Co‐localization of inducible nitric oxide synthase and phosphorylated Akt in the lesional skins of patients with melasma

Abstract

Activation of the inducible nitric oxide synthase (iNOS)/nitric oxide (NO) pathway in keratinocytes has been reported to be associated with the pathogenesis of melanogenesis. Akt activation plays an important role in the activation of the transcription factor nuclear factor (NF)-kappaB and subsequent elevation of iNOS expression. In the present study, we highly detected both iNOS protein and Akt phosphorylation in keratinocytes of the basal layer of the epidermis at the junction with the dermis of melasma skin biopsy specimens, but not in normal skin tissues, from nine patients using immunohistological analysis. iNOS protein and phosphorylated Akt were co-localized in the lesional skins, and their levels were highly correlated R2= 0.69). Furthermore, iNOS mRNA was also detected in an additional three skin biopsy specimens, but not in normal skin, by reverse transcription polymerase chain reaction. Our results describe that iNOS expression is elevated in human melasma lesions, probably via activation of the Akt/NF-kappaB pathway, indicating that NO production plays an important role in the mechanism of hyperpigmentation in human facial melasma.

Morphologic Changes and the Expression of Alpha-Melanocyte Stimulating Hormone and Melanocortin-1 Receptor in Melasma Lesions: A Comparative Study

“…Tomita et al reported that ultraviolet-B radiation induced prostaglandin secretion and that prostaglandins E 2, thromboxane B 2 , and leukotriene C 4 , particularly, result in larger and more dendritic melanocytes. 37,38 The release of cytokines and prostaglandins following sun exposure could have stimulatory effects on melanocytes in patients with melasma, and thus explain dermal hyperpigmentation and inflammation as it occurs in postinflammatory hyperpigmentation. 37,39 When activated, human dermal fibroblasts secrete several melanogenic cytokines, such as stem cell factor and hepatocyte growth factor, which increased in melasma skin, suggesting that the increase in fibroblast number and activation leads to changes in the fundamental substance, dermal elastosis, and melanocyte activation in ultraviolet-radiated skin.…”

Topical Agents for Melasma: A Perspective on Therapeutic Approaches and their Molecular Bases

“…Other hypotheses on melasma pathogenesis include a) an upregulation of genes modulating Wnt and prostaglandin pathways [68]; b) the involvement of non-coding RNA (H19 gene) [69]; c) the UVmediated increase in inducible nitric oxide synthase (iNOS) levels, which can activate the AKT-NFkB pathway [70,71]. Finally, a genetic predisposition has been suggested in melasma development by reports of family occurrence [72].…”

Clues to the Pathogenesis of Melasma from its Histologic Findings

“…The elevated expression of vascular endothelial growth factor (VEGF) in keratinocytes has led to the hypothesis that VEGF may play a role in the behavior of the melanocytes in the skin, because functioning VEGF receptors were demonstrated in melanocytes in vitro [26]. Elevations in the levels of c-kit, SCF, and inducible nitric oxide synthase have also been observed, which could affect vascularization [27,28].…”