Chronic Ultraviolet Radiation Research Articles

Cutaneous Squamous Cell Carcinoma in Solid Organ Transplant Patients

Solid organ transplant recipients (SOTR) are more likely to develop cutaneous squamous cell carcinoma (CSCC), compared to the general population. This increased incidence is due to several factors including chronic ultraviolet radiation exposure, human papillomavirus (HPV) infection, immunosuppressive medication, among others. Primary prevention is crucial, because not only are cutaneous squamous cell carcinomas more frequent in SOTR, but they are also more aggressive and have therefore a worse prognosis. Newer immunosuppressive drugs are associated with a smaller risk of developing CSCC, but they can have more adverse events, prompting patients to abandon therapy. Concerning treatment options for CSCC, they range from surgery, radiotherapy, and systemic therapy, although there are few studies in SOTR concerning the use of immunotherapy and epidermal growth factor receptor (EGFR) inhibitors.

Interaction of chronic ultraviolet radiation and cytokinin in adaptive reactions of pea plants

Aim. The goal of this study was to study the interaction of chronic ultraviolet (UV-B) radiation and cytokinin 6-benzylaminopurine (BAP) in the adaptation of pea plants (Pisum sativum L.) to the effect of chronic UV-B irradiation. Methods. Pea plants cultivar Aronis were sprayed by BAP solution in concentration 10-5 M before the effect of chronic UV-B radiation at doses of 6 kJ/m2 per day with a power of 1 W/m2 for 12 days. During this time, the growth of plants and their mass were measured, the content of photosynthetic pigments and endogenous hydrogen peroxide (HP) were determined in the leaves. Results. It was established that the effect of chronic UV-B radiation at a dose of 6 kJ/m2 per day on pea plants caused a delay in plant mass accumulation, synthesis of photosynthetic pigments and increasing HP content in leaves. Treatment plants by BAP increased mass, stimulated synthesis of photosynthetic pigments, reduced the content of HP in the leaves of pea plants during the UV-B radiation. Conclusions. It was shown that treatment of pea plants by BAP caused the adaptation of pea plants at the beginning of UV-B radiation. Cytokinins are capable to detoxify reactive oxygen spices, stimulate formation of photosynthetic complex that promotes growth of pea plants under chronic UV-B radiation.
 Keywords: UV-B, BAP, Pisum sativum L., photosynthetic pigments, adaptation.

Effect of chronic UVR exposure on zooplankton molting and growth

Molting is a crucial physiological process in arthropods development, growth, and adult reproduction, where the chitinolytic enzyme chitobiase (CB) and the apoptosis process (caspase-3 activity) play crucial roles. Both molecular endpoints have been observed to be affected by different toxics that may be present in aquatic environments. However, the role of ultraviolet radiation (UVR) in the molting process remains with poor evidence and the possible effect of the previous exposure on F1 generation is unknown. Here, we conducted laboratory experiments with chronic UVR exposure to test the effect on the molting process of Daphnia commutata. Our results showed a clear negative effect of the UVR that affected the molting process with a reduction in individual growth. This trend was also observed in CB and caspase-3 activities. Our results also suggest that the UV dose received by the mother and eggs has an additive effect with the dose received by the offspring. These results imply that the cumulative impact of small UVR doses (2 h per day, daily dose: 2520 J m−2 of 340 nm) on mothers and eggs (which cannot be discriminated in our experiments) can have an additive or synergistic effect along with the generations through a potential increase in lethal effect. Finally, the observed desynchronization in the molting process by UVR will affect the fitness of individuals and population dynamics.

Management Pearls on the Treatment of Actinic Keratoses and Field Cancerization.

Field cancerization (FC) is a chronic disease involving multiple clinical and subclinical actinic keratoses (AK) on large photo-exposed surfaces with multifocal areas of dysplasia and precancerous changes. Patients and treatment must be properly monitored and managed to avoid aggravation and progression of the disease. Management of actinic keratoses includes lesion-directed treatments, such as cryotherapy and field-directed therapies. Field-directed therapies may have the potential to address subclinical damage, reduce AK recurrence rates and potentially reduce the risk of squamous cell carcinoma development. Multiple studies have demonstrated the efficacy of field-directed treatments, including 5-fluorouracil, photodynamic therapy, imiquimod, chemical exfoliation with trichloroacetic acid and diclofenac gel, for multiple AK and FC. The choice of therapy should be based on multiple factors, such as efficacy, tolerability, patient risk profile, costs and cosmetic results. Management of AK includes not only treatment but also prevention. Medical devices, such as sunscreens containing liposome-encapsulated DNA repair enzymes, can repair DNA damage associated with chronic UV radiation and reduce the number of new AK lesions. Here we provide therapeutic pearls and expert opinions on the treatment of AK and FC (as monotherapy or in combination) with the overall aim to achieve better, faster, and well-tolerated clinical responses.

143 Identification of actinic keratosis susceptibility loci

Actinic keratosis (AK) is a keratinocyte-derived precancerous lesion that arises on skin exposed to chronic ultraviolet radiation. AK is highly prevalent, afflicting >58 million Americans, and its treatment costs are estimated at >$1 billion per year. AK can progress to keratinocyte carcinoma, including cutaneous squamous cell carcinoma (cSCC). Genetic risk has been implicated in AK, as evidenced by a genome-wide association study (GWAS), which identified 3 susceptibility loci (IRF4, TYR, and MC1R) among Europeans. To identify additional AK-associated loci, we performed a GWAS in non-Hispanic white participants of the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Participants with a physician-rendered diagnosis of AK were classified as cases (n=16,251), and the non-cases (n=46,454) were assigned to the control group. Genome-wide genotype data were generated on the Affymetrix Axiom European array and imputed to the 1000 Genomes reference panel. Genetic association analysis with AK was performed using logistic regression adjusted for age, sex, and ancestry principal components, and we identified ten genome-wide significant loci for AK (P<5×10-8), including 8 novel loci. Identified loci are implicated in the pigmentation pathway (IRF4, TYR, SLC45A2, BNC2, and HERC2), the Notch signaling pathway (FOXP1), the TGF-ß pathway (SPIRE2), immune regulation (HLA), coactivating receptors including retinoid and vitamin D receptors (NCOA6), and an additional locus DLGAP4 whose biologic relevance to AK risk is currently unknown. Interestingly, some of our AK-associated loci have been previously reported to be cSCC-associated loci (IRF4, TYR, SLC45A2, BNC2, HERC2, FOXP1, and HLA), suggesting common biological pathways in keratinocyte carcinogenesis. Study findings provide new insight into the genetic basis of AK susceptibility and may help identify subjects at higher risk for developing AK and cSCC. Further studies replicating our findings in an independent cohort are needed.

Hypofractionated radiotherapy in patients with non-melanoma skin cancer in the post COVID-19 era: Time to reconsider its role for most patients.

The most frequent cancer worldwide is skin cancer, occurring at epidemic rates in countries exposed to high levels of chronic ultraviolet radiation such as Australia and New Zealand (ANZ). Australia has the highest incidence of non‐melanoma skin cancer (NMSC) in the world. NMSC is predominantly a cancer of the middle aged or elderly and accounts for considerable consulting and treatment time in most radiation oncology departments. Many patients also suffer from medical co‐morbidity, an important factor in any treatment decision.

LOWER LIP SQUAMOUS CELL CARCINOMA WITH EXUBERANT PRESENTATION IN THE FACE: A CASE REPORT

Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm that affects the lower lip more because of chronic UV radiation exposure. The objective of this work is to describe a case of OSCC with exuberant clinical presentation on the face. We report a case of a 63-year-old woman with complaints of the appearance of a painless ulceration with slow growth in the lower lip for 3 years. In the extraoral examination, a huge tumor was observed with ulcerated and necrotic surface. Histologic sections revealed fragments of OSCC. She was referred for cancer treatment. This case reinforces the importance of the stomatologist for the correct diagnosis and treatment orientation. The case reported shows the importance of the diagnosis of oral malignant lesions performed by the stomatologist. Oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm that affects the lower lip more because of chronic UV radiation exposure. The objective of this work is to describe a case of OSCC with exuberant clinical presentation on the face. We report a case of a 63-year-old woman with complaints of the appearance of a painless ulceration with slow growth in the lower lip for 3 years. In the extraoral examination, a huge tumor was observed with ulcerated and necrotic surface. Histologic sections revealed fragments of OSCC. She was referred for cancer treatment. This case reinforces the importance of the stomatologist for the correct diagnosis and treatment orientation. The case reported shows the importance of the diagnosis of oral malignant lesions performed by the stomatologist.

Osmolyte transporter expression is reduced in photoaged human skin: Implications for skin hydration in aging.

Aging is characterized by the deterioration of tissue structure and function. In skin, environmental factors, for example, ultraviolet radiation (UVR), can accelerate the effects of aging such as decline in barrier function and subsequent loss of hydration. Water homeostasis is vital for all cellular functions and it is known that organic osmolyte transport is critical to this process. Therefore, we hypothesized that as we age, these tightly controlled physiological mechanisms become disrupted, possibly due to loss of transporter expression. We investigated this in vivo, using human skin samples from photoprotected and photoexposed sites of young and aged volunteers. We show a reduction in keratinocyte cell size with age and a downregulation of osmolyte transporters SMIT and TAUT with both chronic and acute UVR exposure. Single‐cell live imaging demonstrated that aged keratinocytes lack efficient cell volume recovery mechanisms possessed by young keratinocytes following physiological stress. However, addition of exogenous taurine significantly rescued cell volume; this was corroborated by a reduction in TAUT mRNA and protein in aged, as compared to young, keratinocytes. Collectively, these novel data demonstrate that human epidermal keratinocytes possess osmolyte‐mediated cell volume regulatory mechanisms, which may be compromised in aging. Therefore, this suggests that organic osmolytes—especially taurine—play a critical role in cutaneous age‐related xerosis and highlights a fundamental mechanism, vital to our understanding of the pathophysiology of skin aging.

Are there differences in immune responses following delivery of vaccines through acutely or chronically sun-exposed compared with sun-unexposed skin?

The majority of human vaccines are administered above the deltoid muscle of the arm, a site that is chronically sun-exposed in many people. It is known that exposure of the skin to the UV wavelengths in sunlight stimulates systemic immunosuppression, an outcome that is associated with reduced immunity to microbial infections in animal models. Here we consider whether immunization of humans through a UV-irradiated skin site will lead to a less effective immune response compared with immunization through an unexposed site. Studies showing that the efficacy of vaccination can be reduced when surrogates of increased levels of sun exposure, such as latitude of residence and season of the year, are considered. Results from a limited number of intervention experiments in humans demonstrate a similar pattern. To provide an explanation for these findings, changes in the number and functional potential of immune cells in chronically sun-exposed compared with unexposed skin are outlined. UV radiation-induced changes to skin cells are also relevant when considering skin sites for administration of immune-tolerizing peptides. The review provides the basis for further research into the effects of acute and chronic UV radiation exposure on skin cells in the context of vaccination.

Abstract 5087: Carvedilol prevents skin cancer independently of its antioxidant property

Abstract Carvedilol is an FDA approved β-blocker traditionally prescribed for cardiovascular diseases. Our previous work demonstrated that carvedilol has preventive activity against ultraviolet radiation (UVR)-induced skin damage, inflammation, and carcinogenesis. However, the photoprotective mechanism for carvedilol remains unknown. Interestingly, not all β-blockers have cancer preventive activity, suggesting that targeting the β-adrenergic receptors may not be responsible for carvedilol’s anticancer activity. Since carvedilol has been shown as a potent antioxidant and such property is not shared by majority of other β-blockers (e.g., metoprolol), we hypothesized that the antioxidant property may be, in part, responsible for carvedilol’s protective activity against photocarcinogenesis. The nontumorous mouse epidermal JB6 P+ cells were subjected to various doses of UVR exposure and H2O2 treatment to identify the optimal doses to examine protective activity. UVR and H2O2dose-dependently reduced cell viability. 25mJ/cm2 UVR and 100 μM H2O2 reduced cell viability detected by Trypan blue exclusion assay to 58.1% and 60.6%, respectively. 25mJ/cm2 UVR and 300 μM H2O2 increased the formation of intracellular fluorescent 2',7'-dichlorofluorescein (DCF) fluorescence, a marker of reactive oxidative species (ROS) detected by flow cytometry, to 5- and 4-fold compared to non-treated control, respectively. The cells were treated before or after UVR and H2O2 exposure with metoprolol, carvedilol or 4-hydroxycarbazole (4-OHC). 4-OHC is an intermediate compound for carvedilol synthesis that possesses an identical UV absorption profile as carvedilol. Additionally, the carbazole moiety is likely responsible for the antioxidant activity of carvedilol. Carvedilol, but not metoprolol and 4-OHC, was able to inhibit EGF-induced JB6 transformation in soft agar. Carvedilol, but not metoprolol and 4-OHC, also attenuated UVR and H2O2 induced cell death. Carvedilol, but not 4-OHC, inhibited UVR-induced NF-κB and AP-1 promoter activity. In addition, unlike carvedilol, 4-OHC failed to prevent chronic UVR induced skin carcinogenesis in SKH-1 mice. However, 4-OHC and carvedilol similarly attenuated UVR- and H2O2-induced ROS formation in JB6 P+ cells, while metoprolol had no effect. These results indicate that the photoprotective effects of carvedilol are primarily due to an unknown mechanism that is independent of β-adrenergic receptors and reactive oxygen species scavenging. Citation Format: Mengbing Chen, Sherry Liang, Bradley Andresen, Ying Huang. Carvedilol prevents skin cancer independently of its antioxidant property [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5087.

772 Age-associated alterations in pro-inflammatory cytokine signaling as well as UV-induced DNA damage contribute to increased basal cell carcinoma (BCC) tumor burden in Ptch1+/-/SKH-1 mice

Human BCC incidence is age-dependent. We have developed Ptch1+/-/SKH-1 mice as a model of human BCC pathogenesis. These mice progressively develop spontaneous BCCs, suggesting per se age-related effects on cancer induction irrespective of aberrant hedgehog signaling. Here, utilizing cohorts of young (2 months) and aged (> 20 months) mice, we tested the hypothesis that chronologically aged skin is more susceptible to ultraviolet radiation (UVR)-induced skin damage and BCC growth as compared to young adult skin. UVR-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PPs) were measured in genomic DNA isolated from skin tissues at 24, 48, and 72h post-irradiation (240 mJ/cm2, single exposure). CPD levels peaked at 24h, decreasing gradually and were virtually undetectable after 72h in all cohorts, irrespective of age and sex. A similar pattern was observed for UV-induced 6-4PP in young cohorts. In contrast, skin 6-4PP levels persisted in aged Ptch1+/-/SKH-1 mice, indicating age-related differences in DNA repair capacity. Moreover, circulating levels of inflammatory cytokines known to be altered in cancer and aging (IL1β, IL6, TNFα) were significantly elevated in both aged male and female Ptch1+/-/SKH-1 mice, as well as in UV-irradiated young cohorts. Aged Ptch1+/-/SKH-1 mice subjected to chronic UVR (180 mJ/cm2, 2x/week, 16 weeks) revealed statistically significant increases in tumor burden (UV-irradiated vs. non-irradiated aged cohorts), while we observed < 2-fold increase in BCC burden in UV-irradiated young cohorts vs. non-irradiated controls. These results demonstrate differential susceptibility to UVR-induced BCCs in young and aged Ptch1+/-/SKH-1 mice such that aging enhances BCC burden in Ptch1-deficient skin, and altered DNA damage responses and systemic pro-inflammatory cytokine signaling may contribute to age-dependent enhancement of BCC tumorigenesis in human populations.

Tropospheric ozone and skin aging: Results from two German cohort studies

During the last two decades, it has been well established that a short-term exposure to ozone (O3) elicits an oxidative stress response in human and mouse skin, which leads to aberrant transcriptional expression of genes consistent with increased skin aging. Whether a long-term exposure to ambient O3 is associated with any skin aging traits, has remained unclear. We addressed this question in two elderly German cohorts: the SALIA study (806 women aged 66–79 years), and the BASE-II study (1207 men and women aged 60–84 years). Five-year mean residential exposure to O3 was modeled as the number of days with maximum daily 8-h mean O3 concentrations ≥120 μg/m3 per year in the wider neighborhood (5-digit postcode) of a participant's residence. Extrinsic (environmentally induced) skin aging traits – coarse wrinkles and pigment spots (lentigines) on the face – were assessed by means of SCINEXA™, a validated visual score previously shown to be well suited to measure extrinsic facial skin aging in cohort studies. We observed positive associations of O3 exceedances with coarse wrinkles in the face, but not with pigment spots. These associations were present in each cohort as well as in the combined sample of both cohorts. They were independent of chronic ultraviolet radiation exposure as the most obvious confounder, and also of co-pollutants such as particulate matter and nitrogen dioxide. Thus, long-term exposure to elevated concentrations of tropospheric O3 appears to contribute to skin aging.

The Impact of Sunlight on Skin Aging

In this review, we summarize and discuss the current literature on photoaging. We focus on the molecular effects of UV radiation, and the histological and clinical features of chronically sun-exposed skin. The expression of numerous proteins is altered in habitually sun-exposed skin, including sirtuins and hedgehog signaling proteins. Pharmacological manipulation of the levels of these proteins can potentially downregulate the photoaging process. Mitochondrial and nuclear DNA damage, reactive oxygen species (ROS) production, and altered gene expression patterns are critical components of both photoaging and chronological aging. Chronic UVA and UVB exposure result in the photoaged phenotype through distinct molecular mechanisms, with UVA being primarily ROS-mediated and UVB being DNA damage-mediated. Molecular effects result in an altered dermal and epidermal environment that manifests as the photoaged phenotype. Importantly, skin phototype and environmental influences impact individual responses to chronic UV radiation.

Roles of the KEAP1-NRF2 system in mammalian skin exposed to UV radiation

The KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (NF-E2-related factor 2) system controls the biochemical defense activity against agents toxic to mammals and responds to exogenous and endogenous stressors such as electrophilic and oxidative substances, which can have destructive and genotoxic effects on affected mammalian tissues. Although this system can be activated by various environmental stressors, it remains unclear whether ultraviolet radiation (UVR), which is one of the major environmental agents that has inflammatory and carcinogenic impacts on human skin and eyes, induces NRF2-dependent defense activity. Here, we review the recent progress in the study of the contributions of NRF2 and related factors to protection against UVR. The KEAP1-NRF2 system is not always efficient in responding to UVR, especially to short wavelengths such as UVC/UVB, indicating that UVR is a poor activator of the KEAP1-NRF2 system. However, sustained activation of NRF2 appears to suppress the harmful effects of chronic UVR exposure, such as photoaging of and carcinogenesis in the skin, indicating that NRF2 activation is beneficial for the protection of the skin from the harmful effects of UVR. However, it should be noted that prolonged and strong activation of NRF2 may also have adverse effects on skin, especially in the case of UVR-induced carcinogenesis. We present working models describing mechanisms underlying the involvement of the KEAP1-NRF2 system in skin photoaging and carcinogenesis.

Pharmacokinetic and pharmacodynamic evaluation of ingenol mebutate for the treatment of actinic keratosis

ABSTRACTIntroduction: Actinic keratosis (AK) is a common skin condition that results from exposure to chronic ultraviolet (UV) radiation. AK is characterized by visible, scaly lesions; sub-clinical lesions may also be present within a field of UV-exposed skin. These lesions exist on a disease continuum with squamous cell carcinoma. Field therapies, such as ingenol mebutate, aim to treat the visible and sub-clinical lesions within an area of sun-damaged skin.Areas covered: According to the SmPC, ingenol mebutate has a proposed dual mechanism of action that induces cell death necrosis with the production of a local pro-inflammatory response and stimulation of apoptosis. In clinical trials, efficacy of ingenol mebutate has been shown through clearance of AK lesions. Adverse events and local skin responses generally resolved within 2–4 weeks from the end of treatment, depending on body location.Expert opinion: AK can be treated using lesion-directed or topical therapies. Topical treatment with ingenol mebutate has been shown to have superior efficacy compared with diclofenac/sodium hyaluronate. The short and simple treatment regimen may improve patient adherence to ingenol mebutate and satisfaction with treatment. It might be worth evaluating further indications for ingenol mebutate including treatment of basal cell carcinoma.

Molecular photoprotection of human keratinocytes in vitro by the naturally occurring mycosporine-like amino acid palythine.

SummaryBackgroundSolar ultraviolet radiation (UVR) induces molecular and genetic changes in the skin, which result in skin cancer, photoageing and photosensitivity disorders. The use of sunscreens is advocated to prevent such photodamage; however, most formulations contain organic and inorganic UVR filters that are nonbiodegradable and can damage fragile marine ecosystems. Mycosporine‐like amino acids (MAAs) are natural UVR‐absorbing compounds that have evolved in marine species for protection against chronic UVR exposure in shallow‐water habitats.ObjectivesTo determine if palythine, a photostable model MAA, could offer protection against a range of UVR‐induced damage biomarkers that are important in skin cancer and photoageing.MethodsHaCaT human keratinocytes were used to assess the photoprotective potential of palythine using a number of end points including cell viability, DNA damage (nonspecific, cyclobutane pyrimidine dimers and oxidatively generated damage), gene expression changes (linked to inflammation, photoageing and oxidative stress) and oxidative stress. The antioxidant mechanism was investigated using chemical quenching and Nrf2 pathway activation assays.ResultsPalythine offered statistically significant protection (P < 0·005) against all end points tested even at extremely low concentrations (0·3% w/v). Additionally, palythine was found to be a potent antioxidant, reducing oxidatively generated stress, even when added after exposure.ConclusionsPalythine is an extremely effective multifunctional photoprotective molecule in vitro that has potential to be developed as a natural and biocompatible alternative to currently approved UVR filters.

Impact of Ultraviolet Radiation on Expression of Transforming Growth Factor β, Smad2, Metalloproteinases-1, -3, -8, -9, Cathepsin K and Progerin.

Ultraviolet radiation (UVR) is one of the most important environmental factors involved in photoaging. Exposure to UVR leads to dysregulation of expression of cell cycle-related proteins which play key role in skin photodegradation that pretends to develop carcinogenesis. This study examines the role of various UVB doses on the expression of transforming growth factor beta (TGF-β), Smad2, cathepsin K, progerin and matrix metalloproteinases (MMPs)-1,-3,-8,-9. A group consisting of 63 healthy individuals underwent one of the following treatments: (1) whole body exposed to UVB irradiation on each of 10 consecutive days with 0.7 MED, or (2) whole-body irradiation as described followed by a single erythemal UVB dose on a small body area, or (3) irradiated only with a single erythemal UVB dose on small body area, or (4) were not irradiated at all (control group). When we compared all irradiated groups to the control group, there was significantly higher expression of TGF-β, MMP-1,-3,-9 and cathepsin K proteins evaluated by Western blot method. The results suggest the role of UVB in impairment of proteins expression that is involved in cell cycle's regulation. Changes in the protein expression involved by acute and chronic UVR confirm its essential role in skin photodestruction. Moreover, obtained result indicates the tendency to occurrence of photoadaptation phenomenon.

Primary tumor sites in relation to ultraviolet radiation exposure and skin visibility correlate with survival in cutaneous melanoma.

The prognostic value of detailed anatomic site and ultraviolet radiation (UVR) exposure patterns has not been fully determined in cutaneous melanoma. Thus, we reviewed medical records for detailed site in a population-based retrospective Swedish patient cohort diagnosed with primary invasive melanoma 1976-2003 (n = 5,973). We followed the patients from date of diagnosis until death, emigration or December 31st 2013, and evaluated melanoma-specific survival by subsite in a multivariable regression model adjusting for established prognostic factors. We found that melanoma on chronic UVR exposure sites (face, dorsum of hands; adjusted HR 0.6; CI 0.4-0.7) and moderately intermittent UVR sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6-0.8) were associated with a favorable prognosis compared with highly intermittent sites (chest, back, neck, shoulders and thighs). Further, melanoma on poorly visible skin sites upon self-examination (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area; HR 1.3; CI 1.1-1.5) had a worse prognosis than those on easily visible sites (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). In conclusion, highly intermittent UVR exposure sites and poor skin visibility presumably correlate with reduced melanoma survival, independent of established tumor characteristics. A limitation of the study was the lack of information on actual individual UVR exposure.

Inhibitory effects of rosmarinic acid on pterygium epithelial cells through redox imbalance and induction of extrinsic and intrinsic apoptosis

Pterygium is a common tumor-like ocular disease, which may be related to exposure to chronic ultraviolet (UV) radiation. Although the standard treatment for pterygium is surgical intervention, the recurrence rate of pterygium is high when no effective inhibitory drug is used after surgery. Rosmarinic acid (RA) is a polyphenol antioxidant with many biological activities, including anti-UV and anti-tumor properties. This study aimed to examine the inhibitory effects of RA on pterygium epithelial cells (PECs). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to examine the cell cytotoxicity of PECs after RA treatment. A fluorescent probe, DCFH-DA (2′,7’-dichlorofluorescin diacetate), was stained with PECs to measure intracellular reactive oxygen species (ROS) levels. Antioxidant activity assays were used to measure the levels of superoxide dismutase (SOD) and catalase (CAT) in PECs. Western blot analysis was used to determine the protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), quinone acceptor oxidoreductase 1 (NQO1), and apoptosis-associated proteins. RA significantly reduced the cell viability of the PECs. Treatment with RA remarkably increased the Nrf2 protein expression levels in the nucleus, HO-1 and NQO1 protein expression levels, and the activities of SOD and CAT. As a result, intracellular ROS levels in PECs were decreased. Additionally, the induction of extrinsic apoptosis on PECs by RA was associated with increasing expressions levels of Fas, Fas-associated protein with death domain (FADD), tumor necrosis factor-alpha (TNF-α), and caspase 8 protein. Moreover, the induction of intrinsic apoptotic cell death in PECs was confirmed through upregulation of cytochrome c, Bax, caspase 9, and caspase 3 and downregulation of Bcl-2 and pro-caspase 3. Our study demonstrated that RA could inhibit the viability of PECs through regulation of extrinsic and intrinsic apoptosis pathways. Therefore, RA may have potential as a therapeutic medication for pterygium.

Piperine attenuates UV-R induced cell damage in human keratinocytes via NF-kB, Bax/Bcl-2 pathway: An application for photoprotection

Chronic ultraviolet radiation (UV-R) exposure causes skin disorders like erythema, edema, hyperpigmentation, photoaging and photocarcinogenesis. Recent research trends of researchers have focused more attention on the identification and use of photo stable natural agents with photoprotective properties. Piperine (PIP), as a plant alkaloid, is an important constituent present in black pepper (Piper nigrum), used widely in ayurvedic and other traditional medicines and has broad pharmacological properties. The study was planned to photoprotective efficacy of PIP in human keratinocyte (HaCaT) cell line. We have assessed the UV-R induced activation of transcription factor NF-κB in coordination with cell death modulators (Bax/Bcl-2 and p21). The LC-MS/MS analysis revealed that PIP was photostable under UV-A/UV-B exposure. PIP (10μg/ml) attenuates the UV-R (A and B) induced phototoxicity of keratinocyte cell line through the restoration of cell viability, inhibition of ROS, and malondialdehyde generation. Further, PIP inhibited UV-R mediated DNA damage, prevented micronuclei formation, and reduced sub-G1 phase in cell cycle, which supported against photogenotoxicity. This study revealed that PIP pretreatment strongly suppressed UV-R induced photodamages. Molecular docking studies suggest that PIP binds at the active site of NF-κB, and thus, preventing its translocation to nucleus. In addition, transcriptional and translational analysis advocate the increased expression of NF-κB and concomitant decrease in IkB-α expression under UV-R exposed cells, favouring the apoptosis via Bax/Bcl-2 and p21 pathways. However, PIP induced expression of IkB-α suppress the NF-κB activity which resulted in suppression of apoptotic marker genes and proteins that involved in photoprotection. Therefore, we suggest the applicability of photostable PIP as photoprotective agent for human use.