Chi-Pin Lee

Transepidermal water loss, serum IgE and β-endorphin as important and independent biological markers for development of itch intensity in atopic dermatitis

Background  Although itch is the predominant symptom of atopic dermatitis (AD), it is poorly characterized and subjective. The objective assessment of itch intensity is important for treatment and follow‐up in patients with AD.

Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis

Background  Adult‐onset atopic dermatitis (AD) has recently been recognized as a distinct disease entity, but its risk factors have not yet been clearly defined. Although gestational and perinatal exposure to tobacco smoking may be associated with the development of classic AD, the association between active/passive smoking and adult‐onset AD remains controversial.

Mechanistic correlations between two itch biomarkers, cytokine interleukin-31 and neuropeptide β-endorphin, via STAT3/calcium axis in atopic dermatitis.

Summary Background  Itch is the cardinal symptom of atopic dermatitis (AD). β‐Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)‐31, an itch‐relevant cytokine, activates IL‐31 receptors in keratinocytes. However, how IL‐31 and β‐endorphin interact in AD skin remains elusive.

Lymphocyte α-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses

The molecular functions and pathophysiologic role of the lymphocyte α-kinase gene (ALPK1) in gout are unknown. We aimed to examine ALPK1 expression in patients with gout and investigate its role in monosodium urate monohydrate (MSU)-induced inflammatory responses. Microarray data mining was performed with six datasets containing three clinical gout and three volunteer samples. Real-time quantitative polymerase chain reaction (qPCR) assay was used to profile ALPK1 mRNA expression in 62 independent samples. RNA interference for ALPK1 suppression in THP1 cells (human monocytic cell line) was used to scrutinize the functional role of ALPK1 in MSU-mediated inflammatory responses, and ALPK1 expression in MSU-treated THP1 cells was determined by qPCR and Western blot analysis. Cytokine mRNA expression in HEK293 cells after incubation with different concentrations of MSU crystals in the presence or absence of ALPK1 was also detected by qPCR, and ERK1/2, p38, and JNK expressions were investigated by Western blot analysis. ALPK1 mRNA was overexpressed in the clinical gout samples. MSU treatment promoted ALPK1 expression at the mRNA and protein levels. Furthermore, ALPK1 knockdown in THP1 cells resulted in a markedly decreased IL-1β, TNF-α, and IL-8 mRNA expression; plasmid ALPK1 transfection and MSU stimulation synergistically increased the mRNA expression of these cytokines in a concentration-dependent manner. The synergistic effect also led to ERK1/2 activation. ALPK1 is a gout-susceptible gene involved in MSU-induced inflammatory responses. It may contribute to the development of gout by enhancing the inflammatory responses via the mitogen-activated protein kinase pathway.

A characterization of the antioxidant enzyme activity and reproductive toxicity in male rats following sub-chronic exposure to areca nut extracts.

In the present study, areca nut extracts (ANE) administered to male rats by gavage at a dose of 100mg/kg/day for a period of 15, 30, or 45 days resulted in signs of reproductive toxicity. ANE administration resulted in a significant decline (30-57% in epididymal sperm count and 27-61% in sperm motility) as well as substantial abnormalities in sperm morphology. Significant variances in activities of antioxidant enzymes were also observed. Malondialdehyde (MDA) levels, which represent the level of lipid peroxidation, increased by 16-188% and levels of sialic acid decreased by 2-46% compared with that in controls. These results indicate that ANE induced spermatogenic damage, as indicated by a decrease in sperm counts and sperm motility as well as the activity of antioxidant enzymes, an increase in sperm abnormalities, and alterations in sialic acid and MDA levels. Such effects reflect that ANE administration resulted in reactive oxygen species (ROS)-induced oxidative stress in the testis, cauda epididymis, and sperm of male rats.

ALPK1 genetic regulation and risk in relation to gout

BACKGROUND The present study investigated whether single nucleotide polymorphisms (SNPs) in the alpha-protein kinase 1 (ALPK1) gene are associated with gout in aboriginal and Han Chinese Taiwanese. METHODS A total of 1351 aborigines from the community (511 cases and 840 controls) and 511 Han people from hospital (104 cases and 407 controls) were recruited. SNPs in potentially functional regions of the 38 genes within 4q25 were identified and genotypes determined by direct sequencing. Quantitation of blood ALPK1 mRNA expression levels and luciferase assay of gout-associated rs231253 pGL3-SNP constructs cotransfected with hsa-miR-519e were examined. RESULTS We found that ALPK1 gene was the most determinant of gout. Three SNPs of rs11726117 M861T [C], rs231247 [G] and rs231253 [G] were most associated with gout risk [odd ratios (OR) ≥1.44, P ≤ 3.78 × 10(-6)) in aborigines. A replication set using Han people had risk at rs11726117 and rs231247 (OR ≥1.72, P ≤ 4.08 × 10(-3)). From pooled analysis (Breslow-Day test, P > 0.33) assuming an additive model, each increasing copy of the risk allele of rs11726117 [C], rs231247 [G] and rs231253 [G] showed significantly elevated OR for gout ≥1.42 (P ≥ 1.53 × 10(-6)). Consistently, the composite homozygous of linked 3 SNPs (versus wild-type, OR = 1.83, P = 8.21 × 10(-4)) had strong associations with ALPK1 mRNA expression. Luciferase showed reduced hybridization between hsa-miR-519e and construct carrying gout-associated rs231253 [G] than the wild-type [C] (P = 6.19 × 10(-4)). CONCLUSIONS Our study found that a newly identified ALPK1 gene can effectively interfere with microRNA target recognition and modulates the mRNA expression; and the varying distribution of the implicated SNPs among cases and controls in the two studied populations suggests a significant role in gout susceptibility.

Transforming growth factor‐β enhances matrix metalloproteinase‐2 expression and activity through AKT in fibroblasts derived from angiofibromas in patients with tuberous sclerosis complex

Background  Patients with tuberous sclerosis complex (TSC) develop fibrous tumours in the brain, skin, kidney, heart and lungs due to TSC1/2 mutations. In the skin, patients develop angiofibromas that have vascular and fibrotic components in which transforming growth factor (TGF)‐β and matrix metalloproteinase (MMP)‐2 are important.

ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares.

Gout is characterized by the monosodium urate monohydrate (MSU)-induced arthritis. Alpha kinase-1 (ALPK1) has shown to be associated with MSU-induced inflammation and gout. Here, we used bioinformatics, proteomics, cell models, and twenty in vitro human assays to clarify some of its role in the inflammatory response to MSU. We found myosin IIA to be a frequent interacting protein partner of ALPK1, binding to its N-terminal and forming a protein complex with calmodulin and F-actin, and that MSU-induced ALPK1 phosphorylated the myosin IIA. A knockdown of endogenous ALPK1 or myosin IIA significantly reduced the MSU-induced secretion of tumour necrosis factor (TNF)-α. Furthermore, all gouty patients expressed higher basal protein levels of ALPK1, myosin IIA, and plasma TNF-α, however those medicated with colchicine has shown reduced myosin IIA and TNF-α but not ALPK1. The findings suggest ALPK1 is a kinase that participates in the regulation of Golgi-derived TNF-α trafficking through myosin IIA phosphorylation in the inflammation of gout. This novel pathway could be blocked at the level of myosin by colchicine in gout treatment.

Monoamine oxidase A variants are associated with heavy betel quid use

Few studies have investigated whether genetic abnormalities predispose individuals to heavy betel quid (BQ) use. One of the major ingredients of BQ, arecoline, is known to affect the expression of monoamine oxidase A (MAO‐A). We investigated the extent to which arecoline inhibits MAO‐A expression and the role of MAO‐A polymorphisms in BQ use in Taiwanese aborigines. Cytotoxicity assays, microarrays and quantitative reverse transcriptase‐polymerase chain reaction were used to examine the effects of arecoline and areca nut extract (ANE) on cell viability and MAO‐A expression in neuroblastoma SH‐SY5Y cells. After identifying the effective concentrations of arecoline and ANE in vitro, we examined the in vivo effects of these compounds using a rat model system. Our results indicate that arecoline and ANE inhibit MAO‐A expression both in vitro and in vivo. In addition, we examined the correlation between plasma MAO‐A activity and cumulative exposure to BQ in humans. We recruited 1307 aborigines from a large‐scale community‐based survey to determine whether MAO‐A variants were associated with high BQ use and a preference for use with smoking or alcohol and whether gender bias existed. MAO‐A expression was significantly downregulated by arecoline and ANE at 100–200 µg/ml and in rat whole brains on days 30 and 45. MAO‐A activity levels in human plasma were positively correlated with the extent of BQ exposure, and individuals with at‐risk alleles exhibited lower activity, although this result did not reach statistical significance. We found two single nucleotide polymorphism (SNPs) in aboriginal males [rs2283725, odds ratio (OR) = 2.04; rs5953210, OR = 2.03] and females (rs2283725, OR = 1.54; rs5953210, OR = 1.59) that were associated with heavy BQ use. Those individuals carrying at‐risk alleles who drank alcohol were twice as likely to be heavy BQ users. However, the effects of these SNPs on BQ use were significant even after controlling for alcohol use. Our results suggest that two specific loci may confer a susceptibility to BQ abuse and affect MAO‐A enzymatic activity.

Noninvasive cutaneous blood flow as a response predictor for visible light therapy on segmental vitiligo: a prospective pilot study.

Background  Visible light is a treatment option for segmental vitiligo (SV), and visible light‐induced repigmentation is associated with normalization of sympathetic dysfunction. Currently, it is difficult to predict individual patients’ response to visible light therapy.