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To compare the effectiveness of long-pulsed alexandrite laser (LPAL) with that of pulsed-dye laser (PDL) for rosacea.This was a single-blind randomized controlled trial on 27 patients who were clinically diagnosed with rosacea. Randomly assigned split face in each patient received four times monthly treatment of LPAL plus low-fluence Nd:YAG with the contralateral side serving as the control treated with PDL. At every visit, the erythema index (EI) was measured with skin analysis systems, and two independent dermatologists evaluated digital photographs for five-point global aesthetic improvement scale (GAIS).The EI significantly decreased on both treated sides (LPAL 366.5 ± 101.0 vs. 295.8 ± 90.2, p 0.001, PDL 369.0 ± 124.3 vs. 302.7 ± 92.1, p 0.001) 1 month after fourth treatment (visit 5). Also 3 months after the fourth treatment (visit 6), the reduction in the EI was well maintained on both sides (LPAL 360.3 ± 96.8 vs. 282.0 ± 89.2, p 0.001, PDL 364.3 ± 121.6 vs. 281.6 ± 97.8, p 0.001). When comparing the improvement in the EI between the two groups, the percentage reduction in the EI on the LPAL-treated side was not inferior to the PDL-treated side (visit 5: LPAL 18.7 ± 15.7% vs. PDL 16.4 ± 12.9%, p = 0.501 and visit 6: LPAL 21.7 ± 13.9% vs. PDL 21.9 ± 15.2%, p = 0.943). The GAIS and patient satisfaction were comparable between the LPAL and PDL sides and did not show any significant difference. No serious adverse events occurred on either of the treated sides.This study showed that the decrease in EI in the treatment of rosacea was comparable between PDL and LPAL. Therefore, LPAL could be a promising alternative treatment option with good merits for rosacea, considering no consumables are required for device maintenance.

Nephrin is a type-1 transmembrane protein and a component of the slit diaphragm renal-filtration barrier. It has several functions in actin remodeling and cell-cell adhesion. Nephrin is principally located in the kidney glomerulus, but several studies have reported that nephrin is found in the pancreas, brain, and placenta. However, nephrin expression and its role in human skin have not yet been reported. First, using single-cell RNA sequencing, immunohistochemistry, and immuno-electron microscopy, nephrin expression was confirmed in human-skin epidermal keratinocytes. Nephrin expression colocalized with the expression of zonula occludens-1 in keratinocytes and was closely related to keratinocyte cell density, proliferation, and migration. High glucose treatment decreased nephrin expression and compromised keratinocyte cell migration without yes-associated protein nuclear entry. This reduced cell migration under high glucose conditions was improved in nephrin-overexpressing keratinocytes. Nephrin was highly expressed on the margins of re-epithelized epidermis based on in vivo mice and ex vivo human skin wound models. The results demonstrate that nephrin is expressed in human-skin keratinocytes and functions in cell adhesion, proliferation, and migration. In conclusion, this study suggests that nephrin may have a variety of physiological roles in human skin.

Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing cell cycle arrest and apoptosis in TNBC cells, by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as TCA intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5’ nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through ECAR/OCR analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability.

Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing nucleotide imbalance and apoptosis in triple negative breast cancer cells (TNBC), by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as tricarboxylic acid cycle intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5′ nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability.

Hypoxic conditions induce the activation of hypoxia-inducible factor-1α (HIF-1α) to restore the supply of oxygen to tissues and cells. Activated HIF-1α translocates into the nucleus and binds to hypoxia response elements to promote the transcription of target genes. Cathepsin L (CTSL) is a lysosomal protease that degrades cellular proteins via the endolysosomal pathway. In this study, we attempted to determine if CTSL is a hypoxia responsive target gene of HIF-1α, and decipher its role in melanocytes in association with the autophagic pathway. The results of our luciferase reporter assay showed that the expression of CTSL is transcriptionally activated through the binding of HIF1-α at its promoter. Under autophagy-inducing starvation conditions, HIF-1α and CTSL expression is highly upregulated in melan-a cells. The mature form of CTSL is closely involved in melanosome degradation through lysosomal activity upon autophagosome–lysosome fusion. The inhibition of conversion of pro-CTSL to mature CTSL leads to the accumulation of gp100 and tyrosinase in addition to microtubule-associated protein 1 light chain 3 (LC3) II, due to decreased lysosomal activity in the autophagic pathway. In conclusion, we have identified that CTSL, a novel target of HIF-1α, participates in melanosome degradation in melanocytes through lysosomal activity during autophagosome–lysosome fusion.

High mobility group box 1 (HMGB1) is one of intracellular damage associated molecular patterns which is released from keratinocytes in response to external stressors and affects neighboring melanocytes by inducing apoptosis and suppressing melanogenesis. HMGB1 levels in the blood and its expression in skin tissues are increased in psoriasis, alopecia areata, dystrophic epidermolysis bullosa, and vitiligo.

Particulate matter (PM) is believed to be related to cardiovascular and respiratory diseases. The skin is also known to be affected by PM exposure as a result of skin barrier dysfunction, cutaneous inflammation, and apoptotic cell death. Epidemiological studies have suggested that PM is related to pigment spots. Recently, diesel exhaust particles are reported to cause a tanning response mediated by oxidative stress. However, the direct effects of PM on melanogenesis and the related mechanisms have not yet been clarified. Our study showed that PM can increase melanin production in melanocyte, mouse skin, and human skin models. RNA-sequencing analyses of melanocytes revealed that the expressions of unfolded protein response molecules were increased after PM exposure. In particular, IRE1α signaling pathway, which was consistently upregulated, was related to PM-triggered melanogenesis. In addition, PM-induced melanogenesis was abrogated by an IRE1α inhibitor. Therefore, our findings corroborate previous findings in melanocytes and in mouse and human models and also illuminate the involvement of the IRE1α pathway as a mechanism of PM-induced melanogenesis.

Background: Early-onset and severe atopic dermatitis (AD) in patients increase the probability of the development of allergic rhinitis or asthma. Treatment and prevention strategies in infants and young children with AD are targeted toward treating the symptoms, restoring skin barrier functions, and reducing the absorption of environmental allergens in an attempt to attenuate or block the onset of asthma and food allergy. Objective: Given that the initiating events in AD remain poorly understood, identifying those at risk and implementing strategies to prevent AD is necessary. Methods: Whole-exome sequencing (WES) was performed in a 43 control group and a disease group with 20 AD patients without atopic march (AM) and 20 with AM. Sanger sequencing was carried out to validate found variants in cohorts. Results: DOCK8, IL17RA, and KLK12 single-nucleotide polymorphisms were identified by WES as missense mutations: c.1289C＞A, p.P97T (rs529208); c.1685C＞A, p.P562G (rs12484684); and c.457+27＞C, rs3745540, respectively. A case-control study show that total immunoglobulin E (IgE) level was significantly increased in the AA genotype of DOCK8 compared to the CA genotype in allergic patients. The rs12484684 of IL17RA increased risk of adult-onset AD (odds ratio: 1.63) compared to the control for (A) allele frequency. AD and AM Patients with the IL17RA CA genotype also had elevated IgE levels. rs3745540 of KLK12 was associated with AD in dominant model (odds ratio: 2.86). Conclusion: DOCK8 (rs529208), IL17RA (rs12484684), and KLK12 (rs3745540), were identified using a new WES filtering method. the result suggests that polymorphism of DOCK8 and IL17RA might be related to increase the total IgE level. (Ann Dermatol 32(3) 197∼205, 2020)