The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.

/pdf/molecular-mechanisms-of-uv-induced-apoptosis-and-its-effects-480ox7ziv0.pdf

Molecular mechanisms of UV-induced apoptosis and its effects on skin residential cells: The implication in UV-based phototherapy

Ultraviolet radiation (UVR) is known to be one of the most important environmental hazards acting on the skin. It was revealed that chronic exposure to UVR accelerates skin aging, induces immunosuppression and may lead to the development of skin cancers. On the other hand, UVR has been shown to be effective in the treatment of numerous skin diseases and thus, various phototherapy modalities have been developed to date. Narrow-band ultraviolet B (NB-UVB) emitting a light with a peak around 311 nm has been demonstrated to be effective in the treatment of various skin disorders; currently it is one of the most commonly used phototherapy devices. Despite NB-UVB has been developed more than 30 years ago, the exact mechanism of its therapeutic action remains poorly understood. To date, most of NB-UVB effects were attributed to its influence on immune cells; however, nearly 90% of NB-UVB irradiation is absorbed by epidermis and keratinocytes seem to be important players in mediating NB-UVB biological activity. Here, we have reviewed the current data about the influence of NB-UVB on epidermal cells, with a special emphasis on cell proliferation and death.

/pdf/effects-of-narrow-band-uvb-311-nm-irradiation-on-epidermal-x9l2zrnq6t.pdf

Effects of narrow band UVB (311 nm) irradiation on epidermal cells.

The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.

/pdf/stress-induced-rnaset2-overexpression-mediates-melanocyte-1rjk7fxuqg.pdf

Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro

Several therapeutic options are available for the treatment of vitiligo; among these phototherapy and topical steroids are the most widely documented. A topical formulation of 0.05% clobetasol propionate foam (CPF) has been introduced in the market, but no data are available about the efficacy and tolerability of this new formulation in the treatment of vitiligo. The aim of this study was to investigate the efficacy and tolerability of CPF in the treatment of vitiligo, in comparison with narrowband-ultraviolet B (NB-UVB) phototherapy. The medical records of the first 60 vitiligo patients treated with NB-UVB phototherapy or with CPF were selected. Response to the treatment was determined for each anatomic site (neck, upper and lower limbs, trunk, hands/wrists, feet/ankles). Based on the area of repigmentation, treatment outcome was calculated according to a scale ranging from 0 (absent) to 4 (excellent). The incidence of adverse effects was also noted as a secondary endpoint. Significance level was set at P = 0.05. For each anatomic site, statistical analyses demonstrated that the efficacy of CPF was significantly higher compared to NB-UVB. Side effects occurred in 4 patients (13.33%) in the CPF group compared to none in the NB-UVB group. Clobetasol propionate has been used in vitiligo in different vehicles, but never in foam. The data showed that CPF is effective and seems to be superior to NB-UVB phototherapy, with furthermore a good safety profile. This new foam formulation of clobetasol propionate may expand the options currently available for vitiligo therapy; however, further investigations are needed to confirm our preliminary observations.

https://link.springer.com/content/pdf/10.1007%252Fs13555-013-0028-8.pdf

Narrow Band-Ultraviolet B Versus Clobetasol Propionate Foam in the Treatment of Vitiligo: A Retrospective Study

Background: Vitiligo is an autoimmune skin condition that affects people globally anywhere, from <0.1% to more than 8% of individuals. The disease destroys skin melanocytes, resulting in a patchy depigmentation of the skin. About 50% of all patients develop the disease before their 20s. Methods: We systematically searched the literature and reviewed the evidence for the use of nutritional supplements and diet in the management of vitiligo. Embase and Medline were searched for diet, herbal, and nutrition-based clinical studies. Additional filters were applied that looked for controlled trial or randomized controlled trial and article or article in press or letter and English and clinical study. We selected clinical studies in humans that showed how diet or natural supplements can improve the symptoms of vitiligo in all of our searches. Results: There were 62 manuscripts that resulted from the PubMed search and 259 from the Embase search. A final of 26 studies were reviewed, and other supplemental case and case-control studies were used to introduce diet components that may influence either exacerbation or amelioration of vitiligo. Possible mechanisms of action are introduced for natural and supplemental interventions. Conclusion: Some of the supplements reviewed include Gingko biloba, oral Polypodium leucotomos, alpha lipoic acid, vitamins B12, D, and E, folic acid, phenylalanine, canthaxanthin, Nigella sativa oil, and other combined herbal bio-actives. Overall, the growing evidence is promising, but more studies are needed in this area to further explore the impact that supplements and diet can have on vitiligo management. The most promising therapies included oral phenylalanine as adjuvant therapy with UVA therapy, oral G. biloba as monotherapy, both of which can be used with other traditional therapies, and oral P. leucotomos with phototherapy or photochemotherapy.

A Systematic Review of Nutrition, Supplement, and Herbal-Based Adjunctive Therapies for Vitiligo

The effects of NB-UVB on the hair follicle-derived neural crest stem cells differentiating into melanocyte lineage in vitro

Background: Phototherapy is an important method to treat vitiligo. However, it is unclear how phototherapy affects melanocyte precursors and skin neural crest stem cells. Objective: To investigate the underlying mechanisms of narrow- band ultraviolet B (NB-UVB) induced melanocyte lineage differentiated from human scalp-derived neural crest stem cells (HS-NCSCs). Methods: HS-NCSCs were expanded from scalp hair follicles. The c-Kit-/CD57- HS-NCSCs were isolated by cell sorting. Different doses of NB-UVB were used to irradiate these HS-NCSCs. Cell ultrastructure was examined by transmission electron microscope. Melanocyte marker expression was analyzed by Quantitative RT-PCR and Western blot. Cell proliferation and migration were also evaluated. Results: The c-Kit-/CD57- HS-NCSCs expressed embryonic NCSC biomarkers. NB-UVB at a dose of 100 mJ of NB-UVB had little effect on the cell proliferation of differentiated melanocytes from c-Kit-/CD57- HS-NCSCs, while 700 mJ inhibited cell proliferation significantly. The dendritic processes of differentiated melanocytes increased after radiation. The tyrosinase and Melanocortin 1 receptor (Mc1R) expression of differentiated melanocytes increased after NB-UVB exposure. The effect of NB-UVB on tyrosinase expression was modulated by signaling inhibitors H89 and PD98059 as well as Mc1R level in the cells. The migration ability of differentiated melanocytes was enhanced under 100 mJ exposure. Conclusion: These data demonstrate that NB-UVB facilitates melanocytic differentiation of the HSNCSCs and enhances migration of these cells. Mc1R and cAMP pathway play a critical role in NB-UVB induced melanocytic differentiation. (Ann Dermatol 32(4) 289∼297, 2020)

https://anndermatol.org/pdf/10.5021/ad.2020.32.4.289

NB-UVB Induces Melanocytic Differentiation of Human Hair Follicle Neural Crest Stem Cells

Background The increasing maturity of sequencing technology provides a convenient approach to studying the role of skin microorganisms in acne pathogenesis. However, there are still too few studies about the skin microbiota of Asian acne patients, especially a lack of detailed analysis of the characteristics of the skin microbiota in the different acne sites. Methods In this study, a total of 34 college students were recruited and divided into the health, mild acne, and severe acne groups. The bacterial and fungal flora of samples were separately detected by 16S and 18S rRNA gene sequencing. The biomarkers of different acne grades and different acne sites [forehead, cheek, chin, torso (including chest and back)] were excavated. Results and Discussion Our results indicated that there was no significant difference in species diversity between groups. The genera like Propionibacterium, Staphylococcus, Corynebacterium, and Malassezia, which have a relatively high abundance in the skin microbiota and were reported as the most acne-associated microbes, were no obvious differences between groups. On the contrary, the abundance of less reported Gram-negative bacteria (Pseudomonas, Ralstonia, and Pseudidiomarina) and Candida has a significant alteration. Compared with the health group and the mild group, in the severe group, the abundance of Pseudomonas and Ralstonia sharply reduced while that of Pseudidiomarina and Candida remarkably raised. Moreover, different acne sites have different numbers and types of biomarkers. Among the four acne sites, the cheek has the greatest number of biomarkers including Pseudomonas, Ralstonia, Pseudidiomarina, Malassezia, Saccharomyces, and Candida, while no biomarker was observed for the forehead. The network analysis indicated that there might be a competitive relationship between Pseudomonas and Propionibacterium. This study would provide a new insight and theoretical basis for precise and personalized acne microbial therapy.

New insights into the characteristic skin microorganisms in different grades of acne and different acne sites

Phototherapy is an effective therapeutic option in the treatment of vitiligo; however, responses varied among the different types. The underlying mechanism has scarcely been investigated. To investigate and compare the effects of phototherapy on the mutation of melanocyte lineage differentiated from human scalp-derived neural crest stem cells (HS-NCSCs) with p75 neurotrophin receptor expression positive and p75 neurotrophin receptor expression negative group in vitro, the HS-NCSCs were isolated from fetal scalp tissue, which is identified by immunofluorescent staining. The p75(+) and p75(-) cells from HS-NCSCs were isolated by magnetic cell sorting, respectively. The embryonic neural crest stem cell biomarkers were detected by RT-PCR. Narrow-band UVB (NB-UVB) was used to irradiate the cells. Cell proliferation was evaluated by cell count. Tyrosinase, Tyrp1, and Tyrp2 gene expression were measured by quantitative RT-PCR. Tyrosinase and GRCR protein levels were investigated by Western blot analysis. The electrophoretic strip showed that Sox2, Oct4, Sox10, and Nestin of p75(+) HS-NCSCs were brighter than the p75(-) HS-NCSCs. After the same dose radiation with NB-UVB, the cell proliferation of p75(+) group showed less inhibitory rate compared with the p75(-) HS-NCSCs. The tyrosinase mRNA and protein expression of differentiated melanocytes increased significantly in the group of p75(+) HS-NCSCs compared with the p75(-) group. The melanocytic mutation of p75(+) HS-NCSCs increased significantly compared with the p75(-) HS-NCSCs under NB-UVB, which indicated there were more melanocyte precursors in the differentiated cells from p75(+) HS-NCSCs. This may provide new insights for the different repigmentation efficacy of segmental and non-segmental vitiligo.

Comparison of responses of melanocyte lineages from p75(+) and p75(-) human scalp-derived neural crest stem cells under phototherapy.

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The effects of NB-UVB on the hair follicle-derived neural crest stem cells differentiating into melanocyte lineage in vitro

NB-UVB Induces Melanocytic Differentiation of Human Hair Follicle Neural Crest Stem Cells

New insights into the characteristic skin microorganisms in different grades of acne and different acne sites

Comparison of responses of melanocyte lineages from p75(+) and p75(-) human scalp-derived neural crest stem cells under phototherapy.