Isopsoralen treatment stimulates the accumulation of cartilage nodules in a dose-dependent manner. Isopsoralen increases the expression of chondrogenic marker genes like collagen II, collagen X, OCN, Smad4 and Sox9 in a time-dependent manner. Additionally, isopsoralen induces the activation of p38 MAP kinase and extracellular signal-regulated kinase (ERK), but not of c-jun N-terminal kinase (JNK). Isopsoralen significantly increases BMP-2 protein expression in a time-dependent manner and, through BMP-2 or MAPK signaling pathways, mediates a chondromodulating effect.

In mice with sex hormone deprivation, isopsoralen has a significant osteoprotective effect on both male and female mice. Isopsoralen treatment for 8 weeks results in improved trabecular bone microstructure and increased bone strength. The elimination half-life of isopsoralen after intravenous administration to wistar rats is 5.35 hours. Kidney > lung > liver > heart > spleen > brain is the order in which the area under the tissues' curves for isopsoralen decrease. The elimination half-life of isopsoralen after oral administration to Wistar rats is 5.56 h, and its bioavailability is 70.35%.

ATDC5 cells are plated in 96-well plates at a density of 5×103 cells per well, incubated for an overnight period in media containing 10% FBS, and then subjected to various isopsoralen concentrations. Following a 24-hour incubation period, cells are treated with media containing 100 g/ml MTT for 2 hours at 37°C after being washed with phosphate-buffered saline (PBS). Following a PBS wash, the cells are dissolved in 200 l of DMSO. By using a spectrophotometer to measure the absorbance at a wavelength of 540 nm, the resulting solubilized purple formazan is quantified.

Absorption, Distribution and Excretion
OBJECTIVE: To investigate the nasal absorption regularities of psoralen and isopsoralen of different concentrations. METHOD: Building an experimental model of rat in situ nasal recirculation and determining the contents of psoralen and isopsoralen by HPLC. RESULT: The nasal absorption of psoralen and isopsoralen fitted in with zero order kinetics, getting saturated with the increase of concentration. CONCLUSION: A suitable concentration is necessary for the preparation of nasal remedies psoralen and isopsoralen.
Coumarin components from Psoralea corylifolia L. are novel drugs in which psoralen and isopsoralen are the active components. The pharmacokinetics, tissue distribution and excretion of the two compounds were studied by liquid chromatography-tandem mass spectrometry after intravenous administration to Wistar rats. The elimination half-lives of psoralen and isopsoralen were 4.88 and 5.35 hr. After dosing, the area under the curves of the tissues decreased in the following order: liver > lung > heart > kidney > spleen > brain for psoralen; and kidney > lung > liver > heart > spleen > brain for isopsoralen. After dosing, 51.27% of psoralen and 56.25% of isopsoralen were excreted as prototype, and urine was the major excretion route. In addition, the pharmacokinetics of psoralen and isopsoralen after oral administration to Wistar rats were also studied. The elimination half-lives of psoralen and isopsoralen were 4.13 and 5.56 hr, and their relative bioavailabilities were 61.45% and 70.35%. Overall, the results show that coumarin components from P. corylifolia L. have high oral bioavailability, they are rapidly and widely distributed into tissues after intravenous administration, but they are slowly cleared and excreted

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Biological Half-Life
...The elimination half-lives of psoralen and isopsoralen /after iv administration to Wistar rats/ were 4.88 and 5.35 hr. ...The elimination half-lives of psoralen and isopsoralen /after oral administration to Wistar rats/ were 4.13 and 5.56 hr...

Toxicity Summary
IDENTIFICATION AND USE: Isopsoralen is a natural furocoumarin. It has been tested as experimental therapy. HUMAN STUDIES: Isopsoralen acted in vitro as ERalpha receptor agonists and promoted MCF-7 cell proliferation significantly. Angelicin forms DNA monoadducts when photoactivated. In human cells isopsoralen promoted sister-chromatid exchanges. ANIMAL STUDIES: Isopsoralen had potent tranquilizing, anticonvulsant, and central muscle relaxant activity in rats, mice, and rabbits when given both ip and orally. Isopsoralen was photomutagenic in bacterial and animal cells generating DNA monoadducts.
The mechanism of action many furocoumarins is based on their ability to form photoadducts with DNA and other cellular components such as RNA, proteins, and several proteins found in the membrane such as phospholipases A2 and C, Ca-dependent and cAMPdependent protein-kinase and epidermal growth factor. Furocoumarins intercalate between base pairs of DNA and after ultraviolet-A irradiation, giving cycloadducts. (L579)

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Interactions
Photochemical genotoxicity can be detected using appropriately adapted versions of most of the standard in vitro genotoxicity assays. The most sensitive approach to detect potentially photogenotoxic agents seems to be the investigation of DNA damage (DNA strand breakage, chromosomal aberrations, micronuclei) in mammalian cells in vitro. In a previous paper, we proposed the use of the micronucleus assay in Chinese hamster V79 cells for this purpose. This assay was found suitable to detect various photogenotoxic compounds with different photoactivation mechanisms. In order to extend the experimental experiences with this assay, we present here further data from a screening mode testing of 16 different potential photosensitizers. The photoclastogenic and photocytotoxic potential of the compounds was investigated concomitantly. So far, all substances detected in the photo-micronucleus assay as photogenotoxins also exhibited photocytotoxic properties but not vice versa. Among the compounds tested in the present study, tiaprofenic acid, 5-MOP, angelicin, nitrazepam, bendroflumethiazide, and dacarbazine were photogenotoxic and photocytotoxic. Further, 6-mercaptopurine, a metabolite of azathioprine was positive for both endpoints, whereas azathioprine was found negative. Azathioprine seems to be an example of a compound which lacks photo(geno)toxic properties in vitro but may be converted to a photosensitizer by enzymatical metabolization. With the results obtained in this study, the data base for the photo-micronucleus assay was extended to 35 compounds, which were tested using the same protocol and the same irradiation conditions. The photogenotoxicity results of all these compounds are summarized and discussed in correlation to their different photoactivation mechanisms, photocytotoxicity and photocarcinogenicity.
In this study we have found that the crude extract of Psoraleae Fructus inhibited acetylcholinesterase activity in vitro and ameliorated impairment of the inhibitory avoidance response and of the water maze spatial performance caused by scopolamine in rats. Among all fractions, the chloroform fraction showed the best inhibitory effect on acetylcholinesterase activity and could reduce the scopolamine-induced inhibitory avoidance response impairment. Psoralen and isopsoralen, two major constituents of the chloroform fraction of Psoraleae Fructus identified by high performance liquid chromatography, also reduced the extent of the inhibitory avoidance response impairment. The results suggest that psoralen and isopsoralen are the major active ingredients of Psoraleae Fructus responsible for the progressive reversal of scopolamine-induced amnesia, whose effects are partially associated with inhibition of AchE activity and hence activation of the central cholinergic neuronal system.
Monofunctional psoralens, plus UVA radiation are not erythemogenic and are less mutagenic than bifunctional psoralens plus UVA radiation. Thus, they have received considerable attention in recent years as potential therapeutic agents for various skin diseases. The purpose of this study was to examine the immunologic side effects following treatment of mice with a monofunctional psoralen plus UVA radiation. We report that angelicin plus UVA radiation suppressed the induction of contact hypersensitivity to dinitrofluorobenzene. This decreased immune response was associated with the presence of splenic suppressor cells that transferred suppression to normal recipients. Treatment with angelicin and UVA radiation also decreased the number of Thy-1+ and Ia+ dendritic epidermal cells in the treated site. We conclude that although this monofunctional psoralen is not phototoxic, it has immunosuppressive activity in mice.
Because of the undesirable side effects associated with the use of 8-methoxypsoralen and long-wave ultraviolet A (UVA) radiation in the treatment of skin disorders such as psoriasis, the use of monofunctional psoralens, which are less erythemogenic, less mutagenic, and generally non-phototoxic, has received considerable attention. Little is known, however, about the immunosuppressive properties of monofunctional psoralens. The purpose of this study was to examine the effect of parenteral administration of a monofunctional psoralen, angelicin, plus exposure to UVA radiation on the immune response. Injection of angelicin followed by exposure to UVA radiation significantly suppressed delayed-type hypersensitivity to alloantigen in a dose-dependent fashion. Similarly, the capacity of spleen cells from the angelicin and UVA-treated animals to proliferate to alloantigen was significantly suppressed. The suppression was specific for the alloantigen used to sensitize the angelicin and UVA-treated animals and was associated with the appearance of splenic antigen-specific suppressor T lymphocytes. These data demonstrate that the effect of systemic administration of a monofunctional psoralen followed by UVA exposure on the immune response is similar to that seen following the injection of bifunctional psoralens. These findings also suggest that the severe skin phototoxicity associated with the use of a bifunctional psoralen and UVA radiation is not necessary for the induction of systemic immuno-suppression. Furthermore, the induction of systemic antigen-specific immunosuppression by angelicin plus UVA, without overt skin phototoxicity, suggests the possibility of using this and related compounds to specifically inhibit unwanted immune reactions.
For more Interactions (Complete) data for Isopsoralen (12 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mice i.p. 254 mg/kg
LD50 Rat i.p. 165 mg/kg
LD50 Rat oral 322 mg/kg

[1]. Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells. Molecular and Cellular Biochemistry October 2012, Volume 369, Issue 1-2, pp 95-104.

[2]. Antiviral activity of angelicin against gammaherpesviruses. Antiviral Research Volume 100, Issue 1, October 2013, Pages 75–83.

[3]. Angelicin regulates LPS-induced inflammation via inhibiting MAPK/NF-κB pathways. Journal of Surgical Research Volume 185, Issue 1, November 2013, Pages 300–309.

Angelicin is a furanocoumarin.
Angelicin has been reported in Hoita macrostachya, Mandragora autumnalis, and other organisms with data available.
Angelicin is found in coriander. Angelicin is a constituent of roots and leaves of angelica (Angelica archangelica). Angelicin is found in roots and on surface of parsnips and diseased celery.Angelicin is a furanocoumarin. It can be found in Bituminaria bituminosa. It is present in the list of IARC Group 3 carcinogens (Angelicin plus ultraviolet A radiation). (Wikipedia).
See also: Angelica archangelica root (part of); Cullen corylifolium fruit (part of).

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Mechanism of Action
The combined action of 365 NM UV light & angelicin inhibited the injection of phage lambda into the host. The inhibition of injection is discussed in terms of photochemically induced crosslinking of the dna inside the phage heads. The electronic structures in the 1st excited states calculated by means of quantum chemistry according to the ppp method were very similar for xanthotoxin, psoralen, & angelicin.

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Therapeutic Uses
/EXPL THER/ BACKGROUND: Modern studies have shown that psoralen has a significant inhibitory effect on tumor growth in a variety of animals and humans. OBJECTIVE: To obtain coumarin compounds - psoralen and isopsoralen - from traditional Chinese medicine Psoralea corylifolia L. using chromatographic techniques and isolation and purification methods, and to observe the transplanted tumor growth inhibitory effects and adverse reactions of psoralen and isopsoralen in nude rats with osteosarcoma. METHODS: Dried ripe fruits of Psoralea corylifolia L. were taken as the raw material to prepare crude extract of Psoralea corylifolia L. by ethanol reflux method. Column chromatography was used to isolate the crude extract; compounds were structurally identified based on (1)H-NMR, (13)C-NMR spectra, the two compounds were identified as psoralen andisopsoralen, and their contents were 99.7% and 99.6, respectively. Nude rat model of osteosarcoma was established; the rats were randomized into: normal saline group, psoralen low- and high-dose groups, isopsoralen low- and high-dose groups, and cisplatin group. Osteosarcoma volume and weight inhibition rates in nude rats in each group were observed; radioimmunoassay was used to determine the serum alkaline phosphatase activity; peripheral blood cell and bone marrow nucleated cell counts were determined; light microscopy was used to observe heart, liver, spleen, lung, kidney, and tumor histopathology; and electron microscopy was used to observe the fine structure of tumor cells. RESULTS: Tumor volume inhibition rates were 43.75% and 40.18%, respectively, in the psoralen and isopsoralen low-dose groups, and tumor weight inhibition rates were 38.83% and 37.77%. Tumor volume inhibition rates were 67.86% and 66.96%, respectively, in the psoralen and isopsoralen high-dose groups, and tumor weight inhibition rates were 49.47% and 47.87%. Psoralen and ispsoralen markedly lowered serum AKP level. Psoralen and isopsoralen induced apoptosis or necrosis of osteosarcoma. After administration of high doses of psoralen and isopsoralen, toxic reactions such as writhing, lassitude, and hypoactivity were seen. Kidney histopathology showed tubulointerstitial dilatation and congestion, and inflammatory cell aggregation in the renal intercellular space. Psoralen and isopsoralen did not cause any significant toxic side effects to the bone marrow, or other organs such as heart, lung, liver, and spleen. CONCLUSION: Psoralen and isopsoralen have growth inhibitory effects on transplanted tumor in nude rats with osteosarcoma, and can induce tumor cell apoptosis or necrosis, without significant toxic effects.
/EXPL THER/ Angelicin, a furocoumarin found in Psoralea corylifolia L. fruit, has been reported to have anti-inflammatory activity. The purpose of this study was to determine the protective effects of angelicin on allergic asthma induced by ovalbumin (OVA) in mice. Mice were sensitized to OVA (on days 0 and 14) and challenged with OVA three times (on days 21 to 23). Angelicin (2.5, 5, 10 mg/kg) was given intraperitoneally 1 hr before OVA treatment after the initial OVA sensitization. The production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum were measured by ELISA. Lung histological changes were detected by using hematoxylin and eosin (H&E) stain. The results showed that angelicin significantly inhibited inflammatory cells infiltration into the lungs. Histological studies showed that angelicin significantly attenuated OVA-induced lung injury. Meanwhile, treatment of angelicin dose-dependently inhibited OVA-induced the production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum. Furthermore, angelicin was found to inhibit airway hyperresponsiveness and NF-kB activation. In conclusion, our results suggested that angelicin inhibited allergic airway inflammation and hyperresponsiveness by inhibiting NF-kB activation.
/EXPL THER/ Isopsoralen is a type of furocoumarin that exhibits estrogen-like activities. The aim of this study was to determine the estrogen-like neuroprotection of isopsoralen in an animal model of spinal cord injury (SCI). Results indicated that isopsoralen (intraperitoneal injection of 5 and 10 mg/kg per day for two weeks) significantly enhanced the hindlimb locomotor functions of mice with SCI, as revealed in the BMS score and angle of inclined plane tests. Morphological data showed that isopsoralen significantly attenuated the injury of the gray matter of spinal cord and induced the up-regulation of ERa levels. The neuroprotective effects of isopsolaren were blocked by the ERa antagonist MPP (0.3 mg/kg), but not by the ERbeta receptor antagonist PHTPP (0.3 mg/kg). Isopsolaren treatment increased phosphorylated PI3K and AKT (P-PI3K and P-AKT) in the spinal cord of SCI mice and showed a significant anti-apoptotic activity. These results suggest that isopsoralen performs estrogen-like neuroprotection against SCI-induced apoptosis by activating ERa and regulating the PI3K/AKT pathway.
/EXPL THER/ Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated. The present results revealed that angelicin induced apoptosis in liver cancer cells in a dose- and time-dependent manner. Furthermore, in HepG2 and Huh-7 cells, angelicin-induced apoptosis was demonstrated to be mitochondria dependent, involving the phosphatidylinositol-4,5-bisphosphate 3-kinase/RAC-a serine/threonine-protein kinase signaling pathway. In addition, administration of angelicin to mice bearing liver tumor xenografts inhibited tumor growth, without producing significant secondary adverse effects. These results suggested that angelicin may have potential as a novel therapeutic agent for the treatment of patients with liver cancer.
/EXPL THER/ BACKGROUND: Angelicin is a furocoumarin found in Psoralea corylifolia L. fruit. The purpose of this study was to investigate the protective ability of angelicin against inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and LPS-induced in vivo acute lung injury model. MATERIALS AND METHODS: The concentrations of tumor necrosis factor alpha (TNF-a) and interleukin (IL)-6 in the culture supernatants of RAW 264.7 cells were determined 24 hr after LPS administration. ALI was induced by intratracheal instillation of LPS. Six hours after LPS inhalation, bronchoalveolar lavage fluid and lung tissue samples were obtained for enzyme-linked immunosorbent assay, histologic, and Western blotting analyses. RESULTS: The results showed that pretreatment with angelicin markedly downregulated TNF-a and IL-6 levels in vitro and in vivo, and significantly decreased the amount of inflammatory cells, lung wet-to-dry weight ratio, and myeloperoxidase activity in LPS-induced ALI mice. Furthermore, Western blotting analysis results demonstrated that angelicin blocked the phosphorylation of IkappaBa, NF-kappaBp65, p38 MAPK, and JNK in LPS-induced ALI. CONCLUSIONS: These results suggest that angelicin was potentially advantageous to prevent inflammatory diseases by inhibiting NF-kappaB and MAPK pathways. Our data indicated that angelicin might be a potential new agent for prevention of inflammatory reactions and diseases in the clinic.

C11H6O3

186.16354

186.031

C, 68.89; H, 5.44; N, 9.45; O, 5.40; S, 10.82

523-50-2

29462-18-8; 29462-19-9 (HCl)

10658

White to off-white solid powder

1.4±0.1 g/cm3

362.6±27.0 °C at 760 mmHg

132-134ºC

173.1±23.7 °C

0.0±0.8 mmHg at 25°C

1.667

2.01

0

3

0

14

284

0

O=C1C=CC2=CC=C(OC=C3)C3=C2O1

XDROKJSWHURZGO-UHFFFAOYSA-N

InChI=1S/C11H6O3/c12-10-4-2-7-1-3-9-8(5-6-13-9)11(7)14-10/h1-6H

furo[2,3-h]chromen-2-one

Knoll brand of bentazepam; QM 6008; QM-6008; Bentazepam; Thiadipone; Tiadipone; Bentazepam [USAN:INN]; CI-718; Tiadipona; Thiadipone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 14~33.3 mg/mL (75.2~179.0 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (13.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (13.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)