Degradation of Tyrosinase by Melanosomal pH Change and a New Mechanism of Whitening with Propylparaben

Many active cosmetic ingredients formulated as medicated whitening products (quasi-drugs) achieve their effect through inhibition of tyrosinase activity, but no products can achieve this effect through degradation of intramelanosomal tyrosinase. Melanin is synthesized by tyrosinase, which is localized to the membrane of melanosomes in melanocytes. It has been reported that the optimal pH of tyrosinase activity is nearly neutral and decreases under acidic conditions. The environment in melanosomes that tyrosinase acts on has attracted attention from researchers. We found that tyrosinase was degraded by acidification of melanosomes, thereby decreasing its activity. We found that both inhibitors of aspartic protease and cysteine protease decreased the degradation of tyrosinase. It is thought that aspartic protease and cysteine protease are participating in the degradation of tyrosinase in acid melanosome. Melanosomal pH is regulated by Na+/H+ exchangers and V-ATPase. We investigated the mechanisms of the inhibitory effect of melanin production of propylparaben using B16 melanoma cells. The expression level of mRNA of tyrosinase and related proteins (Trp-1 and Dct) was not affected by propylparaben; however, the protein levels in melanosomes decreased. We investigated the mechanisms of the inhibitory effect of propylparaben on melanin production using B16 melanoma cells. The effects of propylparaben on the mRNA expression of Na+/H+ exchangers and Na+/Ca2+ exchangers, as well as the melanosome pH levels were examined. Propylparaben decreased gene expression in both exchangers. It was confirmed that propylparaben decreased melanosomal pH by staining using an intracellular pH indicator. The results suggest that propylparaben down-regulated melanin production through acidification of melanosomes

Dual Nature of RAGE in Host Reaction and Nurturing the Mother–Infant Bond

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors