DNA-psoralen: single-molecule experiments and first principles calculations

The authors measure the persistence and contour lengths of DNA-psoralen complexes, as a function of psoralen concentration, for intercalated and crosslinked complexes. In both cases, the persistence length monotonically increases until a certain critical concentration is reached, above which it abruptly decreases and remains approximately constant. The contour length of the complexes exhibits no such discontinuous behavior. By fitting the relative increase of the contour length to the neighbor exclusion model, we obtain the exclusion number and the intrinsic intercalating constant of the psoralen-DNA interaction. Ab initio calculations are employed in order to provide an atomistic picture of these experimental findings.Comment: 9 pages, 4 figures in re-print format 3 pages, 4 figures in the published versio

Psoralen and ultraviolet A light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing

Psoralen and ultraviolet A light (PUNTA) are used to kill pathogens in blood products and as a treatment of aberrant cell proliferation in dermatitis, cutaneous T-cell lymphoma, and graft versus-host disease. DNA damage is well described, but the direct effects of PUVA on cell signal transduction are poorly understood. Because platelets are anucleate and contain archetypal signal transduction machinery, they are ideally suited to address this. Lipidomics on platelet membrane extracts showed that psoralen forms adducts with unsaturated carbon bonds of fatty acyls in all major phospholipid classes after PUVA. Such adducts increased lipid packing as measured by a blue shift of an environment-sensitive fluorescent probe in model liposomes. Furthermore, the interaction of these liposomes with lipid order-sensitive proteins like amphipathic lipid-packing sensor and a-synuclein was inhibited by PUVA. In platelets, PUVA caused poor membrane binding of Akt and Bruton's tyrosine kinase effectors following activation of the collagen glycoprotein VI and thrombin protease-activated receptor (PAR) 1. This resulted in defective Akt phosphorylation despite unaltered phosphatidylinositol 3,4,5-trisphosphate levels. Downstream integrin activation was furthermore affected similarly by PUVA following PAR1 (effective half-maximal concentration (EC), 8.4 +/- 1.1 versus 4.3 +/- 1.1 mu M) and glycoprotein VI (EC50, 1.61 +/- 0.85 versus 0.26 +/- 0.21 mu g/ml) but not PAR4 (EC50, 50 +/- 1 versus 58 +/- 1 mu m) signal transduction. Our findings were confirmed in T-cells ftom graft-versus-host disease patients treated with extracorporeal photopheresis, a form of systemic PUVA. In conclusion, PUVA increases the order of lipid phases by covalent modification of phospholipids, thereby inhibiting membrane recruitment of effector kinases

The Patient's Guide to Psoriasis Treatment. Part 2: PUVA Phototherapy.

BackgroundPUVA treatment is photochemotherapy for psoriasis that combines psoralen with UVA radiation. Although PUVA is a very effective treatment option for psoriasis, there is an absence of patient resources explaining and demonstrating the process of PUVA. Studies have shown that patients who viewed videos explaining the treatment procedures for various medical conditions had a greater understanding of their treatment and were more active participants in their health.ObjectiveTo present a freely available online guide and video on PUVA treatment designed for patient education on PUVA.MethodsThe PUVA treatment protocol used at the University of California-San Francisco Psoriasis and Skin Treatment Center as well as available information from the literature was reviewed to design a comprehensive guide for patients receiving PUVA treatment.ResultsWe created a printable guide and video resource that reviews the benefits and risks of PUVA, discusses the three types of PUVA (hand-foot soak, full body soak, and systemic), demonstrates the PUVA process, and provides practical tips for safe use.ConclusionOnline media and video delivers material in a way that is flexible and often familiar to patients. This new format is beneficial for prospective patients planning to undergo PUVA treatment, health-care providers, and trainees who want to learn more about this treatment

The Effect of Psoralens on Hepatic and Cutaneous Drug Metabolizing Enzymes and Cytochrome P-450

Psoralens are tricyclic furocoumarins with potent photosensitizing properties in the skin and are now widely used in the treatment of several dermatologic diseases. In this study the effect of 3 different psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and isopsoralen on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 has been assessed in mice and rats. 8-MOP administered orally to CD-1 mice daily for 6days caused 2–3 fold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP, to hairless mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH; whereas chronically administered TMP had no significant effect on any of these parameters. Isopsoralen and TMP administered orally to CD-1 mice daily for 6days had no effect on any of these liver enzymes or on hepatic drug-metabolizing enzymes and cytochrome P-450 to a lesser extent than do the barbituaes and suggest that this drug could influence the rate of biotransformation of concomitantly administered drugs in patients undergoing PUVA therapy

Effect of psoralens and ultraviolet radiation on murine dendritic epidermal cells

AbstractMonofunctional psoralens produce less phototoxicity than bifunctional psoralens after ultraviolet A (UVA) irradiation. We investigated the effect of repetitive treatments with angelicin (isopsoralen), a monofunctional psoralen, plus UVA radiation (IPUVA) on the number and morphology of dendritic epidermal cells (dEC). This effect was compared with that of 8-methoxypsoralen plus UVA radiation (PUVA), UVA alone, and UVB radiation. C3H/HeN mice were treated topically with the drugs three times/wk for 4 consecutive wk; followed each time by 1 or 2.5 J/cm2 of UVA radiation. Other groups of mice were treated with the drugs alone, UVA alone, or 0.81 J/cm2 of UVB. Epidermal sheets were stained for ATPase, Ia, and Thy-1 markers. Mice treated with PUVA and UVB exhibited severe phototoxicity, whereas no overt phototoxicity was observed in mice treated with IPUVA, UVA alone, or the drugs alone. Early during the PUVA and UVA treatments the ATPase marker was lost from dEC, followed by loss of the Ia marker; the Ia marker was lost before the ATPase marker from dEC in animals treated with IPUVA. At the end of the treatment, however, nearly total depletion of ATPase+, Ia+, and Thy-1+ dEC was observed in mice treated with PUVA and IPUVA. UVB radiation caused rapid depletion of Thy-1+ dEC as well as ATPase+ and Ia+ cells. During treatments with IPUVA, PUVA, UVA, and UVB, the Langerhans cells became rounded and lost their dendrites. These changes were quantitated by image analysis. We conclude that alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that monofunctional and bifunctional psoralens plus low dose of UVA radiation may have different effects on dEC markers

Effectiveness and Safety of Topical Phototherapy in the Treatment of Dermatological Diseases

Phototherapy consists in the use of ultraviolet (UV) radiation from artificial sources for therapeutic purposes. Despite the introduction of new and powerful drugs (including biological and target therapies), phototherapy remains an established, lower cost, and effective option for the treatment of many common skin diseases