Low-Toxicity Self-Photosensitized Biohybrid Systems for Enhanced Light-Driven H2 Production.

Nanoparticles (NPs) represent a potential optoelectronic source capable of significantly boosting hydrogen production; however, their inevitable cytotoxicity may lead to oxidative damage of bacterial cell membranes. In this study, we employed non-photosynthetic Escherichia coli K-12 as a model organism and utilized self-assembled cadmium sulfide (CdS) nanoparticles to construct a low-toxicity and hydrogen-production-enhancing self-photosensitive hybrid system. To mitigate the cytotoxicity of CdS NPs and synthesize biocompatible CdS NPs on the cell surface, we employed engineered E. coli (efeB/OE) for bioremediation, achieving this goal through the overexpression of the peroxidase enzyme (EfeB). A comparative analysis with E. coli-CdS revealed a significant downregulation of genes encoding oxidative stress proteins in efeB/OE-CdS post-irradiation. Atomic force microscopy (AFM) confirmed the stability of bacterial cell membranes. Due to the enhanced stability of the cell membrane, the hydrogen yield of the efeB/OE-CdS system increased by 1.3 times compared to the control, accompanied by a 49.1% reduction in malondialdehyde (MDA) content. This study proposes an effective strategy to alleviate the toxicity of mixed biological nanoparticle systems and efficiently harness optoelectronic electrons, thereby achieving higher hydrogen production in bioremediation.

Dermatitis versus nonaccidental trauma: A systematic review of initial pediatric misdiagnoses.

BACKGROUND/OBJECTIVES: Pediatric dermatitis and nonaccidental trauma (NAT) may have overlapping cutaneous presentations, posing a risk of misdiagnosis and subsequent emotional distress and further harm. Through a systematic literature review, we reviewed pediatric (<18 years old) patients investigated for both dermatitis and NAT. METHODS: EMBASE and MEDLINE databases were searched. English publications with original data involving pediatric patients investigated for both dermatitis and NAT were included. Nonhuman studies and incomplete articles/conference abstracts were excluded. Data extracted included the first author, year of publication, study design, participant count, sex of the population, age of the population, cutaneous presentation, timing of presentation, Child Protective Services involvement, and case relation to dermatitis and NAT. RESULTS: This review included 21 case reports or series encompassing 29 patients. Among 26 patients initially investigated as NAT (26.9% involving Child Protective Services), final diagnoses included irritant contact dermatitis (53.8%), phytophotodermatitis (30.8%), allergic contact dermatitis (7.7%), perianal infectious dermatitis (3.8%), and atopic dermatitis (3.8%). Three patients initially diagnosed with nontraumatic dermatitis were later found to be victims of physical (2/3; 66.7%) or sexual abuse (1/3; 33.3%). CONCLUSIONS: Effective history-taking and physical examinations should encompass a history of laxative use, contact with furocoumarin-containing plants/fruit, parallel family/peer cutaneous presentations, caregiver involvement, financial burden, patient discomfort, birthmark assessment, and lesions aligning with diaper borders or toilet seats. Limitations of this review include potential underreporting and the inclusion of low-quality study designs and evidence.

Potential therapeutic efficacy of photodynamic therapy on female hormonal-dependent cancers in a hormonal simulated microenvironment.

BACKGROUND: Photodynamic Therapy (PDT) is a clinically approved cancer treatment. Sex hormones, the key drivers for the development of female hormonal dependent cancers, might affect cancer treatment. There are seldom studies to evaluate the effect of sex hormones mimicked the menstrual cycle on the PDT mediated by prodrug 5-aminolevulinic acid (ALA) and its ester derivatives to the hormonal dependent cancers. AIMS: To evaluate the efficacy of sex hormones on Hexyl-ALA-PDT in hormonal dependent cancers and the effect of the sex hormones on heme biosynthetic pathway. METHODS: Cell culture system that mimicked the fluctuation of sex hormones 17ß-estradiol (E2) and progesterone (PG) in the menstrual cycle was developed. Two pairs of hormonal-independent and hormonal dependent uterine sarcoma and breast cancer cell lines were used as cell models. Hexyl-ALA induced PpIX production and intracellular localization were examined. Key enzymes for PpIX synthesis were analysed. Hexyl-ALA-PDT mediated phototoxicity was evaluated. RESULTS: The PpIX generation was increased in the hormonal-dependent cells (28-50 %) when cultured in the hormonal microenvironment with long incubation of Hexyl-ALA for 15 and 24 h compared to that cultured without hormones; whereas only slight difference in PpIX generation in their hormonal-independent counterpart. The PpIX generation was in a time-dependent manner. The CPOX, PPOX and FECH expressions were significantly enhanced by Hexyl-ALA-PDT in uterine sarcoma cells in hormonal microenvironment. Hexyl-ALA-PDT triggered significant increase of PPOX expression in breast cancer cells in hormonal microenvironment. The Hexyl-ALA-PDT phototoxicity was enhanced by 18-40 % in cells cultured in the hormonal system in a dose-dependent manner. CONCLUSION: The PpIX generation and the efficacy of Hexyl-ALA-PDT in both uterine sarcoma and breast cancer cells was significantly enhanced by the sex hormones via cultured in the hormonal microenvironment.

Photosensitizing antihypertensive medication and risk of skin cancer among postmenopausal women.

BACKGROUND: Few prospective studies exist with an evaluation of a dose-response relationship between use of some photosensitizing antihypertensive medications and skin cancer. PATIENT AND METHODS: We used prospective data from the Women's Health Initiative Observational Study to investigate the association between antihypertensive use and risk of non-melanoma skin cancer (NMSC) and melanoma in postmenopausal women aged 50-79 years at baseline (n  =  64,918). Multivariable Cox proportional hazards regression models were used and hazard ratios (HRs) and 95 confidence intervals (CIs) were calculated. RESULTS: 8,777 NMSC and 1,227 melanoma cases were observed. Use of antihypertensives (HR [95% CI]: 1.12 [1.07-1.18]), ACE inhibitors (1.09 [1.01-1.18]), calcium channel blockers (1.13 [1.05-1.22]), diuretics (1.20 [1.12-1.27]), loop diuretics (1.17 [1.07-1.28]), and thiazides (1.17 [1.03-1.33]) were each associated with higher NMSC risk. NMSC risk linearly increased with use of multiple antihypertensives (p-trend  =  0.02) and with longer duration of use (p-trend < 0.01). Antihypertensives (1.15 [1.00-1.31]), angiotensin-II receptor blockers (1.82 [1.05-3.15]), and diuretics (1.34 [1.13-1.59]) were each associated with elevated melanoma risk. Effect modification by solar radiation exposure was found between antihypertensive use and incidence of melanoma (p-interaction  =  0.02). CONCLUSIONS: Use of antihypertensives overall, and several individual classes thereof, were associated with higher incidence of NMSC and melanoma with dose-response relationship.

Fitofotodermatosis: el peligro del sol y las plantas para la piel / Phytofotodermatosis: the danger of the sun and plants for the skin

Presentamos el caso de un paciente que padeció una reacción cutánea intensa tras el contacto con los frutos y las hojas de una higuera y posterior exposición solar. Se trata de una reacción no inmunológica llamada fitofotodermatosis. Es una erupción inflamatoria de la piel que se produce tras el contacto con sustancias fototóxicas (furocumarinas o psoralenos) y que puede llegar a ser de gran intensidad. Por ello requiere una anamnesis exhaustiva y su conocimiento por parte del equipo médico de Atención Primaria y pediatría, ya que su diagnóstico diferencial puede ser muy complejo.(AU)

We report the case of a patient who developed an intense skin reaction after contact with the fruits and leaves of a fig tree and subsequent sun exposure. This is a non-immunological reaction called phytophotodermatosis. It is an inflammatory skin rash that occurs after contact with phototoxic substances (furocoumarins or psoralens) and could be very intense. That is why it requires an in-depth history; its knowledge by primary care physicians and paediatricians, is important because the differential diagnosis could be very complex.(AU)

Phototoxic Reactions Inducted by Hydrochlorothiazide and Furosemide in Normal Skin Cells-In Vitro Studies on Melanocytes and Fibroblasts.

Hypertension is known to be a multifactorial disease associated with abnormalities in neuroendocrine, metabolic, and hemodynamic systems. Poorly controlled hypertension causes more than one in eight premature deaths worldwide. Hydrochlorothiazide (HCT) and furosemide (FUR), being first-line drugs in the treatment of hypertension, are among others the most frequently prescribed drugs in the world. Currently, many pharmacoepidemiological data associate the use of these diuretics with an increased risk of adverse phototoxic reactions that may induce the development of melanoma and non-melanoma skin cancers. In this study, the cytotoxic and phototoxic potential of HCT and FUR against skin cells varied by melanin pigment content was assessed for the first time. The results showed that both drugs reduced the number of metabolically active normal skin cells in a dose-dependent manner. UVA irradiation significantly increased the cytotoxicity of HCT towards fibroblasts by approximately 40% and melanocytes by almost 20% compared to unirradiated cells. In the case of skin cells exposed to FUR and UVA radiation, an increase in cytotoxicity by approximately 30% for fibroblasts and 10% for melanocytes was observed. Simultaneous exposure of melanocytes and fibroblasts to HCT or FUR and UVAR caused a decrease in cell viability, and number, which was confirmed by microscopic assessment of morphology. The phototoxic effect of HCT and FUR was associated with the disturbance of redox homeostasis confirming the oxidative stress as a mechanism of phototoxic reaction. UVA-irradiated drugs increased the generation of ROS by 10-150%, and oxidized intracellular thiols. A reduction in mitochondrial potential of almost 80% in melanocytes exposed to HCT and UVAR and 60% in fibroblasts was found due to oxidative stress occurrence. In addition, HCT and FUR have been shown to disrupt the cell cycle of normal skin cells. Finally, it can be concluded that HCT is the drug with a stronger phototoxic effect, and fibroblasts turn out to be more sensitive cells to the phototoxic effect of tested drugs.

Surfactants for stabilization of dermal emulsions and their skin compatibility under UVA irradiation: Diacyl phospholipids and polysorbate 80 result in high viability rates of primary human skin cells.

Phospholipids are versatile formulation compounds with high biocompatibility. However, no data on their effect on skin in combination with UVA radiation exist. Thus, it was the aim of this work to (i) develop o/w nanoemulsions (NEs) differing in surfactant type and to investigate their physicochemical stability at different storage temperatures, (ii) establish a standardized protocol for in vitro phototoxicity testing using primary human skin cells and (iii) investigate the phototoxicity of amphoteric phospholipids (S45, S75, E80, S100, LPC80), sodium lauryl ether sulfate (SLES) and polysorbate 80 (PS80). Satisfying systems were developed with all surfactants except S100 due to low zeta potential (-21.4 mV ± 4.69). SLES and PS80-type NEs showed the highest stability after eight weeks; temperature-dependent variations in storage stability were most noticeable for phospholipid surfactants. For phospholipid-based NEs, higher phosphatidylcholine content led to unstable formulations. Phototoxicity assays with primary skin fibroblasts confirmed the lack of UVA-related phototoxicity but revealed cytotoxic effects of LPC80 and SLES, resulting in cell viability as low as 2.7 % ±0.78 and 1.9 % ±1.57 compared to the control. Our findings suggest that surfactants S45, S75 and PS80 are the most promising candidates for skin-friendly emulsifiers in sensitive applications involving exposure to UV light.

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.

Phototoxic action of meloxicam contributes to dysregulation of redox homeostasis in normal human skin cells - Molecular and biochemical analysis of antioxidant enzymes in melanocytes and fibroblasts.

The phototoxic effect of meloxicam (MLX) raises the question of the effect of the drug on the redox homeostasis of normal human skin cells. The main objective of the study was to analyze the effect of MLX and/or UVA radiation (UVAR) on the redox homeostasis of human normal skin cells - melanocytes and fibroblasts. MLX was found to affect the activity and expression of enzymes of the antioxidant system differently depending on the cell line used. The drug decreased the activity and expression of superoxide dismutase type 1 and 2 (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPx) in fibroblasts, while increasing the activity of these enzymes in melanocytes. UVA radiation enhanced the effects of the drug. In conclusion, MLX in combination with UVAR induces oxidative stress in melanocytes and fibroblasts, however, the analyses showed that the drug's effect the activity and expression of SOD, CAT and GPx differently, depending on the cell line. The observed dissimilarity between tested cell lines may result from the presence of melanin pigments.

Novel 2-(5-Arylthiophen-2-yl)-benzoazole Cyclometalated Iridium(III) dppz Complexes Exhibit Selective Phototoxicity in Cancer Cells by Lysosomal Damage and Oncosis.

A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.

Hypericin-Based Photodynamic Therapy Displays Higher Selectivity and Phototoxicity towards Melanoma and Squamous Cell Cancer Compared to Normal Keratinocytes In Vitro.

The aim of this study was to explore the potential of hypericin, a naturally occurring photosensi-tizer, for photodynamic therapy (PDT) in skin cancer, investigating its phototoxic effects and mechanisms of action in cancer cells compared to normal skin keratinocytes, squamous cell cancer (SCC-25) cells and melanoma (MUG-Mel2) cells. Hypericin was applied at concentrations ranging from 0.1-40 µM to HaCaT, SCC-25, and MUG-Mel2 cells. After 24 h of incubation, the cells were exposed to orange light at 3.6 J/cm2 or 7.2 J/cm2. Phototoxicity was assessed using MTT and SRB tests. Cellular uptake was measured by flow cytometry. Apoptosis-positive cells were estimated through TUNEL for apoptotic bodies' visualization. Hypericin exhibited a higher phototoxic reaction in cancer cells compared to normal keratinocytes after irradiation. Cancer cells demonstrated increased and selective uptake of hypericin. Apoptosis was observed in SCC-25 and MUG-Mel2 cells following PDT. Our findings suggest that hypericin-based PDT is a promising and less invasive approach for treating skin cancer. The higher phototoxic reaction, selective uptake by cancer cells, and observed proapoptotic properties support the promising role of hypericin-based PDT in skin cancer treatment.

Aggregation-induced emission (AIE)-active metallacycles with near-infrared emission for photodynamic therapy.

Multifunctional metallacycles with solid-state emission are highly important in cancer therapy. Here, an aggregation-induced emission (AIE)-active metallacycle of DTPABT-MC-R is developed with efficient emission in the NIR region in the solid state (PLQYs = 4.92%). DTPABT-MC-R-based nanoparticles also display excellent photo-stability, and impressive photosensitive characteristics (ROS efficiency = 10.74%), finally leading to applications in cellular imaging and photodynamic therapy (PDT).

Development and content validation of a sunlight exposure diary in patients with erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on health-related quality of life, though there is variable disease severity. Accurately capturing how much time individuals with EPP can spend outdoors before they develop symptoms is critical to understanding HRQoL and measuring therapeutic response. Therefore, the goal of this study was to develop a comprehensive and content valid sun exposure diary to assess the efficacy of new therapies in individuals with EPP. METHODS: Qualitative interviews were conducted with adult and adolescent EPP participants, as well as five clinical experts, to obtain their input on the content of an existing sun exposure diary. Revisions to the diary were made based on evidence generated in cognitive debriefing interviews analyzed in eight consecutive groups of EPP participant. RESULTS: Interviews were conducted with 17 adults and 6 adolescents with EPP. The average age of adults was 40 years and of adolescents was 14 years. Clinical experts thought the original diary needed clarification on the description of symptoms, how time outdoors was captured, and the distinction between direct vs. indirect sunlight. Participants with EPP also noted these items needed revision, and that the distinction between prodromal symptoms and full reaction symptoms should be clarified. In the final diary version, participants with EPP found most items to be clear and easy to complete/think about. Seventy-six percent of participants (13/17) asked thought the diary was easy to complete. The remainder thought the majority of the diary was easy to complete with the exception of select questions. CONCLUSIONS: Evaluating a new treatment for EPP requires accurately capturing time in sunlight and symptoms in this unique disorder. The newly developed sun exposure diary is content valid and can be used to assess important aspects of symptoms and daily life and therefore evaluate clinically meaningful therapeutic response.

Hybrid protein-peptide system for the selective pH-dependent binding and photodynamic ablation of cancer cells.

Creating new tools for the early diagnosis and treatment of cancer is one of the most important and intensively developing areas of modern medicine. Currently, photodynamic cancer therapy (PDT) is attracting increasing attention as a unique modality of minimally invasive treatment and due to the absence of acquired resistance. However, PDT is associated with undesirable activities, such as non-specific photodynamic effects of sunlight on healthy tissues. Therefore, an important fundamental task is the development of improved PDT agents that selectively act on the affected areas. Here, we report the development of a hybrid protein-peptide system for the selective pH-dependent binding and subsequent photodynamic cancer cells ablation. It is known that a distinctive feature of cancer cells is a decreased pH level in the extracellular space. In this study we exploited a peptide fragment (pHLIP) as a targeting module, which spontaneously binds and embeds into the cell membrane when pH decreases below neutral. A mutant of miniSOG protein fused to pHLIP was used as a photosensitizing constituent. We demonstrate that this protein-peptide photosensitizing system selectively binds to HeLa cells at pH below 6.8 and kills them when exposed to light. These findings demonstrate the feasibility of using genetically encoded MiniSOG fusions with pHLIP for the targeted delivery of PSs to cancer cells and subsequent highly precise photodynamic therapy.