Search Results (34)

Background/Objective: Ultraviolet (UV) B radiation leads to DNA damage by generating cyclobutane pyrimidine dimers (CPDs). UVB-induced CPDs can also result in immune suppression, which is a major risk factor for non-melanoma skin cancer (NMSC). UVB-induced CPDs are repaired by nucleotide repair mechanisms (NER) mediated by xeroderma pigmentosum complementation group A (XPA). The purpose of this study was to investigate the use of TH as a chemopreventive agent against the development of skin cancer. Method: SKH-1 hairless mice were exposed were fed with TH (0.1% v/v) for two weeks and exposed to a single dose of UVB (180 mJ/cm²). Dorsal skin was harvested 24 h post-UVB exposure for evaluation of DNA damage and repair. Lymph nodes were also harvested to prepare single cell suspension for flow cytometric evaluation. For carcinogenesis experiments, SKH-1 hairless mice were given TH (0.1% v/v) ad libitum and exposed to UVB (180 mJ/cm²) thrice a week for 30 weeks. Results: Feeding SKH-1 hairless mice with TH (0.1% v/v) for two weeks prior to a single dose of UVB (180 mJ/cm²) led to a significant increase in XPA in skin and DNA repair cytokines IL-12 and IL-23 in draining lymph nodes. Furthermore, when subjected to the photocarcinogenesis protocol; mice fed with TH developed significantly fewer tumors in comparison to mice fed on drinking water. Conclusions: Our data demonstrate that TH has a protective effect against UVB-induced DNA damage, immune suppression, and skin cancer. Future studies will further investigate the potential of TH as a preventive treatment for NMSC. Full article

Background: In recent decades, a significant global increase in the incidence of non-melanoma skin cancer has been observed. To explore the pathogenesis of and potential therapeutic approaches for squamous cell carcinoma, various in vivo studies using mouse models have been conducted. However, investigations comparing different hairless mouse models, with or without melanin, as well as models with hypercholesterolemia and immunosuppression, in terms of their ability to induce squamous cell carcinoma have yet to be undertaken. Methods: Four mouse strains, namely SKH-hr1, SKH-hr2, SKH-hr2+ApoE, and immunodeficient Nude (Foxn1 knockout), were exposed to UVA and UVB radiation three times per week, initially to 1 Minimal Erythemal Dose (MED), incrementally increased weekly to a maximum dose of 3 MED. Clinical evaluation, photodocumentation, and biophysical parameters were monitored, along with proteasome protein activity and histopathological assessments. Results: The SKH-hr1 model primarily developed actinic keratosis without significant progression to invasive squamous cell carcinoma (SCC), while the SKH-hr2 and SKH-hr2+ApoE models exhibited a higher likelihood and intensity of papilloma and aggressive SCC formation, with the latter showing upregulated proteasome activity. Histopathological analysis confirmed the presence of poorly differentiated, invasive SCCs in the SKH-hr2 and SKH-hr2+ApoE models, contrasting with the less aggressive SCCs in the Nude mice and the mixed lesions observed in the SKH-hr1 mice. Conclusions: The SKH-hr2+ApoE and SKH-hr2 mice were identified as the most suitable for further exploration of squamous cell carcinogenesis. In contrast, the SKH-hr1 mice were found to be the least suitable, even though they are albino. Notably, proteasome analysis revealed a potential role of proteasome activity in squamous cell carcinogenesis. Full article

This study explores the previously uncharted territory of the effects of ultraviolet (UV) radiation on diabetic skin, compared to its well-documented impact on normal skin, particularly focusing on carcinogenesis and aging. Employing hairless SKH-hr2, Type 1 and 2 diabetic, and nondiabetic male mice, the research subjected these to UV radiation thrice weekly for eight months. The investigation included comprehensive assessments of photoaging and photocarcinogenesis in diabetic versus normal skin, measuring factors such as hydration, trans-epidermal water loss, elasticity, skin thickness, melanin, sebum content, stratum corneum exfoliation and body weight, alongside photo documentation. Additionally, oxidative stress and the presence of hydrophilic antioxidants (uric acid and glutathione) in the stratum corneum were evaluated. Histopathological examination post-sacrifice provided insights into the morphological changes. Findings reveal that under UV exposure, Type 1 diabetic skin showed heightened dehydration, thinning, and signs of accelerated aging. Remarkably, Type 1 diabetic mice did not develop squamous cell carcinoma or pigmented nevi, contrary to normal and Type 2 diabetic skin. This unexpected resistance to UV-induced skin cancers in Type 1 diabetic skin prompts a crucial need for further research to uncover the underlying mechanisms providing this resistance. Full article

Background: Increasing evidence points at an important physiological role of the timekeeping system, known as the circadian clock (CC), regulating not only our sleep–awake rhythm but additionally many other cellular processes in peripheral tissues. It was shown in various cell types that environmental stressors, including ultraviolet B radiation (UV-B), modulate the expression of genes that regulate the CC (CCGs) and that these CCGs modulate susceptibility for UV-B-induced cellular damage. It was the aim of this pilot study to gain further insights into the CCs’ putative role for UV-B-induced photocarcinogenesis of skin cancer. Methods: Applying RT-PCR, we analyzed the expression of two core CCGs (brain and muscle ARNT-like 1 (Bmal1) and Period-2 (Per2)) over several time points (0–60 h) in HaCaT cells with and without 1,25-dihydroxyvitamin D (D₃) and/or UV-B and conducted a cosinor analysis to evaluate the effects of those conditions on the circadian rhythm and an extended mixed-effects linear modeling to account for both fixed effects of experimental conditions and random inter-individual variability. Next, we investigated the expression of these two genes in keratinocytes representing different stages of skin photocarcinogenesis, comparing normal (Normal Human Epidermal Keratinocytes—NHEK; p53 wild type), precancerous (HaCaT keratinocytes; mutated p53 status), and malignant (Squamous Cell Carcinoma SCL-1; p53 null status) keratinocytes after 12 h under the same conditions. Results: We demonstrated that in HaCaT cells, Bmal1 showed a robust circadian rhythm, while the evidence for Per2 was limited. Overall expression of both genes, but especially for Bmal1, was increased following UV-B treatment, while Per2 showed a suppressed overall expression following D₃. Both UVB and 1,25(OH)₂D₃ suggested a significant phase shift for Bmal1 (p < 0.05 for the acrophase), while no specific effect on the amplitude could be evidenced. Differential effects on the expression of BMAL1 and Per2 were found when we compared different treatment modalities (UV-B and/or D₃) or cell types (NHEK, HaCaT, and SCL-1 cells). Conclusions: Comparing epidermal keratinocytes representing different stages of skin photocarcinogenesis, we provide further evidence for an independently operating timekeeping system in human skin, which is regulated by UV-B and disturbed during skin photocarcinogenesis. Our finding that this pattern of circadian rhythm was differentially altered by treatment with UV-B, as compared with treatment with D₃, does not support the hypothesis that the expression of these CCGs may be regulated via UV-B-induced synthesis of vitamin D but might be introducing a novel photoprotective property of vitamin D through the circadian clock. Full article

Solar radiation can cause damage to the skin, leading to various adverse effects such as sunburn, reactive oxygen species production, inflammation, DNA damage, and photoaging. To study the potential of photoprotective agents, full-thickness skin models are increasingly being used as in vitro tools. One promising approach to photoprotection involves targeting the redox-sensitive transcription factor Nrf2, which is responsible for regulating various cellular defense mechanisms, including the antioxidant response, inflammatory signaling, and DNA repair. Obacunone, a natural triterpenoid, has been identified as a potent Nrf2 agonist. The present study aims to evaluate the relevance of full-thickness (FT) skin models in photoprotection studies and to explore the potential photoprotective effects of obacunone on those models and in human keratinocytes. Phenion^® full-thickness skin models and keratinocytes were incubated with increasing concentrations of obacunone and irradiated with solar-simulated radiation (SSR). Various photodamage markers were evaluated, including histological integrity, oxidative stress, apoptosis, inflammation, photoaging-related dermal markers, and photocarcinogenesis markers. Increasing doses of SSR were found to modulate various biomarkers related to sun damage in the FT skin models. However, obacunone attenuated cytotoxicity, inflammation, oxidative stress, sunburn reaction, photoaging, and photocarcinogenesis in both keratinocytes and full thickness skin models exposed to SSR. These results suggest that obacunone may have potential as a photoprotective agent for preventing the harmful effects of solar radiation on the skin. Full article

UV radiation (UVR) is responsible for inducing both harmful and beneficial effects on skin health. Specifically, it has been reported to disrupt oxidant and antioxidant levels, leading to oxidative stress conditions in skin tissue. This phenomenon might trigger photo-carcinogenesis, resulting in melanoma, NMSC (non-melanoma skin cancer), such as BCC (basal cell carcinoma) and SCC (squamous cell carcinoma), and actinic keratosis. On the other hand, UVR is essential for the production of adequate vitamin D levels, a hormone with important antioxidant, anticancer and immunomodulatory properties. The exact mechanisms implicated in this two-fold action are not well understood, as there still no clear relation established between skin cancer and vitamin D status. Oxidative stress seems to be a neglected aspect of this complex relation, despite its role in both skin cancer development and vitamin D deficiency. Therefore, the aim of the present study is to examine the correlation between vitamin D and oxidative stress in skin cancer patients. A total of 100 subjects (25 with SCC, 26 with BCC, 23 with actinic keratosis, and 27 controls) were assessed in terms of 25-hydroxyvitamin D (25(OH) D) and redox markers such as thiobarbituric acid reactive substances (TBARS), protein carbonyls, total antioxidant capacity (TAC) in plasma, glutathione (GSH) levels and catalase activity in erythrocytes. The majority of our patients revealed low vitamin D levels; 37% of the subjects showed deficiency (<20 ng/mL) and 35% insufficiency (21–29 ng/mL). The mean 25(OH) D level of the NMSC patients (20.87 ng/mL) was also found to be significantly lower (p = 0.004) than that of the non-cancer patients (28.14 ng/mL). Furthermore, higher vitamin D levels were also correlated with lower oxidative stress (positive correlation with GSH, catalase activity TAC index and negative correlation with TBARS and CARBS indices). NMSC patients diagnosed with SCC showed lower catalase activity values compared to non-cancer patients (p < 0.001), with the lowest values occurring in patients with a chronic cancer diagnosis (p < 0.001) and vitamin D deficiency (p < 0.001). Higher GSH levels (p = 0.001) and lower TBARS levels (p = 0.016) were found in the control group compared to the NMSC group, and to patients with actinic keratosis. Higher levels of CARBS were observed in patients with SCC (p < 0.001). Non-cancer patients with vitamin D sufficiency showed higher TAC values compared to non-cancer patients with vitamin D deficiency (p = 0.023) and to NMSC patients (p = 0.036). The above-mentioned results indicate that NMSC patients reveal increased levels of oxidative damage markers compared to control levels, while vitamin D status plays a critical role in the determination of individuals’ oxidative status. Full article

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face. Full article

Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6–12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis (p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer. Full article

The calcium-sensing receptor (CaSR) is an important regulator of epidermal function. We previously reported that knockdown of the CaSR or treatment with its negative allosteric modulator, NPS-2143, significantly reduced UV-induced DNA damage, a key factor in skin cancer development. We subsequently wanted to test whether topical NPS-2143 could also reduce UV-DNA damage, immune suppression, or skin tumour development in mice. In this study, topical application of NPS-2143 (228 or 2280 pmol/cm²) to Skh:hr1 female mice reduced UV-induced cyclobutane pyrimidine dimers (CPD) (p < 0.05) and oxidative DNA damage (8-OHdG) (p < 0.05) to a similar extent as the known photoprotective agent 1,25(OH)₂ vitamin D3 (calcitriol, 1,25D). Topical NPS-2143 failed to rescue UV-induced immunosuppression in a contact hypersensitivity study. In a chronic UV photocarcinogenesis protocol, topical NPS-2143 reduced squamous cell carcinomas for only up to 24 weeks (p < 0.02) but had no other effect on skin tumour development. In human keratinocytes, 1,25D, which protected mice from UV-induced skin tumours, significantly reduced UV-upregulated p-CREB expression (p < 0.01), a potential early anti-tumour marker, while NPS-2143 had no effect. This result, together with the failure to reduce UV-induced immunosuppression, may explain why the reduction in UV-DNA damage in mice with NPS-2143 was not sufficient to inhibit skin tumour formation. Full article

Exposure to ultraviolet radiation induces photodamage towards cellular macromolecules that can progress to photoaging and photocarcinogenesis. The topical administration of compounds that maintain the redox balance in cells presents an alternative approach to combat skin oxidative damage. Cerium oxide nanoparticles (CNPs) can act as antioxidants due to their enzyme-like activity. In addition, a recent study from our group has demonstrated the photoprotective potential of tannic acid (TA). Therefore, this work aimed to synthesize CNPs associated with TA (CNP-TA) and investigate its photoprotective activity in L929 fibroblasts exposed to UVB radiation. CNP conjugation with TA was confirmed by UV–Vis spectra and X-ray photoelectron spectroscopy. Bare CNPs and CNP-TA exhibited particle sizes of ~5 and ~10 nm, superoxide dismutase activity of 3724 and 2021 unit/mg, and a zeta potential of 23 and −19 mV, respectively. CNP-TA showed lower cytotoxicity than free TA and the capacity to reduce the oxidative stress caused by UVB; supported by the scavenging of reactive oxygen species, the prevention of endogenous antioxidant system depletion, and the reduction in oxidative damage in lipids and DNA. Additionally, CNP-TA improved cell proliferation and decreased TGF-β, metalloproteinase-1, and cyclooxygenase-2. Based on these results, CNP-TA shows therapeutic potential for protection against photodamage, decreasing molecular markers of photoaging and UVB-induced inflammation. Full article

An abnormal growth of cells in the brain, often known as a brain tumor, has the potential to develop into cancer. Carcinogenesis of glial cells in the brain and spinal cord is the root cause of gliomas, which are the most prevalent type of primary brain tumor. After receiving a diagnosis of glioblastoma, it is anticipated that the average patient will have a survival time of less than 14 months. Magnetic resonance imaging (MRI) is a well-known non-invasive imaging technology that can detect brain tumors and gives a variety of tissue contrasts in each imaging modality. Until recently, only neuroradiologists were capable of performing the tedious and time-consuming task of manually segmenting and analyzing structural MRI scans of brain tumors. This was because neuroradiologists have specialized training in this area. The development of comprehensive and automatic segmentation methods for brain tumors will have a significant impact on both the diagnosis and treatment of brain tumors. It is now possible to recognize tumors in photographs because of developments in computer-aided design (CAD), machine learning (ML), and deep learning (DL) approaches. The purpose of this study is to develop, through the application of MRI data, an automated model for the detection and classification of brain tumors based on deep learning (DLBTDC-MRI). Using the DLBTDC-MRI method, brain tumors can be detected and characterized at various stages of their progression. Preprocessing, segmentation, feature extraction, and classification are all included in the DLBTDC-MRI methodology that is supplied. The use of adaptive fuzzy filtering, often known as AFF, as a preprocessing technique for photos, results in less noise and higher-quality MRI scans. A method referred to as “chicken swarm optimization” (CSO) was used to segment MRI images. This method utilizes Tsallis entropy-based image segmentation to locate parts of the brain that have been injured. In addition to this, a Residual Network (ResNet) that combines handcrafted features with deep features was used to produce a meaningful collection of feature vectors. A classifier developed by combining DLBTDC-MRI and CSO can finally be used to diagnose brain tumors. To assess the enhanced performance of brain tumor categorization, a large number of simulations were run on the BRATS 2015 dataset. It would appear, based on the findings of these trials, that the DLBTDC-MRI method is superior to other contemporary procedures in many respects. Full article

Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC. Full article

Within solar ultraviolet (UV) light, the longest UVA1 wavelengths, with significant and relatively constant levels all year round and large penetration properties, produce effects in all cutaneous layers. Their effects, mediated by numerous endogenous chromophores, primarily involve the generation of reactive oxygen species (ROS). The resulting oxidative stress is the major mode of action of UVA1, responsible for lipid peroxidation, protein carbonylation, DNA lesions and subsequent intracellular signaling cascades. These molecular changes lead to mutations, apoptosis, dermis remodeling, inflammatory reactions and abnormal immune responses. The altered biological functions contribute to clinical consequences such as hyperpigmentation, inflammation, photoimmunosuppression, sun allergies, photoaging and photocancers. Such harmful impacts have also been reported after the use of UVA1 phototherapy or tanning beds. Furthermore, other external aggressors, such as pollutants and visible light (Vis), were shown to induce independent, cumulative and synergistic effects with UVA1 rays. In this review, we synthetize the biological and clinical effects of UVA1 and the complementary effects of UVA1 with pollutants or Vis. The identified deleterious biological impact of UVA1 contributing to clinical consequences, combined with the predominance of UVA1 rays in solar UV radiation, constitute a solid rational for the need for a broad photoprotection, including UVA1 up to 400 nm. Full article

Ultraviolet A (UVA) radiation can pass through the epidermis and reach the dermal skin layer, contributing to photoaging, DNA damage, and photocarcinogenesis in dermal fibroblasts. High-dose UVA exposure induces erythema, whereas low-dose, long-term UVA exposure causes skin damage and cell senescence. Biomarkers for evaluating damage caused by low-dose UVA in fibroblasts are lacking, making it difficult to develop therapeutic agents for skin aging and aging-associated diseases. We performed RNA-sequencing to investigate gene and pathway alterations in low-dose UVA-irradiated human skin-derived NB1RGB primary fibroblasts. Differentially expressed genes were identified and subjected to Gene Ontology and reactome pathway analysis, which revealed enrichment in genes in the senescence-associated secretory phenotype, apoptosis, respiratory electron transport, and transcriptional regulation by tumor suppressor p53 pathways. Insulin-like growth factor binding protein 7 (IGFBP7) showed the lowest p-value in RNA-sequencing analysis and was associated with the senescence-associated secretory phenotype. Protein–protein interaction analysis revealed that Fos proto-oncogene had a high-confidence network with IGFBP7 as transcription factor of the IGFBP7 gene among SASP hit genes, which were validated using RT-qPCR. Because of their high sensitivity to low-dose UVA radiation, Fos and IGFBP7 show potential as biomarkers for evaluating the effect of low-dose UVA radiation on dermal fibroblasts. Full article

Sunscreen and sunblock are crucial skincare products to prevent photoaging and photocarcinogenesis through the addition of chemical filters to absorb or block ultraviolet (UV) radiation. However, several sunscreen and sunblock ingredients, mostly UV filters, have been associated with human and environmental safety concerns. Therefore, the exploration and discovery of promising novel sources of efficient and safer compounds with photoprotection-related activities are currently required. Marine invertebrates, particularly their associated microbiota, are promising providers of specialized metabolites with valuable biotechnological applications. Nevertheless, despite Actinobacteria members being a well-known source of bioactive metabolites, their photoprotective potential has been poorly explored so far. Hence, a set of methanolic extracts obtained from Cliona varians-derived actinomycetes was screened regarding their antioxidant and UV-absorbing capacities (i.e., photoprotection-related activities). The active extract-producing strains were identified and classified within genera Streptomyces, Micrococcus, Gordonia, and Promicromonospora. This is the first report of the isolation of these microorganisms from C. varians (an ecologically important Caribbean coral reef-boring sponge). The in vitro cytotoxicity on dermal fibroblasts of oxybenzone and the selected active extracts revealed that oxybenzone exerted a cytotoxic effect, whereas no cytotoxic effect of test extracts was observed. Accordingly, the most active (SPFi > 5, radical scavenging > 50%) and nontoxic (cell viability > 75%) extracts were obtained from Streptomyces strains. Finally, LC-MS-based characterization suggested a broad chemical space within the test strains and agreed with the reported streptomycetes’ chemodiversity. The respective metabolite profiling exposed a strain-specific metabolite occurrence, leading to the recognition of potential hits. These findings suggest that marine Streptomyces produce photoprotectants ought to be further explored in skincare applications. Full article