Molecular and histological characterization of age spots.

Age spots, also called solar lentigines and lentigo senilis, are light brown to black pigmented lesions of various sizes that typically develop in chronically sun-exposed skin. It is well known that age spots are strongly related to chronic sun exposure and are associated with photodamage and an increased risk for skin cancer; however, the mechanisms underlying their development remain poorly understood. We used immunohistochemical analysis and microarray analysis to investigate the processes involved in their formation, focusing on specific markers associated with the functions and proliferation of melanocytes and keratinocytes. A total of 193 genes were differentially expressed in age spots, but melanocyte pigment genes were not among them. The increased expression of keratins 5 and 10, markers of basal and suprabasal keratinocytes, respectively, in age spots suggests that the increased proliferation of basal keratinocytes combined with the decreased turnover of suprabasal keratinocytes leads to the exaggerated formation of rete ridges in lesional epidermis which in turn disrupts the normal processing of melanin upwards from the basal layer. Based on our results, we propose a model for the development of age spots that explains the accumulation of melanin and the development of extensive rete ridges in those hyperpigmented lesions.

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin.

Interactions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color.

Short- and long-term effects of UV radiation on the pigmentation of human skin.

The incidence of skin cancer, including cutaneous melanoma, has risen substantially in recent years, and epidemiological and laboratory studies show that UV radiation is a major causative factor of this increase. UV damage also underlies photoaging of the skin, and these deleterious effects of UV can be, in part, prevented in skin with higher levels of constitutive pigmentation. We review the clinical studies we have made in recent years regarding the rapid and the long-term responses of the pigmentary system in human skin to UV exposure.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 32-35; doi:10.1038/jidsymp.2009.10.

Validation of health screening questionnaire used for screening gastrointestinal disorder in worker's special health examination for night time work.

BACKGROUND: Since the night time work was introduced as a 'harmful factor' for the worker's special health examination (WSHE) in 2014, the validation of the questionnaire used for screening gastrointestinal (GI) disorder has not been conducted. The purpose of this study is to verify the validity of the questionnaire using the data of specific health screening cluster. METHODS: We used WSHE screening data for 3 years, from 2014 to 2016, in health screening cluster. The subjects who had received upper GI endoscopy in opportunistic screening and WSHE simultaneously regardless of the results of the questionnaire were selected. We tested the validity of the questionnaire using upper GI endoscopy as a gold standard. RESULTS: This study was conducted on 5,057 examinees in 2014, 8,352 examinees in 2015, and 10,587 examinees in 2016. The validity of the questionnaire for each year was as follows: sensitivity 12.3% (95% confidence interval [CI], 11.1-13.4), specificity 88.6% (95% CI, 87.2-90.1), accuracy 41.1% (95% CI, 39.8-42.5) in 2014, sensitivity 5.9% (95% CI, 5.2-6.5), specificity 93.6% (95% CI, 92.7-94.4), accuracy 38.6% (95% CI, 37.6-39.6) in 2015, sensitivity 6.0% (95% CI, 5.4-6.5), a specificity of 9.42% (95% CI, 93.4-95.0), accuracy of 34.2% (95% CI, 33.3-35.1) in 2016. In generally, questionnaire showed sensitivity of 10%, specificity of 90%, and accuracy of 40%. CONCLUSIONS: Despite the purpose of WSHEs aiming to identify target disease early, the sensitivity of the questionnaire for GI disease was too low as 10%. The reasons for this are the problem of the question itself, and the problem of ambiguous target disease. In the future, the questionnaire should be improved to meet the purpose of the WSHE, and further correction of the target disease should be made.

Work-related COPD after years of occupational exposure.

BACKGROUND: Cigarette smoking is known as the most important risk factor of chronic obstructive pulmonary disease (COPD). However, occupational exposure to other substances can result in COPD. CASE REPORT: A 76-year-old man with occupational exposures to mixtures of silica dust, gas, and fumes for 10 years and with a 25 pack-year smoking history was diagnosed with COPD. His computed tomogram scan revealed some hyperinflation with emphysematous change in both upper lobes. In the pulmonary function tests, his post-bronchodilator forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC% were 2.20 L (67% of the predicted value), 1.12 L (52% of the predicted value), and 51%, respectively, indicating moderate COPD. This case of COPD was confirmed as a work-related disease by the Occupational Lung Disease Research Institute in Korea Workers' Compensation & Welfare Service. CONCLUSION: Exposure to various substances such as silica dust, gas, and fumes from furnace and boiler installation was likely the cause of COPD in this patient. Thus, occupational exposure should be considered an important risk factor of COPD.

Characterization of the bioactive motif of neuregulin-1, a fibroblast-derived paracrine factor that regulates the constitutive color and the function of melanocytes in human skin.

Interactions between melanocytes and neighboring cells in the skin (keratinocytes and fibroblasts) play important roles in regulating human skin color. We recently reported that neuregulin-1 (NRG1) is highly expressed in fibroblasts from Fitzpatrick type VI skin (the darkest) and at least in part determines the constitutive color of human skin. We have now characterized the bioactive motif of NRG1 that is involved in modulating melanin production in human melanocytes. We found that 8-mer motifs (PSRYLCKC and LCKCPNEF) increased melanin production but did not increase the proliferation of melanocytes; the minimum fragment that could elicit that effect was the tetrapeptide LCKC. This smaller bioactive peptide might have an advantage in clinical applications in which it modulates only pigmentation and does not stimulate melanocyte proliferation.

The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.

The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis.

Regulation of human skin pigmentation in situ by repetitive UV exposure: molecular characterization of responses to UVA and/or UVB.

UV radiation is a major environmental factor that affects pigmentation in human skin and can eventually result in various types of UV-induced skin cancers. The effects of various wavelengths of UV on melanocytes and other types of skin cells in culture have been studied, but little is known about gene expression patterns in situ following in situ exposure of human skin to different types of UV (UVA and/or UVB). Paracrine factors expressed by keratinocytes and/or fibroblasts that affect skin pigmentation might be regulated differently by UV, as might their corresponding receptors expressed on melanocytes. To test the hypothesis that different mechanisms are involved in the pigmentary responses of the skin to different types of UV, we used immunohistochemical and whole human genome microarray analyses to characterize human skin in situ to examine how melanocyte-specific proteins and paracrine melanogenic factors are regulated by repetitive exposure to different types of UV compared with unexposed skin as a control. The results show that gene expression patterns induced by UVA or UVB are distinct-UVB eliciting dramatic increases in a large number of genes involved in pigmentation as well as in other cellular functions, whereas UVA had little or no effect on these. The expression patterns characterize the distinct responses of the skin to UVA or UVB, and identify several potential previously unidentified factors involved in UV-induced responses of human skin.

Regulation of human skin pigmentation and responses to ultraviolet radiation.

Pigmentation of human skin is closely involved in protection against environmental stresses, in particular exposure to ultraviolet (UV) radiation. It is well known that darker skin is significantly more resistant to the damaging effects of UV, such as photocarcinogenesis and photoaging, than is lighter skin. Constitutive skin pigmentation depends on the amount of melanin and its distribution in that tissue. Melanin is significantly photoprotective and epidermal cells in darker skin incur less DNA damage than do those in lighter skin. This review summarizes current understanding of the regulation of constitutive human skin pigmentation and responses to UV radiation, with emphasis on physiological factors that influence those processes. Further research is needed to characterize the role of skin pigmentation to reduce photocarcinogenesis and to develop effective strategies to minimize such risks.