Recently, it has become clear that Na⁺/H⁺ exchanger 1 (NHE1) plays an important role in the acidification of skin surface. NHE1 exists on the cell membrane of keratinocytes and regulates intracellular pH by effectively extruding H⁺ ions from intracellular compartments in exchange for external sodium ions, which also controls the acidification of extracellular microdomains and, consequently, was suggested to contributes to skin surface pH. Our previous study using human skin suggested that NHE1 protein amount, skin surface pH, and the onset of rough skin are related to each other. In this study, we investigated how NHE1 participated in skin surface pH, and the water holding capacity and the barrier function of the stratum corneum in human keratinocytes. A NHE1 activator significantly increased the mRNA expression of filaggrin (FLG) and serine palmitoyl transferase (SPT), a ceramide synthesis enzyme, while a NHE1 inhibitor significantly decreased the mRNA expression of both. Environmental and mental stress factors decreased the NHE1 mRNA expression in human keratinocytes. Moreover, a mild acidic environment significantly decreased the FLG and SPT mRNA expression in human keratinocytes. On the basis of these results, NHE1 was suggested to play an important role in not only controlling skin surface pH but also maintaining water holding capacity and barrier function of stratum corneum. Furthermore, decreased level of NHE1 due to environmental and mental stress was assumed to decrease water holding capacity and barrier function of stratum corneum, followed by the onset of rough skin. Therefore, to improve rough skin, preventing the depression of NHE1 function was considered to be more important than mere acidification of skin surface.

Recently, in the field of dermatology, the number of patients, especially adults, with atopic dermatitis (AD) has increased. In addition to conventional drug treatments, the appropriate use of skin care products can help in the recovery of normal skin conditions, thus improving the quality of life (QOL) of patients with AD. Therefore, an appropriate use of skin care products is expected to help facilitate self-medication. This study investigated efficacy of skin care products containing tranexamic acid in AD patients. After using prototype skin care products for 4 weeks, a significant recovery from drying and itching symptoms was observed. The average water content of the stratum corneum increased significantly from 70.5 to 95.5 AU. Approximately 65% of the subjects realized the importance of skin care. Assessment of skin irritation by patch testing in patients with dermatitis showed that prototype skin care products caused almost no irritation, and no severe adverse events were detected in the clinical trial. Overall, this study indicated that daily skin care may play a partial role in preventing the recurrence of dermatitis. It was shown that the appropriate use of skin care products was beneficial for patients with AD and could contribute to the promotion of self-medication among patients with AD.

Elastic fibers are extracellular matrix components that confer resilience on tissues such as skin, lung, and arteries. Deterioration of elastic fibers by elastase secreted from macrophages or neutrophils induced by UV or smoking, together with aging directly causes loose skin, emphysema, and arteriosclerosis. The turnover rate of elastic fibers is very slow, and it has been believed to be difficult to regenerate elastic fibers. There are several steps required in elastogenesis: (1) formation of microfibril meshwork or bundles, (2) micro-aggregation of tropoelastin (elastin monomer), (3) deposition of elastin on microfibrils, and (4) cross-linking of elastins by lysyl oxidase. We have identified several secreted proteins, Fibulin-4, -5, and LTBP-2, -4 that are necessary for each step. Elucidating the function of these elastogenic proteins may lead to novel clinical application of elastic fiber regeneration.

Second-harmonic-generation (SHG) microscopy has attracted attentions for in situ visualization of human dermal collagen fibers. Due to its specific collagen selectivity without staining, non-invasiveness, and high-resolution 3D imaging capability, collagen fiber structure can be visualized as high-contrast SHG image in situ. However, it is difficult to extract quantitative parameters reflecting the collagen fiber structure from SHG image. Also, its practical use is limited in the dermatological field due to its bulky and complicated setup. In this review paper, we first review the application of the two-dimensional auto-correlation analysis for SHG image of the dermal collagen fibers in the human cheek skin. The extracted index for the collagen fiber structure significantly decreased with aging. Furthermore, we confirmed the moderate correlation between the collagen fiber structure index and the skin elasticity measured by Cutometer^®. This correlation indicated that the dermal collagen fiber structure play an important role to determine the skin elasticity. In other words, the auto-correlation analysis of SHG image can be used for evaluation of the skin elasticity from the viewpoint of the dermal collagen. We next review the construction of a photonic-crystal-fiber (PCF)-coupled, hand-held SHG microscope for in situ monitoring of collagen fibers in human skin. While the ultrashort pulse light is delivered from a laser source to the SHG microscope via a large mode area PCF, SHG microscope was enclosed into a hand-held probe head. We compare the imaging performance between the conventional SHG microscope and the hand-held SHG microscope, and confirmed the comparable performance to each other. Finally, we demonstrated in situ visualization of collagen fibers in human skin. The combination of quantitative texture analysis with the hand-held SHG microscope will move SHG microscopy closer to the clinical applications in fields of skin cosmetics and anti-aging dermatology.

With the progressive aging of society, anti-aging cosmetics with high efficacy are strongly demanded. Since wrinkles in particular are well known to influence an aged appearance, cosmetic companies have made huge efforts at developing anti-wrinkle products. However, there were no standardized, objective methods for evaluating wrinkles. To establish a method for evaluating wrinkles, the Japanese Cosmetic Science Society organized a task force committee and published the “Guideline for evaluation of anti-wrinkle products” in 2006. We herein review an anti-wrinkle ingredient whose effect was examined using this guideline. In addition, a detailed explanation of the molecular mechanism to demonstrate an anti-wrinkle effect is also required by the Japanese Ministry of Health, Labour and Welfare for all quasi-drug ingredients. We found that neutrophils, the most abundant white blood cells in mammals, localized constitutively in the skin around the outer corner of the eye, a site at which wrinkles are likely to form. Neutrophil elastase (NE)， a serine protease secreted by neutrophils, has a broad substrate specificity, including collagen, elastin, and proteoglycans. Given the role of NE for digesting the extracellular matrix, NE inhibition appears to be a promising target for anti-wrinkle treatments. We found that the NE inhibitor NEI-L1 has a strong NE inhibitory effect and also improves wrinkles, suggesting that NE inhibitors will prove to be novel and effective anti-wrinkle treatments.

Melanin pigments play a pivotal role in protecting our body from harmful ultraviolet radiation, but their excess deposition often causes freckles and skin spots. To prevent undesirable melanin deposition, it is important to understand the molecular mechanisms of formation, maturation, and transport of melanosomes, specialized organelles that synthesize and store melanin in melanocytes. Melanosomes are formed and matured at the perinuclear region of melanocytes (step 1). In this step, melanogenic enzymes such as tyrosinase and tyrosinase-related protein 1 (Tyrp1) are transported to immature melanosomes by several protein complexes such as BLOC-1–3 complexes and a complex composed of small GTPases Rab32/38, their effector Varp, and v-SNARE VAMP7. Mature melanosomes are first transported from the perinucleus to the cell periphery by microtubule-dependent motors such as Kif5b (i.e., Rab1A/SKIP/Kif5b complex) (step 2) and then transported to just beneath the plasma membrane by an actin-dependent motor myosin-Va (i.e., Rab27A/Slac2-a/myosin-Va complex) (step 3). The melanosomes anchored to the plasma membrane are finally transferred to neighboring keratinocytes or hair matrix cells through dendrites of melanocytes (step 4) to achieve skin and hair pigmentation. Recent advances in molecular biology techniques have allowed us to dissect the molecular machineries regulating each melanosome transport step. For example, knockdown of Varp by specific siRNAs or overexpression of Varp in melanocytes inhibits transport of melanogenic enzymes to immature melanosomes, which leads to a hypopigmentation phenotype in cultured melanocytes. On the other hand, functional ablation of Rab27A or its effector Slac2-a inhibits actin-based melanosome transport, which leads to a perinuclear melanosome aggregation phenotype (i.e., typical phenotype observed in melanocytes from Griscelli syndrome patients). Thus, screening and identification of new substances or plant extracts that inhibit (or promote) the function of these transport machineries will enable us to develop new cosmetics for skin whitening (or new drugs that prevent gray hair) in the future.

In recent years, it is reported that UV light affect DNA damage, skin cancer and photo-aging such as age-spots and wrinkle. Along with the increasing awareness to protect the skin from UV light in these days, multi-functionalization is required to sunscreen not only for pool, sea and sports use, but also for daily use. Functions of sunscreen are needed to have high UV protection efficacy and less burden use feeling on the skin such as transparency after applying, moisturizing effect and comfortable feeling. In addition to that, it is reported that friction resistant function is important from the view point of actual consumer dairy life. This article reviews sunscreen formulations with high UVA protection efficacy and moisturizing of W/O technology by using plate like zinc oxide, and even protection film O/W technology by using α-gel capsule of UV absorbers. Furthermore, it also reviews UV protect evaluation method of sunscreen and sunscreen effects for photodermatosis, skin cancer and photo-aging such as age-spot, wrinkle and skin color evenness.

In Japan, there are values that prefer the state where the skin is white and has no spots or dullness. Therefore, spots and freckles are becoming one of the skin troubles for many consumers. The term “skin whitening” is used as a term referring to skin care for skin troubles such as spots and freckles. Products used for skin whitening purposes, so-called whitening products, generally refer to quasi-drugs containing skin whitening active ingredients. Various mechanisms of action for skin whitening have been elucidated so far, and various skin whitening active ingredients have been developed accordingly. In this article, the functional mechanism of skin whitening active ingredients blended in skin whitening quasi-drugs and the effects on human skin were outlined.