Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin.

Orange peel extract appears to exhibit beneficial effects on skin whitening, inflammation, UVB protection, as well as keratinocyte proliferation. In the present study, we determine whether topical hesperidin influences epidermal permeability barrier function and its underlying mechanisms. Hairless mice were treated topically with 2% hesperidin or 70% ethanol alone twice daily for 6 days. At the end of treatment, basal transepidermal water loss (TEWL) was measured 2 and 4 h post barrier disruption. Epidermal proliferation and differentiation were evaluated by immunohistochemical staining and Western blot analysis. Additionally, lamellar body density and secretion were assessed by electron microscopy. Although there were no significant differences in basal barrier function, in comparison with control animals, topical hesperidin significantly accelerated barrier recovery at both 2 and 4 h after acute barrier abrogation. Enhanced barrier function in hesperidin-treated skin correlated with stimulation of both epidermal proliferation and differentiation, as well as enhanced lamellar body secretion. These results indicate that topical hesperidin enhances epidermal permeability barrier homeostasis at least in part due to stimulation of epidermal proliferation, differentiation, as well as lamellar body secretion.

Topical herbal extract (Huangdang mixture) exhibits both preventive and therapeutic effects in murine acute irritant contact dermatitis.

BACKGROUND: Contact dermatitises, including allergic contact dermatitis and irritant contact dermatitis, are among the most common skin disorders in humans. Chinese herbal medicines (CHM) have been used in treating contact dermatitises for centuries. Systemic administration of CHM, including ingredients in huangdang mixture containing Chinese angelica, radix Paeonlae rubra, cat nut, and phelloden dron, rhizoma alismatis, rhizoma smilacis glabrae, and rhizome of swordlike, improves allergic contact dermatitis induced by l-fluoro-2,4-dinitrobenzene. Whether topical applications of these herbal extracts display preventive and/or therapeutic effects on contact dermatitis, thereby avoiding the potential side effects of systemic CHM, remains largely unknown. AIMS: To determine whether this topical CHM extract exerts preventive and/or therapeutic effects, we assessed its efficacy in both allergic contact dermatitis and irritant contact dermatitis murine models. MATERIALS AND METHODS: Allergic contact dermatitis and irritant contact dermatitis murine models were established by topical oxazolone and a phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA), respectively. Ear thickness was assessed in both dermatitis models. RESULTS: Our results demonstrate that this topical CHM extract exhibits both therapeutic and preventive effects in acute irritant contact dermatitis but no demonstrable efficacy in murine allergic contact dermatitis. CONCLUSION: These results suggest that this topical CHM extract could provide an alternative regimen for the prevention and treatment of irritant contact dermatitis.

Cutaneous resonance running time varies with age, body site and gender in a normal Chinese population.

BACKGROUND/OBJECTIVES: One phenomenon of skin aging is loss of cutaneous elasticity. Measurement of cutaneous resonance running time (CRRT) is a method to assess skin elasticity. Yet, information regarding the directional changes of CRRT associated with age, body sites and gender is not yet available. In the present study, we assessed whether changes in CRRT vary with age, body sites and gender in a normal Chinese population. METHODS: A Reviscometer was used to measure CRRTs in various directions on the left dorsal hand, the forehead and the left canthus of 806 normal Chinese volunteers, aged 2.5-94 years. RESULTS: With aging, CRRTs decreased in all directions on the hand, the forehead and the canthus. A more dramatic reduction in CRRTs on the forehead and the canthus was observed in both the 2-8 and the 3-9 o'clock directions. CRRTs in males aged 11-20 years were longer than those in females in some directions on all three body sites. Females aged between 21 years and 40 years showed longer CRRTs than males in some directions of the hand. There were no gender differences in subjects aged 0-10 (except on the canthus) and those over 80 years old. CONCLUSION: CRRTs vary with age, body sites and gender.

The role of CD44 in cutaneous inflammation.

CD44 is a transmembrane glycoprotein expressed in various tissues including the skin. Previous studies indicated that CD44 is required for epidermal permeability barrier homeostasis and keratinocyte differentiation. Yet, while some studies have demonstrated that CD44 is critical for the development of inflammation, others have shown that CD44 is not essential for the development of cutaneous inflammation. In this study, we evaluated the changes in epidermal CD44 expression in a variety of skin inflammatory models and determined whether CD44 is required for the development of cutaneous inflammation. Inflammatory responses were compared in CD44 KO versus wild-type mice in acute models of irritant and allergic contact dermatitis, as well as in a subacute allergic contact dermatitis induced by repeated hapten treatment. Inflammatory responses were assessed by measuring ear thickness and epidermal hyperplasia in haematoxylin & eosin-stained sections. Our results demonstrate that: (i) epidermal CD44 expression increases in both acute and subacute cutaneous inflammatory models; and (ii) acute disruption of the epidermal permeability barrier function increases epidermal CD44 expression. Whereas inflammatory responses did not differ between CD44 KO and wild-type mice in acute models of irritant and allergic contact dermatitis, both inflammatory responses and epidermal hyperplasia increased in CD44 KO mice following repeated hapten challenges. These results show first, that permeability barrier disruption and inflammation stimulate epidermal CD44 expression, and second, that CD44 modulates epidermal proliferation and inflammatory responses in a subacute murine allergic contact dermatitis model.

Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site.

The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens. An affinity-improved version of bH1 inhibits both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. Such "two-in-one" antibodies challenge the monoclonal antibody paradigm of one binding site, one antigen. They could also provide new opportunities for antibody-based therapy.

Basis for abnormal desquamation and permeability barrier dysfunction in RXLI.

Mutations in the gene for steroid sulfatase (SSase), are responsible for recessive x-linked ichthyosis (RXLI). As a consequence of SSase deficiency, its substrate, cholesterol sulfate (CSO4), accumulates in the epidermis. Accumulation of this amphipathic lipid in the outer epidermis provokes both a typical scaling phenotype and permeability barrier dysfunction. Research on RXLI has illuminated several, potentially overlapping pathogenic mechanisms and provided insights about the role of SSase and CSO4 in normal differentiation, barrier maintenance, and desquamation. We now show here that SSase is concentrated in lamellar bodies (LB), and secreted into the SC interstices, along with other LB-derived lipid hydrolases. There, it degrades CSO4, generating some cholesterol for the barrier, while the progressive decline in CSO4 (a serine protease (SP) inhibitor) permits corneodesmosome (CD) degradation leading to normal desquamation. Two molecular pathways contribute to disease pathogenesis in RXLI: 1) excess CSO4 produces nonlamellar phase separation in the stratum corneum (SC) interstices, explaining the barrier abnormality. 2) The increased CSO4 in the SC interstices inhibit activity sufficiently to delay CD degradation, leading to corneocyte retention. We also show here that increased Ca++ in the SC interstices in RXLI could contribute to corneocyte retention, by increasing CD and interlamellar cohesion. RXLI represents one of the best understood diseases in dermatology--from the gene to the SC interstices, its etiology and pathogenesis are becoming clear, and assessment of disease mechanisms in RXLI led to new insights about the role of SSase and CSO4 in epidermis terminal differentiation.