psoralea corylifolia by bioassay-guided fractionation based on the efficacy of anti-ich encysted tomonts, were evaluated. In vitro antiprotozoal efficacy of psoralidin is much better than that of isopsoralen. Psoralidin can kill all theronts at concentrations of 0.8 mg/L or more during 4 h exposure; and terminate reproduction of I. multifiliis post 6 h exposure of protomonts to 0.9 mg/L and encysted tomonts to 1.2 mg/L. In vivo trials showed that 5 h exposure of infected fish to 2.5 mg/L of psoralidin significantly reduced the number of theronts released from tomonts. Furthermore, we observed that a part of protomonts, collected from infected fish post treatment, presented characteristic morphological changes of apoptosis after staining with Annexin V-EGFP/propidium iodide, indicating the possible mechanism of psoralidin against I. multifiliis trophont in situ. On the basis of these results, psoralidin can be used as a potential lead compound for the development of commercial drug against I. multifiliis.


Subject(s)
Benzofurans/pharmacology , Ciliophora Infections/veterinary , Coumarins/pharmacology , Fish Diseases/parasitology , Furocoumarins/pharmacology , Hymenostomatida/drug effects , Psoralea/chemistry , Animals , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Benzofurans/administration & dosage , Benzofurans/chemistry , Ciliophora Infections/drug therapy , Ciliophora Infections/parasitology , Coumarins/administration & dosage , Coumarins/chemistry , Dose-Response Relationship, Drug , Furocoumarins/administration & dosage , Furocoumarins/chemistry , Goldfish , Molecular Structure
19.
J Pharm Sci ; 103(10): 3120-6, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25070929

ABSTRACT

This study investigated the effect of skin viability on its permeability to psoralen delivered by ethosomes, as compared with liposomes. With decreasing skin viability, the amount of liposome-delivered psoralen that penetrated through the skin increased, whereas skin deposition of psoralen from both ethosomes and liposomes reduced. Psoralen delivery to human-immortalized epidermal cells was more effective using liposomes, whereas delivery to human embryonic skin fibroblast cells was more effective when ethosomes were used. These findings agreed with those of in vivo studies showing that skin psoralen deposition from ethosomes and liposomes first increased and then plateaued overtime, which may indicate gradual saturation of intracellular drug delivery. It also suggested that the reduced deposition of ethosome- or liposome-delivered psoralen in skin with reduced viability may relate to reduced cellular uptake. This work indicated that the effects of skin viability should be taken into account when evaluating nanocarrier-mediated drug skin permeation.


Subject(s)
Furocoumarins/administration & dosage , Liposomes , Skin/physiopathology , Animals , Cell Line , Chromatography, High Pressure Liquid , Humans , Rats
20.
Biomed Res Int ; 2014: 480545, 2014.
Article in English | MEDLINE | ID: mdl-24800231

ABSTRACT

Aim. Ducrosia anethifolia is used as flavoring additive. There have been little detailed phytochemical reports on this genus and the antidiabetic activity of this plant is not yet evaluated. Method. Structure of compounds was deduced by spectroscopic analyses. Preliminary in vitro evaluation of the antidiabetic activity of crude extract and its furanocoumarins was carried out ( α -amylase, α -glucosidase, and ß -galactosidase). The in vivo activity was investigated by measuring some oxidative stress markers. Biomarkers of liver injury and kidney were also determined. Results. Eight linear furanocoumarins, psoralen, 5-methoxypsoralen, 8-methoxypsoralen, imperatorin, isooxypeucedanin, pabulenol, oxypeucedanin methanolate, oxypeucedanin hydrate, and 3-O-glucopyranosyl- ß -sitosterol, were isolated. All compounds were reported for the first time from the genus Ducrosia except pabulenol. The blood glucose level, liver function enzymes, total protein, lipid, and cholesterol levels were significantly normalized by extract treatment. The antioxidant markers, glucolytic, and gluconeogenic enzymes were significantly ameliorated and the elevated level of kidney biomarkers in the diabetic groups was restored. The compounds showed inhibitory activity in a concentration dependant manner. Imperatorin and 5-methoxypsoralen showed the most potent inhibiting power. Conclusion. D. anethifolia extract showed hypoglycemic, hypolipidemic, and antioxidant effect as well as ameliorating kidney function. This extract and some linear furanocoumarins exhibited carbohydrate metabolizing enzymes inhibitory effect.


Subject(s)
Apiaceae/chemistry , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/diagnosis , Diabetes Mellitus, Experimental/drug therapy , Furocoumarins/administration & dosage , Furocoumarins/chemistry , Plant Extracts/administration & dosage , Animals , Apiaceae/classification , Diabetes Mellitus, Experimental/blood , Dose-Response Relationship, Drug , Food Additives , Furocoumarins/isolation & purification , Hypoglycemic Agents/administration & dosage , Male , Pilot Projects , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Rats , Rats, Wistar , Species Specificity , Treatment Outcome
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