benzofurans and psoralidin

Psoralidin, a prenylated coumestrol isolated from the seed of a traditional Chinese medicine

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Benzofurans; Coumarins; Estrogens; Humans; Metabolic Networks and Pathways; Neuroprotective Agents; Plant Extracts

Psoralidin (PSO) is a natural phenolic coumarin that is extracted from the seeds of Psoralea corylifolia L. PSO possesses a variety of pharmacological activities, including anti-oxidative, antibacterial, anti-inflammatory, anti-depressive and estrogenic-like effects. Other studies have indicated that PSO plays a beneficial role in multiple disease, especially cancer and osteoporosis. In this review, we first outline the basic background of PSO. Then we introduced the molecular mechanisms and signaling pathways of PSO in multiple cancers to elucidate its anticancer potential via inducing oxidative stress and apoptosis, inhibiting proliferation, promoting autophagy-dependent cell death, and activating the estrogen receptors (ER)-signaling pathway. Finally, we recommend the direction of future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information to help design PSO in other research and future efforts.

Topics: Animals; Antineoplastic Agents; Benzofurans; Coumarins; Humans; Neoplasms; Osteoporosis

Psoralidin (

Topics: Antioxidants; Benzofurans; Humans; Keratinocytes; Reactive Oxygen Species

Topics: Apoptosis; Benzofurans; Caspase 3; Cell Line, Tumor; Colonic Neoplasms; Coumarins; Humans; Oxidative Stress; Psoralea; Reactive Oxygen Species

Psoralidin (PSO) is a natural phenolic coumarin extracted from the seeds of Psoralea corylifolia L. Growing preclinical evidence indicates that PSO has anti-inflammatory, anti-vitiligo, anti-bacterial, and anti-viral effects. Growth arrest-specific gene 6 (GAS6) and its receptor, Axl, modulate cellular oxidative stress, apoptosis, survival, proliferation, migration, and mitogenesis. Notably, the neuroprotective role of the GAS6/Axl axis has been identified in previous studies. We hypothesize that PSO ameliorates cerebral hypoxia/reoxygenation (HR) injury via activating the GAS6/Axl signaling. We first confirmed that PSO was not toxic to the cells and upregulated GAS6 and Axl expression after HR injury. Moreover, PSO exerted a marked neuroprotective effect against HR injury, represented by restored cell viability and cell morphology, decreased lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) generation. Furthermore, PSO pretreatment also elevated the levels of nuclear factor-related factor 2 (Nrf-2), NAD(P)H dehydrogenase quinone-1 (NQO1), heme oxygenase-1 (HO-1), silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), uncoupling protein 2 (UCP2), and B-cell lymphoma 2 (BCl2) both in the condition of baseline and HR injury. However, GAS6 siRNA or Axl siRNA inhibited the neuroprotective effects of PSO. Our findings suggest that PSO pretreatment attenuated HR-induced oxidative stress, apoptosis, and mitochondrial dysfunction in neuroblastoma cells through the activation of GAS6/Axl signaling.

Topics: Benzofurans; Coumarins; Humans; Hypoxia; Hypoxia, Brain; Intercellular Signaling Peptides and Proteins; Neuroprotective Agents; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering

Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers.. The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms.. ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling.. PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1.. In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.

Topics: Animals; Benzofurans; Cardiotoxicity; Coumarins; Doxorubicin; Mice; PPAR gamma; Sirtuin 1

Psoralidin as a compound of the. In this study, 4T1 tumor-bearing Balb/c mice were treated by intraperitoneal administration of Psoralidin, and Paraffin, as a control group to investigate anti-tumor, anti-angiogenic, and immunostimulatory activities in breast cancer. Body weight and tumor volume measurement were performed. Hematoxylin and Eosin (H&E) staining as well as immunohistochemistry for Ki-67, CD31 and VEGF markers were conducted. In addition, ELISA assay was performed for evaluating the serum level of IFN-γ and IL-4. Moreover, real time assay was performed to evaluate the expression of angiogenesis and immunostimulatory related genes.. There were no significant changes in the body weight of all animal groups. The anti-cancer effects of Psoralidin were significantly observed after 24 days of the last treatment, confirmed by smaller tumor volume and also H&E staining. The expression level of Ki-67, CD31 and VEGF were significantly decreased in tumor tissues of the Psoralidin-treated group in comparison with Paraffin-treated group. Moreover, there was a significant reduction in the serum level of IL-4 in tumor-bearing mice after Psoralidin treatment while the serum level of IFN-γ was significantly augmented in all groups. Moreover, the reduction in expression of VEGF-a and IL-1β was observed. Interestingly Psoralidin treatment led to expression increase of FOXp3.. Psoralidin shows the anti-cancer potential in an animal model of breast cancer; however, further studies are recommended to elucidate its mechanisms of action.

Topics: Animals; Benzofurans; Cell Line, Tumor; Coumarins; Disease Models, Animal; Mice; Mice, Inbred BALB C

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor(TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI.

Topics: Animals; Benzofurans; Cells, Cultured; Chemical and Drug Induced Liver Injury; Coumarins; Disease Models, Animal; Female; Inflammasomes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Phytochemicals; Psoralea

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ m

Topics: Animals; Benzofurans; Coumarins; Dogs; Glucuronides; Glucuronosyltransferase; Kinetics; Mice; Microsomes, Liver; Phenotype; Rats; Species Specificity; Swine; Swine, Miniature

The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with K

Topics: Animals; Benzofurans; Chalcones; Coumarins; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Isoflavones; Microsomes, Liver; Rats, Sprague-Dawley

A method for the simultaneous quantification of 13 bioactive compounds (psoralen, isopsoralen, isobavachin, bakuchalcone, neobabaisoflavone, bavachin, corylin, psoralidin, isobavachalcone, bavachinin, corylifol A, bavachalcone, and bakuchiol) by ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry has been developed and validated in rat plasma. Osthol was used as an internal standard and plasma samples were pretreated with one-step liquid-liquid extraction. These analytes were separated using a gradient mobile phase system of water and acetonitrile at a flow rate of 0.2 mL/min on a reverse-phase C18 column and analyzed in the selected multiple reactions monitoring mode. All calibration curves were linear (r > 0.9952) over the tested ranges. The intra- and interday accuracy and precisions of these analytes at three different concentration levels were within the acceptable limits of <15% at all concentrations. The mean recoveries of these analytes at three concentrations were more than 60.2% and the matrix effects were in the range of 85-115%. Stability studies proved that the analytes were stable under the tested conditions. The developed method was applied to evaluating the pharmacokinetic study of 13 bioactive compounds after oral administration of Psoraleae Fructus in rat of different genders. Some active compounds in Psoraleae Fructus had sex-related pharmacokinetics.

Topics: Animals; Benzofurans; Chalcones; Chromatography, High Pressure Liquid; Coumarins; Female; Ficusin; Flavones; Flavonoids; Furocoumarins; Male; Mass Spectrometry; Molecular Structure; Phenols; Psoralea; Rats; Rats, Sprague-Dawley

Stimulus-responsive therapy permits precise control of therapeutic effect only at lesion of interest, which determines it a promising method for diagnosis and imaging-guided precision therapy. The acid environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical markers in osteoarthritis (OA), which enables the development of stimulus-responsive drug delivery system with high specificity for OA. We herein demonstrate a nano-micelle based stimuli-responsive theranostic strategy with reporting and drug release controlled by acidic pH and MMP-13 for OA therapy. Such nanoplatform is incorporated with a motif specifically targeting on cartilage, a motif responsive to matrix metalloproteinases-13 to specifically report OA condition and biodynamics of nano-micelles, an anti-inflammatory drug (e.g., psoralidin (PSO)) from traditional Chinese medicine, and a biocompatible polymeric skeleton for sustainable drug release in response to the acidic OA condition. The high effectiveness of this targeted precision therapy is demonstrated comprehensively by both in vitro and vivo evidences.

Topics: Animals; Benzofurans; Cells, Cultured; Chondrocytes; Coumarins; Hydrogen-Ion Concentration; Matrix Metalloproteinase 13; Mice; Mice, Inbred C57BL; Osteoarthritis; Theranostic Nanomedicine

Psoralidin (PL), a prenylated coumestrol, is isolated from Psoralea corylifolia L. (Fabaceae), which is frequently used for treatment of osteoporosis.. This study was designed to investigate the dual effects and potential mechanism of PL on promoting osteogenesis and inhibiting adipogenesis.. PL promoted osteogenesis via mediating classical ER pathway, and inhibited adipocytes formation by regulating combined classical and membrane ER pathways. PL might be a potential candidate for the treatment of postmenopausal osteoporosis by modulating the competitive relationship between osteogenesis and adipogenesis of bone marrow mesenchymal stem cells.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Benzofurans; beta Catenin; Cell Differentiation; Coumarins; Fulvestrant; Glycogen Synthase Kinase 3 beta; Male; Mesenchymal Stem Cells; Mice; Osteogenesis; Rats, Sprague-Dawley; Receptors, Estrogen; Signal Transduction

To test the role of psoralidin in human liver cancer HepG2 cells in vitro.. Cell viability was assessed by methylthiazolyldiphenyl-tetrazolum bromide assay and apoptotic cells were labeled by annexin V then sorted by flow cytometry. Protein expressions of caspase-3, caspase-8, caspase-9, Bax, Bid, Bcl-2, Bcl-xL and p53 were examined by western blot while activity of caspase-3, -8 and -9 were also determined.. Psoralidin reduces cell viability greatly in a time dependent manner (64%, 40%, 21%, 12% at 2, 6, 24 and 48 h treatment with 64 μmol/L psoralidin respectively) and up-regulates activities of caspase-3, -8 and -9 in a concentration dependent manner (between 4 to 64 μmol/L). Psoralidin also increases the expression of pro-apoptosis genes Bax, Bid and p53 while decreases the expression of pro-survival genes Bcl-2 and Bcl-xL, both in a concentration dependent manner between 4 and 64 μmol/L (P<0.05 at 16 and 64 μmol/L). Caspase-3 inhibitor (Ac-DEVD-CHO at concentrations between 10 to 20 μmol/L), p53 inhibitor (pifithrin-α at 5 μmol/L) and cyclosporin A can attenuate the apoptotic effect of psoralidin.. The cytotoxic role of psoralidin might work through both intrinsic and extrinsic apoptotic pathway.

Topics: Apoptosis; Benzofurans; Caspases; Cell Line, Tumor; Cell Survival; Coumarins; Hep G2 Cells; Humans; Psoralea; Seeds; Tumor Cells, Cultured

Chondrocyte apoptosis serves a key role in the pathogenesis of osteoarthritis. The present study aimed to investigate the protective effects of psoralidin on interleukin (IL)‑1β‑induced chondrocyte apoptosis and explore the underlying mechanisms. Chondrocytes were isolated from the articular cartilage of Sprague‑Dawley rats and were treated with 10 ng/ml IL‑1β and various doses of psoralidin (5, 10 or 15 µM). The ratio of apoptosis was measured by Annexin V/propidium iodide double‑labeling fluorescence‑activated cell sorting (FACS) analysis. Caspase‑3 and ‑9 activity was determined using a quantitative colorimetric assay. Intracellular levels of reactive oxygen species (ROS) were assessed using a dichlorofluorescein diacetate‑labeling FACS analysis, and the release of nitric oxide (NO) was measured using the Griess reaction method. In addition, protein expression levels were detected by western blotting. The results of the present study demonstrated that psoralidin may reduce IL‑1β‑induced chondrocyte apoptosis. Psoralidin pretreatment also reversed the inhibitory effects of IL‑1β on B‑cell lymphoma 2 (Bcl‑2) expression, and decreased the IL‑1β‑induced expression of Bcl‑2‑associated X protein, matrix metalloproteinase (MMP)‑1 and MMP‑13. Furthermore, psoralidin decreased IL‑1β‑induced caspase‑3 and ‑9 activity, NO release, ROS production and nuclear factor (NF)‑κB nuclear translocation. In addition, the NF‑κB inhibitor pyrriolidine‑dithiocarbamate exerted similar effects to psoralidin, thus suggesting that IL‑1β induced proapoptotic effects in rat chondrocytes via an NF‑κB‑dependent pathway. Since psoralidin could protect chondrocytes from IL‑1β‑induced apoptosis and MMP expression, the present results suggested that psoralidin may be considered a drug candidate for the treatment of osteoarthritis.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Benzofurans; Cells, Cultured; Chondrocytes; Coumarins; Estrogen Receptor Modulators; Interleukin-1beta; Osteoarthritis; Psoralea; Rats, Sprague-Dawley

Prenylation of bioactive natural compounds has been postulated to be able to enhance the utilization rate and affinity of the compounds with cell membranes, thus promote their bioactivities. Coumestrol, isolated from Medicago sativa, has been known as a phytoestrogen which has bone health benefits. In our previous work, psoralidin, a prenylated coumestrol, was proved to have a higher ability than coumestrol to promote bone formation and to attenuate resorption in vitro. However, it remains to be investigated whether psoralidin will have stronger bone health benefits than coumestrol. In the current study, psoralidin was isolated from Psoralea corylifolia L. and the osteotropic activities of coumestrol and psoralidin were compared in ovariectomized (OVX) rats. Both coumestrol and psoralidin were found to suppress OVX-induced bone loss in vivo, as shown by improved total bone mineral content (t-BMC) or density (t-BMD) and mineral apposition rate, bone biomechanical properties, microstructure and trabecular bone formation, enhanced osteogenic differentiation but suppressed adipogenic differentiation of bone marrow stromal cells (BMSCs), and activation of PI3K/Akt axis and downstream factors such as GSK3β/β-catenin and Nrf-2/HO-1. However, psoralidin was shown to have higher activities than coumestrol in the above measurements/indices. Our findings demonstrate that psoralidin, as a novel anti-osteoporosis candidate, could suppress bone loss in OVX rats and have better osteoprotective effects than coumestrol, which may be related to the presence of the isopentenyl group in psoralidin.

Topics: Adipogenesis; Animals; Antioxidants; Benzofurans; Biomarkers; Biomechanical Phenomena; Bone Density; Bone Remodeling; Calcification, Physiologic; Coumarins; Coumestrol; Estradiol; Female; Mesenchymal Stem Cells; Minerals; Osteoclasts; Osteogenesis; Ovariectomy; Oxidation-Reduction; Pentanes; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Tartrate-Resistant Acid Phosphatase; Uterus; Weight Gain

Topics: Animals; Benzofurans; Coumarins; Female; Furocoumarins; Imiquimod; Keratinocytes; Mice, Inbred BALB C; Mice, Nude; Phenols; Photochemotherapy; Psoralea; Psoriasis; PUVA Therapy; Skin; Skin Absorption; Swine; Ultraviolet Rays

Upon synaptic stimulation and glutamate release, glutamate receptors are activated to regulate several downstream effectors and signaling pathways resulting in synaptic modification. One downstream intracellular effect, in particular, is the expression of immediate-early genes (IEGs), which have been proposed to be important in synaptic plasticity because of their rapid expression following synaptic activation and key role in memory formation. In this study, we screened a natural compound library in order to find a compound that could induce the expression of IEGs in primary cortical neurons and discovered that psoralidin, a natural compound isolated from the seeds of Psoralea corylifolia, stimulated synaptic modulation. Psoralidin activated mitogen-activated protein kinase (MAPK) signaling, which in turn induced the expression of neuronal IEGs, particularly Arc, Egr-1, and c-fos. N-methyl-D-aspartate (NMDA) receptors activation and extracellular calcium influx were implicated in the psoralidin-induced intracellular changes. In glutamate dose-response curve, psoralidin shifted glutamate EC

Topics: Animals; Benzofurans; Cells, Cultured; Cerebral Cortex; Coumarins; Dose-Response Relationship, Drug; Female; Gene Expression; Genes, Immediate-Early; Mice; Mice, Inbred ICR; Neuronal Plasticity; Neurons; Pregnancy; Synapses

Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated.. Psoralidin was studied using cadmium-transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo.. Cadmium-transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFκB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression.. These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis.

Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Benzofurans; Blotting, Western; Cadmium; Carcinogenesis; Cell Proliferation; Cells, Cultured; Coumarins; Fluorescent Antibody Technique; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Lysosomes; Male; Mice, Nude; Neoplasm Transplantation; NF-kappa B; Polymerase Chain Reaction; Prostate; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-bcl-2

Psoralidin is a metabolic product from the seed of psoraleacorylifolia, possessed anti-inflammatory and immunomodulatory effects. We speculated that psoralidin might impact osteoclastogenesis and bone loss. By using both in vitro and in vivo studies, we observed psoralidin strongly inhibited RANKL induced osteoclast formation during preosteoclast cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. At the molecular level, by using MAPKs specific inhibitors (U-0126, SB-203580 and SP-600125) we demonstrated that psoralidin markedly abrogated the phosphorylation of p38, ERK, JNK. Moreover, the RANKL induced NF-κB/p65 phosphorylation and I-κB degradation were significantly inhibited by psoralidin. Further, psoralidin significantly suppressed osteoclastogenesis marker genes of TRAP, Cathepsin K and OSCAR. These were accompanied by the decreased expression of c-Fos and NFATc1 transcription factors. Consistent with in vitro results, our in vivo and serologic studies showed psoralidin inhibited lipopolysaccharide induced bone resorption by suppressing the inflammatory cytokines: TNF-α and IL-6 expression, as well as the ratio of RNAKL : OPG. These results collectively suggested that psoralidin could represent a novel therapeutic strategy for osteoclast-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Cell Differentiation; Cells, Cultured; Coumarins; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred ICR; NF-kappa B; Osteoclasts; Osteogenesis; Osteolysis; RANK Ligand; Signal Transduction

Traditional Chinese medicines (TCM) have been proven to prevent osteoporosis, but their clinical applications are not widely recognized due to their complicated ingredients. Psoralidin, a prenylated coumestan, has been reported to prevent bone loss of ovariectomized rats, but detailed mechanisms are still not clear. In current study, we found that both psoralidin and coumestrol promoted osteoblast proliferation and differentiation, as evidenced by improvements in cell proliferation and alkaline phosphatase activity; increased formation of ALP colonies and calcified nodules; enhanced secretion of collagen-I, BMP-2, osteocalcin and osteopontin; and stimulation of the expression of IGF-1, β-catenin, Runx-2, Osterix, and OPG, as well as the mRNA ratio of OPG/RANKL, while significantly decreasing the expression of RANKL. In addition, both psoralidin and coumestrol inhibited osteoclast formation and osteoclastic bone resorption, as demonstrated by the lower tartrate-resistant acid phosphatase activity and smaller area, with fewer resorption pits formed. Interestingly, psoralidin showed much stronger effects than coumestrol at enhancing osteoblast proliferation/differentiation or inhibiting osteoclast differentiation and bone resorption. Moreover, we found that both psoralidin and coumestrol suppressed COX-2 and ROS production in rat osteoblastic calvarias cells, and psoralidin showed stronger effects than coumestrol. Furthermore, we detected that by blocking estrogen receptors with ICI 182.780 (an estrogen receptor antagonist), the osteoprotective effects of psoralidin and coumestrol were also blocked. Our findings demonstrated that psoralidin and coumestrol exert their bone-protective effects by enhancing bone formation of osteoblasts and inhibiting bone resorption of osteoclasts. These roles might be mediated by their antioxidant activity and transduced through estrogen receptor signaling.

Topics: Alkaline Phosphatase; Animals; Benzofurans; Bone Resorption; Cell Differentiation; Cell Proliferation; Coumarins; Dose-Response Relationship, Drug; Osteoclasts; Osteogenesis; Osteoporosis; Prenylation; Rats; Rats, Sprague-Dawley; Skull

Psoralidin (PL) has recently been attracting more attention as a new anticancer agent candidate. Nevertheless, peroral administration of PL is largely challenged by its insoluble nature and intestinal efflux. This article aimed to develop a nanoencapsulation formulation of PL using water-soluble chitosan and Eudragit S100 and to evaluate its potential for bioavailability enhancement. PL-loaded nanocapsules (PL-NCs) were prepared by a solvent diffusion and high-pressure homogenization technique with Poloxamer 188 as a stabilizer. The resultant PL-NCs were approximately 132.5nm in particle size and possessed a high entrapment efficiency (98.1%). In vitro release showed that PL was released less from the nanocapsules due to electrostatic complexation. A lipolytic experiment demonstrated that our prepared PL-NCs were not degraded by lipase, in contrast with the most commonly used lipid nanoparticles. Furthermore, PL-NCs appeared to have less affinity for intestinal mucins. Following oral administration, the bioavailability of PL was significantly enhanced via the PL-NCs, with a value of 339.02% relative to the reference (suspensions). Excellent intestinal adhesion and transepithelial permeability accounted for the enhancement of oral bioavailability. Taken together, these results indicate that nanoencapsulation of PL with chitosan and Eudragit S100 is a promising strategy for improved PL oral delivery.

Topics: Administration, Oral; Animals; Benzofurans; Biological Availability; Chemistry, Pharmaceutical; Chitosan; Coumarins; Nanocapsules; Polymethacrylic Acids; Random Allocation; Rats; Rats, Sprague-Dawley

Psoralidin (PSO), a natural phenolic coumarin, was reported to have anti-cancer activities. PSO induced reactive oxygen species (ROS) generation in cancer cells. The role of ROS in its anti-cancer effect remains unclear.. This study was designed to investigate the potential roles of ROS in PSO-induced anti-cancer effect in MCF-7 breast cancer cells.. Effect of PSO on cancer cell proliferation was determined by MTT assay. Comet assay was used to determine DNA damage. Protein expression was detected by Western blotting. Autophagic vacuoles were detected by monodansylcadaverine (MDC) staining. ROS generation was measured by fluorescent probe. NOX4 localization was determined by immunofluorescence staining.. PSO treatment caused proliferation inhibition in time- and dose- dependent manners, which was partially reversed by N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI). PSO induced DNA damage and increased protein expression of γ-H2AX, phosphorylation of ATM, ATR, Chk1, and Chk2. PSO induced autophagy as evidenced by the accumulation of autophagic vacuoles and alterations of autophagic protein expression. PSO-induced cell death was enhanced by autophagy inhibitor chloroquine (CQ). Furthermore, PSO treatment induced ROS formation, which was reversed by NAC or DPI pretreatment. The expression of NOX4 was significantly enhanced by PSO. Both NAC and DPI could reverse PSO-induced DNA damage and autophagic responses. In addition, silencing NOX4 by siRNA inhibited PSO-induced ROS generation, DNA damage, and autophagy.. Taken together, these results showed that PSO induced DNA damage and protective autophagy mediated by ROS generation in a NOX4-dependent manner in MCF-7 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzofurans; Breast Neoplasms; Cadaverine; Cell Proliferation; Coumarins; DNA Damage; Dose-Response Relationship, Drug; Female; Fluorescent Dyes; Gene Silencing; Humans; MCF-7 Cells; NADPH Oxidase 4; NADPH Oxidases; Reactive Nitrogen Species; RNA, Small Interfering

Psoralidin has shown a variety of biological and pharmacological activities such as anti-tumor anti-oxidant, anti-bacterial, anti-depressant and anti-inflammatory activities. Herein, we reported the metabolism of psoralidin among different species and its inhibitory effect against UGTs and CYP450s. Liquid chromatography was used to investigate the inhibitory activity of psoralidin against ten different UGTs and eight distinct CYP450 isoforms. In addition, we characterized the CYP450 isoforms involved in the psoralidin metabolism on the basis of chemical inhibition studies and screening assays with recombinant human cytochrome P450s. In vitro metabolic profiles and metabolites of psoralidin from varying liver microsomes obtained from human (HLMs), monkey (MLMs), rat (RLMs), dog (DLMs), minipig (PLMs) and rabbit (RAMs) were determined by LC-MS/MS. In vivo pharmacokinetic profiles were investigated by injecting psoralidin (2mg/kg) into the tail vein of Wistar rats. Molecular modeling studies were carried out in order to assess the binding profile and recognition motif between psoralidin and the enzymes. Psoralidin showed potent and noncompetitive inhibition against UGT1A1, UGT1A7, CYP1A2 and CYP2C8 with IC50 values of 6.12, 0.38, 1.81, 0.28μM, respectively. The metabolism of psoraldin exhibited significant differences among humans, monkeys, dogs, minipigs, rabbits and rats; however, monkeys showed the highest similarity to humans. Furthermore, eleven metabolites were observed among these species and their structures were characterized by LC-MS/MS. CYP2C19 played a key role in the metabolism of psorslidin in human liver microsomes. These findings could be used to advance the understanding of psoralidin.

Topics: Animals; Benzofurans; Chromatography, Liquid; Coumarins; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dogs; Drugs, Chinese Herbal; Glucuronosyltransferase; Haplorhini; Humans; Male; Microsomes, Liver; Molecular Docking Simulation; Rabbits; Rats; Rats, Wistar; Species Specificity; Swine; Swine, Miniature; Tandem Mass Spectrometry

To modify the structure of psoralidin using in vitro enzymatic glycosylation to improve its water solubility and stability.. A new psoralidin glucoside (1) was obtained by enzymatic glycosylation using a UDP- glycosyltransferase. The chemical structure of compound 1 was elucidated by HR-ESI-MS and nuclear magnetic resonance (NMR) analysis. The high-performance liquid chromatography (HPLC) peaks were integrated and sample solution concentrations were calculated. MTT assay was used to detect the cytotoxicity of the compounds against 3 cancer cell lines in vitro. Results Based on the spectroscopic data, the new psoralidin glucoside was identified as psoralidin-6',7-di-O-β-D- glucopyranoside (1), whose water solubility was 32.6-fold higher than that of the substrate. Analyses of pH and temperature stability demonstrated that compound 1 was more stable than psoralidin at pH 8.8 and at high temperatures. Only psoralidin exhibited a moderate cytotoxicity against 3 human cancer cell lines. Conclusion In vitro enzymatic glycosylation is a powerful approach for structural modification and improving water solubility and stability of compounds.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Chromatography, High Pressure Liquid; Coumarins; Glucosides; Glycosylation; Glycosyltransferases; Humans; Magnetic Resonance Spectroscopy; Solubility

Herb-drug interaction strongly limits the clinical utilization of herbs and drugs. Irinotecan-induced diarrhea is closely related with the UDP-glucuronosyltransferase 1A1-catalyzed glucuronidation of SN-38 which has been widely regarded to be the toxic substance basis of irinotecan. The present study aims to determine the influence of herbal component psoralidin toward the toxicity of irinotecan. In vitro inhibition potential of psoralidin toward the glucuronidation of SN-38 was firstly investigated using human intestinal microsomes incubation system. Dose-dependent inhibition of psoralidin toward SN-38 glucuronidation was observed. Furthermore, Dixon plot showed that the intersection point was located in the second quadrant, indicating the competitive inhibition of psoralidin toward the glucuronidation of SN-38. Through the data fitting using competitive inhibition fitting equation, the inhibition kinetic parameter (K i) was calculated to be 5.8 μM. The translation of these in vitro data into the in vivo situation showed that pre-treatment with psoralidin significantly increased the toxicity of irinotecan, as indicated by the increased body weight loss and more severe colon histology damage. All these data indicated the herb-drug interaction between irinotecan and psoralidin-containing herbs.

Topics: Animals; Benzofurans; Camptothecin; Colon; Coumarins; Dose-Response Relationship, Drug; Herb-Drug Interactions; Humans; Irinotecan; Male; Mice; Mice, 129 Strain

In this study, we aimed to determine the glucuronidation potential of psoralidin in humans and to perform validation on use of psoralidin-3-O-glucuronidation as a functional marker for UGT1A9. Glucuronidation kinetics was determined using human liver microsomes (HLMs), human intestine microsomes (HIM), and expressed UDP-glucuronosyltransferase (UGT) enzymes. The chemical structures of metabolites were determined by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy analyses. Validation of psoralidin-3-O-glucuronidation as a UGT1A9 marker was performed using combined approaches including reaction phenotyping, chemical inhibition, activity correlation analysis, and determination of relative activity factor (RAF). HLM and UGT1A9 generated two monoglucuronides (9-O-glucuronide and 3-O-glucuronide) from psoralidin, whereas HIM, UGT1A1, UGT1A7, and UGT1A8 generated one only (9-O-glucuronide). Formation of 3-O-glucuronide in HLM was markedly inhibited by the UGT1A9-selective inhibitors magnolol and niflumic acid. Further, psoralidin-3-O-glucuronidation was strongly correlated with propofol-glucuronidation in a group of nine individual HLMs (r = 0.978, p < 0.001). Strong correlation was also observed between psoralidin-3-O-glucuronidation and the UGT1A9 protein levels measured by Western blotting (r = 0.944, p < 0.001). Moreover, UGT1A9 was responsible for 99.6% of psoralidin-3-O-glucuronidation in HLM based on the RAF approach. In conclusion, psoralidin was subjected to efficient glucuronidation, generating one or two monoglucuronides depending on UGT isozymes. Also, psoralidin-3-O-glucuronidation was an excellent in vitro marker for UGT1A9.

Topics: Benzofurans; Biomarkers; Biphenyl Compounds; Coumarins; Glucuronides; Glucuronosyltransferase; Humans; Intestinal Mucosa; Isoenzymes; Kinetics; Lignans; Microsomes, Liver; Niflumic Acid; UDP-Glucuronosyltransferase 1A9

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.

Topics: Animals; Antiprotozoal Agents; Benzofurans; Ciliophora Infections; Coumarins; Dose-Response Relationship, Drug; Fish Diseases; Furocoumarins; Goldfish; Hymenostomatida; Molecular Structure; Psoralea

Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis.

Topics: Acetylcysteine; Antioxidants; Apoptosis; Benzofurans; beta Catenin; Cadherins; Caspase 3; Caspase 9; Catalase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coumarins; Cytochromes c; Enzyme Activation; Epithelial-Mesenchymal Transition; Humans; Male; Membrane Potential, Mitochondrial; Neoplasm Invasiveness; Oxidative Stress; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Reactive Oxygen Species; Snail Family Transcription Factors; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factors; Transcription, Genetic

A novel biological activity of psoralidin as an agonist for both estrogen receptor (ER)α and ERβ agonist has been demonstrated in our study. Psoralidin has been characterized as a full ER agonist, which activates the classical ER-signaling pathway in both ER-positive human breast and endometrial cell lines as well as non-human cultured cells transiently expressing either ERα or ERβ. The estrogenic activity was determined using the relative expression levels of either reporter or the endogenous genes dependent on the agonist-bound ER to the estrogen response element (ERE). Psoralidin at 10 μM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of psoralidin are mediated by ER. Psoralidin was also able to induce the endogenous estrogen-responsive gene, pS2, in human breast cancer cells MCF-7. It was observed that activation of the classical ER-signaling pathway by psoralidin is mediated via induction of ER conformation by psoralidin and direct binding of the psoralidin-ER complex to the EREs present in the promoter region of estrogen-responsive genes, as shown by chromatin immunoprecipitation assay results. Finally, molecular docking of psoralidin to the ligand binding pocket of the ERα showed that psoralidin is able to mimic the binding interactions of E2, and thus, it could act as an ER agonist in the cellular environment.

Topics: Benzofurans; Binding Sites; Cell Line; Cell Proliferation; Coumarins; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Psoralea; Receptors, Estrogen; Signal Transduction

To observe the effect of psoralidine in rats with ovariectomy, and preliminarily study its mechanism.. Sixty female Sprague-Dawley rats were divided into 5 groups: the sham operation group, the model group, the psoralidine low-dose group (4 mg x kg(-1)), the psoralidine high-dose group (16 mg x kg(-1)) and the Zhuangguzhitong capsule group, with 12 rats in each group. Thirteen weeks later, their blood and bone samples were collected to detect bone density, bone biochemistry, pathomorphology, serum E2 and CT.. Psoralidine could up-regulate the bone density of lumbar vertebra and thighbone of rats with ovariectomy (P < 0.05), the maximum bending strength of thighbone (P < 0.05), and serum E2 and CT (P < 0.05).. Psoralidine has a good active effect on postmenopausal antiosteoporosis. Its mechanism may be related to such pathways as E2 and CT.

Topics: Animals; Benzofurans; Bone Density; Coumarins; Drugs, Chinese Herbal; Estradiol; Female; Humans; Osteoporosis, Postmenopausal; Rats; Rats, Sprague-Dawley

Breast cancer stem cells (BCSCs) are characterized by high aldehyde dehydrogenase (ALDH) enzyme activity and are refractory to current treatment modalities, show a higher risk for metastasis, and influence the epithelial to mesenchymal transition (EMT), leading to a shorter time to recurrence and death. In this study, we focused on examination of the mechanism of action of a small herbal molecule, psoralidin (Pso) that has been shown to effectively suppress the growth of BSCSs and breast cancer cells (BCCs), in breast cancer (BC) models.. ALDH(-) and ALDH(+) BCCs were isolated from MDA-MB-231 cells, and the anticancer effects of Pso were measured using cell viability, apoptosis, colony formation, invasion, migration, mammosphere formation, immunofluorescence, and western blot analysis.. Psoralidin significantly downregulated NOTCH1 signaling, and this downregulation resulted in growth inhibition and induction of apoptosis in both ALDH(-) and ALDH(+) cells. Molecularly, Pso inhibited NOTCH1 signaling, which facilitated inhibition of EMT markers (β-catenin and vimentin) and upregulated E-cadherin expression, resulting in reduced migration and invasion of both ALDH(-) and ALDH(+) cells.. Together, our results suggest that inhibition of NOTCH1 by Pso resulted in growth arrest and inhibition of EMT in BCSCs and BCCs. Psoralidin appears to be a novel agent that targets both BCSCs and BCCs.

Topics: Antineoplastic Agents, Phytogenic; Benzofurans; Breast Neoplasms; Cell Movement; Cell Proliferation; Coumarins; Drug Resistance, Neoplasm; Female; Gene Silencing; Humans; Neoplasm Invasiveness; Neoplastic Stem Cells; Receptor, Notch1; Signal Transduction; Tumor Cells, Cultured

Coumarins are a very common type of secondary plant metabolites with a broad spectrum of biological activities. Psoralidin is a naturally occurring furanocoumarin isolated from Psoralea corylifolia possessing anticancer and chemopreventive properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in cancer cells with no toxicity toward normal tissues. Endogenous TRAIL plays an important role in immune surveillance and defence against cancer cells. Coumarins can modulate TRAIL-mediated apoptosis in cancer cells. We examined the cytotoxic and apoptotic activities of psoralidin in combination with TRAIL on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining and mitochondrial membrane potential was evaluated using DePsipher staining by fluorescence microscopy. Death receptor (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression was analyzed using flow cytometry. Psoralidin enhanced TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2 death receptor and depolarization of mitochondrial membrane potential. Our study indicated that psoralidin augmented the anticancer effects of TRAIL and confirmed a potential use of coumarins in cancer chemoprevention.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Coumarins; Drug Synergism; Gene Expression; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Receptors, Death Domain; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand

Psoralidin has been reported to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, but the mechanisms of the action remain unclear. Thus, the impact of psoralidin on signaling pathways known to be implicated in NO synthesis was explored in LPS-activated RAW264.7 macrophages by using RT-PCR and Western blotting. Consistent with NO inhibition, psoralidin suppressed LPS-induced expression of inducible NO synthase (iNOS) by abolishing IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathway might also be phosphoinositide-3-kinase (PI3K) dependent. By using Src inhibitor PP2, Janus kinase 2 (JAK-2) inhibitor AG490, Bruton's tyrosine kinase (Btk) inhibitor LFM-A13 and spleen tyrosine kinase (Syk) inhibitor piceatannol, the results showed that piceatannol clearly repressed NO production more potently than the other inhibitors. Furthermore, piceatannol significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IκB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/Akt-mediated signaling. In fact, transfection with siRNA targeting Syk obviously reduced iNOS expression. Interestingly, LPS-induced phosphorylations of Syk and PI3K-p85 were both significantly blunted by psoralidin treatment. The present results show that interfering with Syk-mediated PI3K phosphorylation might contribute to the NO inhibitory effect of psoralidin via blocking IKK/IκB signaling propagation in LPS-stimulated RAW 264.7 macrophages.

Topics: Active Transport, Cell Nucleus; Animals; Benzofurans; Cell Line; Cell Nucleus; Coumarins; Enzyme Activation; Gene Expression Regulation, Enzymologic; I-kappa B Kinase; I-kappa B Proteins; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Macrophages; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; RNA, Messenger; Signal Transduction; Syk Kinase

Numerous compounds detected in medical plants and dietary components or supplements possess chemopreventive, antitumor and immunomodulatory properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anticancer factor that induces apoptosis selectively in cancer cells. However, some tumor cells are resistant to TRAIL-mediated apoptosis. Naturally occurring agents could sensitize TRAIL-resistant cancer cells and augment their apoptotic activity.We examined the cytotoxic and apoptotic effects of neobavaisoflavone and psoralidin in combination with TRAIL on LNCaP prostate cancer cells. The cytotoxicity was evaluated by MTT and LDH assays. The apoptosis was detected using Annexin V-FITC by flow cytometry and fluorescence microscopy. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrated that neobavaisoflavone and psoralidin sensitized TRAIL-resistant cells and markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Cotreatment of LNCaP cells with 100 ng/ml TRAIL and 50 μM neobavaisoflavone or 50 μM psoralidin increased the percentage of the apoptotic cells to 77.5±0.5% or 64.4±0.5%, respectively. The data indicate the potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Flow Cytometry; Humans; Isoflavones; Male; Microscopy, Fluorescence; Prostatic Neoplasms; Psoralea; TNF-Related Apoptosis-Inducing Ligand

Radiotherapy is the most significant non-surgical cure for the elimination of tumor, however it is restricted by two major problems: radioresistance and normal tissue damage. Efficiency improvement on radiotherapy is demanded to achieve cancer treatment. We focused on radiation-induced normal cell damage, and are concerned about inflammation reported to act as a main limiting factor in the radiotherapy. Psoralidin, a coumestan derivative isolated from the seed of Psoralea corylifolia, has been studied for anti-cancer and anti-bacterial properties. However, little is known regarding its effects on IR-induced pulmonary inflammation. The aim of this study is to investigate mechanisms of IR-induced inflammation and to examine therapeutic mechanisms of psoralidin in human normal lung fibroblasts and mice. Here, we demonstrated that IR-induced ROS activated cyclooxygenases-2 (COX-2) and 5-lipoxygenase (5-LOX) pathway in HFL-1 and MRC-5 cells. Psoralidin inhibited the IR-induced COX-2 expression and PGE(2) production through regulation of PI3K/Akt and NF-κB pathway. Also, psoralidin blocked IR-induced LTB(4) production, and it was due to direct interaction of psoralidin and 5-lipoxygenase activating protein (FLAP) in 5-LOX pathway. IR-induced fibroblast migration was notably attenuated in the presence of psoralidin. Moreover, in vivo results from mouse lung indicate that psoralidin suppresses IR-induced expression of pro-inflammatory cytokines (TNF-α, TGF-β, IL-6 and IL-1 α/β) and ICAM-1. Taken together, our findings reveal a regulatory mechanism of IR-induced pulmonary inflammation in human normal lung fibroblast and mice, and suggest that psoralidin may be useful as a potential lead compound for development of a better radiopreventive agent against radiation-induced normal tissue injury.

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Arachidonate 5-Lipoxygenase; Benzofurans; Cells, Cultured; Coumarins; Cyclooxygenase 2 Inhibitors; Humans; Lipoxygenase Inhibitors; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Phosphatidylinositol 3-Kinases; Pneumonia; Proto-Oncogene Proteins c-akt; Radiation-Protective Agents

To study the chemical constituents of Psoralea corylifolia.. Column chromatography was used in the isolation procedure. The structures of isolated compounds were elucidated by spectral data.. Seven compounds were isolated and their structures were identified as isopsoralen (1), psoralen (2), bavachalcone (3), 4", 5"-dehydroisopsoralidin (4), methyl 4-hydroxybenzoate (5), psoralidin (6), corylin (7).. Compounds 4 and 5 are obtained from Psoralea for the first time.

Topics: Benzofurans; Chalcones; Coumarins; Ficusin; Flavones; Fruit; Magnetic Resonance Spectroscopy; Molecular Structure; Parabens; Plants, Medicinal; Psoralea

The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-alpha and its downstream prosurvival signaling molecules such as NF-kappaB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-alpha and NF-kappaB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

Topics: Androgens; Animals; Apoptosis; Benzofurans; Caspases; Cell Line, Tumor; Cell Survival; Coumarins; Down-Regulation; Drug Resistance, Neoplasm; Humans; Male; Mice; NF-kappa B; Prostatic Neoplasms; Receptors, Death Domain; Recombinant Proteins; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH(2)-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC.

Topics: Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Down-Regulation; Enzyme Activation; ErbB Receptors; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Mice; Phosphorylation; Prostatic Neoplasms; Transfection; Transplantation, Heterologous

The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.

Topics: Animals; Benzofurans; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Plant Preparations; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

A base-catalyzed condensation of phenyl acetate with acid chloride, followed by intramolecular cyclization and microwave-assisted cross-metathesis reaction, leads to the first total synthesis of psoralidin, a natural product with a broad range of biological activities, in a highly convergent and regioselective manner.

Topics: Antineoplastic Agents; Benzofurans; Biological Products; Coumarins; Molecular Structure; Stereoisomerism

Quinone reductase (QR) is a protective phase II enzyme against mutagens and carcinogens which is inducible by a number of chemical compounds in plants. This study was carried out to investigate effects of the fractions from the seeds of Psoralea corylifolia on the induction of QR with Hepa 1c1c7 murine hepatoma cell line. The ethyl acetate-soluble fraction of the methanolic extract from the seeds was found to induce QR and the concentration of 1.5 fold QR induction (1.5 FIC) was 1.2 mug/mL. We obtained as an active compound, psoralidin, isolated from the ethyl acetate-soluble fraction after further sequential fractionation with column chromatography and 1.5 FIC of psoralidin was 0.5 mug/mL. The seeds of Psoralea corylifolia and psoralidin might be a candidate for developing QR inducers.

Topics: Acetates; Animals; Anticarcinogenic Agents; Benzofurans; Cell Line, Tumor; Coumarins; Dose-Response Relationship, Drug; Liver Neoplasms; Methanol; Mice; NAD(P)H Dehydrogenase (Quinone); Psoralea; Seeds; Solvents; Up-Regulation

The antidepressant-like effects of psoralidin isolated from the seeds of Psoralea corylifolia were investigated in the forced swimming test (FST) in ICR strain of male mice. Psoralidin significantly decreased immobility time and increased swimming behavior without altering climbing behavior in the mouse FST after oral administration for 1 h or 3 consecutive days. Psoralidin did not affect locomotor activity in the open-field test. After a 3-day treatment, psoralidin significantly increased 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions, as well as, changed dopamine (DA) levels in striatum in mice exposed to FST. Psoralidin also ameliorated the elevations in serum corticotropin-releasing factor (CRF), adrenal corticotropin-releasing hormone (ACTH) and corticosterone concentrations induced by swimming stress in mice. These results suggested that psoralidin possessed potent antidepressant-like properties that were mediated via the monoamine neurotransmitter and the hypothalamic-pituitary-adrenal (HPA) axis systems.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Behavior, Animal; Benzofurans; Corticosterone; Corticotropin-Releasing Hormone; Coumarins; Exploratory Behavior; Hydroxyindoleacetic Acid; Hypothalamo-Hypophyseal System; Immobility Response, Tonic; Male; Mice; Mice, Inbred ICR; Models, Animal; Motor Activity; Pituitary-Adrenal System; Prefrontal Cortex; Psoralea; Seeds; Serotonin; Swimming; Synaptic Transmission; Tissue Distribution

Fructus Psoraleae, a widely used traditional Chinese medicine, is well known as a health supplement ingredient. In our study, an improved and comprehensive HPLC fingerprint of Fructus Psoraleae was established. Two important new benzofuran glycosides, psoralenoside and isopsoralenoside, were identified as characteristic constituents for the first time. HPLC separation was performed on an RP-C8 column. The mobile phase was acetonitrile and 0.1% acetic acid solution with linear gradient change of acetonitrile from 10 to 82% in 40 min. The flow rate was 1.0 mL/min, and the detection wavelength was set at 310 nm. The HPLC chromatograms of twenty-six samples from different regions of China showed a similar pattern. Twelve peaks were selected as characteristic peaks and further identified as psoralenoside, isopsoralenoside, psoralen, isopsoralen, bavachromene, corylifolin, corylin, psoralidin, isobavachalcone, bavachinin, corylifol A, and bakuchiol, respectively. Nine of them were simultaneously quantitatively analyzed for the first time. A more comprehensive analytical method was established for the fingerprint of Fructus Psoraleae. It is very useful for authentication and quality assessment of the crude drug.

Topics: Benzofurans; Chalcones; Chromatography, High Pressure Liquid; Coumarins; Drugs, Chinese Herbal; Ficusin; Flavonoids; Fruit; Furocoumarins; Glycosides; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Phenols; Psoralea; Solvents

High-performance liquid chromatography (HPLC) was developed for fingerprint analysis of Psoralea corylifolia. Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MSn) technique was first employed to identify the components of the fingerprint. The samples were separated with an Alltima C18 column (250 mm x 4.6 mm, 5 microm) by linear gradient elution using water-acetic acid (A; 100:0.1, v/v) and acetonitrile (B; 0 min, 40%; 15 min, 50%; 35 min, 60%; 45 min, 70%; 55 min, 80%; and maintained for 5 min) as mobile phase at a flow rate of 1.0 ml/min and detector wavelength at 245 nm. A standard procedure was developed for HPLC fingerprint analysis. Average chromatogram of 10 batches of P. corylifolia L. from Sichuan and Henan Provinces, PR China, which has been considered as the original and genuine herbal medicine for a long time, was first established as the characteristic fingerprint. There are 12 common peaks in this fingerprint. Ten of these common peaks were identified by MS data. This profile was then used to identify and assess the differences among the herb grown in various areas of China. The HPLC fingerprint analysis is specific and may serve for quality identification and comprehensive evaluation of P. corylifolia.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Coumarins; Ficusin; Flavonoids; Isoflavones; Psoralea; Spectrometry, Mass, Electrospray Ionization

A coumestan derivative, psoralidin (1) was found to be a cytotoxic principle of the seeds of Psoralea corylifolia L. (Leguminosae) with the IC50 values of 0.3 and 0.4 microg/ml against the HT-29 (colon) and MCF-7 (breast) human cancer cell lines, respectively. A coumarin, angelicin (2) was also isolated as a marginally cytotoxic agent along with an inactive compound, psoralen (3) from the plant. The isolates 1-3 were not active against the A541 (lung) and HepG2 (liver hepatoma) cancer cell lines.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Survival; Chemical Phenomena; Chemistry, Physical; Coumarins; Drug Screening Assays, Antitumor; Furocoumarins; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Plants, Medicinal; Psoralea; Rats; Seeds; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Tumor Cells, Cultured

A cytotoxic coumestan derivative, psoralidin (1), was isolated from the seed of Psoralea corylifolia. The IC50 values of 1 against SNU-1 and SNU-16 carcinoma cell lines were 53 and 203 micrograms/ml, respectively, indicating cytotoxic activity against stomach carcinoma cell lines.

Topics: Antineoplastic Agents, Phytogenic; Benzofurans; Cell Survival; Coumarins; Etoposide; Humans; Plants, Medicinal; Seeds; Tumor Cells, Cultured