Exposome and Skin. Part 2. The Influential Role of the Exposome, Beyond UVR, in Actinic Keratosis, Bowen's Disease and Squamous Cell Carcinoma: A Proposal.

Actinic keratosis (AK) is the main risk factor for the development of cutaneous invasive squamous cell carcinoma (SCC). It represents the first sign of severe chronic ultraviolet radiation exposure, which has a clear significant effect. Nevertheless, the skin is exposed to many other exposome factors which should be thoroughly considered. Our aim was to assess the impact of exposome factors other than ultraviolet radiation (UVR) on the etiopathology of AK and Bowen's disease (BD) and progression of AK to SCC and to design tailored prevention strategies. We performed an exhaustive literature search in September 2021 through PubMed on the impact of exposome factors other than UVR on AK, BD and SCC. We conducted several parallel searches combining terms of the following topics: AK, BD, SCC and microbiome, hormones, nutrition, alcohol, tobacco, viral infections, chemical contaminants and air pollution. Notably, skin microbiome studies have shown how Staphylococcus aureus infections are associated with AK and AK-to-SCC progression by the production of chronic inflammation. Nutritional studies have demonstrated how a caloric restriction in fat intake, oral nicotinamide and moderate consumption of wine significantly reduce the number of premalignant keratoses and SCC. Regarding lifestyle factors, both alcohol and smoking are associated with the development of SCC in a dose-dependent manner. Relevant environmental factors are viral infections and chemical contaminants. Human papillomavirus infections induce deregulation of cellular proliferation and are associated with AK, BD and SCC. In addition to outdoor jobs, occupations such as industrial processing and farming also increase the risk of developing keratoses and SCC. The exposome of AK will undoubtedly help the understanding of its etiopathology and possible progression to SCC and will serve as a basis to design tailored prevention strategies.

A Treatment Combination of Peels, Oral Antioxidants, and Topical Therapy for Refractory Melasma: A Report of 4 Cases.

BACKGROUND: Melasma is a difficult-to-treat, recurrent pigmentary disease. Combined therapy gives better, longer-lasting results. OBJECTIVE: To determine the clinical effects of a treatment protocol of trichloroacetic acid, phytic acid and ascorbic acid peel combined with oral antioxidant supplement and topical treatment for refractory melasma. PATIENTS AND METHODS: We present four cases of patients with melasma, who, despite multiple treatments including hydroquinone, showed no improvement. We initiated a 16-week protocol involving 3 in-clinic peels (4 weeks apart) and a daily home treatment. The peels contained 30% trichloroacetic acid, 2% phytic acid, 8% L-ascorbic acid, Camellia sinensis leaf extract and Vitis vinifera seed extract. The home treatment was a depigmenting serum (4-butyl resorcinol, hydroxy-phenoxy propionic acid and niacinamide), a specific SPF50+ sunscreen, and an oral supplement (Polypodium leucotomos; green tea extract; Vitis vinifera; vitamins C, E, and D; and carotenoids), all in the morning, and, at night, a compounded gel-cream (4% hydroquinone, 0.025% tretinoin and 1% hydrocortisone). After 16 weeks, the gel-cream was stopped; the rest of the regimen (topical and oral) was continued for 12 further weeks. Melasma was assessed using the melasma severity scale (MSS) before starting the protocol, and at 4 and 12 weeks after the last peel. Photographs were taken before treatment and at the last evaluation. Patients indicated their satisfaction on a 5-point scale. RESULTS: All patients had good tolerance to the procedures. Three showed an excellent (>75%) improvement and one showed a good (50-75%) improvement. All four were very satisfied. At follow-up (12 weeks after last peel), no patients had recurrence. CONCLUSION: This protocol of trichloroacetic acid, phytic acid and ascorbic acid peel combined with an oral supplement and topical daily treatment is a viable treatment option for refractory melasma.

Prospective Evaluation of the Efficacy of a Food Supplement in Increasing Photoprotection and Improving Selective Markers Related to Skin Photo-Ageing.

INTRODUCTION: Skin exposure to ultraviolet radiation (UVR) can cause oxidative stress, particularly in the absence of adequate protective measures or in individuals with a sensitive skin type. Most commonly, protection from UVR entails the use of topical sunscreens. Sunscreens, however, have various limitations. The objective of this study was to evaluate the efficacy and tolerability of an oral food supplement containing a combination of actives with mainly antioxidative properties (vitamins A, C, D3, E, selenium, lycopene, lutein, as well as green tea, polypodium and grape extracts) in the context of photoprotection. METHODS: Photoprotective efficacy was assessed in a 12-week-long, open, prospective and monocentric clinical study with 30 subjects (27 women and 3 men) having a Fitzpatrick skin type I-III and manifesting clinical ageing signs. The study included several visits (14, 28, 56, and 84 days after starting supplement intake), in which photoprotection was evaluated by the measurement of the minimal erythema dose (MED), while the antioxidant capacity of the skin was assessed through ferric reducing antioxidant power (FRAP) and malondialdehyde (MDA) assays. Additionally, several skin parameters (including radiance, elasticity, and moisture) were evaluated. Product evaluation was performed throughout the length of the study by means of a self-assessment questionnaire, and safety was monitored through a self-recording of all observed adverse reactions. RESULTS: The MED levels increased significantly compared to baseline throughout the study visits, reaching an increase of + 8.1% at T84, p < 0.001. FRAP results also indicated a significant increase in the antioxidant capacity of the skin compared to baseline (+ 22.7% at T84, p < 0.001), while the MDA assay showed a significant decrease in MDA concentration compared to baseline (- 6.4% at T84, p < 0.001) which, in line with the FRAP results, indicated enhanced antioxidative protection of the skin. All assessed skin parameters, including radiance (+ 36.1% at T84, p < 0.001), gross elasticity (+ 13.2% at T84, p < 0.001), net elasticity (+ 28.0% at T84, p < 0.001), and moisture (+ 13.8% at T84, p < 0.001) were also significantly improved. The product was well tolerated as no adverse events were attributed by the investigators to the use of the product. Additionally, the global score obtained from the self-assessment questionnaires provided overwhelmingly positive feedback from the study subjects. CONCLUSIONS: The food supplement evaluated in this study was effective and well-tolerated by the subjects, demonstrating a beneficial effect in terms of photoprotection, enhancing the antioxidative status of the skin and improving general skin condition. TRIAL REGISTRATION: Retrospectively registered 3rd October 2019, ISRCTN18121679.

Novel Non-Steroidal Facial Cream Demonstrates Antifungal and Anti-Inflammatory Properties in Ex Vivo Model for Seborrheic Dermatitis.

INTRODUCTION: Seborrheic dermatitis (SEBD) is a chronic, recurrent skin disorder that typically occurs as an inflammatory response to fungi of the genus Malassezia. The development of an ex vivo model that mimics the fungal proliferation and skin inflammation of SEBD would play an important role in screening formulations for their efficacy in treating SEBD. METHODS: An ex vivo model for SEBD using human skin explants that had been mechanically manipulated to facilitate colonization of Malassezia furfur was developed. This model was used to evaluate the efficacy of a novel non-steroidal facial cream (NSFC) in inhibiting M. furfur proliferation and reducing inflammatory cytokine levels. RESULTS: This model reproduced some of the key pathological features of SEBD, including M. furfur proliferation and inflammatory cytokine production. Topical application of NSFC facial cream reduced M. furfur counts by 92% (p < 0.05) and levels of interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) by 82% and 40%, respectively (p < 0.05, both). CONCLUSION: The proposed ex vivo model for SEBD could be a useful tool to evaluate topical antifungal treatments. The novel NSFC tested in this study reduced M. furfur proliferation and inflammatory cytokine levels following topical application and may be helpful in the management of SEBD. FUNDING: ISDIN.

A novel Nitrizinc Complex® solution for topical treatment of seborrhoeic keratosis: an interventional clinical study.

Seborrheic keratosis (SK) is a benign, common disease affecting mostly the middle aged and elderly population. SK lesions are characterized by pigmented skin growth, a warty surface, and sharp margins. Current therapies (curettage or cryotherapy) are invasive and painful. A non-invasive treatment is evaluated in this clinical study. Objectives: To assess the efficacy, safety, and tolerability of Nitrizinc Complex® topical solution (NZCS) for treatment of SK, after one to two topical applications. Thirty-two SK patients with a total of 59 lesions were treated with NZCS. Outcomes were determined by the dermatologist at clinical visits at one, three, six, and 12 months post-procedure and by subjective evaluation of patients through questionnaires. Six months after treatment, complete elimination was observed in 80% of the lesions (72% of the patients), while 93.3% of the lesions showed at least 50% reduction. Treatment ended with 100% cosmetic benefit as no scars or dyschromia were observed in the treated areas. Subjective treatment and cosmetic satisfaction were evaluated and corresponded to 8.66/10 and 8.07/10, respectively. The product was preferred over all other options previously used by all patients. Treatment was highly tolerable as discomfort, such as pain and itching/burning sensations, was minimal. No relapse cases have been observed at 12 months after treatment. This study demonstrates that NZCS is an efficient, easy-to-apply, safe and well tolerated treatment for SK lesions, and may therefore be considered as a potential topical non-invasive alternative for SK treatment.

Review of Clinical Evidence over 10 Years on Prevention and Treatment of a Film-Forming Medical Device Containing Photolyase in the Management of Field Cancerization in Actinic Keratosis.

Actinic keratosis (AK) is a common pathology that afflicts sun-exposed areas of the skin. It predominantly affects older and fair-skinned individuals suggesting an accumulative damage attributable to chronic sun exposure. The prevalence of AK has risen in the past decades and is expected to continue to rise. Apart from visible hyperkeratotic, hyperplastic lesions, AK is also associated with the presence of subclinical lesions adjacent to tumor tissue, which has led to the use of the concept "cancerization field". Although lesion- and field-targeting treatments are currently available, many are associated with local side effects and recurrence of new lesions. This review provides information on AK pathophysiology and treatment options and summarizes the available clinical evidence supporting the use of Eryfotona AK-NMSC, a film-forming medical device with SPF 100+ containing the DNA repair enzyme photolyase, for managing AK, based on the analysis of the results of 228 patients treated with the product. FUNDING: ISDIN funded the Article Processing Charges.

Antiaging effects of a novel facial serum containing L-Ascorbic acid, proteoglycans, and proteoglycan-stimulating tripeptide: ex vivo skin explant studies and in vivo clinical studies in women.

BACKGROUND: With age, decreasing dermal levels of proteoglycans, collagen, and elastin lead to the appearance of aged skin. Oxidation, largely driven by environmental factors, plays a central role. AIM: The aim of this study was to assess the antiaging efficacy of a topical serum containing L-Ascorbic acid, soluble proteoglycans, low molecular weight hyaluronic acid, and a tripeptide in ex vivo and in vivo clinical studies. METHODS: Photoaging and photo-oxidative damage were induced in human skin explants by artificial solar radiation. Markers of oxidative stress - reactive oxygen species (ROS), total glutathione (GSH), and cyclobutane pyrimidine dimers (CPDs) - were measured in serum-treated explants and untreated controls. Chronological aging was simulated using hydrocortisone. In both ex vivo studies, collagen, elastin, and proteoglycans were determined as measures of dermal matrix degradation. In women aged 21-67 years, hydration was measured up to 24 hours after a single application of serum, using Corneometer and hygrometer. Subjects' perceptions of efficacy and acceptability were assessed via questionnaire after once-daily serum application for 4 weeks. Studies were performed under the supervision of a dermatologist. RESULTS: In the photoaging study, irradiation induced changes in ROS, CPD, GSH, collagen, and elastin levels; these changes were reversed by topical serum application. The serum also protected against hydrocortisone-induced reduction in collagen, elastin, and proteoglycan levels, which were significantly higher in the serum-treated group vs untreated hydrocortisone-control explants. In clinical studies, serum application significantly increased skin moisture for 6 hours. Healthy volunteers perceived the product as efficient in making the skin brighter, more hydrated, and decreasing wrinkles and wished to continue using it. The serum was well tolerated and noncomedogenic. CONCLUSION: The serum protected against oxidative damage and dermal protein loss caused by photo- and chronological aging in human skin explants. In-vivo, the serum hydrated skin for 6 hours, and users perceived increased skin brightness, hydration, and fewer wrinkles.

Clinical Impact and Cosmetic Acceptability of Chlorhexidine-enriched Toothpaste and Mouthwash Application on Periodontal Disease: A Randomized Clinical Study.

AIMS: Oral hygiene is key to prevent periodontal disease (PD). The efficacy of chlorhexidine-containing products has been largely proven, often being tooth discoloration an unwanted associated side-effect. Importantly, some differences related to the pharmaceutical presentation of these products have also been reported. This study aimed to evaluate the efficacy of two different pharmaceutical forms [toothpaste (TP) and mouthwash (MW)] of a new product containing chlorhexidine, dexpanthenol, allantoin and bioadhesive excipient (CDAB) (Bexident® Gums Coadjuvant Treatment) on volunteers with PD. Their preferences, acceptability and cosmetic properties, as well as tooth discoloration, were also assessed. MATERIALS AND METHODS: Total 60 subjects showing mild-moderate symptoms of gingivitis were randomly assigned to two different groups: one receiving TP (n = 30) and the other one receiving MW (n = 30). Periodontal disease index (PDI) was used to evaluate clinical signs at baseline (T0) and after 21 days (T21) of daily use of the products. Satisfaction was assessed through the affirmative/negative answers obtained with the visual analog scale (VAS). RESULTS: All participants completed the study. A significant improvement of PDI score after treatment was reported in both groups (T21/T0) (p < 0.001). Thus, gingivitis improved from moderate to negative [increase = 20.0% (TP)/36.7% (MW)] and from mild to negative [increase = 56.7% (TP)/50.0% (MW)]. After treatment, all subjects reported to have healthier and/or less bleeding teeth (TP 9.0/9.4; MW 8.0/8.2) and would recommend the product (TP:100%/MW:96.6%) with no specific preference regarding its presentation. No change of teeth color was observed. CONCLUSION: Subjects with PD who received oral care with a new formulation of either chlorhexidine-containing TP or MW for 21 days, reported a significant improvement of their symptoms and resolution of the gingivitis with no associated tooth discoloration. Patients did not show a specific preference for any of the pharmaceutical presentations. CLINICAL SIGNIFICANCE: This new formulation of a chlorhexidine-containing product in both TP and MW forms resulted effective for PD treatment and well accepted by the patients.

Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study.

BACKGROUND: Skin aging is accelerated by multiple extrinsic factors: ultraviolet radiation, smoking and pollution increase oxidative activity, damaging cellular and extracellular components such as DNA, proteins, and lipids. With age, collagen and hyaluronic acid levels decline, resulting in loss of elasticity and moisture of the skin. Over time this damage leads to characteristic signs that make the skin look older: altered facial contour, sagging skin, wrinkles, and an uneven complexion. This study evaluated the anti-aging effects of a new facial cream formulated with carnosine, Alteromonas ferment extract, crosspolymer hyaluronic acid, and a tripeptide. METHODS: An open-label intra-individual study to assess the anti-aging efficacy of the investigational product in 33 women aged 45 to 65 years. The product was applied twice daily for 56 days. Facial contour and skin deformation, elasticity, hydration, and complexion were measured with specialized equipment at baseline and days 28 and 56. Additionally, subjects completed questionnaires at days 28 and 56 on the perceived efficacy and cosmetic characteristics of the product. RESULTS: After 56 days of use of the investigational product, a redefining effect was observed, with a significant decrease in sagging jawline (7%). Skin was significantly more hydrated (12%), firmer (29%), and more elastic (20%) (P<0.001 for all). On complexion assessment, skin texture (a measure of skin smoothness) and spots (brown and red skin lesions) also improved significantly (12% and 6% decrease, respectively). In the subjective self-evaluation, the majority of subjects reported that the skin was visibly tightened and more elastic, flexible, and moisturized (91%, 88%, 91%, and 90%, respectively). The product was well tolerated with no adverse events reported during the study. CONCLUSION: This new cosmetic product demonstrated anti-aging effects after 56 days of use, most notably a redefined facial contour and improved complexion. It is a safe and effective anti-aging product.