Thesis (M.Sc. (Clinical Tropical Medicine))--Mahidol University, 1984.

No / The skin pigment melanin is produced in melanocytes in highly specialized organelles known as melanosomes. Melanosomes are related to the organelles of the endosomal/lysosomal pathway and can have a low internal pH. In the present study we have shown that melanin synthesis in human pigment cell lysates is maximal at pH 6.8. We therefore investigated the role of intramelanosomal pH as a possible control mechanism for melanogenesis. To do this we examined the effect of neutralizing melanosomal pH on tyrosinase activity and melanogenesis in 11 human melanocyte cultures and in 3 melanoma lines. All melanocyte cultures (9 of 9) from Caucasian skin as well as two melanomacell lines with comparable melanogenic activity showed rapid (within 24 h) increases in melanogenesis in response to neutralization of melanosomal pH. Chemical analysis of total melanin indicated a preferential increase in eumelanin production. Electron microscopy revealed an accumulation of melanin and increased maturation of melanosomes in response to pH neutralization. In summary, our findings show that: (i) near neutral melanosomal pH is optimal for human tyrosinase activity and melanogenesis; (ii) melanin production in Caucasian melanocytes is suppressed by low melanosomal pH; (iii) the ratio of eumelanin/phaeomelanin production and maturation rate of melanosomes can be regulated by melanosomal pH. We conclude that melanosomal pH is an essential factor which regulates multiple stages of melanin production. Furthermore, since we have recently identified that pink locus product (P protein) mediates neutralization of melanosomal pH, we propose that P protein is a key control point for skin pigmentation. We would further propose that the wide variations in both constitutive and facultative skin pigmentation seen in the human population could be associated with the high degree of P-locus polymorphism.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2008. / Härtill 4 uppsatser.

No description available.

No / The present invention relates to compositions and methods useful in studying or modulating melanin pigmentation in the skin. Particularly, the invention relates to compositions comprising a substance capable of modulating the activity or expression of ALK6 (SEQ ID 2) or Cdc42 which in turn are capable of modulation of the transfer of melanin from melanocytes to keratinocytes and potentially from keratinocytes to keratinocytes. The invention also relates to assays for identifying such compositions, and methods of modulating skin pigmentation.

Adverse effects of amiodarone are rarely seen in pediatric patients, but may occur if amiodarone is applied for long-term treatment. Two rather rare phenomena are blue-gray skin pigmentation and pulmonary mass. They represent important differential diagnoses from more common clinical complications like pneumonia and drug-induced toxic skin lesions.

O melanoma é uma doença complexa, associada com diversos fatores de risco genéticos e ambientais. Este o tipo mais agressivo de câncer de pele e origina-se nos melanócitos, as células da pele produtoras de pigmento nos mamíferos. Polimorfismos de base única (Single Nucleotide Polymorphisms - SNPs) presentes em genes envolvidos na pigmentação têm sido descritos envolvidos na modulação de risco para o melanoma, porém o conhecimento neste campo ainda é bastante limitado. Neste estudo, foi avaliado o efeito de quatro SNPs em quatro genes de pigmentação: TYR (rs1126809), HERC2 (rs1129038), SLC24A5 (rs1426654) e SLC45A2 (rs16891982) no aumento de risco para melanoma, usando análises de regressão logística multivariada e redução de dimensão multifatorial (MDR), em uma abordagem caso-controle. Em 255 indivíduos (120 pacientes com melanoma e 135 controles sem melanoma) provenientes do Rio Grande do Sul, Brasil, identificamos associação com o risco para melanoma em três dos quatro SNPs investigados (HERC2 rs1129038, P=0.017; SLC24A5 rs1426654, P<0.001; e SLC45A2 rs16891982, P=0.002). Além disso, a interação entre rs1426654 e rs16891982 (genótipos AA e GG, respectivamente), aumentou significamente o risco para melanoma nas análises de regressão logística multivariada e análises de MDR [OR = 6.936 (CI 95%: 1.607 – 50.294), P= 0.022]. Estes resultados contribuem para o conhecimento atual, indicando que esses SNPs contribuem para o aumento de risco de desenvolvimento de melanoma. / The melanoma is a complex disease, associated with several environmental and genetic risk factors. This is the most aggressive type of skin cancer and originates in melanocytes, the pigment producing skin cells in mammals. Single nucleotide polymorphisms (SNPs) in pigmentation genes have been describe in melanoma risk modulation but our knowledge in the field is still limited. Here, we assessed the effect of SNPs in four pigmentation genes – TYR (rs1126809), HERC2 (rs1129038), SLC24A5 (rs1426654), and SLC45A2 (rs16891982) on increase of melanoma risk using multivariate logistic regression and a multifactorial dimension reduction (MDR) analysis, in a case-control approach. In 255 individuals (120 melanoma patients and 135 controls free melanoma) from Rio Grande do Sul, Brazil, we identified an association of melanoma risk with three of the four SNPs studied (HERC2 rs1129038, P=0.017; SLC24A5 rs1426654, P<0.001; and SLC45A2 rs16891982, P=0.002). In addition, the interaction between rs1426654 and rs16891982 (AA and GG genotypes, respectively) significantly increased the risk of melanoma [OR = 6.936 (CI 95%: 1.607 – 50.294), P= 0.022] in both MRD and multivariate logistic regression analyses. Our results contribute to the current knowledge, indicating that SNPs contribute to the increase risk of melanoma.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.

The inability to tan properly after sun exposure strongly correlates with increased incidence of skin cancer. The melanocortin 1 receptor (MC1R) is a transmembrane Gs-coupled cell surface receptor found on epidermal melanocytes that transmits pro-survival and pro-differentiation signals mediated by the second messenger cAMP. Humans carrying loss-of-function polymorphisms in MC1R signaling exhibit higher incidences of skin cancers including melanoma. This study focused on the physiologic effects of topical application of forskolin, an adenylate cyclase activator, in extension (Mc1re/e) K14-SCF animals, which model the fair-skinned UV-sensitive human. Twice daily application of the drug promoted accelerated pigmentation, increased skin darkening due to epidermal deposition of melanin pigment, and induced epidermal melanin, which protected the skin against UV injury as judged by “minimal erythematous dose” (MED). Moreover, MC1R signaling regulated the expression of antioxidant enzymes at the transcriptional level. The human melanoma cell line A375, known to harbor a loss-of-function signaling mutation in MC1R, was used to determine effects of cAMP stimulation on the expression of antioxidant enzymes. We observed increases in expression of genes that control the biosynthesis and regulation of glutathione including the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione peroxidase, GPX, and glutathione reductase GSR. In addition, there is an increase in manganese superoxide dismutase (MnSOD) at the protein level. There was accumulation of MnSOD in the mitochondria after pharmacologic induction of cAMP with forskolin. Addition of the oxidative agent H2O2 enhanced the expression of MnSOD at the protein level as early as one hour after MC1R stimulation. Oxygen consumption rate on mitochondria was measured using Seahorse analysis; pharmacologic activation of MC1R/cAMP signaling did not affect mitochondrial metabolism. In addition, topical application of a crude extract of Solidago inhibited UV-induced inflammation in K14-SCF mice. Several UV-induced cytokines, including TNF-α, were down-regulated at the transcriptional level after topical application of Solidago extract. Together, these results indicate that MC1R signaling protects melanocytes from UV damage by regulating antioxidant enzyme expression and suggest that pharmacologic cAMP induction may be a useful preventive mechanism against UV-mediated skin sunburn and oxidative injury.