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Toxicology and Applied Pharmacology Aug 2012Nano-sized titanium dioxide (TiO(2)) is among the top five widely used nanomaterials for various applications. In this study, we determine the phototoxicity of TiO(2)...
Nano-sized titanium dioxide (TiO(2)) is among the top five widely used nanomaterials for various applications. In this study, we determine the phototoxicity of TiO(2) nanoparticles (nano-TiO(2)) with different molecular sizes and crystal forms (anatase and rutile) in human skin keratinocytes under UVA irradiation. Our results show that all nano-TiO(2) particles caused phototoxicity, as determined by the MTS assay and by cell membrane damage measured by the lactate dehydrogenase (LDH) assay, both of which were UVA dose- and nano-TiO(2) dose-dependent. The smaller the particle size of the nano-TiO(2) the higher the cell damage. The rutile form of nano-TiO(2) showed less phototoxicity than anatase nano-TiO(2). The level of photocytotoxicity and cell membrane damage is mainly dependent on the level of reactive oxygen species (ROS) production. Using polyunsaturated lipids in plasma membranes and human serum albumin as model targets, and employing electron spin resonance (ESR) oximetry and immuno-spin trapping as unique probing methods, we demonstrated that UVA irradiation of nano-TiO(2) can induce significant cell damage, mediated by lipid and protein peroxidation. These overall results suggest that nano-TiO(2) is phototoxic to human skin keratinocytes, and that this phototoxicity is mediated by ROS generated during UVA irradiation.
Topics: Blood Gas Monitoring, Transcutaneous; Blotting, Western; Cell Line; Dermatitis, Phototoxic; Electron Spin Resonance Spectroscopy; Enzyme-Linked Immunosorbent Assay; Humans; Keratinocytes; Lipid Peroxidation; Metal Nanoparticles; Reactive Oxygen Species; Titanium; Ultraviolet Rays
PubMed: 22705594
DOI: 10.1016/j.taap.2012.06.001 -
Cellular and Molecular Gastroenterology... 2019Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria... (Review)
Review
Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
Topics: Animals; Carcinoma, Hepatocellular; Dermatitis, Phototoxic; Heme; Humans; Liver; Liver Neoplasms; Mice; Oxidation-Reduction; Oxidative Stress; Photosensitivity Disorders; Porphyrias; Porphyrins; Protein Aggregates; Protoporphyrins; Uroporphyrins; Zebrafish
PubMed: 31233899
DOI: 10.1016/j.jcmgh.2019.06.006 -
Frontiers in Pharmacology 2023Gefitinib (GFT) is a selective epidermal growth factor receptor (EGFR) inhibitor clinically used for the treatment of patients with non-small cell lung cancer....
Gefitinib (GFT) is a selective epidermal growth factor receptor (EGFR) inhibitor clinically used for the treatment of patients with non-small cell lung cancer. Bioactivation by mainly Phase I hepatic metabolism leads to chemically reactive metabolites such as O-Demethyl gefitinib (DMT-GFT), 4-Defluoro-4-hydroxy gefitinib (DF-GFT), and O-Demorpholinopropyl gefitinib (DMOR-GFT), which display an enhanced UV-light absorption. In this context, the aim of the present study is to investigate the capability of gefitinib metabolites to induce photosensitivity disorders and to elucidate the involved mechanisms. According to the neutral red uptake (NRU) phototoxicity test, only DF-GFT metabolite can be considered non-phototoxic to cells with a photoirritation factor (PIF) close to 1. Moreover, DMOR-GFT is markedly more phototoxic than the parent drug (PIF = 48), whereas DMT-GFT is much less phototoxic (PIF = 7). Using the thiobarbituric acid reactive substances (TBARS) method as an indicator of lipid photoperoxidation, only DMOR-GFT has demonstrated the ability to photosensitize this process, resulting in a significant amount of TBARS (similar to ketoprofen, which was used as the positive control). Protein photooxidation monitored by 2,4-dinitrophenylhydrazine (DNPH) derivatization method is mainly mediated by GFT and, to a lesser extent, by DMOR-GFT; in contrast, protein oxidation associated with DMT-GFT is nearly negligible. Interestingly, the damage to cellular DNA as revealed by the comet assay, indicates that DMT-GFT has the highest photogenotoxic potential; moreover, the DNA damage induced by this metabolite is hardly repaired by the cells after a time recovery of 18 h. This could ultimately result in mutagenic and carcinogenic effects. These results could aid oncologists when prescribing TKIs to cancer patients and, thus, establish the conditions of use and recommend photoprotection guidelines.
PubMed: 37351506
DOI: 10.3389/fphar.2023.1208075 -
International Journal of Molecular... Aug 2023Skin photoaging due to ultraviolet B (UVB) exposure generates reactive oxygen species (ROS) that increase matrix metalloproteinase (MMP). Chlorin e6-photodynamic therapy...
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.
Topics: Animals; Mice; Humans; Curcumin; Hexanes; Matrix Metalloproteinase 2; Antioxidants; Propane; Reactive Oxygen Species; Fibroblasts; Dermatitis, Phototoxic; Glycols; Photochemotherapy; Collagen
PubMed: 37686273
DOI: 10.3390/ijms241713468 -
International Journal of Molecular... Nov 2020Genetically encoded photosensitizers are increasingly used as optogenetic tools to control cell fate or trigger intracellular processes. A monomeric red fluorescent...
Genetically encoded photosensitizers are increasingly used as optogenetic tools to control cell fate or trigger intracellular processes. A monomeric red fluorescent protein called SuperNova has been recently developed, however, it demonstrates suboptimal characteristics in most phototoxicity-based applications. Here, we applied directed evolution to this protein and identified SuperNova2, a protein with S10R substitution that results in enhanced brightness, chromophore maturation and phototoxicity in bacterial and mammalian cell cultures.
Topics: Escherichia coli; HEK293 Cells; HeLa Cells; Humans; Luminescent Proteins; Mutation; Optogenetics; Photosensitizing Agents; Recombinant Proteins; Red Fluorescent Protein
PubMed: 33233801
DOI: 10.3390/ijms21228800 -
JAAD Case Reports Mar 2022
PubMed: 35146099
DOI: 10.1016/j.jdcr.2021.12.019 -
Yakugaku Zasshi : Journal of the... 2021Considerable attention has been drawn to predict a photosafety hazard on new chemicals. A number of phototoxins tend to generate reactive oxygen species (ROS) via energy... (Review)
Review
Considerable attention has been drawn to predict a photosafety hazard on new chemicals. A number of phototoxins tend to generate reactive oxygen species (ROS) via energy transfer mechanisms following UV/VIS excitation, including superoxide and singlet oxygen. Then, ROS assay has been designed to assess photoreactivity of pharmaceuticals, of which the principle is to monitor types I and II photochemical reactions of the test chemicals when exposed to simulated sunlight. This simple analytical test could be used to screen potential chemical scaffolds, leads, and candidate drugs to identify and/or select away from those having phototoxic potential. The validation study for the ROS assay has been being carried out by the Japan Pharmaceutical Manufacturers Association (JPMA), supervised by the Japanese Center for the Validation of Alternative Methods (JaCVAM). Although several false positives appeared, the ROS assay on 42 coded chemicals has provided no false negative predictions. The validation study tentatively indicates satisfactory outcomes in terms of transferability, intra- and inter-laboratory variability, and predictive capacity. Thus, a negative result in this ROS assay would indicate a very low probability of phototoxicity, whereas a positive result would be a flag for follow-up assessment. Upon international harmonization activities supported by several agencies and industrial groups, ROS assay was successfully adopted as International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) S10 guideline (2014) and Organisation for Economic Co-operation and Development (OECD) test guideline 495 (2019).
Topics: Dermatitis, Phototoxic; Drug-Related Side Effects and Adverse Reactions; Guidelines as Topic; Humans; International Cooperation; Oxidants, Photochemical; Pharmaceutical Preparations; Reactive Oxygen Species; Safety; Toxicity Tests
PubMed: 34078785
DOI: 10.1248/yakushi.20-00217-4 -
Environmental Toxicology and Chemistry May 2015Titanium dioxide nanoparticles are photoactive and produce reactive oxygen species under natural sunlight. Reactive oxygen species can be detrimental to many organisms,... (Review)
Review
Titanium dioxide nanoparticles are photoactive and produce reactive oxygen species under natural sunlight. Reactive oxygen species can be detrimental to many organisms, causing oxidative damage, cell injury, and death. Most studies investigating TiO2 nanoparticle toxicity did not consider photoactivation and performed tests either in dark conditions or under artificial lighting that did not simulate natural irradiation. The present study summarizes the literature and derives a phototoxicity ratio between the results of nano-titanium dioxide (nano-TiO2 ) experiments conducted in the absence of sunlight and those conducted under solar or simulated solar radiation (SSR) for aquatic species. Therefore, the phototoxicity ratio can be used to correct endpoints of the toxicity tests with nano-TiO2 that were performed in absence of sunlight. Such corrections also may be important for regulators and risk assessors when reviewing previously published data. A significant difference was observed between the phototoxicity ratios of 2 distinct groups: aquatic species belonging to order Cladocera, and all other aquatic species. Order Cladocera appeared very sensitive and prone to nano-TiO2 phototoxicity. On average nano-TiO2 was 20 times more toxic to non-Cladocera and 1867 times more toxic to Cladocera (median values 3.3 and 24.7, respectively) after illumination. Both median value and 75% quartile of the phototoxicity ratio are chosen as the most practical values for the correction of endpoints of nano-TiO2 toxicity tests that were performed in dark conditions, or in the absence of sunlight.
Topics: Animals; Aquatic Organisms; Cladocera; Light; Metal Nanoparticles; Reactive Oxygen Species; Titanium; Toxicity Tests
PubMed: 25640001
DOI: 10.1002/etc.2891 -
Anais Brasileiros de Dermatologia 2022The therapeutic approach to metastatic melanoma has revolutionized the clinical course of this disease. Since 2011, different immunotherapeutic drugs have been approved....
The therapeutic approach to metastatic melanoma has revolutionized the clinical course of this disease. Since 2011, different immunotherapeutic drugs have been approved. Nivolumab is a humanized immunoglobulin IgG4 monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with his ligand PD-L1. The authors present a new case of photosensitivity induced by nivolumab. The photo exposed distribution of the eruption, the sun exposure prior to the beginning of the eruption, and the chronological relationship with the beginning of the treatment are data that have allowed us to confirm the suspected clinical diagnosis.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dermatitis, Phototoxic; Exanthema; Humans; Melanoma; Nivolumab; Programmed Cell Death 1 Receptor
PubMed: 35811193
DOI: 10.1016/j.abd.2021.07.007 -
Journal of the American Chemical Society Jul 2023To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Phphen)(OH)], was conjugated to the...
To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Phphen)(OH)], was conjugated to the RGD-containing Ac-MRGDH-NH peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[]Cl and Δ-[]Cl. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made []Cl amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin ( = 0.061 μM for the binding of Λ-[]Cl to αβ), which resulted in the receptor-mediated uptake of the conjugate . Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of []Cl were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, studies in a subcutaneous U87MG glioblastoma mice model showed that []Cl efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex []Cl. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer .
Topics: Animals; Humans; Mice; Ruthenium; Prodrugs; Integrins; Peptides, Cyclic; Peptides; Brain Neoplasms; Cell Line, Tumor; Coordination Complexes; Antineoplastic Agents
PubMed: 37379365
DOI: 10.1021/jacs.3c04855