Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging.

INTRODUCTION: The analysis of the role of the mitochondria in oxidative damage and skin aging has been a significant aspect of dermatological research. Mitochondria generate most reactive oxygen species (ROS) which, in excess, are cytotoxic and DNA-damaging and promote (photo-)aging. However, ROS also possesses key physiological and regulatory functions and mitochondrial dysfunction is prominent in several not primarily senescence-associated skin diseases and skin cancers. Although many standard dermatotherapeutics modulate mitochondrial function, dermatological therapy rarely targets the mitochondria. Accordingly, there is a rationale for 'mitochondrial dermatology'-based approaches to be applied to therapeutic research, as we advocate here. AREAS COVERED: This paper examines the functions of mitochondria in cutaneous physiology beyond energy (ATP) and ROS production. Keratinocyte differentiation and epidermal barrier maintenance, appendage morphogenesis and homeostasis, photoaging and skin cancer are considered. Based on related PubMed search results, the paper evaluates thyroid hormones, glucocorticoids, Vitamin D3 derivatives, retinoids, cannabinoid receptor agonists, PPARγ agonists, thyrotropin, and thyrotropin-releasing hormone as instructive lead compounds. Moreover, the mitochondrial protein MPZL3 as a promising new drug target for future 'mitochondrial dermatology' is highlighted. EXPERT OPINION: Future dermatological therapeutic research should have a mitochondrial medicine emphasis. Focusing on selected lead agents, protein targets, in silico drug design, and model diseases will fertilize a mito-centric approach.

Human papillomavirus vaccine initiation and up-to-date vaccine coverage for adolescents after the implementation of school-entry policy in Puerto Rico.

The human papillomavirus (HPV) vaccine has been proven effective in the prevention of infection with high-risk HPV types, which can lead to the development of six HPV-related cancers. Puerto Rico (PR) adopted a mandatory HPV vaccination school-entry policy that took effect in August 2018. While school-entry requirements are generally accepted as an effective approach for increasing vaccination rates, there are few studies that have documented their impact on improving HPV vaccination rates. The objective of this study was to evaluate the impact of the HPV school-entry policy in PR on HPV vaccine coverage. We used a pre-post natural experiment. The study population included adolescents registered in the PR Immunization Registry during 2008-2019. We calculated HPV vaccine initiation and up-to-date (UTD) vaccine coverage rates. We estimated age-standardized rates (ASR) and standardized rate ratio with 95%CI. Vaccine data corresponding to a total of 495,327 adolescents were included for analysis; 50.9% were male and 49.1% were females. After policy implementation, a marked increase in raw HPV vaccine initiation among 11- to 12-year-old adolescents was observed across years 2017 (a pre-policy year), 2018, and 2019 (58.3%, 76.3%, and 89.8%, respectively). UTD coverage also showed a moderate increase after policy implementation among 11- to 12-year-old adolescents. The gap between sexes in vaccine initiation and UTD coverage narrowed over time; the ASRs in 2019 showed an increase of 19% in initiation and 7% increase in UTD relative to 2017 for males and females combined (both significant at p<0.05). This study demonstrated evidence of improvement in HPV vaccination rates following implementation of the school-entry policy and a narrowed sex gap in vaccine rates over time in PR. Future analyses should assess how the policy continues to affect vaccine coverage in subsequent years and how the COVID-19 pandemic has impacted HPV vaccination uptake.

Microneedle-based devices for point-of-care infectious disease diagnostics.

Recent infectious disease outbreaks, such as COVID-19 and Ebola, have highlighted the need for rapid and accurate diagnosis to initiate treatment and curb transmission. Successful diagnostic strategies critically depend on the efficiency of biological sampling and timely analysis. However, current diagnostic techniques are invasive/intrusive and present a severe bottleneck by requiring specialist equipment and trained personnel. Moreover, centralised test facilities are poorly accessible and the requirement to travel may increase disease transmission. Self-administrable, point-of-care (PoC) microneedle diagnostic devices could provide a viable solution to these problems. These miniature needle arrays can detect biomarkers in/from the skin in a minimally invasive manner to provide (near-) real-time diagnosis. Few microneedle devices have been developed specifically for infectious disease diagnosis, though similar technologies are well established in other fields and generally adaptable for infectious disease diagnosis. These include microneedles for biofluid extraction, microneedle sensors and analyte-capturing microneedles, or combinations thereof. Analyte sampling/detection from both blood and dermal interstitial fluid is possible. These technologies are in their early stages of development for infectious disease diagnostics, and there is a vast scope for further development. In this review, we discuss the utility and future outlook of these microneedle technologies in infectious disease diagnosis.

Individual and combined effects of the infrared, visible, and ultraviolet light components of solar radiation on damage biomarkers in human skin cells.

The ability of solar ultraviolet (UV) to induce skin cancer and photoaging is well recognized. The effect of the infrared (IR) and visible light (Vis) components of solar radiation on skin and their interaction with UV is less well known. This study compared the effects of physiologically relevant doses of complete (UV + Vis + IR) solar-simulated light and its individual components on matched primary dermal fibroblasts and epidermal keratinocytes from human donors on three biomarkers of cellular damage (reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA), and nuclear DNA (nDNA) damage). There was a greater induction of ROS, mtDNA, and nDNA damage with the inclusion of the visible and IR components of solar-simulated light in primary fibroblast cells compared to primary keratinocytes (P < .001). Experiments using exposure to specific components of solar light alone or in combination showed that the UV, Vis, and IR components of solar light synergistically increased ROS generation in primary fibroblasts but not primary keratinocytes (P < .001). Skin cell lines were used to confirm these findings. These observations have important implications for different skin cell type responses to the individual and interacting components of solar light and therefore photodamage mechanisms and photoprotection interventions.

Optimised detection of mitochondrial DNA strand breaks.

Intrinsic and extrinsic factors that induce cellular oxidative stress damage tissue integrity and promote ageing, resulting in accumulative strand breaks to the mitochondrial DNA (mtDNA) genome. Limited repair mechanisms and close proximity to superoxide generation make mtDNA a prominent biomarker of oxidative damage. Using human DNA we describe an optimised long-range qPCR methodology that sensitively detects mtDNA strand breaks relative to a suite of short mitochondrial and nuclear DNA housekeeping amplicons, which control for any variation in mtDNA copy number. An application is demonstrated by detecting 16-36-fold mtDNA damage in human skin cells induced by hydrogen peroxide and solar simulated radiation.

Effect of an Educational Video to Increase Calls and Screening into an Anal Cancer Clinical Trial Among HIV+ Hispanics in PR: Results from a Randomized Controlled Behavioral Trial.

Anal cancer incidence is higher in persons living with HIV/AIDS (PLWHA) than in the general population. Participation of PLWHA in anal cancer clinical trials (CTs) is essential; Hispanic PLWHA are underrepresented in CTs. We conducted a behavioral CT among 305 PLWHA in Puerto Rico to measure the efficacy of an educational video in increasing calls and screening into an anal cancer CT. Participants received printed educational materials on anal cancer and CTs; the intervention group also received an educational video. Outcome assessment based on follow-up interviews showed that printed materials increased awareness about CTs and high-resolution anoscopy (HRA), and willingness to participate in an anal cancer CT in both groups. However, the addition of the video increased the likelihood of participants to call the CT for orientation (RRadjusted = 1.66, 95% CI 1.00-2.76; p = 0.05) and pre-screening evaluation (RRadjusted = 1.70, 95% CI 0.95-3.03; p = 0.07). This intervention could help increase participation of Hispanics into anal cancer-related CTs.

Disparities in human papillomavirus-related cancer incidence and survival among human immunodeficiency virus-infected Hispanics living in the United States.

BACKGROUND: Human papillomavirus (HPV) causes 10% of cancers among human immunodeficiency virus (HIV)-infected people in the United States. Because Hispanics are disproportionally affected by the HIV epidemic and by infection-related cancers, this study compared incidence rates for HPV-related cancers and survival between Hispanics and non-Hispanic whites (NHWs) and non-Hispanic blacks (NHBs) in the HIV-infected US population. METHODS: Based on data from the HIV/AIDS Cancer Match Study, standardized incidence ratios (SIRs) were used to estimate cancer risk in HIV-infected Hispanics and the general US Hispanic population. Among HIV-infected people, cancer rates were compared with incidence rate ratios (IRRs), and survival was compared with hazard ratios between Hispanics and NHWs and NHBs. RESULTS: Five hundred two HPV-related cancers occurred in 864,067 person-years of follow-up among HIV-infected Hispanics. Except for oropharyngeal cancer, the risk of HPV-related cancers was higher among HIV-infected Hispanics than in the general population (SIR range, 3.59 [cervical cancer] to 18.7 [anal cancer in men]). Among HIV-infected females, Hispanics had higher cervical cancer rates than NHWs (IRR, 1.70; 95% confidence interval [CI], 1.19-2.43) but lower vulvar cancer rates than NHWs (IRR, 0.40; 95% CI, 0.24-0.67) and NHBs (IRR, 0.62; 95% CI, 0.41-0.95). Among HIV-infected males, Hispanics had higher penile cancer rates than NHWs (IRR, 2.60; 95% CI, 1.36-4.96) but lower anal cancer rates than NHWs (IRR, 0.54; 95% CI, 0.46-0.63) and NHBs (IRR, 0.65; 95% CI, 0.56-0.77). Among HIV-infected Hispanics, 5-year survival was greater than 50% across HPV-related cancer types, with no major differences by racial/ethnic group. CONCLUSIONS: HIV-infected Hispanics have an elevated risk for HPV-related cancers. Similarly to the general population, HIV-infected Hispanics have higher rates of cervical and penile cancer than NHWs and NHBs. HPV vaccination should be promoted among HIV-infected individuals to reduce the burden of HPV-related cancers.

UVA-induced carbon-centred radicals in lightly pigmented cells detected using ESR spectroscopy.

Ultraviolet-A and melanin are implicated in melanoma, but whether melanin in vivo screens or acts as a UVA photosensitiser is debated. Here, we investigate the effect of UVA-irradiation on non-pigmented, lightly and darkly pigmented melanocytes and melanoma cells using electron spin resonance (ESR) spectroscopy. Using the spin trap 5,5 Dimethyl-1-pyrroline N-oxide (DMPO), carbon adducts were detected in all cells. However, higher levels of carbon adducts were detected in lightly pigmented cells than in non-pigmented or darkly pigmented cells. Nevertheless, when melanin levels were artificially increased in lightly pigmented cells by incubation with L-Tyrosine, the levels of carbon adducts decreased significantly. Carbon adducts were also detected in UVA-irradiated melanin-free cell nuclei, DNA-melanin systems, and the nucleoside 2'-deoxyguanosine combined with melanin, whereas they were only weakly detected in irradiated synthetic melanin and not at all in irradiated 2'-deoxyguanosine. The similarity of these carbon adducts suggests they may be derived from nucleic acid- guanine - radicals. These observations suggest that melanin is not consistently a UVA screen against free-radical formation in pigmented cells, but may also act as a photosensitizer for the formation of nucleic acid radicals in addition to superoxide. The findings are important for our understanding of the mechanism of damage caused by the UVA component of sunlight in non-melanoma and melanoma cells, and hence the causes of skin cancer.

Population-Based Study of Tobacco Use Among People Living With HIV in Puerto Rico.

BACKGROUND: Despite substantial advances in the era of highly active antiretroviral therapy, HIV-positive persons are at high risk of tobacco-related disease and mortality. This study describes the prevalence and sociodemographic factors associated with current tobacco use among HIV-positive men and women 18 years and older receiving HIV care in Puerto Rico. METHODS: Data from the 2009 Medical Monitoring Project (MMP) was used. A three-stage sampling design was conducted to obtain annual cross-sectional probability samples of HIV-infected adults in care. Factors associated with current tobacco use were identified using logistic regression models. All analyses were performed using STATA version 11.0. RESULTS: The estimated prevalence of current cigarette use among the population was 29.0% (95%CI: 23.5%-35.2%), daily smoking was reported in 76.7% of them. Multivariate logistic regression models, showed that male drug users (injected and noninjected) were up to nine times more likely to be current smokers (OR = 9.9; 95%CI = 3.1, 31.5) as compared to nonusers. CONCLUSION: Findings highlight the need for smoking cessation strategies in this population, particularly among male HIV+ drug users.

Anal Cancer Risk Among People With HIV Infection in the United States.

Purpose People with HIV infection have an elevated risk of anal cancer. However, recent calendar trends are incompletely described, and which population subgroups might benefit from cancer screening is unknown. Methods We used linked data from HIV and cancer registries in nine US areas (1996 to 2012). We calculated standardized incidence ratios to compare anal cancer incidence in people with HIV infection with the general population, used Poisson regression to evaluate anal cancer incidence among subgroups of people with HIV and to assess temporal trends, and estimated the cumulative incidence of anal cancer to measure absolute risk. Results Among 447,953 people with HIV infection, anal cancer incidence was much higher than in the general population (standardized incidence ratio, 19.1; 95% CI, 18.1 to 20.0). Anal cancer incidence was highest among men who have sex with men (MSM), increased with age, and was higher in people with AIDS than in those without AIDS (ie, HIV only; adjusted incidence rate ratio, 3.82; 95% CI, 3.27 to 4.46). Incidence among people with HIV increased steeply during 1996 to 2000 (annual percentage change, 32.8%; 95% CI, -1.0% to 78.2%), reached a plateau during 2001 to 2008, and declined during 2008 to 2012 (annual percentage change, -7.2%; 95% CI, -14.4% to 0.6%). Cumulative incidence after a 5-year period was high for MSM with HIV only age 45 to 59 or ≥ 60 years (0.32% to 0.33%) and MSM with AIDS age 30 to 44, 45 to 59, or ≥ 60 years (0.29% to 0.65%). Conclusion Anal cancer incidence is markedly elevated among people with HIV infection, especially in MSM, older individuals, and people with AIDS. Recent declines may reflect delayed benefits of HIV treatment. Groups with high cumulative incidence of anal cancer may benefit from screening.

A pilot study investigating reactive oxygen species production in capillary blood after a marathon and the influence of an antioxidant-rich beetroot juice.

We report that reactive oxygen species (ROS), as measured in capillary blood taken from the finger-tip, increased after a marathon (+128% P < 0.01; effect size = 1.17), indicating that this collection method might be useful for measuring ROS in field settings. However, mitochondrial DNA damage remained unchanged. Beetroot juice, taken before and after exercise, was unable to mitigate exercise-induced ROS production, questioning its use an antioxidant-rich food.

Aware, motivated and striving for a 'safe tan': an exploratory mixed-method study of sun-protection during holidays.

Background: This article presents an exploratory study, aiming to explore the correspondence between knowledge, motivation and sun-protection practices during holidays. Methods: Seventeen participants aged 21-62 years old, recruited from community settings took part in individual face-to-face semi-structured interviews, completed sun sensitivity questions and an objective assessment of sunscreen use. Holidaymakers' knowledge about sun-safe messages, intentions and perceptions of barriers and facilitators for sun-protection were assessed. Qualitative data were analysed using thematic analysis and integrated with quantitative data, using a pragmatic theory-informed approach to synthesise the findings. Results: Participants were well informed about sun-safe messages, highly motivated to protect themselves from solar UV radiation (UVR) and they perceived themselves as well protected. However, they did not seem to use effective protective practices. Sunscreen was the preferred method of sun-protection, but most participants used considerably less than the recommended amount and significantly overestimated the amount of time they could be safely exposed. Seeking shade was the least used method of sun-protection and covering-up strategies were mostly implemented as a partial protection (i.e. hats or sunglasses). The desire to reach an optimal balance between getting a tan and using sun-protection to avoid sunburns was preeminent. Several additional barriers and facilitators for sun-protection were identified. Conclusions: Holidaymakers might have a false sense of security when it comes to sun-exposure. They are aware of the need to protect from solar UVR, but the motive for a safe tan, the overreliance on sunscreen, the overestimation of the safe sun-exposure time for their skin type and the insufficient application of sunscreen leaves holidaymakers motivated to protect their skin at significant risk of overexposure, sunburn and skin cancer. Public health messages need to address how to implement effective sun-safe strategies.

Systematic and Iterative Development of a Smartphone App to Promote Sun-Protection Among Holidaymakers: Design of a Prototype and Results of Usability and Acceptability Testing.

BACKGROUND: Sunburn and intermittent exposure to ultraviolet rays are risk factors for melanoma. Sunburn is a common experience during holidays, making tourism settings of particular interest for skin cancer prevention. Holidaymakers are a volatile populations found at different locations, which may make them difficult to reach. Given the widespread use of smartphones, evidence suggests that this might be a novel, convenient, scalable, and feasible way of reaching the target population. OBJECTIVE: The main objective of this study was to describe and appraise the process of systematically developing a smartphone intervention (mISkin app) to promote sun-protection during holidays. METHODS: The iterative development process of the mISkin app was conducted over four sequential stages: (1) identify evidence on the most effective behavior change techniques (BCTs) used (active ingredients) as well as theoretical predictors and theories, (2) evidence-based intervention design, (3) co-design with users of the mISkin app prototype, and (4) refinement of the app. Each stage provided key findings that were subsequently used to inform the design of the mISkin app. RESULTS: The sequential approach to development integrates different strands of evidence to inform the design of an evidence-based intervention. A systematic review on previously tested interventions to promote sun-protection provided cues and constraints for the design of this intervention. The development and design of the mISkin app also incorporated other sources of information, such as other literature reviews and experts' consultations. The developed prototype of the mISkin app was evaluated by engaging potential holidaymakers in the refinement and further development of the mISkin app through usability (ease-of-use) and acceptability testing of the intervention prototype. All 17 participants were satisfied with the mISkin prototype and expressed willingness to use it. Feedback on the app was integrated in the optimization process of the mISkin app. CONCLUSIONS: The mISkin app was designed to promote sun-protection among holidaymakers and was based on current evidence, experts' knowledge and experience, and user involvement. Based on user feedback, the app has been refined and a fully functional version is ready for formal testing in a feasibility pilot study.

Determination of the Action Spectrum of UVR-Induced Mitochondrial DNA Damage in Human Skin Cells.

Biological responses of human skin to UVR including cancer and aging are largely wavelength-dependent, as shown by the action spectra of UVR-induced erythema and nuclear DNA (nDNA) damage. A molecular dosimeter of UVR exposure is therefore required. Although mitochondrial DNA (mtDNA) damage has been shown to be a reliable and sensitive biomarker of UVR exposure in human skin, its wavelength dependency is unknown. The current study solves this problem by determining the action spectrum of UVR-induced mtDNA damage in human skin. Human neonatal dermal fibroblasts and primary human adult keratinocyte cells were irradiated with increasing doses of UVR. Dose-response curves of mtDNA damage were produced for each of the UVR sources and cell types, and an action spectrum for each cell type was determined by mathematical induction. Similarities between these mtDNA damage action spectra and previously determined nDNA damage were observed, with the most detrimental effects occurring over the shorter UVR wavelengths. Notably, a statistically significant (P<0.0001) greater sensitivity to mtDNA damage was observed in dermal fibroblasts compared with keratinocytes at wavelengths >300 nm, possibly indicating a wider picture of depth dependence in sensitivity. This finding has implications for disease/photodamage mechanisms and interventions.

Sebum, inflammasomes and the skin: current concepts and future perspective.

Increasing evidence has identified ultraviolet radiation (UVR) as the skins most potent mutagen as over exposure results in sunburn, inflammation and DNA damage, thus contributing to a photo-ageing phenotype and possibly skin carcinogenesis. The lipid-rich sebum secreted onto the surface of the skin plays an important physiological role in protecting the skin against external challenges. When skin is photosensitised by UVR, the lipid constituents of sebum are easily oxidised, generating several lipid photo-oxidative products (e.g. squalene peroxides). These photo-oxidative products have been shown to exert diverse toxicological, biological and immunological effects in the skin and have therefore been implicated in several detrimental skin alterations including premature skin ageing. The involvement of lipid peroxidation products in UVR-induced inflammatory responses has been inadequately studied and highly controversial. Furthermore, it is unclear to what extent these oxidative products contribute to the underlying mechanisms of skin photo-ageing. Therefore, this viewpoint essay will discuss the current knowledge on the effect of UVR exposure on skin surface lipids and how these may mediate UVR-induced inflammatory responses which may be key contributors to photo-damage in skin. This essay will also examine the potential role of inflammasomes (innate immune complexes) in the inflammatory response associated with UVR-induced lipid peroxidation. Limited evidence is available on the interactions between sebaceous lipids, downstream mediators and concomitant immune response in sun-exposed skin and clearer elucidation may lead to novel biomarkers of photo-ageing and the incorporation of new molecules into current skin therapies which better target oxidised lipids and or downstream mediators/pathways.

Impact of hyperpigmentation on superoxide flux and melanoma cell metabolism at mitochondrial complex II.

Melanogenesis is a highly conserved process of cytophotoprotection from UV radiation present in many species. Although both mitochondrial function and UV radiation insults are well-documented promoters of increased cellular stress, their individual molecular relationships with skin pigmentation have not been clearly resolved. This study provides evidence for a direct relationship between cellular melanin content, superoxide flux, and mitochondrial function at complex II. Direct and significant correlation between increased pigmentation and complex II turnover was observed in genetically different melanoma cell lines of varied basal pigmentation states (P < 0.01). The same trend was also observed when comparing genetically identical cell cultures with increasing levels of induced pigmentation (P < 0.005). The observation of increased steady-state levels of the catalytic complex II succinate dehydrogenase subunit A alongside hyperpigmentation suggested coregulation of activity and pigment production (P < 0.01). The study also presents novel evidence for a relationship between hyperpigmentation and increased superoxide-generating capacity at complex II. By amperometrically monitoring superoxide flux from differently pigmented FM55 melanocytes and their isolated mitochondria, a dynamic and responsive relationship between pigmentation, complex II function, and intracellular superoxide generation was observed (P < 0.005). The data support hyperpigmentation as a protective antioxidant mechanism in response to complex II-mediated reactive oxygen species generation.

A role for human mitochondrial complex II in the production of reactive oxygen species in human skin.

The mitochondrial respiratory chain is a major generator of cellular oxidative stress, thought to be an underlying cause of the carcinogenic and ageing process in many tissues including skin. Previous studies of the relative contributions of the respiratory chain (RC) complexes I, II and III towards production of reactive oxygen species (ROS) have focussed on rat tissues and certainly not on human skin which is surprising as this tissue is regularly exposed to UVA in sunlight, a potent generator of cellular oxidative stress. In a novel approach we have used an array of established specific metabolic inhibitors and DHR123 fluorescence to study the relative roles of the mitochondrial RC complexes in cellular ROS production in 2 types of human skin cells. These include additional enhancement of ROS production by exposure to physiological levels of UVA. The effects within epidermal and dermal derived skin cells are compared to other tissue cell types as well as those harbouring a compromised mitochondrial status (Rho-zero A549). The results show that the complex II inhibitor, TTFA, was the only RC inhibitor to significantly increase UVA-induced ROS production in both skin cell types (P<0.05) suggesting that the role of human skin complex II in terms of influencing ROS production is more important than previously thought particularly in comparison to liver cells. Interestingly, two-fold greater maximal activity of complex II enzyme was observed in both skin cell types compared to liver (P<0.001). The activities of RC enzymes appear to decrease with increasing age and telomere length is correlated with ageing. Our study showed that the level of maximal complex II activity was higher in the MRC5/hTERT (human lung fibroblasts transfected with telomerase) cells than the corresponding wild type cells (P=0.0012) which can be considered (in terms of telomerase activity) as models of younger and older cells respectively.

Comparing the effects of mitochondrial targeted and localized antioxidants with cellular antioxidants in human skin cells exposed to UVA and hydrogen peroxide.

Skin cancer and aging are linked to increased cellular reactive oxygen species (ROS), particularly following exposure to ultraviolet A (UVA) in sunlight. As mitochondria are the main source of cellular ROS, this study compared the protective effects of mitochondria-targeted and -localized antioxidants (MitoQ and tiron, respectively) with cellular antioxidants against oxidative stress-induced [UVA and hydrogen peroxide (H2O2)] mitochondrial DNA (mtDNA) damage in human dermal fibroblasts. With the use of a long quantitative PCR assay, tiron (EC50 10 mM) was found to confer complete (100%) protection (P<0.001) against both UVA- and H2O2-induced mtDNA damage, whereas MitoQ (EC50 750 nM) provided less protection (17 and 32%, respectively; P<0.05). This particular protective effect of tiron was greater than a range of cellular antioxidants investigated. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway provides cellular protection against oxidative stress. An ELISA assay for the Nrf2 target gene heme oxygenase-1 (HO-1) and studies using Nrf2 small interfering RNA both indicated that tiron's mode of action was Nrf2 independent. The comet assay showed that tiron's protective effect against H2O2-induced nuclear DNA damage was greater than the cellular antioxidants and MitoQ (P<0.001). This study provides a platform to investigate molecules with similar structure to tiron as potent and clinically relevant antioxidants.

Whales use distinct strategies to counteract solar ultraviolet radiation.

A current threat to the marine ecosystem is the high level of solar ultraviolet radiation (UV). Large whales have recently been shown to suffer sun-induced skin damage from continuous UV exposure. Genotoxic consequences of such exposure remain unknown for these long-lived marine species, as does their capacity to counteract UV-induced insults. We show that UV exposure induces mitochondrial DNA damage in the skin of seasonally sympatric fin, sperm, and blue whales and that this damage accumulates with age. However, counteractive molecular mechanisms are markedly different between species. For example, sperm whales, a species that remains for long periods at the sea surface, activate genotoxic stress pathways in response to UV exposure whereas the paler blue whale relies on increased pigmentation as the season progresses. Our study also shows that whales can modulate their responses to fluctuating levels of UV, and that different evolutionary constraints may have shaped their response strategies.

Stressed out mitochondria: the role of mitochondria in ageing and cancer focussing on strategies and opportunities in human skin.

Mitochondrial DNA damage has been used as a successful and unique biomarker of tissue stress. A valuable example of this is sun damage in human skin which leads to ageing and skin cancer. The skin is constantly exposed to the harmful effects of sunlight, such as ultraviolet radiation, which causes it to age with observable characteristic features as well as clinical precancerous lesions and skin cancer. Formation of free radicals by the sun's harmful rays which contribute to oxidative stress has been linked to the induction of deletions and mutations in the mitochondrial DNA. These markers of mitochondrial DNA damage have been proposed to contribute to the mechanisms of ageing in many tissues including skin and are associated with many diseases including cancer. In this article we highlight the role of this important organelle in ageing and cancer with particular emphasis on experimental strategies in the skin.