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Vitiligo is a common acquired disease of pigment loss. In lesions recalcitrant to non-invasive treatment, transplantation of cultured autologous melanocytes is an emerging choice. Conventionally, the recipient site is often prepared by laser-mediated or mechanical dermabrasion. Such preparation procedures have disadvantages including prolonged transplantation duration, long period for reepithelialization and potential scarring. We propose a method of preparing recipient sites by psoralen and controlled ultraviolet A (PUVA)-induced blistering followed by transplanting suspended melanocytes. We introduced this method in 10 patients with segmental vitiligo on their recipient site 3 to 5 days before transplantation and blistering developed in 2 to 3 days afterwards. On the day of transplantation, the blister roof could be peeled off easily without bleeding and the recipient site preparation could be completed in 20 min. The recipient site became reepithelialized within 1 week. Progressive repigmentation was observed for up to 6 months, with an average of 65.06% repigmentation in the recipient site without scarring at the end of follow-up. Hence, preparation of the recipient site by controlled PUVA-induced sunburn-like blistering can potentially facilitate melanocyte transplantation and prevent scarring.

Night shift workers have been associated with circadian dysregulation and metabolic disorders, which are tightly coevolved with gut microbiota. The chronic impacts of light-emitting diode (LED) lighting at night on gut microbiota and serum lipids were investigated. Male C57BL/6 mice were exposed to blue or white LED lighting at Zeitgeber time 13.5-14 (ZT; ZT0 is the onset of “lights on” and ZT12 is the “lights off” onset under 12-hour light, 12-hour dark schedule). After 33 weeks, only the high irradiance (7.2 J/cm2) of blue LED light reduced the alpha diversity of gut microbiota. The high irradiance of white LED light and the low irradiance (3.6 J/cm2) of both lights did not change microbial alpha diversity. However, the low irradiance, but not the high one, of both blue and white LED illuminations significantly increased serum total cholesterol (TCHO), but not triglyceride (TG). There was no significant difference of microbial abundance between two lights. The ratio of beneficial to harmful bacteria decreased at a low irradiance but increased at a high irradiance of blue light. Notably, this ratio was negatively correlated with serum TCHO but positively correlated with bile acid biosynthesis pathway. Therefore, chronic blue LED lighting at a high irradiance may harvest gut dysbiosis in association with decreased alpha diversity and the ratio of beneficial to harmful bacteria to specifically dysregulates TCHO metabolism in mice. Night shift workers are recommended to be avoid of blue LED lighting for a long and lasting time.

Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.

Background: Infection can upregulate T helper 17 (Th17) signaling and exacerbate psoriasis. Literature has indicated that prenatal infection induces embryonic development toward Th17 signaling and is a risk factor for developing certain Th17-skewing disorders such as autism in offspring. However, it remains unclear if a prenatal infection is a risk factor for developing psoriasis in offspring. Objectives: We investigated if a prenatal infection predisposes mice offspring to enhanced susceptibility to psoriatic inflammation. Methods: Pregnant C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid poly I:C to simulate prenatal bacterial and viral infection, respectively. Phosphate-buffered saline (PBS) injection was used as the control. When mice offspring were at the age of 9–10 weeks, imiquimod (IMQ) cream or control vehicle was applied topically on ears for 5 consecutive days to induce psoriasiform dermatitis. The extent of epidermal hyperplasia and the number of Munro microabscesses were examined by histologic analysis. Protein expressions of neutrophil marker Ly6 g and Th17-associated cytokines were measured by western blotting. Results: Prenatal infection with LPS or poly I:C induced a greater extent of epidermal hyperplasia and more Munro microabscesses after IMQ application as compared with prenatal PBS injection. Mice offspring with prenatal infection also had higher protein expressions of Ly6 g, IL-17a, and interleukin-23 after IMQ stimulation compared with their PBS controls. Conclusion: Prenatal infection predisposes mice offspring to enhanced susceptibility to IMQ-mediated psoriasiform dermatitis. The data obtained from the present animal study suggest that prenatal infection might be a risk factor for developing psoriasis in offspring.

Reticulate pigmentary disorders (RPDs) are a group of inherited and acquired skin conditions characterized by hyperpigmented and/or hypopigmented macules. Inherited RPDs include dyschromatosis symmetrica hereditaria (DSH), dyschromatosis universalis hereditaria (DUH), reticulate acropigmentation of Kitamura (RAK), Dowling-Degos disease (DDD), dyskeratosis congenita (DKC), Naegeli–Franceschetti–Jadassohn syndrome (NFJS), dermatopathia pigmentosa reticularis (DPR), and X-linked reticulate pigmentary disorder. Although reticulate pattern of pigmentation is a common characteristic of this spectrum of disorders, the distribution of pigmentation varies among these disorders, and there may be clinical manifestations beyond pigmentation. DSH, DUH, and RAK are mostly reported in East Asian ethnicities. DDD is more common in Caucasians, although it is also reported in Asian countries. Other RPDs show no racial predilection. This article reviews the clinical, histological, and genetic variations of inherited RPDs.

Psoriasis is a chronic inflammatory skin disease characterized by the appearance of clearly demarcated erythematous and scaly plaques. It can be divided into various types, including plaque, nail, guttate, inverse, and pustular psoriasis. Plaque psoriasis is the most commonly occurring type, though there is another rare but severe pustular autoinflammatory skin disease called generalized pustular psoriasis (GPP), which manifests with acute episodes of pustulation and systemic symptoms. Though the etiopathogenesis of psoriasis is not yet fully understood, a growing body of literature has demonstrated that both genetic and environmental factors play a role. The discovery of genetic mutations associated with GPP has shed light on our comprehension of the mechanisms of the disease, promoting the development of targeted therapies. This review will summarize genetic determinants as known and provide an update on the current and potential treatments for GPP. The pathogenesis and clinical presentation of the disease are also included for a comprehensive discussion.

Autoimmune bullous skin disorders are a group of disorders characterized by the formation of numerous blisters and erosions on the skin and/or the mucosal membrane, arising from autoantibodies against the intercellular adhesion molecules and the structural proteins. They can be classified into intraepithelial or subepithelial autoimmune bullous dermatoses based on the location of the targeted antigens. These dermatoses are extremely debilitating and fatal in certain cases, depending on the degree of cutaneous and mucosal involvement. Effective treatments should be implemented promptly. Glucocorticoids serve as the first-line approach due to their rapid onset of therapeutic effects and remission of the acute phase. Nonetheless, long-term applications may lead to major adverse effects that outweigh the benefits. Hence, other adjuvant therapies are mandatory to minimize the potential harm and ameliorate the quality of life. Herein, we summarize the current therapeutic strategies and introduce promising therapies for intractable autoimmune bullous diseases.

Impaired sympathetic response is frequently observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). On the other hand, chronic insomnia disorder (CID) is also often accompanied by activation of sympathetic nerves. Considering that cutaneous microcirculation reflects sympathetic tone, we hypothesized that baseline cutaneous microcirculation in fingers, as detected by laser Doppler flowmetry (LDF), differs among patients with mild cognitive impairment (MCI), AD, and CID. As light therapy is one of the adjunctive treatments for AD and CID, we designed a randomized controlled cross-over trial of light therapy through eyes for 12 weeks with red light as treatment and green light as control limb, and examined if light therapy has an impact on cutaneous microcirculation. Before light therapy, patients with AD had significantly lower baseline cutaneous perfusion than those with CID in left and right first to fourth fingers. After red light therapy, however, cutaneous perfusion of fingers in CID patients significantly decreased (right fingers, before vs. after = 227.25 ± 62.00 vs. 162.00 ± 49.34, p = 0.007; left fingers, before vs. after = 228.99 ± 58.80 vs. 177.41 ± 59.41, p = 0.003) while cutaneous perfusion of fingers in CID patients did not significantly change after green light therapy. Light therapy with red light also significantly increased cutaneous finger perfusion in patients with AD (right fingers, before vs. after = 130.13 ± 49.82 vs. 172.38 ± 38.32, p = 0.043). Our results suggest that cutaneous perfusion is a useful tool to detect sympathetic dysfunction in patients with CID and AD, and that light therapy with red light is a potential therapeutic intervention to reverse impaired sympathetic function in patients with CID and patients with AD.

Abstract Based on the oxidative stress theory, aging derives from the accumulation of oxidized proteins induced by reactive oxygen species (ROS) in the cytoplasm. Hydrogen peroxide (H2O2) elicits ROS that induces skin aging through oxidation of proteins, forming disulfide bridges with cysteine or methionine sulfhydryl groups. Decreased Ca2+ signaling is observed in aged cells, probably secondary to the formation of disulfide bonds among Ca2+ signaling-related proteins. Skin aging processes are modeled by treating keratinocytes with H2O2. In the present study, H2O2 dose-dependently impaired the adenosine triphosphate (ATP)-induced Ca2+ response, which was partially protected via co-treatment with β-mercaptoethanol, resulting in reduced disulfide bond formation in inositol 1, 4, 5-trisphosphate receptors (IP3Rs). Molecular hydrogen (H2) was found to be more effectively protected H2O2-induced IP3R1 dysfunction by reducing disulfide bonds, rather than quenching ROS. In conclusion, skin aging processes may involve ROS-induced protein dysfunction due to disulfide bond formation, and H2 can protect oxidation of this process.

Blaschko lines are manifestations of cutaneous mosaicism, with apparent contrast between normal cells and abnormal cells, which carry postzygotic mutations. Linear cutaneous lupus erythematosus is a rare subset of cutaneous lupus erythematosus (CLE), characterized by skin lesions along Blaschko lines. In this paper, we presented a 47-year-old female with subacute CLE lesions along Blaschko lines. Although the antinuclear antibody and anti-Ro titers were remarkably high, there were no systemic symptoms. The histopathology showed atrophic epidermis with vacuolization of basal keratinocytes and papillary edema. While no typical linear lupus band was found, the direct immunofluorescence revealed cytoid bodies with immunoglobulin G, immunoglobulin M, C3, and C4 depositions in the papillary dermis. The skin lesions completely resolved after topical tacrolimus treatment, and the clinical course was 10 months without recurrence. We reviewed the literature and summarized that CLE along Blaschko lines supports the functional role of Ro antigens and keratinocytes in the development of CLE.

Transforming growth factor-β (TGF-β) is an important target for treating systemic sclerosis (SSc). However, our study revealed three levels of TGF-β1 expression in SSc patients, indicating that inhibiting TGF-β is not sufficient to treat SSc. A previous clinical trial also displayed disappointing results. Thus, our study attempted to search for a potential novel approach. Ingenuity Pathway Analysis (IPA) indicated that the SSc pathological pathways were closely associated with store-operated Ca2+ entry (SOCE)-regulated signals, and SOCE activity was found to be increased in SSc fibroblasts. Further treatment of SSc fibroblasts with SOCE inhibitors, 2APB, and associated calcium channel inhibitors SKF96365, and indomethacin, showed that the SOCE inhibitors selectively decreased fibrosis markers and altered the cell morphology. Consequently, SOCE inhibitors, especially 2APB and indomethacin, caused the dedifferentiation of SSc fibroblasts via cytoskeleton remodeling and altered collagen secretion and restored the cell mobility. We further explained SSc pathogenesis as fibroblast differentiation with SOCE. Treatment with exogenous factors, gelatin-1, FAM20A and human albumin, which were identified from the conditioned medium of SSc fibroblasts, was important for regulating the differentiation of fibroblasts with higher levels of SOCE and α-SMA. Conclusively, to treat SSc, blockage of the increased SOCE activity in SSc induces the dedifferentiation of SSc fibroblasts and simultaneously changes the extracellular matrix (ECM) structure to limit SSc pathogenesis.

BackgroundBehçet's disease (BD) is a recurrent, multisystemic, inflammatory disorder that mainly affects blood vessels. Because recurrent inflammation of blood vessels in the brain plays a crucial role in the development of ischemic stroke, we hypothesized that patients with BD might have an elevated risk of ischemic stroke. This potential association has been suggested in a few case reports, but not epidemiological studies. Hence, the present study aimed to examine the relation between BD and subsequent ischemic stroke in Taiwan using a nationwide, population-based database.MethodsTo establish a study cohort, the longitudinal data of 306 patients newly diagnosed with BD during 2000-2010 were extracted from the National Health Insurance Research Database, Taiwan. For comparison of ischemic stroke incidence, a control cohort of 1224 subjects without BD was established using a frequency-matched ratio of 1:4 for age, sex, and pre-existing comorbidities.ResultsDuring the 10-year follow-up, 13 (4.2%) patients with BD and 20 (1.6%) control subjects experienced ischemic stroke. Kaplan-Meier analysis revealed the higher prevalence of ischemic stroke in the BD group (log-rank test, p = 0.001). After adjusting for comorbidities and demographic characteristics, Cox regression analysis revealed that patients with BD had a 2.77-fold risk of ischemic stroke (95% confidence interval, 1.38-5.57) compared to control subjects.ConclusionsPatients with BD have an elevated risk of ischemic stroke. Hence, BD may affect the vascular system in the brain, resulting in a stroke event.

Ultraviolet-B (UVB) is one of the most cytotoxic and mutagenic stresses that contribute to skin damage and aging through increasing intracellular Ca2+ and reactive oxygen species (ROS). Derinat (sodium deoxyribonucleate) has been utilized as an immunomodulator for the treatment of ROS-associated diseases in clinics. However, the molecular mechanism by which Derinat protects skin cells from UVB-induced damage is poorly understood. Here, we show that Derinat significantly attenuated UVB-induced intracellular ROS production and decreased DNA damage in primary skin cells. Furthermore, Derinat reduced intracellular ROS, cyclooxygenase-2 (COX-2) expression and DNA damage in the skin of the BALB/c-nu mice exposed to UVB for seven days in vivo. Importantly, Derinat blocked the transient receptor potential canonical (TRPC) channels (TRPCs), as demonstrated by calcium imaging. Together, our results indicate that Derinat acts as a TRPCs blocker to reduce intracellular ROS production and DNA damage upon UVB irradiation. This mechanism provides a potential new application of Derinat for the protection against UVB-induced skin damage and aging.

The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.

The purpose of this study was to validate the Impact of Event Scale-Revised (IES-R) for adolescents who had experienced the floods and mudslides caused by Typhoon Morakot in Taiwan. The internal consistency, construct validity, and criteria validity of the instrument were examined. Principal component analysis followed by an oblique rotation was used to derive a three-factor solution. These factors were labeled intrusion, hyperarousal, and avoidance; all three factors together accounted for 58.1% of the variance. The total Cronbach’s alpha of 0.94 reflected the good internal consistency of the instrument. With reference to diagnosis of posttraumatic stress disorder, the IES-R cutoff point for posttraumatic stress disorder was 19 of 20 with a sensitivity of 85.7% and specificity of 84.1%. In conclusion, the IES-R can be used as a reliable and valid instrument when evaluating psychological distress among adolescents who have experienced a natural disaster, such as flooding and mudslides.

It was estimated that, nearly 100 million people are at risk for drinking arsenic (As)-contaminated drinking water. Although the WHO guideline recommends that levels of As in drinking water should not exceed 10 μm/L, it was estimated that more than 30 million people drink As-containing water at levels more than 50 μm/L in Bangladesh and India alone. Therefore, the adverse health effects resulting from chronic As exposure pose a global threat. In Taiwan, studies focusing on the health effects resulting from chronic As exposure through contaminated drinking water have been ongoing for more than 50 years. During the past half century, it was recognized that the impact of high As exposure on human health is much more complicated than originally anticipated. Chronic As exposure resulted in infamous blackfoot disease, which is unique to As endemic areas in Taiwan, and various diseases including cancers and non-cancers. Although the potential-biological outcomes have been well-documented, the pathomechanisms leading from As exposure to occurrence and development of the diseases remain largely unclear. One of the major obstacles that hindered further understanding regarding the adverse health effect resulting from chronic As exposure is documentation of cumulative As exposure from the distant past, which remains difficult as the present technologies mostly document relatively recent As exposure. Furthermore, the susceptibility to As exposure appears to differ between different ethnic groups and individuals and is modified by lifestyle factors including smoking habits and nutrition status. No consensus data has yet been reached even after comparing the study results obtained from different parts of the world focusing on associations between human As toxicity and genetic polymorphisms in terms of cellular detoxification enzymes, tumor suppressor proteins, and DNA repair pathway. With the availability of the new powerful “OMIC” technologies, it may now be possible to gain new path-breaking insights regarding this important environmental health issue. The lessons learned from the past half-century placed Taiwan in an experienced position to actively participate in the international collaborative projects using these novel technologies and standardized methods.

Arsenic (As) is considered as a human carcinogen or tumor-promoting agent. Epidemiological evidences indicated that cancer incidences of residents in arseniasis areas were significantly higher in multiple organs, including urinary bladder, lungs, and especially the skin, than those living in non-arseniasis areas. In the context of skin cancers, keratinocytes are believed to be the main target cells in As carcinogenesis. Therefore, we discuss the significance of keratinocyte-specific effects of As on skin carcinogenesis. As is known to be cytotoxic because of its chemical reactions with the thiol group of proteins and its ability to generate free radicals during cellular metabolism. However, at relatively low concentrations, As shows stimulatory effects, such as cell activation and proliferation. Because long-term As exposure is associated with skin carcinogenesis, we reviewed the mechanisms of As-induced keratinocyte dysfunctions by means of time- and concentration-dependent cellular responses. The mechanisms and interactions underlying As-induced keratinocyte dysfunctions not only provide a model of As in skin carcinogenesis process but also help in understanding the regulation of As carcinogenesis in other internal organs.

Arsenic is a well-known human carcinogen. It also impairs immune functions and activation in many aspects. However, only a small portion of arsenic-exposed population develops skin abnormalities, including Bowen’s disease and skin cancers. Differential immune activation among the individuals might account for the different susceptibilities. In patients with arsenic-induced Bowen’s disease, there is a selective CD4 T-cell apoptosis through tumor necrosis factor-alpha pathway, decrease in macrophage differentiation and phagocytosis, reduced Langerhans cell numbers and dendrites, altered regulatory T-cell distribution, and other immune alterations. Several lines of evidence from mouse and fish studies also confirmed the potent and multifaceted effects of arsenic in the immune system. The molecular bases of immunosuppression by arsenic in lymphocytes may include chromosomal and DNA abnormalities, decreased T-cell receptor activation, and the cellular status of oxidation and methylation. This article also reviews the causative and differential role of selective CD4 cell apoptosis and the carcinogenesis of arsenic-induced Bowen’s disease.

Segmental vitiligo (SV) is a special form of vitiligo occurring in a dermatomal distribution, and an abnormality involving the sympathetic nerves supplying the affected dermatome is known to underlie this disorder. Previously, we have shown that SV is associated with an abnormal increase in cutaneous blood flow and adrenoceptor responses in the affected areas. Since SV is resistant to conventional forms of therapy, its management represents a challenge for dermatologists. Low energy helium-neon lasers (He-Ne laser, wavelength 632.8nm) have been employed as a therapeutic instrument in many clinical situations, including vitiligo management and repair of nerve injury. The purpose of this study was to evaluate the effectiveness and safety of He-Ne lasers in treating SV, and determine their effects on the repair of sympathetic nerve dysfunction. Forty patients with stable-stage SV on the head and/or neck were enrolled in this study. He-Ne laser irradiation was administered locally at 3.0J/cm2 with point stimulation once or twice weekly. Cutaneous microcirculatory assessments in six SV patients were performed using a laser Doppler flowmeter. The sympathetic adrenoceptor response of cutaneous microcirculation was determined by measuring cutaneous blood flow before, during and after iontophoresis with sympathomimetic drugs (phenylephrine, clonidine and propranolol). All measurements of microcirculation obtained at SV lesions were simultaneously compared with contralateral normal skin, both before and after He-Ne laser treatment. After an average of 17 treatment sessions, initial repigmentation was noticed in the majority of patients. Marked repigmentation (> 50%) was observed in 60% of patients with successive treatments. Cutaneous blood flow was significantly higher at SV lesions compared with contralateral skin, but this was normalized after He-Ne laser treatment. In addition, the abnormal decrease in cutaneous blood flow in response to clonidine was improved by He-Ne laser therapy. Our study showed that He-Ne laser therapy is an effective treatment for SV by normalizing dysfunctions of cutaneous blood flow and adrenoceptor responses in SV patients. Thus, the beneficial effects of He-Ne laser therapy may be mediated in part by a reparative effect on sympathetic nerve dysfunction.

As a critical step toward elucidating the mechanism of localization of Tc-99m (V) dimercaptosuccinic acid (DMSA), we investigated its binding and transport in blood in comparison with Ga-67 citrate. The studies were performed in vitro by incubating Tc-99m (V) DMSA with blood (one sample at 4°C and another at 37°C) to assess its binding to plasma proteins using ulrrafilrration, dialysis, electrophoresis, gel filtration chromatography and affinity chromatography A parallel experiment for determining the blood binding of Ga-67 citrate was performed using the same procedures. Using ulrrafilrration, dialysis, electrophoresis and gel filtration chromatography, labeled plasma samples showed that protein binding for Tc-99m (V) DMSA was 45-54% at 37°C and 73-80% at 4°C. The figures for Ga-67 citrate were 43-53% at 37°C and 75-81% at 4°C. Electrophoresis showed that Tc-99m (V) DMSA was mostly bound to plasma albumin (36.05 + 2.48% at 37°C and 60.04 + 1.87% at 4°C), and that the proportion of Ga-67 radioactivity associated with β-globulin was 34.23 + 1.37% at 37°C and 55.71 + 3.69% at 4°C. In affinity chromatography experiments, Tc-99m (V) DMSA did not bind to transferrin, unlike Ga-67 citrate. This study demonstrates that, at the radiopharmaceutical tracer level, most Tc-99m (V) DMSA in blood is protein-bound, primarily to albumin, but not to transferrin. In contrast, Ga-67 citrate was bound primarily to transferrin. The knowledge that albumin is the main transport protein of Tc-99m (V) DMSA may contribute to a better understanding of its biodistribution and pharmacokinetics.

Arsenic is a class I human carcinogen (such as inducing skin cancer) by its prominent chemical interaction with protein thio (-SH) group. Therefore, arsenic may compromise protein S-nitrosylation by competing the -SH binding activity. In the present study, we aimed to understand the influence of arsenic on protein S-nitrosylation and the following proteomic changes. By using primary human skin keratinocyte, we found that arsenic treatment decreased the level of protein S-nitrosylation. This was coincident to the decent expressions of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). By using LC-MS/MS, around twenty S-nitrosoproteins were detected in the biotin-switched eluent. With the interest that arsenic not only regulates posttranslational S-nitrosylation but also separately affects protein’s translation expression, we performed two-dimensional gel electrophoresis and found that 8 proteins were significantly decreased during arsenic treatment. Whether these decreased proteins are the consequence of protein S-nitrosylation will be further investigated. Taken together, these results provide a finding that arsenic can deplete the binding activity of NO and therefore reduce protein S-nitrosylation.

Alkylphenols, such as nonylphenol (NP) and 4-octylphenol (4-OP), have the potential to disturb immune system due to their weak estrogen-like activity, an effect with potential serious public health impact due to the worldwide distribution of these substances. Plasmacytoid dendritic cells (PDCs) can secrete large amounts of type I IFNs and are critical in immune regulation. However, there has been limited study about the influence of alkylphenols on the function of pDCs.The aim of this study was to examine the effect of alkylphenols on pDC functions in vitro and in vivo and then further explored the involved signaling pathways and epigenetic changes.Circulating pDCs from human peripheral blood mononuclear cells were treated with alkylphenols with or without CpG stimulation. Alkylphenol-associated cytokine responses, signaling events, histone modifications and viral activity were further examined. In NP-exposed mice, the effect of NP on splenic pDC function and allergic lung inflammation were also assessed.The results showed that NP increased the expression of TNF-α, but suppressed IL-10 production in the range of physiological doses, concomitant with activation of the MKK3/6-p38 signaling pathway and enhanced levels of acetylated histone 3 as well as histone 4 at the TNFA gene locus. Further, in CpG-stimulated pDCs, NP suppressed type I IFNs production, associated with down-regulation of IRF-7 and MKK1/2-ERK-Elk-1 pathways and led to the impaired anti-enterovirus 71 activity in vitro. Additionally, splenic pDCs from NP-exposed mice showed similar cytokine changes upon CpG stimulation under conditions relevant to route and level of exposure in humans. NP treatment also enhanced allergic lung inflammation in vivo.Alkylphenols may influence pDCs' functions via their abilities to induce expression of a pro-inflammatory cytokine, TNF-α, and to suppress regulatory cytokines, including IL-10, IFN-α and IFN-β, suggesting the potential impact of endocrine disrupting chemicals on immune regulation.

Arsenic exposure results in several human cancers, including those of the skin, lung, and bladder. As skin cancers are the most common form, epidermal keratinocytes (KC) are the main target of arsenic exposure. The mechanisms by which arsenic induces carcinogenesis remains unclear, but aberrant cell proliferation and dysregulated energy homeostasis play a significant role. Protein glycosylation is involved in many key physiological processes, including cell proliferation and differentiation. To evaluate whether arsenite exposure affected protein glycosylation, the alteration of chain length of glycan residues in arsenite treated skin cells was estimated. Herein we demonstrated that the protein glycosylation was adenosine triphosphate (ATP)-dependent and regulated by arsenite exposure by using Fourier transform infrared (FTIR) reflectance spectroscopy, synchrotron-radiation-based FTIR (SR-FTIR) microspectroscopy, and wax physisorption kinetics coupled with focal-plane-array-based FTIR (WPK-FPA-FTIR) imaging. We were able to estimate the relative length of surface protein-linked glycan residues on arsenite-treated skin cells, including primary KC and two skin cancer cell lines, HSC-1 and HaCaT cells. Differential physisorption of wax adsorbents adhered to long-chain (elongated type) and short-chain (regular type) glycan residues of glycoprotein of skin cell samples treated with various concentration of arsenite was measured. The physisorption ratio of beeswax remain/n-pentacosane remain for KC cells was increased during arsenite exposure. Interestingly, this increase was reversed after oligomycin (an ATP synthase inhibitor) pretreatment, suggesting the chain length of protein-linked glycan residues is likely ATP-dependent. This is the first study to demonstrate the elongation and termination of surface protein-linked glycan residues using WPK-FPA-FTIR imaging in eukaryotes. Herein the result may provide a scientific basis to target surface protein-linked glycan residues in the process of arsenic carcinogenesis.

The prevalence of allergic diseases has increased in recent decades. Allergic diseases, particularly asthma, are complex diseases with strong gene-environment interactions. Epidemiological studies have identified a variety of risk factors for the development of allergic diseases. Among them, endocrine-disrupting chemicals (EDCs) play an important role in triggering or exacerbating these diseases. 4-Nonylphenol (NP) and 4-octylphenol (OP)—two major alkylphenols—have been recognized as common toxic and xenobiotic endocrine disrupters. Due to their low solubility, high hydrophobicity, and low estrogenic activity, they tend to accumulate in the human body and may be associated with the adverse effects of allergic diseases. Recently, new evidence has supported the importance of alkylphenols in the in vitro allergic response. This review focuses on the effects of alkylphenols on several key cell types in the context of allergic inflammation.

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.

Students' performance anxiety can impact negatively on the effectiveness of medical education reform, including performance in problem-based learning (PBL) and in using English in discussion. This study aimed to investigate the nature of performance anxiety among Taiwanese medical students in an English-language PBL group. Eighteen Taiwanese, one American and four Asian medical students who were attending an international PBL workshop were enrolled. A questionnaire seeking demographic data and experience in use of PBL and eight questions evaluating performance anxiety were administered. The performance anxiety of Taiwanese medical students was compared to that of the Asians and the one American. Frequencies of each performance anxiety were calculated. The results suggested that the Taiwanese students showed more anxiety than the one student from the United States, but less than other Asian students. The acts of giving a report, being the center of attention, and talking in the PBL group were the most common situations related to anxiety in PBL groups. Using English and working in a new PBL environment are possible sources of anxiety. The presence of anxiety among the Taiwanese medical students in English PBL groups implies the necessity for developing an effective strategy to deal with students' performance anxiety.