Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aß), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aß instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aß associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and ß-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Tracking neuroinflammatory biomarkers in Alzheimer's disease: a strategy for individualized therapeutic approaches?

BACKGROUND: Recent trials of anti-amyloid-ß (Aß) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD. MAIN BODY: Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aß reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aß deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aß ("A"), tau ("T"), and neurodegeneration ("N"), by incorporating a novel inflammatory component ("I"). CONCLUSIONS: The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.

Impact of different job types on serum cytokine levels in apparently healthy individuals: A comparative study among airline pilots, construction workers, and fitness instructors.

BACKGROUND: The impact of occupational factors on serum cytokine concentrations has not been extensively explored. In this preliminary investigation, we measured the amounts of 12 cytokines in the serum of healthy individuals, comparing three diverse professional categories (aviation pilots, building laborers, and exercise trainers) with distinct work settings and lifestyle factors. METHODS: The study sample comprised 60 men from three distinct professional fields - airline pilots, construction laborers, and fitness trainers (20 participants per category) - who were enlisted during regular outpatient occupational health appointments. Serum levels of interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-α, and IFN-γ were measured on a Luminex® platform using a specific kit. Cytokine levels were compared among the three professional groups to determine any significant differences. RESULTS: Among the three occupational groups, fitness instructors demonstrated elevated IL-4 concentrations in comparison to both airline pilots and construction laborers, with no significant difference between the latter two professions. Additionally, a stepwise increase in IL-6 levels was identified, commencing with fitness instructors presenting the lowest quantities, succeeded by construction workers, and culminating with airline pilots, who displayed the most elevated concentrations. CONCLUSION: Serum cytokine levels in healthy individuals can exhibit variations based on their occupation. Given the unfavorable cytokine profile detected in airline pilots, it is crucial for the aviation sector to tackle potential health concerns within their employees.

Topical application of bacteriocins from Bacillus subtilis promotes Staphylococcus aureus decolonization in acneic skin and improves the clinical appearance of mild-to-moderate acne.

Introduction: Patients with mild-to-moderate acne are frequently colonized by Staphylococcus aureus on their skin, which alters microenvironmental skin conditions and exacerbates disease symptoms. Bacteriocins produced by Bacillus subtilis may act as antimicrobial peptides against Gram-positive bacteria. Aim: To investigate whether topical application of bacteriocins from B. subtilis could serve as a potential strategy for promoting S. aureus decolonization from acneic skin. Material and methods: The research product was a cream formulation containing 1% bacteriocins from B. subtilis. First, we conducted a 60-day pilot study on the effect of topically applied bacteriocins from B. subtilis on the absolute abundance of S. aureus in 12 patients with mild-to-moderate acne. Second, we designed an 8-week, uncontrolled, open-label, multicentre clinical study to investigate whether the topical application of bacteriocins from B. subtilis reduces the number of inflammatory and non-inflammatory lesions, as well as Global Acne Grading Scale (GAGS) scores, in 373 patients with mild-to-moderate acne. Results: At the microbiological level, quantitative PCR showed a decrease in the absolute abundance of S. aureus in acne areas after topical application of the research product for 60 days (-38%, p < 0.001). In the clinical study, the number of inflammatory and non-inflammatory lesions was found to decrease at 8 weeks by 59% (p < 0.001) and 58% (p < 0.001), respectively, compared with baseline. A 56% decrease was observed for GAGS scores. Conclusions: Topical bacteriocins from B. subtilis can promote S. aureus decolonization in acneic skin, ultimately improving the clinical appearance of mild-to-moderate acne.

Skin biophysical parameters and serum dermokine levels in airline pilots: a comparative study with office workers.

Introduction: Concerns are growing in the aviation industry about occupational skin diseases like malignant melanoma (MM) among airline pilots (APs), due to the unique working environment that exposes them to various skin stressors. Aim: To compare five skin biophysical parameters in a group of 40 male APs, each matched in terms of age and service tenure (minimum of 5 years) with a control group of 40 male office workers (OWs). Considering the potential role of dermokine (DMKN) in skin barrier dysfunction and the pathogenesis of MM, we further analyzed the serum levels of this molecule and correlated them with the measured skin parameters. Material and methods: Stratum corneum skin hydration, transepidermal water loss (TEWL), sebum content, erythema index (EI), and melanin index (MI) were quantified by non-invasive instruments in the cheek region. Serum DMKN levels were measured using a commercially available enzyme-linked immunosorbent assay kit. Results: Compared with OWs, the skin of APs exhibited a decrease in hydration levels in the stratum corneum, coinciding with a higher TEWL. However, there was no significant variance in sebum content between the groups. MI was notably higher in APs than in OWs, as was EI. In APs, serum DMKN levels were independently associated with MI (ß = 0.56, p < 0.05). Conclusions: We found a significant link between the profession of an airline pilot and changes in skin biophysical parameters. Further research into the interplay between serum DMKN levels and the risk of MM in APs is warranted.

Human dermal fibroblast response to hyaluronic acid-based injectable dermal fillers: an in vitro study.

Introduction: Hyaluronic acid (HA)-based injectable dermal fillers (IDFs) used in aesthetic procedures may increase fibroblast activity and ultimately improve subcutaneous tissue quality. Aim: To further our understanding of fibroblast response to different commercial HA-based IDFs. Material and methods: Normal human dermal fibroblasts (NHDFs) were cultured with four different commercially available HA-based IDFs to assess their effects on the synthesis of extracellular matrix components and regulators (type I collagen, type III collagen, elastin, and transforming growth factor (TGF)-ß1) as well as pro-inflammatory and oxidative DNA damage markers (interleukin (IL)-1ß and 8-hydroxy-2'-deoxyguanosine (8-OHdG)). The six biomarkers were measured in supernatants from NHDF cultures after 24 h, 48 h, and 72 h of exposure to HA-based IDFs. Results: All tested IDFs elicited a higher release of type I collagen in NHDF culture supernatants, although Juvederm Voluma was found to induce the most pronounced increase. Agex Fill Ultra induced the highest production of type III collagen and elastin. Levels of TGF-ß1 and type I collagen in cell culture supernatants were positively correlated to each other (r = 0.57, p < 0.05). Conversely, 8-OHdG concentrations were inversely associated with both type III collagen (r = -0.41, p < 0.05) and elastin (r = -0.46, p < 0.05). Conclusions: Commercially available HA-based IDFs may elicit different in vitro fibroblast responses - a finding with potential implications in the prediction of their effects in aesthetic procedures. Our results also confirm that in vitro experiments may be viable tools for testing the effects of HA-based IDFs without resorting to animal studies.

Physical Exercise and Alzheimer's Disease: Effects on Pathophysiological Molecular Pathways of the Disease.

Alzheimer's disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.

A proprietary herbal extract titred in verbascoside and aucubin suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 in human neutrophils.

INTRODUCTION: Bacterial lipopolysaccharide (LPS) initiates several major cellular responses that play a crucial role in the pathogenesis of inflammation, including activation of neutrophils and production of prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2). MATERIAL AND METHODS: Recent years have witnessed a growing interest in natural compounds as promising alternatives to synthetic COX-2 inhibitors. In this study, we sought to investigate the effect of a proprietary herbal extract from Lippia citriodora and Plantago lanceolata, titred in verbascoside (≥ 5%) and aucubin (≥ 2%), against LPS-stimulated expressions of COX-2 in human neutrophils using both reverse transcription-polymerase chain reaction (RT-PCR) and a PGE2 immunoassay. RESULTS: Our main results indicated that: 1. The proprietary herbal extract titred in verbascoside and aucubin is not significantly cytotoxic as shown by the MTT assay; 2. The extract does not significantly inhibit COX-1, whereas it is able to suppress LPS-elicited COX-2 hyperexpression at the mRNA level in human neutrophils; and 3. The effect of the extract at 5% concentration was comparable to that elicited celecoxib 1%, although, in terms of absolute and relative reduction of COX-2 mRNA expression and production of PGE2 in human neutrophils, the drug significantly outperformed the extract. CONCLUSIONS: In general, these results suggest that the proprietary herbal extract titred in verbascoside and aucubin is safe and may possess significant anti-inflammatory and analgesic effects by acting as a specific COX-2 inhibitor. Further studies are required to confirm the clinical efficacy of the extract.

Supplements with purported effects on muscle mass and strength.

PURPOSE: Several supplements are purported to promote muscle hypertrophy and strength gains in healthy subjects, or to prevent muscle wasting in atrophying situations (e.g., ageing or disuse periods). However, their effectiveness remains unclear. METHODS: This review summarizes the available evidence on the beneficial impacts of several popular supplements on muscle mass or strength. RESULTS: Among the supplements tested, nitrate and caffeine returned sufficient evidence supporting their acute beneficial effects on muscle strength, whereas the long-term consumption of creatine, protein and polyunsaturated fatty acids seems to consistently increase or preserve muscle mass and strength (evidence level A). On the other hand, mixed or unclear evidence was found for several popular supplements including branched-chain amino acids, adenosine triphosphate, citrulline, ß-Hydroxy-ß-methylbutyrate, minerals, most vitamins, phosphatidic acid or arginine (evidence level B), weak or scarce evidence was found for conjugated linoleic acid, glutamine, resveratrol, tribulus terrestris or ursolic acid (evidence level C), and no evidence was found for other supplements such as ornithine or α-ketoglutarate (evidence D). Of note, although most supplements appear to be safe when consumed at typical doses, some adverse events have been reported for some of them (e.g., caffeine, vitamins, α-ketoglutarate, tribulus terrestris, arginine) after large intakes, and there is insufficient evidence to determine the safety of many frequently used supplements (e.g., ornithine, conjugated linoleic acid, ursolic acid). CONCLUSION:  In summary, despite their popularity, there is little evidence supporting the use of most supplements, and some of them have been even proven ineffective or potentially associated with adverse effects.

Clinical effectiveness of parenteral trazodone for the management of psychomotor activation in patients with bipolar disorder.

OBJECTIVES: Trazodone is a multifunctional triazolopyridine drug with antidepressant, anxiolytic, sedative, and hypnotic properties. The current retrospective study was designed to investigate the effectiveness of trazodone for reducing acute psychomotor activation (PA) in patients with bipolar disorder (BD). We specifically reasoned that a parenteral route of administration could offer potential advantages in this clinical setting. METHODS: We assessed the effectiveness and safety of parenteral trazodone in a retrospective study conducted in 64 inpatients with BD and acute PA. The effectiveness assessment was the Clinical Global Impression Scale - Severity Of Illness (CGI-S) rated before the administration of parenteral trazodone (baseline) and at the end of treatment. A post-treatment reduction in CGI-S score ≥ 20% compared with baseline was considered as the primary outcome measure. RESULTS: Administration of parenteral trazodone was associated with significant improvements in CGI-S scores from baseline (5.4 ± 0.9) to the end of the study (4.2 ± 1.0; p < 0.001, Wilcoxon matched-pairs signed-ranks test). A total of 34 patients (53.1%) showed a post-treatment reduction in CGI-S score ≥ 20% compared to baseline. Multivariable binary logistic regression analysis using a forward selection procedure identified treatment duration (in days) as the only independent predictor of post-treatment reduction in CGI-S score ≥ 20% (odds ratio: 1.28; 95% confidence interval: 1.02-1.60, p <0.05). Adverse effects occurred in 13 (20.3%) patients. CONCLUSIONS: Parenteral trazodone is well-tolerated and effective in 53.1% of patients with BP and acute PA. Treatment duration was identified as an independent predictor of response in our sample.

Epistasis, physical capacity-related genes and exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 and APOE.

BACKGROUND: Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. RESULTS: We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P < 0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P < 0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P < 0.05). CONCLUSIONS: The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.

Comparative effects of a fixed Polypodium leucotomos/Pomegranate combination versus Polypodium leucotomos alone on skin biophysical parameters.

OBJECTIVES: Polypodium leucotomos extract is a commonly used systemic photoprotective agent. In an exploratory fashion, the current study aimed to compare the effects of oral supplementation with a fixed Polypodium leucotomos/pomegranate combination (PPmix®) versus Polypodium leucotomos alone (Fernblock®) on skin biophysical parameters of Caucasian adults. METHODS: Forty healthy adult volunteers (20 males and 20 females; mean age: 37.2±5.5 years) were randomized in a 1:1 fashion to a fixed Polypodium leucotomos/pomegranate combination (480 mg/day; n=20) or Polypodium leucotomos alone (480 mg/day; n=20) for 3 months. Six skin biophysical parameters (skin sebum content, hydration, transepidermal water loss [TEWL], erythema index, melanin index, and elasticity) were measured at baseline and after 3 months by personnel blinded to participant allocation. RESULTS: At the end of the study, hydration and elasticity were significantly improved and TEWL was reduced in both groups, without significant intergroup differences. The erythema index was decreased by both treatments, although the fixed Polypodium leucotomos/pomegranate combination was significantly more effective. Finally, melanin index and skin sebum content were reduced by the fixed Polypodium leucotomos/pomegranate combination, whereas Polypodium leucotomos alone did not affect them. CONCLUSIONS: Our results suggest that a fixed Polypodium leucotomos/pomegranate combination provides a greater improvement of skin biophysical parameters compared to Polypodium leucotomos alone in adult Caucasians. Our findings may have implications for optimizing systemic skin photoprotection and beautification strategies.

'Adipaging': ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue.

The increasing ageing of our societies is accompanied by a pandemic of obesity and related cardiometabolic disorders. Progressive dysfunction of the white adipose tissue is increasingly recognized as an important hallmark of the ageing process, which in turn contributes to metabolic alterations, multi-organ damage and a systemic pro-inflammatory state ('inflammageing'). On the other hand, obesity, the paradigm of adipose tissue dysfunction, shares numerous biological similarities with the normal ageing process such as chronic inflammation and multi-system alterations. Accordingly, understanding the interplay between accelerated ageing related to obesity and adipose tissue dysfunction is critical to gain insight into the ageing process in general as well as into the pathophysiology of obesity and other related conditions. Here we postulate the concept of 'adipaging' to illustrate the common links between ageing and obesity and the fact that, to a great extent, obese adults are prematurely aged individuals.

IPSCs, a Promising Tool to Restore Muscle Atrophy.

Induced pluripotent stem cells (iPSCs) are a promising tool for regenerative medicine in chronic conditions associated with muscle atrophy since iPSCs are easier to obtain, pose less ethical limitations and can better capture human genetic diversity compared with human embryonic stem cells. We highlight the potentiality of iPSCs for treating muscle-affecting conditions for which no effective cure is yet available, notably aging sarcopenia and inherited neurometabolic conditions. J. Cell. Physiol. 231: 259-260, 2016. © 2015 Wiley Periodicals, Inc.

Galectin-3, osteopontin and successful aging.

BACKGROUND: Individuals who reach exceptional longevity (100+ years of age) free of common chronic age diseases (i.e. 'dodgers') arguably represent the paradigm of successful aging in humans. As such, identification of potential biomarkers associated with this phenomenon is of medical interest. METHODS: We measured serum levels of galectin-3 and osteopontin, both of which have been shown to be linked with major chronic or aging-related disorders in younger populations, in centenarian 'dodgers' (n=81; 40 men; 100-104 years) and healthy controls (n=41; 24 men, 70-80 years). RESULTS: Both biomarkers showed significantly lower values (p<0.001) in the former (galectin-3: 2.4±1.7 vs. 4.8±2.8 ng/mL; osteopontin: 38.1±27.7 vs. 72.6±33.1 µg/mL). Logistic regression analysis identified the combination of these two biomarkers as a significant predictor variable associated with successful aging regardless of sex (p<0.001). The area under the curve (AUC) classified the ability of galectin-3 and osteopontin to predict the likelihood of successful aging as 'fair' (AUC=0.75) and 'good' (AUC=0.80), respectively. Particularly, the combination of the two biomarkers showed good discriminatory power for successful aging (AUC=0.86), with sensitivity=83% and specificity=74%. CONCLUSIONS: Lower levels of both galectin-3 and osteopontin are associated with successful aging, representing potential biomarkers of this condition. Our cross-sectional data must be however approached with caution. Further research is necessary to replicate the present preliminary results in other cohorts and to identify the potential use of galectin-3 and osteopontin as potential targets (or at least predictors) in future personalized anti-aging therapies.

Baicalin supplementation reduces serum biomarkers of skeletal muscle wasting and may protect against lean body mass reduction in cancer patients: Results from a pilot open-label study.

OBJECTIVES: Muscle wasting in patients with cancer has been linked to an increased activity of nuclear factor κB (NF-κB) and higher circulating levels of activin-A (ActA), a negative growth factor for muscle mass. Baicalin is a natural flavonoid that can reduce skeletal muscle atrophy in animal models of cancer cachexia by inhibiting NF-κB. This pilot open-label study assessed the effects of baicalin supplementation (50 mg daily for 3 months) in cancer patients who showed involuntary weight loss >5% over the past 6 months. METHODS: A total of 20 patients were investigated. Participants were evaluated at baseline and at the end of the 3-month study period for the following endpoints: 1) changes from baseline in serum NF-κB and ActA levels; and 2) change from baseline in lean body mass (LBM). RESULTS: We observed significant reduction in both NF-κB (p<0.05) and ActA (p<0.05) serum levels from baseline to 3 months. At 3 months, patients also showed a significant mean increase in LBM (+0.8 kg, p<0.05 compared with baseline). CONCLUSION: Our pilot open-label data suggest that baicalin supplementation is potentially useful for contrasting lean body mass reduction in cancer patients with involuntary weight loss, an effect which is likely mediated by the inhibition of negative growth factors for muscle mass.

Comparative Effects of Sunscreens Alone vs Sunscreens Plus DNA Repair Enzymes in Patients With Actinic Keratosis: Clinical and Molecular Findings from a 6-Month, Randomized, Clinical Study.

Recent experimental irradiation studies have shown that the addition of DNA repair enzymes (photolyase and endonuclease) to traditional sunscreens may reduce ultraviolet radiation (UVR)-induced molecular damage to the skin to a greater extent than sunscreens alone. In this 6-month, randomized, clinical study, we sought to compare the clinical and molecular effects of sunscreens plus DNA repair enzymes vs. those of traditional sunscreens alone in patients with actinic keratosis (AK). A total of 28 AK patients were randomized to topically apply sunscreens plus DNA repair enzymes (enzyme group; n = 14) or sunscreens alone (sunscreen group; n = 14) for 6 months. The main outcome measures included 1) hyperkeratosis, 2) field cancerization (as measured by fluorescence diagnostics using methylaminolaevulinate), and 3) levels of cyclobutane pyrimidine dimers (CPDs) in skin biopsies. Both regimens produced a significant reduction of hyperkeratosis at 6 months, with no difference between the two groups. Field cancerization was significantly reduced by both regimens, but the decrease observed in the enzyme group was significantly more pronounced than in the sunscreen group (P < 0.001). At 6 months, CPDs decreased by 61% in the enzyme group and by 35% in the sunscreen group compared with baseline values (P < 0.001). These findings indicate that, despite a similar effect on hyperkeratosis, the addition of DNA repair enzymes to sunscreens was more effective in reducing field cancerization and CPDs than sunscreens alone. Taken together, our findings indicate that sunscreens plus DNA repair enzymes may be superior to traditional sunscreens alone in reducing field cancerization and UVR-associated molecular signatures (CPDs) in AK patients, potentially preventing malignant transformation into invasive squamous cell carcinoma in a more efficient manner.

From DNA repair to proteome protection: new molecular insights for preventing non-melanoma skin cancers and skin aging.

Non-melanoma skin cancers (NMSC) are the most common human neoplasms and continue to represent an important public health issue with greater than one million cases diagnosed each year. The primary factor contributing to the molecular pathogenesis of NMSC is unprotected skin exposure to ultraviolet (UV) radiation, ie, UVA (wavelength: 315-400 nm) and UVB rays (wavelength: 280-315 nm) with additional albeit less damaging factors of infrared radiation (wavelength: ~750 nm-1 mm) and environmental pollutants. Skin carcinogenesis by DNA damage is the current predominant paradigm of UV toxicity, which may be caused by direct damaging effects of energy deposited by photons or indirect oxidative action of short-lived reactive oxygen species (ROS) formed from water that reacts with biomacromolecules. UV rays are capable to induce direct both DNA damages, mainly consisting in the formation of helix-distorting photoproducts such as cyclobutane pyrimidine dimers (CPDs), as well as oxidative damage to DNA bases, including the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8OHdG). Growing evidence also suggests that the efficiency of DNA repair after exposure to UV radiation is crucially dependent on the levels of oxidative protein damage, including but not limited to DNA repair proteins. Besides DNA lesions, UV-induced oxidative stress can indeed result in carbonylation of proteins, a major form of irreversible protein damage that inactivates their biological function. Interestingly, microorganisms characterized by extreme resistance to UV rays have an intrinsic capacity to protect their proteome, rather than genome, from radiation-induced damage, suggesting that protein carbonylation (PC) may serve as a reliable and innovative biomarker of UV photodamage. This review discusses the main DNA and protein markers of UV-induced damage (eg, CPDs, 8OHdG, and PC) and their relationship and importance to the current understanding of skin carcinogenesis. The identification of key DNA and protein signatures of photodamage may represent a therapeutic target for translational studies of innovative therapeutic and preventive approaches for reducing both skin aging and the morbidity and mortality associated with NMSC.