Search Results (1,144)

Keratinocytes are key epidermal cells that are highly susceptible to ultraviolet (UV)-induced damage, which can lead to DNA mutations and the development of malignancies. In parallel, UV radiation induces lipid peroxidation (LPO), potentially facilitating the activation of ferroptosis, a form of programmed cell death. We hypothesized that UV-mediated DNA damage, resulting in the formation of cyclobutane pyrimidine dimers (CPDs), occurs preferentially in cells with elevated LPO levels, and that mild induction of ferroptosis in proliferating keratinocytes selectively eliminates cells with high CPD levels. A human keratinocyte cell line was exposed to UVB radiation and subsequently treated with the ferroptosis inducers RSL3 and erastin. Cell death was assessed using LDH analysis, LPO was measured using the fluorescent probe BODIPY™ 581/591 C11, and CPD formation was quantified by ELISA. Using different doses of UVB, we confirmed UVB irradiation simultaneously increases the cell death rate and LPO and CPDs levels in proliferating keratinocytes. Mild induction of ferroptosis in these cells led to a slight increase in the cell death rate and simultaneously to a drastic reduction in CPD levels, suggesting that there is a specific pool of cells predominantly susceptible to UVB in terms of DNA damage and LPO induction. Our findings support our hypothesis that induction of ferroptosis in proliferating keratinocytes exposed to UVB radiation preferentially eliminates cells with elevated CPD levels and may therefore serve as a protective mechanism against UV-induced carcinogenesis. Full article

Proton therapy spares normal tissues better than photon therapy, potentially reducing toxicity while maintaining tumor control. However, challenges remain due to variations in proton dose distribution, particularly at the distal edge of the spread-out Bragg peak (SOBP); for organs at risk, such variation is crucial. We evaluated the biological effects by comparing two positions of the proton profile, the entrance plateau (EP) and SOBP, in a murine model and investigated distinct metabolomic and proteomic signatures. Mice exposed to the EP beam segment (LET_d = 0.8 keV/µm) exhibited less weight reduction than their SOBP-irradiated counterparts (LET_d = 2.6 keV/µm). Two hours post-irradiation, the SOBP caused more severe DNA damage in the hippocampus and thalamus. Hematoxylin and eosin staining revealed eosinophil aggregation in both groups, with more surviving neurons in the EP group. Metabolomic profiles differed more between the EP and SOBP groups at 2 h than at 3 days post-irradiation. Relative to EP, SOBP irradiation at 2 h increased fructose-1,6-bisphosphate (FBP), dihydroxyacetone phosphate (DHAP), and inosine but decreased prostaglandin F2α; subsequently, proteomic analysis at day 3 showed that calcium signaling, NF-κB, and endocytosis pathways were enriched in the SOBP group. Combined multi-omics analysis further demonstrated that SOBP irradiation significantly activated the pentose phosphate pathway, purine metabolism, and phospholipase D signaling, while concurrently suppressing arachidonic acid metabolism. Our findings underscore the need for early detection of proton-induced brain toxicity and demonstrate that the higher-LET SOBP segment causes more severe damage than the EP. Targeting these dysregulated multi-omics pathways may offer a promising strategy for mitigating radiation-induced brain injury during proton therapy. Full article

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionarily conserved indoleamine with potent antioxidant and cytoprotective properties. Due to its amphiphilic nature, melatonin readily accumulates in mitochondria, where it regulates redox homeostasis and bioenergetic function. Although melatonin has been implicated in cutaneous protection against ultraviolet radiation (UVR), the mitochondrial mechanisms underlying its effects in UVB-exposed keratinocytes remain insufficiently characterized. In this study, we investigated the mitochondrial-centered protective effects of melatonin in human epidermal keratinocytes (NHEKs) subjected to UVB irradiation. UVB exposure induced a dose-dependent decrease in cell viability and proliferation, accompanied by excessive reactive oxygen species (ROS) production, mitochondrial membrane depolarization (ΔΨm), ATP depletion, caspase-3 activation, and increased expression of DNA damage- and senescence-associated markers, including γH2AX, p53, and p16^INK4a. Pre-treatment with melatonin attenuated these alterations by reducing oxidative stress, preserving ΔΨm, maintaining ATP production, suppressing apoptotic signaling, and modulating DNA damage- and senescence-related pathways. Collectively, our findings suggest that mitochondria are a central target of melatonin in UVB-exposed keratinocytes and demonstrate that maintenance of mitochondrial redox balance and bioenergetic integrity is associated with reduced apoptotic and senescence-related changes. Full article

Ultraviolet B (UVB) radiation is a major environmental factor contributing to skin photoaging through excessive reactive oxygen species (ROS) generation, activation of stress-responsive signaling pathways, DNA damage, cellular senescence, and extracellular matrix (ECM) degradation. Mangiferin, a naturally occurring xanthone glucoside with potent antioxidant and anti-inflammatory properties, has attracted considerable interest as a potential photoprotective agent. The present study investigated the protective effects of mangiferin against UVB-induced photoaging in human dermal fibroblasts (HDFs). The effects of mangiferin on oxidative stress, RAGE/NF-κB/MAPK signaling, DNA damage, cellular senescence, and ECM degradation were evaluated. Mangiferin significantly suppressed UVB-induced ROS accumulation and attenuated activation of the RAGE/NF-κB/MAPK signaling cascade. Furthermore, mangiferin reduced γ-H2AX expression, indicating protection against UVB-mediated DNA damage, while decreasing p16, p21, and p53 expression and restoring LMNB1 levels. Mangiferin also inhibited MMP-2 and MMP-9 activities as well as collagenase, elastase, and hyaluronidase activities, suggesting preservation of ECM homeostasis. These findings demonstrate that mangiferin protects dermal fibroblasts against UVB-induced photoaging through suppression of oxidative stress, inhibition of RAGE/NF-κB/MAPK signaling, attenuation of DNA damage and cellular senescence, and preservation of ECM integrity, supporting its potential application in photoprotective and anti-photoaging dermocosmetic formulations. Full article

Radiotherapy is a cornerstone of breast cancer treatment, but its efficacy is frequently limited by intrinsic and acquired radioresistance as well as dose-limiting toxicity to surrounding normal tissues. Nanoparticle-mediated radiosensitization has emerged as a promising strategy to enhance the therapeutic index of irradiation by combining physical dose amplification with biological, microenvironmental, and immunological modulation. In this systematic review, we evaluated preclinical evidence on nanoparticle-mediated radiosensitization in breast cancer, with emphasis on nanoplatform design, mechanistic patterns, therapeutic efficacy, and translational relevance. A total of 66 studies published between 2015 and 2026 were included. The identified systems encompassed a broad range of materials, including gold-, silver-, platinum-, bismuth-, gadolinium-, polymer-, lipid-, and hybrid-based nanoplatforms, frequently incorporating targeting ligands, catalytic components, biomimetic coatings, or therapeutic payloads. Enhanced radiation responses were most commonly associated with high-atomic-number (high-Z)-mediated energy deposition, increased reactive oxygen species generation, and enhanced DNA damage persistence. Additional mechanisms, including redox modulation, hypoxia targeting, regulated cell death, and immune activation, reflect the evolution of nanoparticle-assisted radiotherapy from predominantly physical radioenhancement toward multifunctional physicobiological strategies. Triple-negative breast cancer models predominated throughout the literature. Across preclinical models, nanoparticle-assisted irradiation consistently improved clonogenic survival, tumor control, and, in selected studies, survival. However, substantial heterogeneity in study design and limited use of rigorous radiobiological endpoints restricted cross-study comparability. The available preclinical evidence indicates that the most promising nanoparticle-mediated radiosensitization strategies integrate physical dose enhancement with biologically active mechanisms targeting oxidative stress, hypoxia, persistent DNA damage, immune signaling, and tumor microenvironmental resistance. Collectively, these findings suggest that the field is evolving from predominantly physical radioenhancement toward multifunctional, mechanism-driven physicobiological strategies. However, clinical translation remains constrained by methodological heterogeneity and limited radiobiological validation, highlighting the need for standardized preclinical evaluation and clinically feasible nanoplatforms tailored to subtype-specific mechanisms of radioresistance. Full article

Stereotactic radiosurgery (SRS) delivers high doses of focused ionizing radiation (IR) to a defined target while sparing surrounding tissues. The delivery of focused doses of IR has proven to be an effective modality for the treatment of brain tumors, cerebrovascular lesions, and primary neuropathic pain conditions. More recently, the emerging concept of “radiomodulation” to rewire neural circuitry through the delivery of focused IR to specific neural relay centers has emerged as an alternative way to treat neurological conditions, such as essential tremor, trigeminal neuralgia, and psychiatric illnesses. In this article, we performed a scoping review of the existing data supporting the ability of focused doses of ionizing radiation to achieve modulation of neural circuits for the treatment of neurological conditions. We review the current understanding of the neurophysiological mechanisms of radiomodulation, the gaps in knowledge limiting its widespread use for in-human applications and stress the unmet need for ongoing research to rigorously prove that radiomodulation may be the “final frontier” as a non-invasive, non-pharmacological, versatile, and tunable modality for the treatment of a multitude of neurological conditions. Full article

Acute myeloid leukaemia (AML) remains a highly lethal malignancy with poor prognosis in adults above 60 years old and often occurs after radiation exposure. Emerging evidence suggests that circadian rhythm disruption, prevalent in shift workers, may contribute to cancer development. Clock genes (CGs) regulate fundamental cellular processes, including the DNA damage response (DDR), cell cycle progression, and haematopoiesis. In the absence of substantial experimental data, this review examines the potential pathways linking circadian clock dysregulation to radiation-induced AML (rAML) and evaluates how temporal disruption may modulate leukaemogenesis and radiation-induced effects. The evidence was synthesised on core clock components (BMAL1, CLOCK, PER, CRY, REV-ERB, ROR), their dysregulation in AML, and their roles in radiation response. Epigenetic and post-transcriptional regulatory mechanisms, including m⁶A RNA modification and sirtuin-mediated chromatin remodelling, were evaluated for their contribution to circadian-regulated DNA repair capacity. Multiple CGs demonstrated aberrant expression in AML, with BMAL1 showing tissue-specific dysregulation, and PER1/2/3 was consistently downregulated in peripheral blood. Clock proteins directly regulate DNA damage checkpoints through interactions with ATM/CHK2 and p53 pathways. Circadian disruption enhances inflammatory signalling, promotes accumulation of myeloid-derived suppressor cells, and accelerates immune senescence. Moreover, radiation exposure modulates CG expression, which may alter repair fidelity and increase leukaemogenic risk. Understanding these connections in the context of disrupted circadian rhythms could help identify at-risk populations and improve shift workplace health policies. Full article

This prospective single-center study investigated the impact of iodinated contrast agents (Ultravist/iopromide and Visipaque/iodixanol) on DNA double-strand breaks during pediatric chest computed tomography (CT). Twenty-six children underwent medically indicated chest CT between March 2022 and November 2024: unenhanced (n = 7), Ultravist-enhanced (n = 10), and Visipaque-enhanced (n = 9). Blood samples were collected before and 30 min post-CT. DNA damage was quantified by analyzing γ-H2AX and 53BP1 foci formation in peripheral lymphocytes using immunofluorescence microscopy. All groups showed significant increases in DNA damage following CT. The absolute increases were 0.915 ± 0.250 foci/cell (unenhanced), 0.972 ± 0.279 (Ultravist), and 1.261 ± 0.251 (Visipaque), representing 6.2% and 37.8% higher values in contrast groups. However, these differences between groups were not statistically significant (p = 0.579, Kruskal–Wallis test), with small effect sizes (Cohen’s d < 0.5 for all comparisons). Contrast-enhanced protocols employed higher radiation doses than unenhanced scans (CTDIvol: 4.04–4.57 mGy vs. 2.66 mGy). When DNA damage was normalized for CTDIvol, no significant differences were observed between groups (p = 0.659). DNA damage showed no significant correlation with dosimetric parameters. When accounting for radiation dose differences, iodinated contrast agents do not enhance radiation-induced DNA double-strand breaks in pediatric chest CT, confirming the safety of contrast-enhanced CT. Full article

Exposure to ultraviolet (UV), particularly UVA radiation, is a primary driver of photoaging due to its deep dermal penetration, which triggers DNA damage, collagen degradation, and immune suppression. Chebulinic acid (CA), a polyphenolic compound from Terminalia chebula, exhibits potent antioxidant and anti-inflammatory properties against UVB-induced skin damage. However, its large molecular weight hinders transdermal delivery and the TAT_47–57 peptide (core of HIV-1 TAT) enables rapid transmembrane transport. Large particles with double-layer membrane structure and a diameter exceeding 1000 nm were obtained during the separation of plant-derived exosome-like nanoparticles (PELNs), which are not considered as PELNs (50–500 nm), after a mixture with TAT anchored to the surface of engineered artificial vesicles (EAVs) and extrusion causes membrane fusion, employed as novel nanocarriers to overcome the difficulty in skin penetration by leveraging their lipid bilayer structure and surface membrane-anchored TAT for efficient epidermal fusion and intercellular penetration. Furthermore, CA-loaded TAT-ePELNs demonstrate significant efficacy in mitigating UVA-induced photoaging. Collectively, this study expands the anti-UVR damage application spectrum of CA from UVB to UVA exposure and establishes a green, efficient, and biosafe strategy for transdermal drug delivery by utilization of non-PELNs generated during the preparation process of PELNs. Full article

Ultraviolet B (UVB) radiation-induced corneal injury poses a significant public health challenge. However, its underlying molecular mechanisms remain incompletely understood, hindering the development of effective interventions. This study identified a key molecular pathway in UVB-induced corneal damage, revealing that UVB exposure triggers a rapid intracellular burst of reactive oxygen species (ROS), which in turn upregulates and aberrantly activates the receptor tyrosine kinase Ephrin type-A receptor 2 (EphA2), thereby collectively accelerating DNA damage and photoaging in corneal epithelial cells. Based on this mechanism, we developed the natural compound Penicophenone F (PP-F), which was screened and identified from the Arctic fungus Penicillium sp. MYA5, as a novel therapeutic strategy against UVB-induced corneal damage. In vitro and in vivo experiments suggest that PP-F may mediate its therapeutic effects via a dual mechanism. On one hand, it may counteract UVB damage by modulating ROS levels through regulation of endogenous antioxidant enzymes, inhibiting aberrant EphA2 activation, and promoting cellular proliferation and DNA repair. On the other hand, it may upregulate IRF6 to activate the cGAS pathway, which could enhance antioxidant defenses and significantly contribute to the restoration of epithelial barrier integrity and overall corneal physiology. These results underscore the safety and potential of PP-F in treating UVB-induced corneal damage and other oxidative stress-related ocular surface diseases. Full article

Desiccation, ionizing radiation, ultraviolet exposure, and oxidative stress impose severe physicochemical stress that threatens the integrity of both DNA and RNA. Water loss promotes molecular crowding, protein and membrane destabilization, and the accumulation of reactive oxygen species (ROS), while rehydration can intensify oxidative injury and expose lesions accumulated during metabolic suppression. As a result, stress-tolerant metazoans must do more than survive water loss: they must also protect, monitor, and restore nucleic-acid integrity. Here, we review how tardigrades, bdelloid rotifers, Artemia, nematodes, and selected insect species preserve genomic and transcriptomic integrity under extreme dehydration, oxidative stress, and radiation-related insults. We compare conserved defence systems, including antioxidant enzymes, trehalose, LEA proteins, heat shock proteins, and core DNA repair pathways. These pathways include base excision repair, nucleotide excision repair, homologous recombination, and non-homologous end joining. We then examine how these conserved mechanisms contrast with lineage-specific innovations, such as the tardigrade proteins Dsup, TDR1, and TRID1, as well as the unusual genome plasticity of bdelloid rotifers. We argue that stress biology of these organisms is best understood through a framework that distinguishes damage prevention during drying from repair and recovery during rehydration. In this framework, extremotolerant metazoans provide biologically informative models for understanding oxidative nucleic-acid damage, redox defence and the molecular logic underlying radioprotection and dry-state preservation. Full article

Radiation therapy is a fundamental pillar in cancer treatment, yet its clinical efficacy is frequently compromised by the development of intrinsic and acquired tumor radioresistance. This review provides a comprehensive analysis of the molecular mechanisms underlying radioresistance, with a specific focus on the Epithelial–Mesenchymal Transition (EMT) and its regulation by microRNAs (miRNAs). EMT is recognized as a key driver of therapeutic resistance, enabling cancer cells to acquire enhanced migratory capacity, stem-like characteristics, and resistance to apoptosis. Importantly, ionizing radiation can itself function as a cellular stressor that induces EMT through major signaling pathways, including TGF-β, Wnt, and Notch, thereby establishing a self-reinforcing loop that promotes resistance. In addition, this review highlights the pivotal role of miRNAs as post-transcriptional regulators within this network. Dysregulated miRNAs, acting as either tumor suppressors or oncogenes, modulate EMT-transcription factors and DNA damage repair pathways to influence cellular radiosensitivity. The complex interplay between these factors and the tumor microenvironment is also explored. Finally, emerging therapeutic strategies designed to break this resistance loop, such as EMT inhibitors, miRNA mimics, and antagomirs, as well as combination therapies, are evaluated. Collectively, these approaches hold significant promise for restoring radiosensitivity and improving clinical outcomes in precision oncology. Full article

Background/Objectives: The G protein-coupled estrogen receptor (GPER) is known to interact with cellular stress responses and DNA damage pathways. Therefore, exposure to ionizing radiation may modulate the biological consequences of single-nucleotide polymorphisms in the GPR30 gene. This study aims to evaluate the association between GPER polymorphisms and radiation sensitivity. Methods: The study included 50 healthcare workers exposed to ionizing radiation and 36 healthy individuals with no known occupational exposure to radiation. Genomic DNA was isolated and PCR products were purified using GeneAll kits. Genomic regions encompassing three GPER single-nucleotide polymorphisms (rs3808350, rs3808351, and rs11544331) were amplified by polymerase chain reaction (PCR), followed by DNA sequencing analysis using the BigDye Cycle Sequencing Kit. In addition, an in silico functional and clinical annotation of rs11544331 was performed using Ensembl VEP, SIFT, PolyPhen-2, AlphaMissense, CADD, UniProt, and ClinVar. Results: Genotypic, dominant, and allelic analyses revealed no significant association between radiation exposure and the rs3808350 or rs3808351 polymorphisms. In contrast, a statistically significant association was observed for rs11544331. The frequency of individuals carrying the CT and TT genotypes (CT + TT) was significantly higher in the ionizing radiation-exposed group compared with the control group (OR = 2.981; 95% CI: 1.106–7.904; p = 0.0241). In allelic analysis, the T allele was more prevalent in the exposed group and was significantly associated with radiation exposure (OR = 2.959; 95% CI: 1.282–6.606; p = 0.0110). In silico analysis confirmed that rs11544331 corresponds to the p.Pro16Leu substitution in GPER1; however, SIFT, PolyPhen-2, AlphaMissense, CADD, and ClinVar consistently indicated a tolerated, benign, likely benign, or low-deleteriousness profile. Conclusions: GPER-mediated stress responses and genetic polymorphisms may play a potential role in determining genetic susceptibility following exposure to ionizing radiation. Full article

Background/Objective: Ultraviolet A and B (UVAB) radiation is a major environmental factor that induces DNA damage and upregulates programmed death-ligand 1 (PD-L1) expression in skin cells, thereby contributing to immune evasion and impaired tissue repair. This study evaluated the protective effects of two purified compounds, Cinnamtannin B1 (CTB-1) and Cinnamtannin D1 (CTD-1), as well as cinnamon extract, in UVAB-irradiated human keratinocyte HaCaT cells. Methods: HaCaT cells were exposed to low (20 kJ/m² UVA, 1.3 kJ/m² UVB), medium (30 kJ/m² UVA, 2 kJ/m² UVB), and high (40 kJ/m² UVA, 2.7 kJ/m² UVB) UVAB doses of UVAB radiation. Dose-dependent effects of CTB-1 and CTD-1 (0, 5, 10, 25, and 50 µg/ mL) and cinnamon extract (0, 5, 10, 50, and 100 µg/mL), as well as time-dependent effects (12, 24, and 72 h), were evaluated by measuring PD-L1 expression, cell viability, and DNA damage. Results: CTD-1 was the most effective compound, significantly reducing UVAB-induced PD-L1 expression and DNA double-strand breaks without compromising cell viability. CTB-1 also demonstrated protective effects at specific doses and time points; however, higher concentrations reduced cell viability. Cinnamon extract was protective at low concentrations but cytotoxic at higher doses. Conclusions: CTD-1, CTB-1, and cinnamon extract attenuated UVAB-induced cellular damage in HaCaT cells, with CTD-1 demonstrating the most favorable protective profile. These findings support the potential of cinnamon-derived compounds as therapeutic candidates for preventing UVAB-induced skin damage and immune dysregulation. Full article

Background/Objectives: Ultraviolet (UV) radiation is a major environmental carcinogen responsible for skin damage through oxidative stress, DNA damage, and inflammation. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a central role in regulating cellular antioxidant defences against UV-induced damage. This scoping review aims to evaluate the potential role of sulforaphane (SFN), a known Nrf2 inducer, in protecting against UV-induced skin damage and photocarcinogenesis. Methods: A literature search was conducted in PubMed and Scopus from inception to 27 January 2026, to identify original experimental studies investigating SFN, glucoraphanin, or broccoli sprout extracts in the context of UV-induced skin damage. Eligible studies included in vitro, ex vivo, in vivo, and human models assessing outcomes related to oxidative stress, inflammation, molecular signalling pathways, and tumour development. Following screening and eligibility assessment, twelve studies were included in the qualitative synthesis. Results: The included studies suggest that SFN exerts photoprotective effects across multiple experimental models. In murine studies, SFN and SFN-rich extracts were associated with a reduction in tumour incidence, multiplicity, and volume following UV exposure. In human studies, topical SFN application reduced UV-induced erythema and induced cytoprotective enzyme expression, although clinical evidence remains limited. Mechanistically, SFN consistently activated the Nrf2 pathway, leading to increased expression of antioxidant and phase II detoxifying enzymes, and was associated with modulation of inflammatory responses and inhibition of MAPK/AP-1 signalling. Emerging evidence also indicates potential effects on UV-induced metabolic and epigenetic alterations. Conclusions: Current evidence supports a potential role for sulforaphane in mitigating UV-induced skin damage through activation of endogenous defence pathways. However, the available data are predominantly preclinical, and further well-designed clinical studies are needed to clarify its efficacy and translational relevance in humans. Full article