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Genes Nov 2022Fluoroquinolones are a widely used class of chemotherapeutics within veterinary medicine, prized for their broad-spectrum bactericidal activity. These drugs present a...
Fluoroquinolones are a widely used class of chemotherapeutics within veterinary medicine, prized for their broad-spectrum bactericidal activity. These drugs present a known risk of retinal phototoxicity in domestic cats (); therefore, using lower doses and alternative antibiotic classes is encouraged in this species. This adverse drug effect of fluoroquinolones, and enrofloxacin specifically, has been determined to be species-specific in domestic felids. Four feline-specific missense variants in result in four amino acid changes (E159M, S279L, H283Q, and T644I) that are unique to the domestic cat compared with multiple other nonfeline mammalian species. These changes alter the ABCG2 protein involved with the cellular transmembrane transport of drugs, including fluoroquinolones, making the protein functionally defective in domestic cats. The predisposition to fluoroquinolone-mediated phototoxicity in nondomestic felids was explored in this study. At least eight nondomestic felids share the four missense variants with domestic cats, and eleven other felids shared at least three of the four domestic cat variants. Taken together, these results suggest the genetic potential for nondomestic felids to also experience fluoroquinolone-induced retinal phototoxicity; therefore, cautions similar to those for domestic cats should be followed for these drugs in the entire feline taxon.
Topics: Animals; Cats; Fluoroquinolones; Felidae; Anti-Bacterial Agents; Retina
PubMed: 36553444
DOI: 10.3390/genes13122178 -
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 -
RIFM fragrance ingredient safety assessment, 2-cyclohexylcyclohexanone, CAS Registry Number 90-42-6.Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. 2-Cyclohexylcyclohexanone was evaluated for genotoxicity, repeated... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. 2-Cyclohexylcyclohexanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data and read-across to 2-tert-butylcyclohexanone (CAS # 1728-46-7) show that 2-cyclohexylcyclohexanone is not expected to be genotoxic. Data on read-across material 2-sec-butylcyclohexanone (CAS # 14765-30-1) provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 2-cyclohexylcyclohexanone is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class II material, and the exposure to 2-cyclohexylcyclohexanone is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; 2-cyclohexylcyclohexanone was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33220392
DOI: 10.1016/j.fct.2020.111871 -
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 -
ACS Nano Jun 2023Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. , a core pathogen of colorectal cancer (CRC), is an important cause of low...
Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. , a core pathogen of colorectal cancer (CRC), is an important cause of low therapeutic efficacy and metastasis. Thus, the modulation of intratumoral pathogens may provide a target for cancer therapy and metastasis inhibition. Herein, we propose an intratumoral -modulating strategy for enhancing the therapeutic efficacy of CRC and inhibiting lung metastasis by designing an antibacterial nanoplatform (Au@BSA-CuPpIX), which produced reactive oxygen species (ROS) under ultrasound and exhibited strong antibacterial activity. Importantly, Au@BSA-CuPpIX reduced the levels of apoptosis-inhibiting proteins by inhibiting intratumoral , thereby enhancing ROS-induced apoptosis. results demonstrated that Au@BSA-CuPpIX effectively eliminated to enhance the therapeutic efficacy of sonodynamic therapy (SDT) for orthotopic CRC and inhibit lung metastasis. Notably, entrapped gold nanoparticles reduced the phototoxicity of metalloporphyrin accumulated in the skin during tumor treatment, preventing severe inflammation and damage to the skin. Therefore, this study proposes a strategy for the elimination of in CRC to enhance the therapeutic effect of SDT, thus providing a promising paradigm for improving cancer treatment with fewer toxic side effects and promoting the clinical translational potential of SDT.
Topics: Humans; Fusobacterium nucleatum; Colorectal Neoplasms; Gold; Reactive Oxygen Species; Metal Nanoparticles
PubMed: 37201179
DOI: 10.1021/acsnano.3c01308 -
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 -
Food and Chemical Toxicology : An... Jul 2021The existing information supports the use of this material as described in this safety assessment. Hexadeca-1,5-lactone was evaluated for genotoxicity, repeated dose... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. Hexadeca-1,5-lactone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from the target material and read-across analog hydroxynonanoic acid, δ-lactone (CAS # 3301-94-8) show that hexadeca-1,5-lactone is not expected to be genotoxic. Data from analog δ-decalactone (CAS # 705-86-2) provide a calculated Margin of Exposure (MOE) > 100 for the repeated dose and reproductive toxicity endpoints. Data from analog δ-octalactone (CAS # 698-76-0) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; hexadeca-1,5-lactone is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). For the hazard assessment based on the screening data, hexadeca-1,5-lactone is not Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. Hexadeca-1,5-lactone could not be risk screened as there were no reported volumes of use for either North America or Europe in the 2015 IFRA Survey.
Topics: Animals; Bacteria; Consumer Product Safety; Endpoint Determination; Humans; Lactones; Odorants; Perfume; Risk Assessment; Stereoisomerism
PubMed: 33839218
DOI: 10.1016/j.fct.2021.112181 -
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 -
Plants (Basel, Switzerland) Nov 2022The present study was aimed to evaluate the oxidative stability as well as to assess the protective effect of the mixture of L. (HAO) and L. (OBO) oils on 3D tissue...
The present study was aimed to evaluate the oxidative stability as well as to assess the protective effect of the mixture of L. (HAO) and L. (OBO) oils on 3D tissue models of skin irritation and phototoxicity. The following methods were used: GS analysis (fatty acids composition), thiobarbituric acid-reactive substances assay (TBA) (lipid oxidation degree of tested samples), 3D EpiDerm models (skin irritation and phototoxicity). For HAO the detected saturated fatty acids (SFA) were palmitic acid (7.179%), stearic acid (3.586%), eicosanoic (0.138%) and docosanoic acid (0.548%) The monounsaturated acids (MUFA) were palmitoleic acid (0.158%) and oleic acid (28.249%) and the polyunsaturated acids (PUFA) were linoleic acid (59.941%) and linolenic acid (0.208%). For OBO the detected SFA were myristic acid (0.325%), pentadecylic acid (0.281%), palmitic (7.2%), stearic (2.88%), and arachidic acid (0.275%). Regarding MUFA, even a lower proportion (8.196%) was observed, predominantly being oleic acid, cis form (7.175%), oleic (n10) (0.558%) and 11-eicosenoic (0.210%) acids. The higher content was found for PUFA (82.247%), the most significant proportions being linoleic acid (72.093%), arachidonic acid (9.812%) and linolenic (0.233%). Obtained data indicate a good oxidative stability and biocompatibility of the mixture on the 3D EpiDerm models with no irritant and no phototoxic effects. L. oil may be an excellent natural choice in order to delay or prevent oxidative damage of L. oil.
PubMed: 36365432
DOI: 10.3390/plants11212977