Eunhyun Choi

The effects of topical α-hydroxyacids on the normal skin barrier of hairless mice

Backgroundu2002α‐hydroxyacids (AHA), such as glycolic acid and lactic acid, have recently been used in cosmetic and dermatological formulations. However, the mechanisms of action of these substances have not been well documented.

Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors.

Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized δ-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the δ-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller γ-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, γ-lactam based HDAC inhibitors showed more potent than δ-lactam analogues.

Property-based optimization of hydroxamate-based γ-lactam HDAC inhibitors to improve their metabolic stability and pharmacokinetic profiles.

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated 8f had potent anticancer activity and high oral bioavailability.

A clinical and histopathological study of 22 patients with membranous lipodystrophy

Membranous lipodystrophy, an uncommon disorder, was described by Nasu et al. in 1973 as a form of regressive degeneration or localized destruction of the adipose tissue.1 Clinical features of the lesions with membranous fat necrosis are variable and the condition can only be diagnosed histopathologically. These peculiar changes in tat tissue have been associated with many local and systemic diseases including lupus erythematosus, diabetes mellitus, erythema nodosum, stasis dermatitis, morphoea and trauma, but occasionally no underlying disease is found. Even though various hypotheses concerning the pathogenesis of membranous lipodystrophy have been proposed, the exact causes are still in dispute.2–4

Topical calcitriol restores the impairment of epidermal permeability and antimicrobial barriers induced by corticosteroids.

Backgroundu2002 The active form of vitamin D3, calcitriol, is widely used for the treatment of psoriasis, with or without topical corticosteroids. Topical corticosteroids are known to disrupt permeability and antimicrobial barriers, even with short‐term use. Yet, the effect of topical calcitriol on epidermal permeability and antimicrobial barriers disrupted by topical corticosteroids has not been determined.

The skin barrier state of aged hairless mice in a dry environment

Summary Backgroundu2003Many elderly people have chronic xerosis, and frequently experience an exacerbation during winter.

Lichen striatus following BCG vaccination

SIR, A htalihy TO-day-old female inlant developed lichen striatus fdllnwinfj; Bacille t^alnicttc-Guerin (BCG) vaccination, lo date, such vaccination has been widely used as a safe and effective accine for protection against tuberculosis, and in adults in particular has come into frequent use in immunotherapy for bladder cancer and malignant melanoma. Many authors have reviewed the dermatolofrical complications oi the vaccination, both specific and nonspecific. Including clinical, histopathological and bacteriological studies (Table 1).

Phorbol myristate acetate differentiates human adipose-derived mesenchymal stem cells into functional cardiogenic cells.

To achieve effective regeneration of injured myocardium, it is important to find physiological way of improving the cardiogenic differentiation of stem cells. Previous studies demonstrated that cardiomyocytes from bone marrow-derived mesenchymal stem cells (BMSCs) activated with phorbolmyristate acetate (PMA), a protein kinase C (PKC) activator, restore electromechanical function in infarcted rat hearts. In this study, we investigated the effect of PMA on cardiogenic differentiation of adipose-derived MSCs (ASCs) for clinical applications. To confirm the effect of PMA, ASCs treated with 1μM PMA were grown for nine days. The expression of cardiac-specific markers (cardiac troponin T, myosin light chain, myosin heavy chain) in PMA-treated MSCs was demonstrated by immunocytochemistry. Alhough few α(1A) receptors exist in ASCs, α(1)-adrenergic receptor subtypes were preferentially expressed in PMA-treated ASCs. Moreover, expression of the β-adrenergic and muscarinic receptors increased in PMA-treated ASCs compared to normal cells. The mRNA levels of Ca(2+)-related factors (SERCA 2a; sarcoplasmic reticulum Ca(2+)-ATPase, LTCC; L-type Ca(2+) channel) in treated ASCs were similar to the levels in cardiomyocytes. Following the transplantation of chemically activated cardiogenic ASCs into infarcted myocardium, histological analysis showed that infarct size, interstitial fibrosis, and apoptotic index were markedly decreased and cardiac function was restored. In conclusion, PMA might induce the cardiogenic differentiation of human ASCs as well as BMSCs. This result suggests successful use of human ASCs in cardiac regeneration therapy.

Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.

Stimulation of epidermal calcium gradient loss increases the expression of hyaluronan and CD44 in mouse skin

Background.u2002 Hyaluronan (HA), a major extracellular matrix component in epidermis, has been found to accumulate in the epidermis after disruption of the epidermal barrier; however, the precise mechanisms underlying this process are not yet clear. Alterations in the epidermal calcium gradient are an important signal for permeability‐barrier homeostasis. Thus, we hypothesized that epidermal calcium‐ions might regulate HA expression.