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Journal of Medicinal Chemistry Jan 2024A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)(dppz)], -, were rationally designed...
A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)(dppz)], -, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was -CFCH or -MeNCH. 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 ( and ) were the best performers, 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 O and/or OH in cell-free media.
Topics: Humans; Coordination Complexes; Iridium; Photosensitizing Agents; Dermatitis, Phototoxic; Lysosomes; Benzothiazoles; Antineoplastic Agents; Cell Line, Tumor; Neoplasms
PubMed: 38141031
DOI: 10.1021/acs.jmedchem.3c01978 -
International Journal of Molecular... Dec 2023High energy visible (HEV) blue light is an increasing source of concern for visual health. Polycyclic aromatic hydrocarbons (PAH), a group of compounds found in high...
Indenopyrene and Blue-Light Co-Exposure Impairs the Tightly Controlled Activation of Xenobiotic Metabolism in Retinal Pigment Epithelial Cells: A Mechanism for Synergistic Toxicity.
High energy visible (HEV) blue light is an increasing source of concern for visual health. Polycyclic aromatic hydrocarbons (PAH), a group of compounds found in high concentrations in smokers and polluted environments, accumulate in the retinal pigment epithelium (RPE). HEV absorption by indeno [1,2,3-cd]pyrene (IcdP), a common PAH, synergizes their toxicities and promotes degenerative changes in RPE cells comparable to the ones observed in age-related macular degeneration. In this study, we decipher the processes underlying IcdP and HEV synergic toxicity in human RPE cells. We found that IcdP-HEV toxicity is caused by the loss of the tight coupling between the two metabolic phases ensuring IcdP efficient detoxification. Indeed, IcdP/HEV co-exposure induces an overactivation of key actors in phase I metabolism. IcdP/HEV interaction is also associated with a downregulation of proteins involved in phase II. Our data thus indicate that phase II is hindered in response to co-exposure and that it is insufficient to sustain the enhanced phase I induction. This is reflected by an accelerated production of endogenous reactive oxygen species (ROS) and an increased accumulation of IcdP-related bulky DNA damage. Our work raises the prospect that lifestyle and environmental pollution may be significant modulators of HEV toxicity in the retina.
Topics: Humans; Xenobiotics; Retinal Pigment Epithelium; Retina; Reactive Oxygen Species; Epithelial Cells; Retinal Pigments; Oxidative Stress
PubMed: 38139215
DOI: 10.3390/ijms242417385 -
Communications Biology Dec 2023Interrogation of subcellular biological dynamics occurring in a living cell often requires noninvasive imaging of the fragile cell with high spatiotemporal resolution...
Interrogation of subcellular biological dynamics occurring in a living cell often requires noninvasive imaging of the fragile cell with high spatiotemporal resolution across all three dimensions. It thereby poses big challenges to modern fluorescence microscopy implementations because the limited photon budget in a live-cell imaging task makes the achievable performance of conventional microscopy approaches compromise between their spatial resolution, volumetric imaging speed, and phototoxicity. Here, we incorporate a two-stage view-channel-depth (VCD) deep-learning reconstruction strategy with a Fourier light-field microscope based on diffractive optical element to realize fast 3D super-resolution reconstructions of intracellular dynamics from single diffraction-limited 2D light-filed measurements. This VCD-enabled Fourier light-filed imaging approach (F-VCD), achieves video-rate (50 volumes per second) 3D imaging of intracellular dynamics at a high spatiotemporal resolution of ~180 nm × 180 nm × 400 nm and strong noise-resistant capability, with which light field images with a signal-to-noise ratio (SNR) down to -1.62 dB could be well reconstructed. With this approach, we successfully demonstrate the 4D imaging of intracellular organelle dynamics, e.g., mitochondria fission and fusion, with ~5000 times of observation.
Topics: Imaging, Three-Dimensional; Microscopy, Fluorescence; Mitochondria
PubMed: 38086994
DOI: 10.1038/s42003-023-05636-x -
JAAD Case Reports Dec 2023
PubMed: 38077162
DOI: 10.1016/j.jdcr.2023.08.019 -
Frontiers in Bioengineering and... 2023MgO nanoparticles (NPs) and carbon dots (C-dots) were synthesized by co-precipitation and hydrothermal techniques. In the next step, as-synthesized NPs were modified by...
MgO nanoparticles (NPs) and carbon dots (C-dots) were synthesized by co-precipitation and hydrothermal techniques. In the next step, as-synthesized NPs were modified by C-dots. Then, polyethylene glycol (PEG) was conjugated with MgO/Cdots. Finally, Doxorubicin (Dox) as an anticancer drug was loaded on MgO/Cdots/PEG nanocomposites. The XRD pattern showed the characteristic peaks of C-dots and MgO. The FTIR spectrum showed that MgO/C-dots possessed the carboxyl functional groups, allowing DOX to be loaded onto MgO/C-dots/PEG through hydrogen bonds. The particle size of MgO, C-dots, MgO/C-dots, and MgO/C-dots/PEG/DOX was 20-30, 5-10, 30-40, and 100-130 nm, respectively, using TEM, DLS, and FESEM techniques. MgO, MgO/C-dots, and MgO/C-dots/DOX were fluorescent NPs when excited by a UV source. Anthracene and methylene blue were used as fluorescent probes to identify the reactive oxygen species (ROS) produced by UV excitation. The activity of MgO/C-dots and MgO/C-dots/DOX against colorectal cancer (C26) cells, after repeated 5-min illumination with both UV-light and red light LEDs, were measured by MTT assay. C26 cancer cells incubated with DOX-loaded MgO/C-dots and exposed to either wavelength (UV and red) killed ∼70% of cells. The green synthesized nanocomposites could act as anti-cancer photosensitizers probably by a photocatalytic mechanism.
PubMed: 38076426
DOI: 10.3389/fbioe.2023.1286955 -
International Journal of Molecular... Nov 2023The 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...
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/cm or 7.2 J/cm. 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.
Topics: Humans; Melanoma; Photochemotherapy; Perylene; Photosensitizing Agents; Dermatitis, Phototoxic; Keratinocytes; Apoptosis; Carcinoma, Squamous Cell; Skin Neoplasms
PubMed: 38069219
DOI: 10.3390/ijms242316897 -
Nature Communications Dec 2023Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its...
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.
Topics: Prodrugs; Photolysis; Drug Delivery Systems; Photosensitizing Agents; Energy Transfer
PubMed: 38062051
DOI: 10.1038/s41467-023-43805-y -
Clinical Ophthalmology (Auckland, N.Z.) 2023Diabetes is associated with ocular complications including diabetic macular edema (DME). Current therapies are invasive and include repeated intravitreal injections and...
PURPOSE
Diabetes is associated with ocular complications including diabetic macular edema (DME). Current therapies are invasive and include repeated intravitreal injections and laser therapy. Photobiomodulation (PBM) is a treatment (Tx) that utilizes selected wavelengths of light to induce cellular benefits including reduction of inflammation and edema. This single-center, open-label, post-hoc analysis explored the utility of multiwavelength PBM in subjects with DME.
METHODS
Analysis included review of data from patients undergoing standard clinical care with an approved and marketed PBM medical device, the Valeda Light Delivery System. Subjects with early-stage DME with good vision (Best-corrected visual acuity (BCVA) > 20/25, logMAR > 0.1) were evaluated in clinic and treated with one series of multiwavelength PBM (Tx delivered 3x/week over 3-4 weeks; total of 9 Tx sessions). Clinical, anatomical, and safety parameters were assessed in addition to subjective quality of life.
RESULTS
A total of 30 eyes (19 subjects) were analyzed. Subjects were predominately male (68.4%) with a mean age of 56 ± 14 years. Reductions in central retinal thickness (CRT), resolution of intraretinal fluid (IRF) and improvement in diabetic retinopathy severity scale scores were observed following PBM treatment in select patients. Baseline BCVA remained stable over the follow-up observation period of 3 months post-PBM. Approximately 64% of patients reported subjective improvements in their ocular condition and decreased influence in everyday life. Detailed OCT evaluations confirmed no safety issues related to phototoxicity up to 16 months.
CONCLUSION
Early-stage DME subjects treated with Valeda multiwavelength PBM showed improvements in clinical and anatomical parameters. The Valeda multiwavelength PBM approach demonstrates a favorable safety profile with no signs of phototoxicity following an independent OCT review. PBM therapy may offer an alternative, non-invasive treatment strategy with a unique mechanism and modality for patients with early-stage DME.
PubMed: 38026594
DOI: 10.2147/OPTH.S415883 -
Pflugers Archiv : European Journal of... Dec 2023Optogenetics is a technology using light-sensitive proteins to control signaling pathways and physiological processes in cells and organs and has been applied in...
Optogenetics is a technology using light-sensitive proteins to control signaling pathways and physiological processes in cells and organs and has been applied in neuroscience, cardiovascular sciences, and many other research fields. Most commonly used optogenetic actuators are sensitive to blue and green light, but red-light activation would allow better tissue penetration and less phototoxicity. Cyp27c1 is a recently deorphanized cytochrome P450 enzyme that converts vitamin A to vitamin A, thereby red-shifting the spectral sensitivity of visual pigments and enabling near-infrared vision in some aquatic species.Here, we investigated the ability of Cyp27c1-generated vitamin A to induce a shift in spectral sensitivity of the light-gated ion channel Channelrhodopsin-2 (ChR2) and its red-shifted homolog ReaChR. We used patch clamp to measure photocurrents at specific wavelengths in HEK 293 cells expressing ChR2 or ReaChR. Vitamin A incubation red-shifted the wavelength for half-maximal currents (λ) by 6.8 nm for ChR2 and 12.4 nm for ReaChR. Overexpression of Cyp27c1 in HEK 293 cells showed mitochondrial localization, and HPLC analysis showed conversion of vitamin A to vitamin A. Notably, the λ of ChR2 photocurrents was red-shifted by 10.5 nm, and normalized photocurrents at 550 nm were about twofold larger with Cyp27c1 expression. Similarly, Cyp27c1 shifted the λ of ReaChR photocurrents by 14.3 nm and increased normalized photocurrents at 650 nm almost threefold.Since vitamin A incubation is not a realistic option for in vivo applications and expression of Cyp27c1 leads to a greater red-shift in spectral sensitivity, we propose co-expression of this enzyme as a novel strategy for red-shifted optogenetics.
Topics: Humans; Vitamin A; Optogenetics; HEK293 Cells; Heart; Channelrhodopsins
PubMed: 37987804
DOI: 10.1007/s00424-023-02880-2 -
Journal of Patient-reported Outcomes Nov 2023Erythropoietic protoporphyria is a rare, inherited disorder presenting in early childhood with severe, painful phototoxicity. EPP has significant impacts on...
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.
Topics: Child, Preschool; Adolescent; Adult; Humans; Protoporphyria, Erythropoietic; Quality of Life; Sunlight; Patients; Dermatitis, Phototoxic; Rare Diseases
PubMed: 37982964
DOI: 10.1186/s41687-023-00655-y