UV-induced Oxidative Stress Research Articles

Quercetin and the ocular surface: What we know and where we are going.

Flavonoids are a class of plant and fungus secondary metabolites that serve functional roles in protecting against UV-induced oxidative stress, mediating auxin signaling, and promoting microbial defense. Flavonoids are extremely abundant in nature where their potent antioxidant capacity and very low toxicity makes them highly attractive as potential therapeutic agents. In terms of clinical applications, neither the Food and Drug Administration (FDA) nor the European Food Safety Authority (EFSA) has approved any health claims or drugs related to the use of flavonoids for therapeutic purposes. Quercetin is a common flavonol that has been shown to have potent antioxidant, anti-inflammatory, and anti-fibrotic activities both invitro and invivo in various tissues. Recently, the application of quercetin as a therapeutic has been gaining attention in the ocular surface scientific community in the study of dry eye, keratoconus, inflammation, and neovascularization of the cornea. This review will discuss the latest findings and the use of quercetin for the treatment of dystrophies of the ocular surface. Impact statement The eye represents a small portion of the human body, accounting for one decimal fraction of the anterior body surface. The cornea is an avascular, transparent tissue that acts as a primary barrier against mechanical and infectious damaging agents, protecting the internal structures of the eye. Corneal survival and function are affected by a number of factors including but not limited to injury, trauma, infection, genetics, and environment. Corneal injury, or trauma, often leads to loss of corneal transparency and even blindness. The concept of "curing" corneal opacity has been discussed in published form for over 200 years. Currently, full corneal transplant is the only treatment option. There is a strong interest in developing natural therapeutic products that come with minimum side effects. A novel antioxidant flavonoid, quercetin, has been gaining traction as a potential therapeutic to prevent the injured cornea. This review discusses the potential of this antioxidant.

MiRNA-141 attenuates UV-induced oxidative stress via activating Keap1-Nrf2 signaling in human retinal pigment epithelium cells and retinal ganglion cells.

Activation of NF-E2-related factor 2 (Nrf2) signaling could protect cells from ultra violet (UV) radiation. We aim to provoke Nrf2 activation via downregulating its inhibitor Keap1 by microRNA-141 (“miR-141”). In both human retinal pigment epithelium cells (RPEs) and retinal ganglion cells (RGCs), forced-expression of miR-141 downregulated Keap1, causing Nrf2 stabilization, accumulation and nuclear translocation, which led to transcription of multiple antioxidant-responsive element (ARE) genes (HO1, NOQ1 and GCLC). Further, UV-induced reactive oxygen species (ROS) production and cell death were significantly attenuated in miR-141-expressing RPEs and RGCs. On the other hand, depletion of miR-141 via expressing its inhibitor antagomiR-141 led to Keap1 upregulation and Nrf2 degradation, which aggravated UV-induced death of RPEs and RGCs. Significantly, Nrf2 shRNA knockdown almost abolished miR-141-mediated cytoprotection against UV in RPEs. These results demonstrate that miR-141 targets Keap1 to activate Nrf2 signaling, which protects RPEs and RGCs from UV radiation.

SC79 protects retinal pigment epithelium cells from UV radiation via activating Akt-Nrf2 signaling.

Excessive Ultra-violet (UV) radiation causes oxidative damages and apoptosis in retinal pigment epithelium (RPE) cells. Here we tested the potential activity of SC79, a novel small molecule activator of Akt, against the process. We showed that SC79 activated Akt in primary and established (ARPE-19 line) RPE cells. It protected RPE cells from UV damages possibly via inhibiting cell apoptosis. Akt inhibition, via an Akt specific inhibitor (MK-2206) or Akt1 shRNA silence, almost abolished SC79-induced RPE cytoprotection. Further studies showed that SC79 activated Akt-dependent NF-E2-related factor 2 (Nrf2) signaling and inhibited UV-induced oxidative stress in RPE cells. Reversely, Nrf2 shRNA knockdown or S40T mutation attenuated SC79-induced anti-UV activity. For the in vivo studies, we showed that intravitreal injection of SC79 significantly protected mouse retina from light damages. Based on these results, we suggest that SC79 protects RPE cells from UV damages possibly via activating Akt-Nrf2 signaling axis.

Sclareol isolated from Salvia officinalis improves facial wrinkles via an antiphotoaging mechanism.

Ultraviolet (UV) irradiation triggers skin photoaging processes, which disrupt the normal three-dimensional integrity of skin. UV-induced oxidative stress, both directly and indirectly, stimulates complex signaling pathways. UV radiation activates skin cell surface receptors on a molecular level and triggers severe changes in extracellular matrix (ECM) proteins, resulting in skin photoaging. Sclareol isolated from Salvia officinalis is widely used as a fragrance material. Sclareol is known to exert various biological activities, but its antiphotoaging effect has not been elucidated to date. Therefore, we evaluated wrinkle improvement efficacy of sclareol. Human dermal fibroblast cell line (Hs68) and a reconstructed human epidermis (RHE) model were used to evaluate the antiphotoaging effect of sclareol in vitro. A clinical study treated with 0.02% sclareol-containing cream was conducted to identify the ability of sclareol to improve wrinkles. First, sclareol enhanced cellular proliferation and blocked UVB-induced cell death. Sclareol inhibited the UVB-induced mRNA expression of matrix metalloproteinases (MMPs) by regulating the protein expression of AP-1 constituents. In RHE model, sclareol recovered the UVB-induced decrease in epidermal thickness and the expression of proliferating cell nuclear antigen (PCNA). In clinical trial, visually assessed changes and several wrinkle parameters were considered to be statistically different between the test and control groups at 12 weeks. In this study, sclareol inhibited various photoaging phenomena in human fibroblasts and RHE model. In addition, sclareol-containing cream improved wrinkles in a clinical trial. Taken together, sclareol alleviates facial wrinkle formation via an antiphotoaging mechanism and may be an effective candidate ingredient.

Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging

Skin is the largest human organ. Skin continually reconstructs itself to ensure its viability, integrity, and ability to provide protection for the body. Some areas of skin are continuously exposed to a variety of environmental stressors that can inflict direct and indirect damage to skin cell DNA. Skin homeostasis is maintained by mesenchymal stem cells in inner layer dermis and epidermal stem cells (ESCs) in the outer layer epidermis. Reduction of skin stem cell number and function has been linked to impaired skin homeostasis (e.g., skin premature aging and skin cancers). Skin stem cells, with self-renewal capability and multipotency, are frequently affected by environment. Ultraviolet radiation (UVR), a major cause of stem cell DNA damage, can contribute to depletion of stem cells (ESCs and mesenchymal stem cells) and damage of stem cell niche, eventually leading to photoinduced skin aging. In this review, we discuss the role of UV-induced DNA damage and oxidative stress in the skin stem cell aging in order to gain insights into the pathogenesis and develop a way to reduce photoaging of skin cells.

The cross-talk between electrophiles, antioxidant defence and the endocannabinoid system in fibroblasts and keratinocytes after UVA and UVB irradiation

BackgroundUV, including UVA and UVB radiation, is one of the most ubiquitous environmental stress factors to human skin and leads to redox imbalance and, consequently, photoaging and cancer development. The aim of the study was to verify which skin cells, keratinocytes or fibroblasts, were more susceptible to UVA or UVB irradiation. ObjectiveKeratinocytes and fibroblasts were subjected to UVA and UVB irradiation. MethodsThe redox potential (superoxide anion generation and antioxidant level/activity), electrophile level and endocannabinoid system were estimated. ResultsThe results presented in this paper demonstrate a strong relationship between UV-induced oxidative stress and changes in the endocannabinoid system. Simultaneously, in irradiated cells, the transcription factors Nrf1, Nrf2 and NFκB are activated to varying degrees. Fibroblasts have a greater susceptibility to ROS generation and transcription factor activation after both UVA and UVB irradiation than keratinocytes. Keratinocytes are more sensitive to changes in the electrophile levels connected with oxidative stress compared to fibroblasts. ConclusionThe differences demonstrated in the response of the tested cells to UV irradiation allow for a better understanding of the mechanisms occurring in the human skin, which may be exploited for future therapies in dermatology.

PP27 - The cross-talk between oxidative stress and endocannabinoid system in keratinocytes after UV irradiation

Daily skin exposure to UV radiation may cause skin damage connected mainly with imbalance in the redox status and metabolic disturbances. Therefore to evaluate the cross-talk between oxidative stress and endocannabinoid system of skin cells following UV, keratinocytes were subjected to UVA and UVB irradiation [30 J/cm2 and 60 mJ/cm2, respectively]. The redox status was estimated by ROS generation and oxidative modifications of lipid and protein were examined. The endocannabinoids and their receptors levels were also measured. Our results showed that UV irradiation caused an increase both in ROS generation and in lipid peroxidation markers in tested cell line. UVA irradiation resulting in even a two-fold increase in the level of 4-HNE in keratinocytes, whereas UVB exerted the strongest increase in 4-HHE level. UVA caused a stronger increase in MDA level than UVB radiation. Simultaneously an increase level of protein oxidative modifications markers such as dityrosine and carbonyl groups was observed. Obtained results also demonstrated that UV irradiation affected the endocannabinoid system. In the case of UVA irradiation, applied dose leads to 2 times reduction in the AEA level in compared to control cells, while UVB irradiation reduces it about 5 times. Further, it was observed that the exposure of cells to UVB irradiation significantly reduced the level of 2-AG. Parallel to these changes a reduction in the amount of endocannabinoids receptors CB1, CB2 and TVR1 in cytoplasm and their increased activation in membrane fraction after cells exposure to UVA or UVB irradiation was shown. In addition, there was a higher expression of Nrf2 and all Nrf2 activators induced stronger by UVB than UVA radiation. Obtained results demonstrate a strong association between changes in endocannabinoid signalization and UV-induced oxidative stress in keratinocytes, which may be important point to searching for the skin protecting method from harmful ultraviolet radiation.

FICZ: A Messenger of Light in Human Skin

Photosensitization, subsequent to photon absorption by chromophores present in the human skin, appears to be a key mechanism of UV-induced oxidative stress. The tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ), an aryl hydrocarbon receptor ligand, has been found to be a potent UVA photosensitizer, effective at nanomolar concentrations. A novel addition to the family of endogenous photosensitizers, the precise mechanism(s) through which it mediates oxidative stress in UVA exposed skin and its response to the UVB spectrum of the solar UV flux remains unexplored. Further studies related to its functionality in the human skin, its utility as a tool against UV-induced adverse effects, and its role in inflammatory skin diseases will have the potential to open up new avenues in the realms of human skin photobiology.

Protective effect of C. sativa leaf extract against UV mediated-DNA damage in a human keratinocyte cell line

Toxic effects of ultraviolet (UV) radiation on skin include protein and lipid oxidation, and DNA damage. The latter is known to play a major role in photocarcinogenesis and photoaging. Many plant extracts and natural compounds are emerging as photoprotective agents. Castanea sativa leaf extract is able to scavenge several reactive species that have been associated to UV-induced oxidative stress. The aim of this work was to analyze the protective effect of C. sativa extract (ECS) at different concentrations (0.001, 0.01, 0.05 and 0.1μg/mL) against the UV mediated-DNA damage in a human keratinocyte cell line (HaCaT). For this purpose, the cytokinesis-block micronucleus assay was used. Elucidation of the protective mechanism was undertaken regarding UV absorption, influence on 1O2 mediated effects or NRF2 activation. ECS presented a concentration-dependent protective effect against UV-mediated DNA damage in HaCaT cells. The maximum protection afforded (66.4%) was achieved with the concentration of 0.1μg/mL. This effect was found to be related to a direct antioxidant effect (involving 1O2) rather than activation of the endogenous antioxidant response coordinated by NRF2. Electrochemical studies showed that the good antioxidant capacity of the ECS can be ascribed to the presence of a pool of different phenolic antioxidants. No genotoxic or phototoxic effects were observed after incubation of HaCaT cells with ECS (up to 0.1μg/mL). Taken together these results reinforce the putative application of this plant extract in the prevention/minimization of UV deleterious effects on skin.

UV-Induced Oxidative Stress in Cyanobacteria: How Life is able to Survive?

UV-Induced Oxidative Stress in Cyanobacteria: How Life is able to Survive?

54. 1a,25-Dihydroxyvitamin D3 reduces several types of UV induced DNA damage in human ex vivo skin

1α,25dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) is produced in skin following exposure to ultraviolet radiation (UVR). On the other hand, UVR can also cause DNA damage. Cyclobutane pyrimidine dimers (CPD) are produced as a direct consequence of UVB exposure. Other photolesions, such as 8-oxo-7,8-dihydroguanosine (8-oxodG) and 8-nitroguanine (8-NG) are produced by UV-induced oxidative and nitrosative stress. All these DNA lesions are potentially mutagenic and may lead to photocarcinogenesis unless repaired promptly through DNA repair processes. Nitric oxide products and reactive nitrogen species (RNS) are known to hinder DNA repair and promote carcinogenesis. Previous studies have shown that 1,25(OH) 2 D 3 and the analog 1α,25(OH) 2 -lumisterol (JN) protect skin cells from UV-induced DNA damage (CPD), immunosuppression and photocarcinogenesis in mice. 1 The aim of this study was to test whether topical application of 1,25(OH) 2 D 3 is also photoprotective in UV-irradiated human skin explants. UV-induced DNA damage was quantified by immunohistochemistry and image analysis using antibodies to 3 different types of DNA damage: CPD, 8-oxodG, and 8-NG. Quantification by image analysis showed 1,25(OH) 2 D 3 post-UVR, significantly reduced all 3 types of DNA damage. CPD was reduced by 57% (±SEM=2.6; p p p 2 D 3 (37% reduction; p p 2 D 3 reduces UV induced nitrosative stress in skin. This data suggests that 1,25(OH) 2 D 3 provides photoprotection in human ex vivo skin through reduction in UV induced CPD, oxidative and nitrosative stress.

The evolving role of the NAD+/nicotinamide metabolome in skin homeostasis, cellular bioenergetics, and aging

Human skin is exposed to daily environmental insults, particularly solar radiation, that triggers a range of molecular responses. These perturbations to the normal homeostatic state can lead to cellular dysfunction and, ultimately, impacts tissue integrity and accelerates skin aging (photoaging). One of the responses is increased oxidative stress which has been shown to disrupt cellular bioenergetics. This can be detected by depletion of the nucleotide energy metabolites NAD+ and ATP as both an acute transient decrease and, over time, a more permanent chronic reduction due in part to cumulative damage of mitochondria. NAD+ and its primary precursor nicotinamide have been known for some time to impact skin homeostasis based on linkages to dietary requirements, treatment of various inflammatory conditions, photoaging, and prevention of cancer. Cellular NAD+ pools are known to be lower in aged skin and treatment with nicotinamide is hypothesized to restore these levels, thereby mitigating cellular bioenergetics dysfunction. In dermal fibroblasts, nicotinamide is able to protect against oxidative stress to glycolysis, oxidative phosphorylation as well as increase mitochondrial efficiency via sirtuin-dependent selective mitophagy. Recent research has found that NAD+ cellular pools are more dynamic than previously thought, oscillating in tandem with free nicotinamide, and serves as a regulatory point and feedback loop in cellular metabolism regulation, maintenance of mitochondrial efficiency, and circadian rhythmicity. Since UV-induced oxidative stress in skin can disrupt these processes, continued molecular understanding of the role of NAD+ and nicotinamide in skin biology is important to identify interventions that would help maintain its normal homeostatic functions and efficient cellular bioenergetics.

Detecting free radicals in sunscreens exposed to UVA radiation using chemiluminescence

One of the current concerns with the application of nanoparticles in sunscreens, and in particular nano-TiO2 and ZnO, is their potential to photogenerate free radicals and reactive oxygen species (ROS) when they absorb ultraviolet wavelengths from sunlight. Free radicals and ROS are known to be associated with UV-induced skin damage and oxidative stress, from which sunscreens are expected to offer significant protection. Here we describe a simple method, based on chemiluminescence emission, for detecting free radicals generated in commercial sunscreens alone, and when applied to various substrates, following exposure to UVA (320–400nm) radiation. This photo-induced chemiluminescence (PICL) technique could be used to optimise sunscreen formulations so as to minimise free radical photogeneration during exposure to sunlight.

Oral administration of Bifidobacterium breve attenuates UV-induced barrier perturbation and oxidative stress in hairless mice skin

Recent studies have shown that some probiotics affect not only the gut but also the skin. However, the effects of probiotics on ultraviolet (UV)-induced skin damage are poorly understood. In this study, we aim to examine whether oral administration of live Bifidobacterium breve strain Yakult (BBY), a typical probiotic, can attenuate skin barrier perturbation caused by UV and reactive oxygen species (ROS) in hairless mice. The mice were orally supplemented with a vehicle only or BBY once a day for nine successive days. Mouse dorsal skin was irradiated with UV from days 6 to 9. The day after the final irradiation, the transepidermal water loss (TEWL), stratum corneum hydration, and oxidation-related factors of the skin were evaluated. We elucidated that BBY prevented the UV-induced increase in TEWL and decrease in stratum corneum hydration. In addition, BBY significantly suppressed the UV-induced increase in hydrogen peroxide levels, oxidation of proteins and lipids, and xanthine oxidase activity in the skin. Conversely, antioxidant capacity did not change regardless of whether BBY was administered or not. In parameters we evaluated, there was a positive correlation between the increase in TEWL and the oxidation levels of proteins and lipids. Our results suggest that oral administration of BBY attenuates UV-induced barrier perturbation and oxidative stress of the skin, and this antioxidative effect is not attributed to enhancement of antioxidant capacity but to the prevention of ROS generation.

Prevention of UVA-induced oxidative damage in human dermal fibroblasts by new UV filters, assessed using a novel in vitro experimental system.

BackgroundUVA rays present in sunlight are able to reach the dermal skin layer generating reactive oxygen species (ROS) responsible for oxidative damage, alterations in gene expression, DNA damage, leading to cell inflammation, photo-ageing/-carcinogenesis. Sunscreens contain UV filters as active ingredients that absorb/reflect/dissipate UV radiation: their efficiency depends on their spectral profile and photostability which should then be reflected in biological protection of underlying skin.MethodsA set of new UV filters was synthesized, and the most photostable one was compared to BMDBM, a widely used UVA filter. Cultured human dermal fibroblasts were exposed to UVA radiation which was filtered by a base cream containing or not UV filters placed above cell culture wells. The endpoints measured were: cell viability (MTT assay), ROS generation (DCFH-DA assay), mitochondrial function (JC-1 assay), DNA integrity (Comet assay) and gene expression (MMP-1, COL1A1) by RT-qPCR.ResultsThe new UV filter resulted more efficient than BMDBM in preserving cell viability, mitochondrial functionality and oxidative DNA damage, despite similar inhibition levels of intracellular ROS. Moreover, expression of genes involved in dermal photoageing were positively affected by the filtering action of the tested molecules.ConclusionsThe experimental model proposed was able to validate the efficacy of the new UV filter, taking into account important cellular events related to UV-induced intracellular oxidative stress, often underestimated in the assessments of these compounds.General SignificanceThe model may be used to compare the actual biological protection of commercial sunscreens and suncare products aside from their SPF and UVA-PF values.

The influence of ambient ultraviolet light on sperm quality and sexual ornamentation in three-spined sticklebacks (Gasterosteus aculeatus)

Exposure to enhanced levels of ambient ultraviolet (UV) radiation (UVR) can have adverse effects on aquatic organisms including damage at the cellular and molecular level and impairment of development, fecundity and survival. Much research has been conducted on the role of the harmful UVB radiation. However, due to its greater penetration in water the more abundant UVA radiation can also act as an environmental stressor. Little is known about UVR effects on sperm characteristics although sperm cells should be especially prone to UV-induced oxidative stress. Moreover, UV-related changes in oxidative status may affect the phenotypic expression of energetically costly sexual ornaments. We investigated the effects of long-term exposure to ecologically relevant levels of simulated UVA radiation on sperm quality and sexual ornamentation in three-spined sticklebacks (Gasterosteus aculeatus). Males were assigned to three spectral exposure treatments differing in the UV spectral part so that they received either enhanced, moderate or no UVA radiation. The results reveal that exposure to enhanced ambient UVA levels had detrimental effects on both male breeding coloration and sperm velocity providing evidence that UVR affects traits targeted by pre- and post-copulatory sexual selection. By highlighting the role of UVA as a factor influencing fitness-relevant traits, our findings may contribute to a better understanding of the consequences of current and future levels of solar UVR for mating systems and life history.

Transcriptomic analysis of UV-treated rice leaves reveals UV-induced phytoalexin biosynthetic pathways and their regulatory networks in rice

Rice produces diterpenoid and flavonoid phytoalexins for defense against pathogen attack. The production of phytoalexins in rice is also induced by UV-irradiation. To understand the metabolic networks involved in UV-induced phytoalexin biosynthesis and their regulation, phytochemical and transcriptomic analyses of UV-treated rice leaves were performed. In response to UV treatment, the accumulation of flavonoids was observed in rice leaves, which may serve as antioxidants against UV-induced oxidative stress. The phytochemical analysis confirmed sakuranetin accumulation and also demonstrated the induction of phenylamide synthesis in rice leaves by UV-irradiation. Transcriptomic analysis established that aromatic amino acid biosynthetic genes were immediately up-regulated after UV treatment. The genes involved in the phenylpropanoid pathway and flavonoid biosynthesis were also up-regulated. These findings suggest that the aromatic amino acid and flavonoid biosynthetic pathways are coordinately activated for the production of flavonoids and phenolic phytoalexins such as sakuranetin and phenylamides. An in silico analysis of UV-induced O-methyltransferase and acyltransferase genes suggested that these genes may be implicated in sakuranetin and phenylamide synthesis, respectively. The transcriptomic analysis also showed up-regulation of both methylerythritol phosphate pathway and the diterpenoid phytoalexin biosynthetic genes in response to UV treatment. A functional gene network analysis of phytoalexin biosynthetic and UV-induced genes for signaling components and transcription factors using RiceNet suggested that regulatory networks comprising signal perceiving receptor kinases, G-proteins, signal transducing mitogen-activated protein kinases and calcium signaling components, and transcription factors control flavonoid and phytoalexin biosynthesis in rice leaves under UV-C stress conditions.

Selenium for the Prevention of Cutaneous Melanoma

The role of selenium (Se) supplementation in cancer prevention is controversial; effects often depend on the nutritional status of the subject and on the chemical form in which Se is provided. We used a combination of in vitro and in vivo models to study two unique therapeutic windows for intervention in the process of cutaneous melanomagenisis, and to examine the utility of two different chemical forms of Se for prevention and treatment of melanoma. We studied the effects of Se in vitro on UV-induced oxidative stress in melanocytes, and on apoptosis and cell cycle progression in melanoma cells. In vivo, we used the HGF transgenic mouse model of UV-induced melanoma to demonstrate that topical treatment with l-selenomethionine results in a significant delay in the time required for UV-induced melanoma development, but also increases the rate of growth of those tumors once they appear. In a second mouse model, we found that oral administration of high dose methylseleninic acid significantly decreases the size of human melanoma xenografts. Our findings suggest that modestly elevation of selenium levels in the skin might risk acceleration of growth of incipient tumors. Additionally, certain Se compounds administered at very high doses could have utility for the treatment of fully-malignant tumors or prevention of recurrence.

ULTRAVIOLET PROTECTIVE PROPERTIES OF LATIN AMERICAN HERBS ON SACCHAROMYCES CEREVISIAE AND LIKELY MODE OF ACTION THROUGH THE PROLINE-LINKED PENTOSE PHOSPHATE PATHWAY: FOCUS ON THE YERBA MATE TEA (ILEX PARAGUARIENSIS)

ABSTRACT The ultraviolet (UV) protective effects of aqueous herb extracts from Latin America such as Yerba Mate (Ilex paraguariensis), Chancapiedra (Phyllanthus niruri L.) and Huacatay (Tagetes minuta) were assessed by using the UV light-induced cell death in Saccharomyces cerevisiae yeast model. UV radiation–mediated oxidative stress promoted cell death of S. cerevisiae by inducing breakdown of its energy metabolism. The addition of high-phenolic herb extracts (61–103 mg gallic acid equivalents/g dw) prior to UV treatment protected yeast from UV-induced oxidative stress and delayed death. This effect appeared to be related with the high free radical scavenging activities shown by all extracts (91%). Insights into the UV protective mechanisms of Yerba Mate extract in yeast model indicated that protection was achieved by maintaining the growth-supporting tricarboxylic acid cycle/NADH–linked system and the proline-linked mitochondrial oxidative phosphorylation coupled to pentose phosphate pathway. Therefore, studied herb extracts show potential protective properties against UV radiation–induced yeast death. PRACTICAL APPLICATIONS Yerba Mate (Ilex paraguariensis), Chancapiedra (Phyllanthus niruri L.) and Huacatay (Tagetes minuta) have been traditionally consumed in Latin American countries because of their potential health benefits. Results from this study using the UV-induced cell death in Saccharomyces cerevisiae yeast model indicate that such high-phenolic herbs (61–103 mg gallic acid equivalents/g dw) would have potential applications as beneficial dietary supplements for protecting eukaryotic cells against UV-induced free radical–mediated damage with potential implications in the dietary management of oxidation-linked diseases in humans. Furthermore, the model for the UV-protective effect of external phenolic phytochemicals in eukaryotic cellular systems proposed by our laboratory was investigated, and according to results from this study, this model could provide a sound rationale for understanding the mechanism of action of phenolic phytochemicals from dietary or medicinal plants in cellular systems and help screen diverse relevant extracts influencing endogenous enzyme response more rapidly.

Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm 2) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes ( HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD.