Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

Phytophotodermatitis as a clinical problem and as a therapeutic option: Case report and review of the literature.

BACKGROUND: Phytophotodermatitis is a contact photodermatitis to furocoumarins, which act as sensitizing psoralens, from certain plants, especially citrus and fig trees. This photosensitizing effect has traditionally been used for the treatment of cutaneous viral warts, a reflection of traditional medicine. However, there are hardly any studies that support this fact. Otherwise, on certain occasions, especially in extensive exposures, they can cause a generalized severe condition that can even put the patient's life at risk. CASE PRESENTATION: We report the case of a 28-year-old man with severe phytophotodermatitis after generalized photoexposure with the manipulation of a fig tree, which required hospital management in a burn unit. RESULTS: A traditional method for the treatment of warts in some rural areas, especially in Iran, comprises the use of fig tree (ficus carica) latex as a local treatment; however, there is no scientific evaluation of its efficacy. It bases its effectiveness on physical destruction due to the sensitizing effect of furocoumarins. Though, in generalized exposures of this tree, as the case of our patient, can cause fatal symptoms. The essential therapeutic pillar is the avoidance of exposure to this tree and of sun exposure. Symptomatically, topical corticosteroids and systemic antihistamines are used. In severe cases, admission to a burn unit may be necessary. CONCLUSION: In conclusion, we highlight the importance the importance of early detection of phytophotodermatitis, an entity that can be caused by the daily handling of trees, including fig trees, a traditional remedy for viral warts and which, without adequate supervision in its application, can cause severe generalized symptoms.

Photoonycholysis: new findings.

First described in 1961, photoonycholysis (PO) is a rare nail alteration that may result from drug intake, from topical aminolevulinate photodynamic therapy or from photosensitive conditions such as porphyria or pseudoporphyria. Spontaneous PO is rare. This review updates the numerous causes of PO and highlights some new ways producing this condition. Four different types of PO are clearly recognized without relationship with the responsible drug. An updated list of potential inducing drug is provided. Some practical points on PO have been raised. The inability to reproduce photoonycholysis experimentally should be emphasized, and the pathogenesis of PO still needs to be clarified.

Dietary furocoumarins and skin cancer: A review of current biological evidence.

Furocoumarins are a class of compounds produced by several plant species, including some popularly consumed by humans. Furocoumarins are known to be well absorbed from food sources, and can be rapidly distributed into several tissues including the skin. In human skin, when exposed to UV radiation, furocoumarins may become photoactivated and form interstrand crosslinks with DNA, thereby disrupting DNA transcription. Because of this property, furocoumarins have been combined as topical or oral agents with UV irradiation as a phototherapy to treat multiple skin conditions, yet these treatments have been shown to increase risk of both melanoma and non-melanoma skin cancer. Whether or not dietary furocoumarin exposure may confer the same risk is not yet known. This review summarizes the current evidence regarding the activities of ingested furocoumarins, with particular focus on how dietary furocoumarins are absorbed, metabolized, and distributed throughout the body, and their interactions with various cellular components that may underlie a potential relationship with skin cancer.

Clinical efficacy of psoralen + sunlight vs. combination of isotretinoin and psoralen + sunlight for the treatment of chronic plaque-type psoriasis vulgaris: a randomized hospital-based study.

BACKGROUND: Isotretinoin has been used in combination with oral psoralen + UVA (PUVA) and narrowband UVB (NBUVB) for treating psoriasis, especially in women of child-bearing age. The efficacy of oral psoralen + sun exposure (PUVAsol) is comparable to that of PUVA. This study was planned to compare the efficacy of oral PUVAsol with that of the combination of oral isotretinoin and PUVAsol in patients with chronic plaque psoriasis. METHODS: Forty patients with psoriasis vulgaris were randomized to two groups. Group A (control group) received PUVAsol only. Group B (intervention group) received PUVAsol + isotretinoin (0.5 mg/kg/day). Psoriasis Area Severity Index (PASI) score was recorded at baseline and weeks 4, 8 and 12. Dermatology Life Quality Index was assessed at baseline and 12 weeks. The end point of the study was PASI 75 or 12 weeks, whichever came earlier. RESULTS: Thirty-five patients completed the study. There were statistically significant differences between the two study groups for the number of patients achieving the endpoint of PASI 75, PASI scores at the end of 12 weeks, mean duration to achieve PASI 75, number of PUVAsol sessions needed to achieve PASI75 and mean cumulative dosage of 8-methoxypsoralen needed to achieve PASI 75. CONCLUSION: The combination of isotretinoin with PUVAsol is more effective compared with PUVAsol alone for treating chronic plaque psoriasis.

Practical pearls in phototherapy.

The following tips are suggested for phototherapy: (i) calibrate the unit with a radiometer every 2-4 weeks; (ii) change all bulbs at the same time every 8-10 months for regularly used machines or when the UV meter shows that the power has reached 3 or 4 mW/cm(2) ; (iii) avoid phototherapy sessions on consecutive days to prevent burn on burn; (iv) in the event of a burn, reduce the last PUVA or UVB dose by 50%, reinitiating when erythema has fully disappeared, which might take two days to two weeks; (v) nausea from oral psoralens can be avoided by taking it with a fixed amount of milk or food, taking an antiemetic with this meal prior to dosing, taking five ginger tablets 15 minutes before dosing, or dividing the dosage; (vi) to achieve 0.03% concentration of 8-methoxypsoralen for hand and foot soak PUVA, dissolve a 10-mg tablet or 1.0 cc of Oxsoralen(®) solution 1% in 3 l of water; and (vii) to achieve 0.000075% concentration of 8-methoxypsoralen for full-body soak PUVA, dissolve 60 mg 8-methoxypsoralen in 80 l of water (i.e. a bath tub).

Differential roles for Chk1 and FANCD2 in ATR-mediated signalling for psoralen photoactivation-induced senescence.

Cellular senescence is a stress-inducible, naturally irreversible cell cycle arrest, which is likely linked with ageing. Premature ageing of the skin is a prominent side effect of psoralen photoactivation, which is used for the treatment of various skin disorders. Previously, we have shown that DNA interstrand crosslink formation by photoactivated psoralens induces a senescent phenotype in primary fibroblasts that is mediated by Ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. Checkpoint kinase 1 (Chk1) initiates cell cycle checkpoints, and FANCD2 is known to be involved in DNA damage-induced S-phase arrest and crosslink repair. In this study, we examined a role for Chk1 and FANCD2 as downstream effectors of ATR in senescence signalling. We demonstrate that Chk1 and FANCD2 are long-lastingly activated after psoralen photoactivation. Separate and combined reduction in Chk1 and FANCD2 expression by small interfering RNA (siRNA) preceding irradiation partly prevented the initiation of the senescence-like phenotype, whereas siRNA (Chk1 and FANCD2) transfection of senesced fibroblasts released cells from growth arrest. We observed that Chk1 and FANCD2 signal equally and additively for senescence induction, while Chk1 is predominantly responsible for maintaining persistent cell cycle arrest. In conclusion, Chk1 and FANCD2 function downstream of ATR in a non-redundant manner for the establishment and maintenance of psoralen photoactivation-induced senescence.

[Consensus document on bath-PUVA therapy. The Spanish Photobiology Group of the Spanish Academy of Dermatology and Venereology]. / Documento de consenso sobre la modalidad terapéutica del baño-PUVA. Grupo Español de Fotobiología de la Academia Española de Dermatología and Venereología.

Bath PUVA is a variant of phototherapy as efficacious as oral PUVA therapy that avoids many of the adverse effects associated to this treatment. Nevertheless, the special features and the specialized equipment required for its employment have limited its application in the dermatologic clinics of our country. Following the trend initiated after the publication of the consensus document on oral PUVA therapy and narrow band (NB) UVB therapy, the Spanish Photobiology Group from the Spanish Academy of Dermatology and Venereology has developed a therapeutic guideline for bath PUVA therapy based on the literature review and the experience of its members. The document aims to be a practical reference guide for those dermatological centres that include phototherapy among their services. It reviews the concept and indications of this type of treatment and proposes recommendations concerning therapeutic procedures, drug associations of interest and prophylaxis and management of adverse effects.

Burns caused by accidental overdose of photochemotherapy (PUVA).

This study was aimed to alert the hazard of accidental adverse reactions of photochemotherapy (Psoralen-UVA or PUVA) that has been used in the treatment for some skin diseases and commercially for cosmetic tanning. Aside from the predictable side effects of PUVA such as erythema and itching, the accidental adverse reactions such as extensive burns could occasionally occur. Our observations indicated that six cases resulted from mistakes of medical personnel, and six other cases resulted from unsupervised mistakes of patients. The conditions that needed photochemotherapy were seven cases of vitiligo, three cases of psoriasis and two cases of tanning. The accidental overdose of UV radiation was about 3-10 times the empirically normal dose. Five of our patients were supposed to undergo topical PUVA, but they were irradiated at the dose of oral PUVA. One patient applied 8-methoxypsoralen (8-MOP) cream together with taking 5-methoxypsoralen (5-MOP) tablets for oral PUVA. Three other patients enjoyed sunbathing 1-3h shortly after finishing PUVA. A young couple chose 5-MOP to enhance tanning and sunbathed about 1h later. When another patient resumed PUVA in a 6-month cessation, he was exposed at a previous dose instead of a starting dose. Erythema and blisters of second degree burns developed in all our cases, 36-72h after PUVA, with 5-25% of body surface involved. Among the 12 patients, 3 were admitted and 9 were treated on an outpatient basis. All patients recovered in 1-3 weeks with no skin graft or no significant sequelae except post-inflammatory hyperpigmentation.

Can dietary furanocoumarin ingestion enhance the erythemal response during high-dose UVA1 therapy?

As phototoxic skin reactions caused by psoralen are induced by wavelengths within the UVA1 spectrum, we assessed the potential of the small amount of psoralen in a normal diet to provoke phototoxicity in volunteers with skin types I and II. Threshold erythema was unaffected by ingestion of a 200-g portion of parsnip.

An unusual cause of burn injury: fig leaf decoction used as a remedy for a dermatitis of unknown etiology.

Medicinal plant extracts are commonly used worldwide. Their use relies mostly on historical and anecdotal evidence and might be so hazardous. Phytophotodermatitis is a well-known entity that is caused by the sequential exposure to certain species of plants containing furocoumarins and then to sunlight. In this article, superficial burn lesions caused by fig leaf decoction that was applied to a patient's both upper extremity as a remedy for a dermatitis of unknown etiology is reported. Direct sun exposure is an essential component of phytophotodermatitis. All reported cases to date have in common that patients are exposed to direct sunlight or to artificial UVA lights (like solarium) of varying durations. In our case neither direct sun exposure, other than inevitable indoor UVA influence, nor blister formation was present. The etiologic factors, symptoms, signs, course, and treatment alternatives for phytophotodermatitis are also reviewed briefly.

Berloque dermatitis induced by "Florida water".

Phytophotodermatitis is a phototoxic dermatitis resulting from contact with psoralen-containing plants such as celery, limes, parsley, figs, and carrots. Berloque dermatitis is a variant of phytophotodermatitis and is caused by high concentrations of psoralen-containing fragrances, most commonly oil of bergamot. Berloque dermatitis is rarely seen today because of the removal of these fragrances from most cosmetic products in the United States. We report, however, a group of patients still at risk for berloque dermatitis. These patients use the colognes "Florida Water" and "Kananga Water," which are popular in Hispanic, African American, and Caribbean populations. These fragrant waters are used for spiritual blessing, treating headaches, and personal hygiene.

Novel angular furo and thieno-quinolinones: synthesis and preliminary photobiological studies.

A number of new furo and thienoquinolinones carrying an electron-withdrawing function or unsubstituted at the position 3 were synthesized in order to obtain new potential photochemotherapeutic agents with increased antiproliferative activity and decreased toxic side effects. Our interest in studying the SAR of these derivatives also prompted us to investigate the influence of N-methylation on biological activity, by preparing N-methyl derivatives. The antiproliferative activity of all the newly synthesized compounds was evaluated and compared to 8-methoxypsoralen (8-MOP), the drug widely used in PUVA-therapy. The 3-unsubstituted thienoquinolinones were generally the most potent derivatives, followed by the furo-analogues. In particular, the unsubstituted thieno[2,3-h]quinoline-2(1H)one showed the highest activity in T2 bacteriophage, HeLa cells and Ehrlich cells tests. All the compounds, assayed on Escherichia coli WP2 TM9, showed a similar mutagenic activity, very close to that of 8-MOP. Except for 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid, which appeared to be very effective, all compounds generated singlet oxygen to slightly larger amounts when compared to 8-MOP. The N-methyl analogues only induced moderate skin erythemas on albino guinea pigs, while all other derivatives appeared to be entirely inactive. On the basis of these results, the unsubstituted thieno[2,3h]quinoline 2(1H)one seems to be the most interesting potential drug for PUVA photochemotherapy and photopheresis.

The role of PUVA in the treatment of psoriasis. Photobiology issues related to skin cancer incidence.

Photochemotherapy with methoxsalen (8-methoxypsoralen) and long wavelength ultraviolet (UV) radiation (referred to as 'PUVA' for psoralen plus UVA) is commonly used to treat psoriasis and vitiligo. These vastly different diseases respond to the therapy by different mechanisms even though the immediate effects of the therapy--the photomodification of cellular biomolecules--is the same for each. Because psoriasis is not cured by PUVA, patients receive many treatments over their lifetime and have a significantly increased risk for the development of skin cancers (primarily squamous cell carcinomas). In this article the basic aspects of psoralen photobiology are reviewed briefly. Several recent studies describing the incidence of skin cancer in UVA treated psoriasis cohorts are comparatively reviewed. In addition the impact of the analysis of mutations in the tumor suppressor gene, p53, are summarized. An unexpected mutation spectrum (very few PUVA type T-->A transversions and frequent UVB solar signature C-->T transitions) suggest that effects other than direct DNA photoadduct formation may be at play. These analyses suggest that it may be possible to improve the therapeutic efficacy of PUVA by a careful evaluation of the mode of delivery. In this review the science behind PUVA is summarized. In addition, the incidence of skin cancer as a long term consequence of repeated treatments is surveyed. To relate clinical observations to molecular events, the nature of p53 mutations found in skin cancers from psoriasis patients is also analyzed. Finally some suggestions for improving the delivery of PUVA therapy are presented.

Relato de caso: dermatite de contato causada por arruda (Ruta graveolens L.) / Case report: contact dermatitis caused by to (Ruta graveolens L.)

Um homem de 26 anos desenvolveu uma reaçäo fototóxica em suas pernaas, após utilizar as partes aéreas frescas da arruda (Ruta graveolens L.), para repelir pernilongos, depois de se expor ao sol. A hipersensibilidade foi causada devido às furanocumarinas (psoralenos) presentes no óleo essencial da arruda.