A Review of Phototoxic Plants, Their Phototoxic Metabolites, and Possible Developments as Photosensitizers.

This study provides a comprehensive overview of the current knowledge regarding phototoxic terrestrial plants and their phototoxic and photosensitizing metabolites. Within the 435,000 land plant species, only around 250 vascular plants have been documented as phototoxic or implicated in phototoxic occurrences in humans and animals. This work compiles a comprehensive catalog of these phototoxic plant species, organized alphabetically based on their taxonomic family. The dataset encompasses meticulous details including taxonomy, geographical distribution, vernacular names, and information on the nature and structure of their phototoxic and photosensitizing molecule(s). Subsequently, this study undertook an in-depth investigation into phototoxic molecules, resulting in the compilation of a comprehensive and up-to-date list of phytochemicals exhibiting phototoxic or photosensitizing activity synthesized by terrestrial plants. For each identified molecule, an extensive review was conducted, encompassing discussions on its phototoxic activity, chemical family, occurrence in plant families or species, distribution within different plant tissues and organs, as well as the biogeographical locations of the producer species worldwide. The analysis also includes a thorough discussion on the potential use of these molecules for the development of new photosensitizers that could be used in topical or injectable formulations for antimicrobial and anticancer phototherapy as well as manufacturing of photoactive devices.

Chlorin E6-Curcumin-Mediated Photodynamic Therapy Promotes an Anti-Photoaging Effect in UVB-Irradiated Fibroblasts.

Skin photoaging due to ultraviolet B (UVB) exposure generates reactive oxygen species (ROS) that increase matrix metalloproteinase (MMP). Chlorin e6-photodynamic therapy (Ce6-PDT), in addition to being the first-line treatment for malignancies, has been shown to lessen skin photoaging, while curcumin is well known for reducing the deleterious effects of ROS. In the current study, PDT with three novel Ce6-curcumin derivatives, a combination of Ce6 and curcumin with various linkers, including propane-1,3-diamine for Ce6-propane-curcumin; hexane-1,6-diamine for Ce6-hexane-curcumin; and 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) for Ce6-dipolyethylene glycol (diPEG)-curcumin, were studied for regulation of UVB-induced photoaging on human skin fibroblast (Hs68) and mouse embryonic fibroblast (BALB/c 3T3) cells. We assessed the antiphotoaging effects of Ce6-curcumin derivatives on cell viability, antioxidant activity, the mechanism of matrix metalloproteinase-1 and 2 (MMP-2) expression, and collagen synthesis in UVB-irradiated in vitro models. All three Ce6-curcumin derivatives were found to be non-phototoxic in the neutral red uptake phototoxicity test. We found that Ce6-hexane-curcumin-PDT and Ce6-propane-curcumin-associated PDT exhibited less cytotoxicity in Hs68 and BALB/c 3T3 fibroblast cell lines compared to Ce6-diPEG-curcumin-PDT. Ce6-diPEG-curcumin and Ce6-propane-curcumin-associated PDT showed superior antioxidant activity in Hs68 cell lines. Further, in UVB-irradiated in vitro models, the Ce6-diPEG-curcumin-PDT greatly attenuated the expression levels of MMP-1 and MMP-2 by blocking mitogen-activated protein kinases (MAPKs), activator protein 1 (AP-1), and tumor necrosis factor-α (NF-κB) signaling. Moreover, Ce6-diPEG-curcumin effectively inhibited inflammatory molecules, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while accelerating collagen synthesis. These results demonstrate that Ce6-diPEG-curcumin may be a potential therapy for treating skin photoaging.

The frontline of alternatives to animal testing: novel in vitro skin model application in drug development and evaluation.

The FDA Modernization Act 2.0 has brought nonclinical drug evaluation into a new era. In vitro models are widely used and play an important role in modern drug development and evaluation, including early candidate drug screening and preclinical drug efficacy and toxicity assessment. Driven by regulatory steering and facilitated by well-defined physiology, novel in vitro skin models are emerging rapidly, becoming the most advanced area in alternative testing research. The revolutionary technologies bring us many in vitro skin models, either laboratory-developed or commercially available, which were all built to emulate the structure of the natural skin to recapitulate the skin's physiological function and particular skin pathology. During the model development, how to achieve balance among complexity, accessibility, capability, and cost-effectiveness remains the core challenge for researchers. This review attempts to introduce the existing in vitro skin models, align them on different dimensions, such as structural complexity, functional maturity, and screening throughput, and provide an update on their current application in various scenarios within the scope of chemical testing and drug development, including testing in genotoxicity, phototoxicity, skin sensitization, corrosion/irritation. Overall, the review will summarize a general strategy for in vitro skin model to enhance future model invention, application, and translation in drug development and evaluation.

Medical Applications and Advancement of Near Infrared Photosensitive Indocyanine Green Molecules.

Indocyanine green (ICG) is an important kind of near infrared (NIR) photosensitive molecules for PTT/PDT therapy as well as imaging. When exposed to NIR light, ICG can produce reactive oxygen species (ROS), which can kill cancer cells and pathogenic bacteria. Moreover, the absorbed light can also be converted into heat by ICG molecules to eliminate cancer cells. In addition, it performs exceptionally well in optical imaging-guided tumor therapy and antimicrobial therapy due to its deeper tissue penetration and low photobleaching properties in the near-infrared region compared to other dyes. In order to solve the problems of water and optical stability and multi-function problem of ICG molecules, composite nanomaterials based on ICG have been designed and widely used, especially in the fields of tumors and sterilization. So far, ICG molecules and their composite materials have become one of the most famous infrared sensitive materials. However, there have been no corresponding review articles focused on ICG molecules. In this review, the molecular structure and properties of ICG, composite material design, and near-infrared light- triggered anti-tumor, and antibacterial, and clinical applications are reviewed in detail, which of great significance for related research.

Phototoxic Potential of Different DNA Intercalators for Skin Cancer Therapy: In Vitro Screening.

Photodynamic therapy is a minimally invasive procedure used in the treatment of several diseases, including some types of cancer. It is based on photosensitizer molecules, which, in the presence of oxygen and light, lead to the formation of reactive oxygen species (ROS) and consequent cell death. The selection of the photosensitizer molecule is important for the therapy efficiency; therefore, many molecules such as dyes, natural products and metallic complexes have been investigated regarding their photosensitizing potential. In this work, the phototoxic potential of the DNA-intercalating molecules-the dyes methylene blue (MB), acridine orange (AO) and gentian violet (GV); the natural products curcumin (CUR), quercetin (QT) and epigallocatechin gallate (EGCG); and the chelating compounds neocuproine (NEO), 1,10-phenanthroline (PHE) and 2,2'-bipyridyl (BIPY)-were analyzed. The cytotoxicity of these chemicals was tested in vitro in non-cancer keratinocytes (HaCaT) and squamous cell carcinoma (MET1) cell lines. A phototoxicity assay and the detection of intracellular ROS were performed in MET1 cells. Results revealed that the IC50 values of the dyes and curcumin in MET1 cells were lower than 30 µM, while the values for the natural products QT and EGCG and the chelating agents BIPY and PHE were higher than 100 µM. The IC50 of MB and AO was greatly affected by irradiation when submitted to 640 nm and 457 nm light sources, respectively. ROS detection was more evident for cells treated with AO at low concentrations. In studies with the melanoma cell line WM983b, cells were more resistant to MB and AO and presented slightly higher IC50 values, in line with the results of the phototoxicity assays. This study reveals that many molecules can act as photosensitizers, but the effect depends on the cell line and the concentration of the chemical. Finally, significant photosensitizing activity of acridine orange at low concentrations and moderate light doses was demonstrated.

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.

Ficus carica L photodermatitis: a report of five cases with histopathologic study and review of the literature.

Phytophotodermatitis is a condition caused by contamination of the skin with phototoxic plant substances, followed by exposure to ultraviolet rays. Ficus carica L 1753, belonging to the Moraceae family, can be responsible for acute photodermatitis. We present five cases of photodermatitis caused by contact with Ficus carica L and subsequent exposure to sunlight. A histopathologic study and review of the literature are included.

Reactive oxygen species (ROS) assay-based photosafety screening for complex ingredients: Modification of the ROS assay protocol.

A reactive oxygen species (ROS) assay has been widely used for photosafety assessment; however, the phototoxic potential of complex materials, including plant extracts, essential oils, and functional polymers, is unevaluable because of their undefined molecular weights. The present study was undertaken to modify the ROS assay protocol for evaluating phototoxic potentials of those materials with use of their apparent molecular weight (aMw). On preparing sample solutions for the ROS assay, aMw ranging from 150 to 350 was tentatively employed for test substances. The modified ROS assays were applied to 45 phototoxic and 19 non-phototoxic substances, including 44 chemicals and 20 complex materials (plant extracts) for clarification of the predictive performance. Generation of ROS from photo-irradiated samples tended to increase as aMW grew, resulting in the largest number of false-positive predictions at aMW of 350. Some false-negative predictions were also observed when aMW was set at 200 or less. At aMw of 250, all tested phototoxic substances could be correctly identified as photoreactive with no false-negative predictions. Based on these observations, aMw of 250 was found to be suitable for the ROS assay on complex materials, and the sensitivity, specificity, and positive and negative predictivity for the proposed ROS assay were calculated to be 100, 52.6, 83.3, and 100%, respectively. Thus, the proposed approach may be efficacious for predicting phototoxic potentials of complex materials and contribute to the development of new products with a wide photosafety margin.

Optimizing Narrowband UVB Phototherapy: Is It More Challenging for Your Older Patients?

Narrowband UVB (NB-UVB) phototherapy remains versatile, safe, and efficacious for multiple dermatologic conditions even with recent pharmacologic treatment advances. Polypharmacy contributes to prescribers pursuing phototherapy as a nonpharmacologic treatment, but some wonder if it is as effective and safe for older patients. This study aimed to determine if NB-UVB is equally effective in both older and younger adults treated with the same protocol and to examine the association between photosensitizing medications, clearance, and erythema rates in older vs younger adults.

The RIFM approach to evaluating Natural Complex Substances (NCS).

The Research Institute for Fragrance Materials, Inc. (RIFM) has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS; 2) verify whether the Threshold of Toxicological Concern (TTC) can be applied; 3) verify whether the NCS risk assessment can be achieved on a component basis; and 4) determine whether data must be generated. Using in silico tools, RIFM examined NCS similarities based on the plant part, processing, and composition of materials across 81 plant families to address data gaps. Data generated from the Creme RIFM Aggregate Exposure Model for over 900 fragrance NCS demonstrate that dermal exposure is the primary route of human exposure for NCS fragrance uses. Over a third of materials are below the most conservative TTC limits. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

Diet-Related Phototoxic Reactions in Psoriatic Patients Undergoing Phototherapy: Results from a Multicenter Prospective Study.

Vegans and vegetarians often consume foods containing photosensitizers capable of triggering phytophotodermatitis. The potential effect of vegan and vegetarian diets on the response of psoriatic patients undergoing phototherapy is not well characterized. We assessed clinical outcomes of vegan, vegetarian and omnivore adult psoriatic patients undergoing band ultraviolet B phototherapy (NB-UVB). In this multicenter prospective observational study, we enrolled 119 adult, psoriatic patients, of whom 40 were omnivores, 41 were vegetarians and 38 were vegans, with phototherapy indication. After determining the minimum erythemal dose (MED), we performed NB-UVB sessions for 8 weeks. The first irradiation dosage was 70.00% of the MED, then increased by 20.00% (no erythema) or by 10.00% (presence of erythema) until a maximum single dose of 3 J/cm2 was reached and constantly maintained. All the enrolled patients completed the 8 weeks of therapy. Severe erythema was present in 16 (42.11%) vegans, 7 (17.07%) vegetarians and 4 (10.00%) omnivores (p < 0.01). MED was lowest among vegans (21.18 ± 4.85 J/m2), followed by vegetarians (28.90 ± 6.66 J/m2) and omnivores (33.63 ± 4.53 J/m2, p < 0.01). Patients with severe erythema were more likely to have a high furocumarin intake (OR 5.67, 95% CI 3.74-8.61, p < 0.01). Vegans consumed the highest amount of furocumarin-rich foods. A model examining erythema, adjusted for gender, age, skin type, MED, phototherapy type, number of phototherapies and furocumarin intake, confirmed that vegans had a lower number of treatments. Vegans had more frequent severe erythema from NB-UVB, even after adjustment of the phototherapy protocol for their lower MED. Assessing diet information and adapting the protocol for vegan patients may be prudent.

Tolerability profile of topical cannabidiol and palmitoylethanolamide: a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin.

BACKGROUND: An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM: To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS: Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS: There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION: These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Margarita Burn: Recognition and Treatment of Phytophotodermatitis.

Phytophotodermatitis is a cutaneous reaction caused by direct contact with phototoxic agents and subsequent sunlight exposure. Furocoumarins and psoralens are 2 phototoxic agents that can cause this reaction, and these organic chemical compounds are found in many plant species consumed by humans. Following contact exposure to such foods and ultraviolet radiation exposure via direct sunlight, phytophotodermatitis can occur. Due to the etiology of these rashes relating closely to the outdoor consumption of margaritas, the rash may be known by patients as "margarita burn." There is a classically described sequence of rash progression: erythematous macules or patches, which later become vesicles and seem similar to second-degree burns, followed by an asymptomatic hyperpigmentation. This case presents a 26-year-old female diagnosed with phytophotodermatitis following use of citrus fruits for margaritas while outdoors in direct sunlight. The diagnosis of phytophotodermatitis is often made clinically but can be complicated due to its similarity in appearance to many other common cutaneous reactions. In this patient, the differential diagnosis included solar erythema, contact dermatitis (type IV hypersensitivity reaction), polymorphic light eruption, or drug-related photosensitivity. Careful history taking is essential in not only narrowing down the differential diagnosis but also in avoiding unnecessary tests or ineffective treatments.

Solanum melongena L. Extract Protects Retinal Pigment Epithelial Cells from Blue Light-Induced Phototoxicity in In Vitro and In Vivo Models.

N-retinylidene-N-retinylethanolamine (A2E) accumulation in the retina is a prominent marker of retinal degenerative diseases. Blue light exposure is considered as an important factor contributing to dry age-related macular degeneration (AMD). Eggplant and its constituents have been shown to confer health benefits, but their therapeutic effects on dry AMD remain incompletely understood. In this study, we showed that an extract of Solanum melongena L. (EPX) protected A2E-laden ARPE-19 cells against blue light-induced cell death via attenuating reactive oxygen species. Transcriptomic analysis demonstrated that blue light modulated the expression of genes associated with stress response, inflammation, and cell death, and EPX suppressed the inflammatory pathway induced by blue light in A2E-laden ARPE-19 cells by inhibiting the nuclear translocation of nuclear factor kappa B and transcription of pro-inflammatory genes (CXCL8 and IL1B). The degradation of intracellular A2E was considered the major mechanism underlying the protective effect of EPX. Moreover, chlorogenic acid isolated from EPX exerted protective effects against blue light-induced cell damage in A2E-laden ARPE-19 cells. In vivo, EPX administration in BALB/c mice reduced the fundus damage and degeneration of the retinal layer in a blue light-induced retinal damage model. Collectively, our findings suggest the potential role of Solanum melongena L. extract for AMD treatment.

Adverse Events Leading to Discontinuation of Phototherapy: An Observational Study.

The aim of this prospective study in a phototherapy unit was to describe adverse events (AEs) associated with discontinuation of phototherapy in a clinical setting. A total of 872 included patients received 1,256 courses of phototherapy treatment: 76.9% narrow-band UVB (NBUVB); 9.6% systemic psoralen plus UVA (PUVA); 11.4% topical PUVA; and 2.1% UVA. Approximately a fifth of the treatments (n = 240, 19.1%) were associated with AEs, the most frequent of which was erythema (8.8%). Systemic PUVA had the highest rate of AEs (32.5%). Mycosis fungoides was the dermatosis with the highest rate of AE (36.9%). A total of 216 (17.2%) patients stopped treatment: 23.6% because of AEs (4.1% of all treatments). Treatment suspension due to AEs was associated with PUVA, both topical and systemic (p < 0.001), and diagnoses of mycosis fungoides (p <0.001), palmoplantar psoriasis (p = 0.002), hand eczema (p = 0.002) and pityriasis lichenoides (p = 0.01). In conclusion, one in every 5 patients receiving phototherapy had an AE, but few stopped treatment for this reason.

The feasibility of using Saffron to reduce the photosensitivity reaction of selected photosensitizers using red blood cells and staphylococcusAureus bacteria as targets.

BACKGROUND: The photosensitivity reaction which appears after a Photodynamic therapy treatment session is a challenge that needs further investigation. The goal of this research is to evaluate the possibility of using saffron to reduce or control this photosensitivity reaction and to present mathematical modeling of the cell survival curves and their dependency on saffron concentration. METHODS: Red blood cells (RBC) and Staphylococcus aureus Bacteria (STB) were used as targets in this study. The Photosensitivity of Rose Bengali, Methylene Blue, and Photofrin independently and incorporated with saffron was investigated for continued irradiation at different Saffron concentrations. Gompertz's function was used to fit the survival curve parameters. The 50% cell survival rate was fit to an empirical formula based on Saffron concentrations. RESULTS: Saffron inhibits the photosensitivity reaction of the three photosensitizers and causes a significant increase in the 50% survival rate time (t50) for RBC`s and STB. Saffron didn't show phototoxicity when incubated alone with RBC`s and STB. The survival curve parameters of the RBCs and STB showed a good fit to the Gompertz function. Saffron concentration is related to the RBC`s t50 based on power dependency of 0.56, 0.38 and 0.31 for Photofrin, Methylene Blue and Rose Bengali respectively and 0.1 on STB for Rose Bengali. CONCLUSION: Saffron can efficiently be used to reduce the photosensitivity reaction of Photosensitizers after a PDT treatment session. Gompertz function was found to be an appropriate mathematical model for survival rate curves. The t50 and the saffron concentration are well related through a power dependence empirical formula.

Synergistic effect of photodynamic therapy at 400 nm and doxycycline against Helicobacter pylori.

Aim: The objective of this study was to investigate the possible synergy between doxycycline and photodynamic therapy against Helicobacter pylori and to evaluate the possible side effects on adenocarcinoma gastric cells with and without protoporphyrin IX. Materials & methods: Three H. pylori strains (ATCC 700392, 43504 and 49503) were grown on solid medium either with, or without, doxycycline at subinhibitory concentrations, and irradiated for 10, 20 and 30 minutes with a 400 nm-peaked light source. The phototoxicity tests on AGS cells were evaluated by MTT assay. Results: The photodynamic therapy and doxycycline combination showed an antibacterial synergistic effect with no significant toxicities. Conclusion: The synergistic treatment could be considered as an interesting therapeutic option.

[Phototoxic reaction due to solar radiation exposure in a psoriatic patient treated with PUVA therapy]. / Reakcja fototoksyczna po ekspozycji na promieniowanie sloneczne u pacjentki leczonej metoda PUVA z powodu luszczycy.

A phototoxic reaction may be induced by additional exposure to solar radiation during photochemotherapy (psoralen, ultra-violet A - PUVA treatment). A woman was admitted to Dermatology and Venereology Clinic in Lódz as an emergency case due to extensive erythematous-vesicular lesions on the skin of the lower limbs, accompanied by pain, itching and burning of the skin. The interview found that the patient was undergoing PUVA phototherapy for psoriatic lesions, with hypertension and nicotine dependence. Physical examination revealed large blisters, filled with serum and congestive erythematous lesions located on the lateral surfaces of the thighs and backs of the feet, as well as marked swelling of the lower limbs. Also, discs coated with thin scales were found on the upper and lower limbs and on the trunk. The entire body was intensely tanned. The patient was diagnosed with acute phototoxic reaction and general corticosteroids, antihistamine drugs, an antibiotic, antihypertensive drugs and topical treatment were introduced. Immunological tests were performed during the first days of hospitalization following the emergence of new blisters. Negative results ruled out bullous pemphigoid and pemphigus. Gradual clinical improvement was observed. To avoid the occurrence of acute phototoxicity during phototherapy, patients require education about the need to avoid UV exposure and to use photoprotection, when receiving UV-sensitizing treatment. Med Pr. 2019;70(6):763-8.