A dermocosmetic formulation containing Vichy volcanic mineralizing water, Vitreoscilla filiformis extract, niacinamide, hyaluronic acid, and vitamin E regenerates and repairs acutely stressed skin

Introduction

The skin exposome is defined as the totality of environmental and internal challenges over the life course that require an adaptive. The effect of the exposome on skin is of increasing concern as the clinical effects may modify the course of skin aging, photoaging, and various skin conditions. Chronic exposure to external exposome factors, such as ultraviolet (UV) radiation and pollution, contributes to wrinkles and lentigines, respectively, and these clinical signs of extrinsic aging are increased when UV and pollution are combined.1-4 It has also been described that tobacco smoking5, 6 and nutrition7 have an effect on signs of skin aging with adverse biological effects on the skin barrier, pigmentation, defenses, and skin structure.4

Similarly, the human skin microbiome balance may be altered by chronic exposure to polycyclic aromatic hydrocarbon pollutants.8 If chronic exposome effects on skin functions have been extensively reviewed, there is a paucity of information on the impact of short-term acute exposures. These acute and sometimes intense or repeated stress responses can be caused by environmental (meteorological factors, solar radiation, pollution, or tobacco smoke) and/or internal factors (unhealthy diet, hormonal variations, lack of sleep, psychosocial stress).9 For example, acute UV exposure can affect skin quality (dryness), pigmentation, or skin immunity (sunburn, herpes labialis reactivation); acute short-term exposure to pollution may cause oxidative stress, skin pigmentation, and inflammation10; acute exposure to combined UV and ozone pollution causes skin barrier alteration and oxy-inflammation11; acute psychological stress is well known to induce flares of several inflammatory skin or scalp conditions,12 but can also have an impact on human skin microbiota,13 which could impact wound healing processes.14

These acute stressors mainly affect the skin barrier and defense functions: Physical barrier alteration causing dryness and accentuated fine lines, sensitive skin, tightening, stinging, burning, dullness. Decreased antioxidant capacities, inflammation/inflammaging causing redness, edema, flare of inflammatory skin conditions. Decreased immune function causing weakened immunity and susceptibility to skin infections.

The complex interplay between the microbiome at the junction of both the physical barrier function and the skin defense function indicates that the skin's microbiota may have a beneficial role in skin health. The skin microbiome is highly individualized and changes in response to a wide variety of internal and external factors.15 For example, immunosuppression induced by acute UV exposure might be mitigated by the skin microbiome.16 A growing body of research suggests topical probiotics may help reinforce both these skin functions by rebalancing the microbiome, acting on the epithelial barrier, and modulating immune responses.17-20 In 2001, the Food and Agriculture Organization of the United Nations and the World Health Organization defined probiotics as live microorganisms which when administered in adequate amounts confer a health benefit on the host.21 However, inactive, semiactive, non-replicating bacterial extracts or soluble fractions may retain similar activity to the live forms and they are of interest for topical preparations designed for nutrition and dermocosmetic purposes.18, 22-24

Vitreoscilla filiformis is a nonpathogenic, Gram-negative bacterium produced on an industrial scale in a tightly controlled biotechnological fermentation process developed for delicate bacteria and patented 25 years ago. After harvesting, the cells are lysed to produce V. filiformis extract (Vfe; lysate including membrane and cytosol), which is used as a cosmetic ingredient. This extract is considered as a probiotic fraction since topical application of this extract has shown activity to maintain good homeostasis of skin defenses and strengthen the skin physical barrier function.

Product formulation

Vichy volcanic mineralizing water (VVMW) is a highly mineralized mineral water, which is well-known for its anti-inflammatory and anti-oxidant properties and has been shown to strengthen the skin against exposome aggressions.25 In previous publications, a formulation containing VVMW and hyaluronic acid (HA; without probiotic fractions) was reported to strengthen the skin barrier and clinical studies showed effectiveness as an adjunct to standard care in various inflammatory facial dermatoses including rosacea, sensitive, reactive skin, and after esthetic procedures including laser treatment.26, 27 Minéral 89 Probiotic Fractions (M89PF, Vichy Laboratories, France) is a new dermocosmetic formulation that contains an extract produced from lysing cells of V. filiformis cultured in medium containing VVMW (VfeV). The M89PF formulation contains 80% VVMW, 5% VfeV, 4% niacinamide (vitamin B3), 0.4% HA, and 0.2% vitamin E.

The effect of VfeV in combination with VVMW on key skin functions are described in another article in this supplement. Briefly, when topically applied, VfeV in combination with VVMW showed beneficial additive effects on strengthening and repairing the skin physical barrier, especially stimulation of filaggrin differentiation marker and claudin-1 tight junction protein synthesis; protecting biochemical immune defenses, especially stimulation of the β-defensin-4A antimicrobial peptide; and regenerating immunological defenses, especially protection of Langerhans cells challenged by UV exposure.

Topical niacinamide (also known as vitamin B3 or nicotinamide) is widely used in dermocosmetics for its antipruritic, antimicrobial, vasoactive, photoprotective, sebostatic and lightening effects.28 Niacinamide has anti-oxidant and anti-inflammatory properties. Within a complex metabolic system, niacinamide controls the NFκB-mediated transcription of signaling molecules by inhibiting the nuclear poly (ADP-ribose) polymerase-1 (PARP-1). Niacinamide reduced edema and vasodilatation induced by substance P and inhibited inflammatory markers interleukin-1β (IL-1β), IL-6, IL-8, TNF-α.29, 30 Niacinamide also improved skin barrier function by stimulating skin differentiation markers31 and reduced transepidermal water loss (TEWL)32 to improve skin hydration.

Niacinamide has depigmenting properties on skin by reversibly blocking the transfer of melanosomes from melanocytes into keratinocytes by inhibiting keratinocyte factors.33-35 To explore the action of niacinamide on melanosome transfer, an in vitro study on reconstructed epidermis was conducted on co-cultured melanocytes and keratinocytes. The disappearance of melanin after 6 days of treatment with niacinamide was monitored by biphotonic microscopy. The results demonstrated an inhibition of melanosome transfer by niacinamide via inhibition of the transfer of the fluorescent marker from melanocytes to keratinocytes.34, 36 Furthermore, in another clinical study on 50 Caucasian women between 40 and 60 years old, topical niacinamide 5% was shown to improve signs of facial skin aging with a depigmenting effect after 12 weeks use, while after 8 weeks of treatment, reductions were observed in the appearance of hyperpigmented spots, red blotchiness, skin sallowness (yellowing), and in fine lines and wrinkles.37 These effects could be related to the action of niacinamide on protein glycation due to its antioxidant properties that could reverse the glycation process.

Hyaluronic acid is the predominant component of the extracellular matrix with viscoelastic and hygroscopic properties with a unique capacity to retain skin moisture and prevent skin dryness.38 A major histochemical change observed in senescent skin is the marked disappearance of epidermal HA, while HA is still present in the dermis, which contribute to characteristics of aged skin, especially dryness, atrophy, and loss of elasticity.38

Vitamin E is an antioxidant. Using ascorbate free radical and an EPR spin-trapping system to detect short-lived radicals, vitamin E (tocopherol sorbate) significantly decreased UV-induced radical flux in skin indicating antioxidant protection against oxidative damage.39 Alpha-tocopherol protects the skin from UVB damage by halting the formation of reactive oxygen species, scavenging free radicals, stabilizing the surface and membranes of cells, reducing the number of apoptotic cells, and minimizing the activation of nuclear factor kappa B.40

In this review, we present in vitro and in vivo studies to evaluate the clinical efficacy in preventing and repairing stressed skin of a dermocosmetic formulation containing VVMW and probiotic fractions.

Skin barrier function Effect of M89PF on repairing, hydrating and restoring the skin physical barrier function after acute stress

The effectiveness of M89PF to hydrate skin exposed to sudden thermal changes was evaluated in 24 women aged 23–65 years old with dry skin. After a single application of M89PF at baseline, the skin was exposed to a temperature of 18 ± 2°C for 1 h, followed by 31 ± 2°C for 1 h, and then 18 ± 2°C for 1 h. Skin hydration corneometric assessments at 0, 1, 2, and 3 h, showed that application of M89PF significantly increased skin hydration by 36%, 42%, and 24% at 1, 2, and 3 h, respectively, compared to untreated skin (all P < 0.05).

The effectiveness of M89PF on skin barrier recovery after aggression was evaluated in 22 Caucasian women, aged 35–65 years old. Skin irritation was induced by tape stripping using D-Squames™ (Monaderm, Monaco). Recovery of treated skin compared to control was evaluated by TEWL measurement, as assessed by Tewameter™ (Courage+Khazaka electronic GmbH, Köln, Germany) on day 1 before tape stripping and after 5 days of twice daily application of M89PF on one volar forearm; the other forearm was left untreated. Mean values for TEWL clearly increased on both test areas after skin barrier damage on day 1, as expected. A steady decrease of TEWL values was detected on both test areas from day 1 until the end of the study on day 5 (Fig. 1). Statistically significantly lower normalized TEWL values were observed for M89PF treated skin in comparison to the untreated control from day 3, and this effect was maintained at day 5 showing faster skin barrier recovery with M89PF. At day 5, normalized values of TEWL (%) were 20.3 for M89PF vs. 31.7 for the untreated control; P < 0.001.

image

Skin barrier recovery after tape stripping. *P < 0.05, **P < 0.001.

Effect on accelerating skin barrier recovery in subjects with lack of sleep

Stress and lack of sleep lead to an increase in TEWL.41, 42 The efficacy of M89PF on TEWL was evaluated by Tewameter in 24 women with a mean (±SD) age of 46 ± 12 years old and who indicated by questionnaire that they sleep badly with a mean of 5 ± 1 h of sleep per night. After tape stripping, M89PF was applied once on a 2 mg/cm² defined area on the forearm. Evaluation of TEWL at T0 before and after stripping at T1h, T2h and T4h of the treated skin vs. the untreated area, showed that M89PF improved the natural skin recovery in bad sleepers by 69.5% after 1 h in the treated area vs. untreated area (+38.5% after 2 h and +28.3% after 3 h; all P < 0.010; Fig. 2).

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Skin barrier recovery with M89PF after tape stripping in bad sleepers compared to control. TEWL, transepidermal water loss, *P < 0.01, **P < 0.001, compared to baseline.

Effect of M89PF on skin renewal

A study in 33 women aged from 39 to 65 years old evaluated the effect of M89PF on skin renewal. At baseline, dansyl chloride patches were placed on both forearms for 24 h before removal. M89PF was applied twice-daily on one forearm (designated by computer-generated randomization) for 5 weeks (2 weeks of pre-treatment + 3 weeks treatment) and the other forearm was left untreated. Skin renewal was assessed by fluorescence measurements using a Wood's lamp. Mean total cumulative fluorescence score at day 22 was lower for M89PF treated skin than untreated skin (65 vs. 71; P < 0.0001), mean cell turnover was faster for M89PF (18 vs. 20 days; P < 0.0001), and the area under the curve was lower for M89PF compared to the untreated skin (Table 1). These results show that M89PF significantly accelerates skin renewal.

Table 1. Dansyl chloride testing to measure epidermal cell proliferation Mean (SD) Control M89PF P Mean cumulative fluorescence score at day 22 71.1 (6.1) 65.2 (6.5) <0.0001 Mean cell turnover time, days 19.8 (2.4) 18.4 (2.7) <0.0001 Mean area under the curve 67.9 (5.9) 62.1 (6.4) <0.0001 Skin defense function Effect on antioxidant defenses under stress from pollution and UVA

Squalene and its oxidized products, squalene mono hydroperoxidation, were selected as the targets in this study to evaluate oxidative stress from UVA and pollution as squalene is the principal target lipid for peroxidation on the human skin surface.43 In an ex vivo test, skin sebum was collected from the forehead of 6 subjects using filter paper. No product was applied to one filter paper, and about 15 mg of M89PF was applied to the other filter paper. The filter papers were then exposed to tobacco smoke pollution followed by UVA (5 J/cm2). Squalene oxidation to squalene monohydroperoxide, as quantified by HPLC-DAD-MS, was reduced by 50% in the presence of M89PF compared to the reference antipollution ingredient ellagic acid. Oxidation of cutaneous sebum after exposure to cigarette smoke and UVA was reduced by a mean (± SD) of 68% (± 9%) with M89PF compared to the untreated sebum (Fig. 3).

image

Oxidation of squalene to squalene monohydroperoxide induced by stress from air pollution and UVA was reduced by M89PF compared to control. Sq, squalene, SqOOH, squalene monohydroperoxide.

Effect on restoring the skin's microbiota

The effect of M89PF serum on the microbiome was evaluated on 33 healthy Caucasian volunteers aged 34.9 (±7.2) years old. Microbiome evaluations were performed before and after skin surface aggression by a harsh cleaning product. Total bacterial load (quantitative) was evaluated by qPCR (region V1-V3 16S rRNA KAPA BIOSYSTEMS (Saint-Quentin-Fallavier, France) kit with SYBER Green). The skin surface aggression significantly decreased the bacterial load (P = 0.000 compared to baseline). Multiple daily applications of M89PF serum for 14 days promoted a significantly better recovery of skin bacterial load after exposure to the harsh cleanser compared to bare skin (P = 0.003).

Effect on clinical signs of stressed skin

Two single-center open studies evaluated the efficacy of M89PF on women who indicated by questionnaire that they had a stressful lifestyle. All subjects (100%) indicated having a lifestyle exposed to environmental aggressions/ stress factors, living in an urban area, and having a job; over 70% went in the sun without systematically applying sunscreen; at least 50% had poor or very poor sleep quality, worked with time constraints, spent more than 1 h on public transport, or did not have a healthy and balanced diet; and 33% were smokers or consumed alcohol.

All skin types were included, 100% had sensitive skin, presented a dull complexion (score >3 and ≤6), fine lines due to stress (score ≥3 and ≤6), loss of plumpness (score >3 and ≤6), uneven skin tone (score >3 and ≤6), loss of elasticity (score >3 and ≤6), and problems of skin texture (score >3 and ≤6). The women applied M89PF twice-daily for 28 ± 2 days and assessments were made by dermatologist clinical scoring on a 10-point scale (from 0 − none to 9 − severe) and subject self-assessment questionnaires.

In the first study, 52 Caucasian women of mean age 38 years old were included. Subject self-assessment responses after application of M89PF for 4 weeks are shown in Fig. 4a, and the dermatologist clinical assessments (all P < 0.001 compared to baseline) are shown in Fig. 5a.

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Subject self-assessment responses after 4 weeks application of M89PF in Caucasian women, N = 52 (a) and Asian women, N = 51 (b).

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Dermatologist-assessed efficacy after 4 weeks twice daily application of M89PF in Caucasian women, N = 42 (a) and Asian women, N = 43 (b).

In a second study including 51 women of Asian origin, the mean age was 20–50 years old, and subject questionnaire responses after application of M89PF for 4 weeks are shown in Fig. 4b. Mean percentage changes in clinical assessments after 28 days of M89PF were a 28% decrease for fine lines, and increases of 57%, 48%, 37%, 37%, and 16%, respectively, for radiance, elasticity, plumpness, evenness, and smoothness (all P < 0.001 compared to baseline; Fig. 5b).

Effect on dark spots

It has been observed that Asian and dark-skinned individuals are more prone to actinic lentigines and hyperpigmentation than other ethnic types.44, 45 Consequently, the depigmenting properties of M89PF were evaluated in a study of 53 Chinese women presenting dark spots; they were aged 23–55 years old, with all skin types, and all had sensitive skin. Pigmenting was assessed by spectrophotometric measurements of the level of grey on a scale of from 0 to 255 (0 = black, 255 = white, an increase represents a depigmenting effect), and P-values were calculated by Anova followed by Dunnett test. M89PF was applied for 56 days, and the designated dark spot areas and color, as well as the color of the surrounding skin, were assessed by Siascope. The grey level (color) and surface of the designated spot and its normal adjacent skin showed that M89PF reduced the area and color of dark spots (see Fig. 6 and Table 2).

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Median case illustrations of skin imaging and computation of darks spots by using Siascope.

Table 2. Effect of M89PF on skin color and surface area of dark spots in Chinese women (N = 53) Parameters Time Mean (±SD) Mean change from baseline (±SD) P % change from baseline Color of designated dark spot (grey level) D0 88.2 ± 23.5 D28 94.3 ± 23.3 6.0 ± 8.4 0.001 +6.8% D56 100.0 ± 24.1 11.8 ± 11.9 <0.001 +13.4% Surface area of designated dark spot (mm²) D0 4.4 ± 2.2 D28 3.6 ± 2.3 −0.8 ± 1.4 0.002 −18.6% D56 2.9 ± 3.1 −1.5 ± 1.9 <0.001 −34.3% Color of surrounding skin area D0 125.4 ± 20.4 D28 126.4 ± 18.7 1.0 ± 9.7 0.691 +0.8% D56 131.3 ± 19.8 6.0 ± 13.2 0.002 +4.8% Contrast D0 −37.2 ± 12.6 D28 −32.1 ± 9.7 5.0 ± 8.5 <0.001 −13.6% D56 −31.3 ± 10.4 5.9 ± 9.4 <0.001 −15.8% Discussion

M89PF was shown to increase skin hydration in skin exposed to sudden thermal changes. Furthermore, M89PF increased skin hydration, reduced TEWL, and accelerated skin renewal to help repair the skin physical barrier function after skin barrier disruption induced by tape stripping. M89PF strengthened antioxidant natural defenses after exposure to stress from UVA plus cigarette smoke aggression and accelerated skin recovery after stress from lack of sleep. M89PF corrected clinical signs of stressed skin due to a stressful lifestyle in both Caucasian and Asian women exposed to various external (pollution, tobacco smoking, solar radiation) and internal (poor sleep, stressful work, unbalanced diet, and alcohol consumption) exposome factors. M89PF, which contains the ingredient niacinamide, also showed depigmenting properties. Furthermore, after skin microbiome challenge using a harsh cleanser, better recovery of skin bacterial load was observed after application of M89PF compared to bare skin.

These properties of M89PF to protect and repair the skin subjected to stress are highly relevant during these times of the ongoing coronavirus (COVID-19) pandemic caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the psychosocial consequences may adversely affect skin health.46 Acute psychosocial stress can elicit a neuroendocrine-immune stress response in the skin.12 Indeed, the skin is both a target and a source of stress mediators.47 Barrier functions altered by stress include a decreased epidermal hydration and increased TEWL due to a decrease of epidermal lipids and structural adhesion proteins. In addition, innate immune cells that reside in the dermis such as the mast cells can be activated by stress to release histamine and inflammatory cytokines that further compromise barrier function.48, 49 Additionally, wearing face masks for extended periods during the pandemic can cause skin barrier disruption due to friction and the higher temperatures and humid environment can cause bacterial proliferation, leading to dry skin, pruritus, and aggravation of pre-existing dermatoses, e.g., acne, seasonal facial dermatitis, seborrheic dermatitis, and rosacea.50-53

Further studies are now warranted to evaluate the efficacy of M89PF as adjuvant care to prevent and repair skin barrier disruption and reinforce skin defenses in skin exposed to acute stress due acute photopollution, facial mask wearing during the COVID-19 pandemic, treatment with topical retinoids, as well as in subjects with sensitive skin and rosacea.

Acknowledgements

Writing and editorial assistance was provided by Helen Simpson, PhD, ISMPP CMPP™, of My Word Medical Writing.

Ethical approval

All clinical studies were conducted according to ICH CPMP Good Clinical Practices guidelines and the Declaration of Helsinki (1964, and its subsequent modifications), and all subjects were healthy volunteers who gave written informed consent. Independent Ethics Committee approval was not required for these cosmetic product studies (the investigational product did not contain and was not derived from material with specific risks, and all the procedures were non-invasive).

Data availability statement

Data may be shared upon submission of a research proposal to the corresponding author. The research proposal will be reviewed, and if agreed, the requestors will need to sign a data sharing agreement.

Data availability statement

Data may be shared upon submission of a research proposal to the corresponding author. The research proposal will be reviewed, and if agreed, the requestors will need to sign a data sharing agreement.

References

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