Mark Boon Yang Tang

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations

Background Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD.

Angiopoietin-like 4 Interacts with Matrix Proteins to Modulate Wound Healing

A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrin-matrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin- focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.

Angiopoietin-Like 4 Interacts with Integrins β1 and β5 to Modulate Keratinocyte Migration

Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins β1 and β5, but not β3, as novel binding partners of ANGPTL4. ANGPTL4-bound integrin β1 activated the FAK-Src-PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis.

Gram-Positive Antimicrobial Activity of Amino Acid-Based Hydrogels

Antimicrobial hydrogels are prepared based on the co-assembly of commercial Fmoc-phenylalanine and Fmoc-leucine, which act as the hydrogelator and antimicrobial building block, respectively. This co-assembled antimicrobial hydrogel is demonstrated to exhibit selective bactericidal activity for gram-positive bacteria while being biocompatible with normal mammalian cells, showing great potential as an antimicrobial coating for clinical anti-infective applications.

A synergistic capture strategy for enhanced detection and elimination of bacteria.

Despite the advanced detection and sterilization techniques available today, the sensitive diagnosis and complete elimination of bacterial infections remain a significant challenge. A strategy is reported for efficient bacterial capture (ca. 90%) based on the synergistic effect of the nanotopography and surface chemistry of the substrate on bacterial attachment and adhesion. The outstanding bacterial-capture capability of the functionalized nanostructured substrate enables rapid and highly sensitive bacterial detection down to trace concentrations of pathogenic bacteria (10 colony-forming units mL(-1)). In addition, this synergistic biocapture substrate can be used for efficient bacterial elimination and shows great potential for clinical antibacterial applications.

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis

Background  Loss‐of‐function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients’ susceptibility to recurrent skin infection.

Retrospective 5-year review of 131 patients with mycosis fungoides and Sézary syndrome seen at the National Skin Centre, Singapore.

A total of 131 new cases of mycosis fungoides and Sézary syndrome were diagnosed clinically and histopathologically at our centre over a 5‐year period. There were 87 males and 44 females with a mean age of 36.3 years (range 3–87 years) and no racial predilection. Of the 62 patients (47.3%) with classical mycosis fungoides, the majority were male (male : female = 4.2:1). There was one patient with Sézary syndrome. Patients aged older than 50 years were more likely to present with a longer duration of symptoms and advanced disease. In contrast to classical mycosis fungoides, the 47 patients diagnosed with hypopigmented mycosis fungoides had early stage disease, were younger, and no gender predilection was noted. The mean duration of follow up was 19.7 months (range 0.2–54.8 months). Complete remission was achieved in 24.7% and 53.8% of patients followed up at 1 and 3 years, respectively, using skin‐directed and systemic treatment modalities appropriate for the stage of disease. There were five patients with progressive disease and three patients with advanced disease who died from disease‐related complications. The most significant prognostic factors for 1‐year and 3‐year outcomes were the patient’s duration of symptoms and stage of disease at presentation.

Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre.

Bullous pemphigoid (BP) is the most common autoimmune‐mediated subepidermal blistering skin disease and is associated with significant morbidity and mortality.

Contact sensitization in patients with chronic venous leg ulcers in Singapore.

Contact sensitization rates are high in patients with chronic venous leg ulcers. Allergic contact dermatitis poses a significant hindrance to the healing of the wounds. There are no published studies examining the rate of contact sensitization in Asian patients. Our objective was to determine the rate of contact sensitization in patients with chronic venous leg ulcer in Singapore and the variation in the common allergens based on local practices in comparison with Western countries. 44 patients were patch tested to the National Skin Centre standard series, steroid series, medicaments, topical Chinese medicaments, and to modern wound dressings used. The overall rate of contact sensitization was 61.4%. The common allergen groups were topical antibiotics (18.2%) and topical traditional Chinese medicaments (TTCM) (15.9%). Individually, colophony (11.3%), Saw Hong Choon skin ointment (Kam Bo Med, Hong Kong, Hong Kong) (11.3%), Balsam of Peru (9.1%), and povidone iodine (9.1%) were among the most frequent allergens. The sensitization rate among users of TTCM was notably high (41%). A high rate of contact sensitization was found in our study, similar to previous reports from the West. TTCM play a major role as possible allergens in our patients. In Asian patients, a history of its usage should be elicited, and patch testing should include the commonly used TTCM where possible.

Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment.

Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.