Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation, aberrant differentiation of keratinocytes, and dysregulated immune responses. WW domain-containing oxidoreductase (WWOX) is a non-classical tumor suppressor gene that regulates multiple cellular processes, including proliferation, apoptosis, and migration. This study aimed to explore the possible role of WWOX in the pathogenesis of psoriasis. Immunohistochemical analysis showed that the expression of WWOX was increased in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model. Immortalized human epidermal keratinocytes were transduced with a recombinant adenovirus expressing microRNA specific for WWOX to downregulate its expression. Inflammatory responses were detected using Western blotting, real-time quantitative reverse transcription polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay. In human epidermal keratinocytes, WWOX knockdown reduced nuclear factor-kappa B signaling and levels of proinflammatory cytokines induced by polyinosinic: polycytidylic acid [(poly(I:C)] in vitro. Furthermore, calcium chelator and protein kinase C (PKC) inhibitors significantly reduced poly(I:C)-induced inflammatory reactions. WWOX plays a role in the inflammatory reaction of epidermal keratinocytes by regulating calcium and PKC signaling. Targeting WWOX could be a novel therapeutic approach for psoriasis in the future.

Systematic review and meta-analysis: Effect of Helicobacter pylori eradication on chronic spontaneous urticaria.

BACKGROUND: Helicobacter pylori (HP) infection is considered to play a role in the pathogenesis of chronic spontaneous urticaria (CSU). However, the efficacy of HP eradication therapy on CSU symptom improvement has not been well established. This meta-analysis was conducted to estimate the association between HP infection and CSU and to evaluate whether HP eradication therapy benefits patients with CSU. MATERIAL AND METHODS: In October 2018, we searched databases for studies investigating the efficacy of HP eradication therapy for patients with CSU. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using random effects models. RESULTS: The meta-analysis included 22 studies with a total of 1385 patients with CSU. When comparing the spontaneous remission of urticarial symptom in patients with HP-positive to HP-negative patients, HP-negative patients showed significantly higher spontaneous remission of urticarial symptoms. (risk ratio 0.39; 95% confidence interval: 0.19-0.81). Among HP-positive CSU patients, remission of CSU was more likely shown in HP eradication therapy group compared to untreated group, aside from achieving HP elimination (risk ratio 2.10; 95% confidence interval: 1.20-3.68). However, there was no significant difference in the remission of CSU whether antibiotic therapy was successful in eradication of HP or not (risk ratio 1.00; 95% confidence interval: 0.65-1.54). CONCLUSIONS: The results of this meta-analysis show that HP might be associated with the occurrence and persistence of CSU. The effectiveness of HP eradication therapy in suppressing CSU symptoms was significant. Interestingly, we found that resolution of CSU was not associated with successful eradication of HP infection. CSU Patients who were undergone antibiotic therapy for HP eradication showed significant higher CSU remission with or without HP eradication. Further studies are recommended to evaluate the mechanisms associated with relation of HP with CSU.

Clinicopathologic Features and Prognostic Factors of Primary Cutaneous Melanoma: a Multicenter Study in Korea.

BACKGROUND: Malignant melanoma is a cutaneous malignancy with a high mortality rate and high potential for metastases. Detailed information on the clinicopathologic characteristics and prognostic factors of cutaneous melanoma is currently limited in Korea. This study aimed to identify the epidemiological and clinicopathologic characteristics of primary cutaneous melanoma in Korean patients, and to assess which prognostic variables could influence both the development of metastases in primary cutaneous melanoma and overall survival (OS). METHODS: A total of 261 patients diagnosed with primary cutaneous melanoma in seven medical centers between 1997 and 2017 were retrospectively investigated with regard to clinical presentation, localization of the tumor, histopathologic subtype, and survival time. RESULTS: The nodular histologic subtype, ulceration, and Breslow thickness were significantly associated with the development of metastasis; and overweight and obesity (body mass index > 23) were significantly associated with increased Breslow thickness. The location of the metastases appeared to influence OS: brain metastases were associated with the highest risk of death, followed by gastrointestinal, lung, and extra-regional lymph node metastases. CONCLUSION: In this study, tumor thickness, nodular histologic subtype, and ulceration predicted metastatic spread of primary cutaneous melanoma. In addition, OS was associated with the location of metastases. Obesity was related to the prognosis of primary cutaneous melanoma. Clinicians should bear these findings in mind when forming a diagnosis because of the risk of a poor prognosis.

Psychological Health Status and Health-related Quality of Life in Adults with Atopic Dermatitis: A Nationwide Cross-sectional Study in South Korea.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Patients with AD often experience psychological distress and poor health-related quality of life (HRQoL). The aim of this study was to investigate the association of several psychological health statuses and poor HRQoL in an adult population with AD in South Korea. A total of 37,578 adults who participated in the Korean National Health and Nutrition Examination Survey, a nationwide, population-based, cross-sectional health survey between 2008 and 2013 were included. HRQoL was assessed by EuroQoL (EQ) 5-dimension questionnaire and EQ-visual analogue scale scores. Multiple logistic regression analysis was performed to identify the association of stress, sleep duration, depressive mood, depression, suicidal ideation, and HRQoL with AD relative to matched controls. After adjusting in patients with AD confounding factors, stress, depressive mood, depression, suicidal ideation and poor HRQoL were significantly associated with AD. Dermatologists should be concerned with improving HRQoL and managing the psychological health status of adult patients with AD.

Relationships of Serum Homocysteine, Vitamin B12, and Folic Acid Levels with Papulopustular Rosacea Severity: A Case-Control Study.

Background: Rosacea is a chronic inflammatory skin disease with a multifactorial etiology. Recently, associations between serum homocysteine (Hcy) levels and inflammatory skin diseases, such as psoriasis and hidradenitis suppurativa, have been reported. However, no study has explored the levels of serum Hcy, folic acid, and vitamin B12 in patients with rosacea. Objective: To investigate serum Hcy, vitamin B12, and folic acid levels in patients with papulopustular rosacea (PPR), we characterized the association of these levels with PPR severity. Methods: This case-control study included 138 PPR patients and 58 healthy controls. The serum levels of Hcy, vitamin B12, and folic acid were measured. A correlation was assessed between disease severity and serum levels of Hcy, vitamin B12, and folic acid. Results: Serum vitamin B12 and folic acid levels were significantly lower in PPR patients than in the healthy controls (p = 0.011 and p = 0.0173, respectively). Although serum Hcy levels did not significantly differ between PPR patients and healthy controls, PPR severity was positively correlated with serum Hcy levels (p < 0.001). Conclusions: Our results suggest a possible association between hyperhomocysteinemia and vitamin B12 deficiency in patients with PPR.

Tetraspanin TM4SF5 mediates loss of contact inhibition through epithelial-mesenchymal transition in human hepatocarcinoma.

The growth of normal cells is arrested when they come in contact with each other, a process known as contact inhibition. Contact inhibition is lost during tumorigenesis, resulting in uncontrolled cell growth. Here, we investigated the role of the tetraspanin transmembrane 4 superfamily member 5 (TM4SF5) in contact inhibition and tumorigenesis. We found that TM4SF5 was overexpressed in human hepatocarcinoma tissue. TM4SF5 expression in clinical samples and in human hepatocellular carcinoma cell lines correlated with enhanced p27Kip1 expression and cytosolic stabilization as well as morphological elongation mediated by RhoA inactivation. These TM4SF5-mediated effects resulted in epithelial-mesenchymal transition (EMT) via loss of E-cadherin expression. The consequence of this was aberrant cell growth, as assessed by S-phase transition in confluent conditions, anchorage-independent growth, and tumor formation in nude mice. The TM4SF5-mediated effects were abolished by suppressing the expression of either TM4SF5 or cytosolic p27Kip1, as well as by reconstituting the expression of E-cadherin. Our observations have revealed a role for TM4SF5 in causing uncontrolled growth of human hepatocarcinoma cells through EMT.

Autophagy Suppresses Toll-Like Receptor 3-Mediated Inflammatory Reaction in Human Epidermal Keratinocytes.

Autophagy, one mechanism of programmed cell death, is fundamental to cellular homeostasis. Previous studies have identified autophagy as a novel mechanism by which cytokines control the immune response. However, its precise role in immune-related inflammatory skin diseases such as psoriasis remains unclear. Thus, this study explored the functional role of autophagy in psoriatic inflammation of epidermal keratinocytes. Strong light chain 3 immunoreactivity was observed in epidermal keratinocytes of both human psoriatic lesions and imiquimod-induced mice psoriatic model, and it was readily induced by polycytidylic acid (poly (I:C)), which stimulates Toll-like receptor 3 (TLR3), in human epidermal keratinocytes in vitro. Rapamycin-induced activation of autophagy significantly reduced poly (I:C)-induced inflammatory reaction, whereas, inhibition of autophagy by 3-methyladeine increased that. Our results indicate that the induction of autophagy may attenuate TLR3-mediated immune responses in human epidermal keratinocytes, thus providing novel insights into the mechanisms underlying the development of inflammatory skin diseases including psoriasis.

Homocysteine, folic acid, and vitamin B12 levels in patients on isotretinoin therapy for acne vulgaris: A meta-analysis.

BACKGROUND: Oral isotretinoin (Iso) is one of the most commonly used drugs for patients with moderate-to-severe acne; however, its use has been associated with several adverse effects. Some studies have suggested an association between Iso therapy and homocysteine (Hcy), folic acid, and vitamin B12 plasma levels. OBJECTIVE: To evaluate the changes in plasma Hcy, folic acid, and vitamin B12 levels during Iso therapy for acne using meta-analytic methods. METHODS: Five scientific databases (MEDLINE, EMBASE, Cochrane Library, SCOPUS, and Web of Science) were searched according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines up to December 2018. A review of 734 publications identified 10 studies that assessed plasma levels of Hcy, folic acid, and vitamin B12 during Iso therapy in acne patients. RESULTS: A total of 10 studies consisting of 592 patients were included in the meta-analysis. Plasma Hcy levels were significantly increased after Iso therapy (weighted mean difference [WMD]: 2.99, 95% confidence interval [CI]: 1.78-4.20, I2  = 86%), whereas folic acid levels were significantly decreased after Iso therapy (WMD: -1.03, 95% CI: -1.90 to -0.17, I2  = 89%). CONCLUSIONS: This meta-analysis found that Iso therapy was associated with changes in plasma levels of Hcy and folic acid in acne patients. However, further evaluation in controlled studies is needed to verify these results.

Regulation of TM4SF5-mediated tumorigenesis through induction of cell detachment and death by tiarellic acid.

mRNA for four-transmembrane L6 family member 5 (TM4SF5), a homolog of tumor antigen L6, was previously shown to be highly expressed in diverse tumors. We recently found that human hepatocarcinoma tissues also overexpressed TM4SF5 protein, in comparison to normal liver tissues. We also found that tiarellic acid (TA) caused cell detachment-related apoptosis in cells expressing endogenous or stably-overexpressing TM4SF5. When cells expressing TM4SF5 were treated with TA, we observed reduced phosphorylation of focal adhesion kinase, paxillin, and p130Cas, but not c-Src. TA treatment also caused focal adhesion loss and reduced cell adhesion, and increased the numbers of floating cells and apoptotic cells. These effects were blocked by overexpression of focal adhesion molecules, suggesting that treatment with TA mediates anoikis of TM4SF5-expressing cells. However, TM4SF5-null cells were not affected by TA, indicating that these effects occur specifically in TM4SF5-positive cells. TA administration reduced tumor formation in nude mice injected with TM4SF5-expressing cells, presumably through increased apoptosis in TM4SF5-positive tumors. These observations indicate that TM4SF5-positive tumorigenesis can be inhibited by TA via induction of cell detachment-related apoptosis, and suggest that TA may be developed as a putative therapeutic reagent against TM4SF5-positive tumorigenesis.

Syndecan-2 overexpression regulates adhesion and migration through cooperation with integrin alpha2.

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is known to serve as an adhesion receptor, but details of the regulatory mechanism governing syndecan-2 cell adhesion and migration remain unclear. Here, we examined this regulatory mechanism, showing that overexpression of syndecan-2 enhanced collagen adhesion, cell migration and invasion of normal rat intestinal epithelial cells (RIE1), and increased integrin alpha2 expression levels. Interestingly, RIE1 cells transfected with either syndecan-2 or integrin alpha2 showed similar adhesion and migration patterns, and a function-blocking anti-integrin alpha2 antibody abolished syndecan-2-mediated adhesion and migration. Consistent with these findings, transfection of integrin alpha2 siRNA diminished syndecan-2-induced cell migration in HCT116 human colon cancer cells. Taken together, these results demonstrate a novel cooperation between syndecan-2 and integrin alpha2beta1 in adhesion-mediated cell migration and invasion. This interactive dynamic might be a possible mechanism underlying the tumorigenic activities of colon cancer cells.

Case Series of Morbihan Disease (Extreme Eyelid Oedema Associated with Rosacea): Diagnostic and Therapeutic Approaches.

Morbihan disease (MD) is a rare form of rosacea that presents with chronic erythema and solid oedema on the upper half of the face. A diagnosis of MD can be made only after eliminating diseases that are similar in terms of clinical and histopathological presentation. The cause of MD remains unclear and no standardised treatment is yet available. MD often tends to be recalcitrant to therapies commonly used to treat rosacea, including systemic corticosteroids, antibiotics, isotretinoin, and topical regimens. Thus, surgical interventions have been attempted but most cases have exhibited unsatisfactory responses. We treated six patients with extreme eyelid lymphoedema without any other cutaneous manifestation. Surgical eyelid reduction was performed in all patients, because ptosis and narrowing of the visual field were the major complaints. Histopathological tests revealed various extents of perivascular and perifollicular inflammation, and dermal oedema. After surgery, patients with severe inflammatory cell infiltration (including mast cells) exhibited a tendency toward recurrence. Other patients with severe dermal oedema exhibited better responses to surgical reduction, and thus no recurrence. We propose that MD should be included in the differential diagnosis of persistent, chronic eyelid oedema even if eyelid oedema is the only manifestation; the histological features may aid in the selection of appropriate therapeutic strategies. We suggest that eyelid reduction surgery can be a useful treatment option for MD patients when there is no massive mast cell infiltration.

Association between Homocysteine Levels and Psoriasis: A Meta-Analysis.

BACKGROUND: Psoriasis is a multifactorial disease associated with an increased risk for metabolic syndrome and cardiovascular diseases. Elevated levels of homocysteine (Hcy) are a marker of cardiovascular risk. Several studies have evaluated the associations between psoriasis and Hcy levels; however, the results remain inconclusive. OBJECTIVE: We performed a systematic review of the literature and a meta-analysis to better understand the relationship between psoriasis and Hcy. METHODS: Five scientific databases (MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science) were searched to identify relevant studies. A review of 307 publications identified 16 studies that directly assessed plasma levels of Hcy in psoriasis patients. RESULTS: A total of 16 studies including 2,091 subjects were included in the meta-analysis. Hcy levels were significantly higher in psoriasis patients relative to healthy controls (weighted mean difference [WMD], 3.30; 95% confidence interval [CI], 1.58∼5.02; I 2=82.1%). Subgroup analyses revealed that patients with higher mean psoriasis area severity index (PASI) scores (PASI>10) had significantly higher Hcy levels compared to healthy controls (WMD, 4.17; 95% CI, 1.18∼7.16; I 2=88.3%), whereas patients with lower mean PASI scores (PASI ≤10) had not (WMD, 0.76; 95% CI, -1.84∼3.35; I 2=72.2%). CONCLUSION: This meta-analysis found that psoriasis patients, in particular those with PASI >10, had significantly higher Hcy levels compared to healthy controls. Further research is needed to determine the association between Hcy levels and psoriasis severity.

Treatment of Hidradenitis Suppurativa Patient with Klinefelter Syndrome by Adalimumab.

Hidradenitis suppurativa (HS) is a chronic, inflammatory and painful skin disease with recurrent nodules and tracts involving the intertriginous regions. It is known that the patient with HS shows an increased risk of metabolic disorders such as diabetes, metabolic syndrome and autoimmune diseases. Klinefelter syndrome (KS) is a sex chromosomal disorder occurring in males due to an abnormality of sexual differentiation, characterized by 47, XXY karyotype. Also, KS is related with somatic comorbidities such as metabolic syndrome, autoimmune and rheumatologic disorders as HS is. We report a HS patient with KS who shows a big improvement while on tumor necrosis factor-alpha inhibitor treatment.

The signaling network of transforming growth factor beta1, protein kinase Cdelta, and integrin underlies the spreading and invasiveness of gastric carcinoma cells.

Integrin-mediated cell adhesion and spreading enables cells to respond to extracellular stimuli for cellular functions. Using a gastric carcinoma cell line that is usually round in adhesion, we explored the mechanisms underlying the cell spreading process, separate from adhesion, and the biological consequences of the process. The cells exhibited spreading behavior through the collaboration of integrin-extracellular matrix interaction with a Smad-mediated transforming growth factor beta1 (TGFbeta1) pathway that is mediated by protein kinase Cdelta (PKCdelta). TGFbeta1 treatment of the cells replated on extracellular matrix caused the expression and phosphorylation of PKCdelta, which is required for expression and activation of integrins. Increased expression of integrins alpha2 and alpha3 correlated with the spreading, functioning in activation of focal adhesion molecules. Smad3, but not Smad2, overexpression enhanced the TGFbeta1 effects. Furthermore, TGFbeta1 treatment and PKCdelta activity were required for increased motility on fibronectin and invasion through matrigel, indicating their correlation with the spreading behavior. Altogether, this study clearly evidenced that the signaling network, involving the Smad-dependent TGFbeta pathway, PKCdelta expression and phosphorylation, and integrin expression and activation, regulates cell spreading, motility, and invasion of the SNU16mAd gastric carcinoma cell variant.

Erratum: Disseminated Superficial Actinic Porokeratosis in a Patient with Psoriasis, after Long-Term Narrowband Ultraviolet B Phototherapy.

[This corrects the article on p. 211 in vol. 30, PMID: 29606819.].

Disseminated Superficial Actinic Porokeratosis in a Patient with Psoriasis, after Long-Term Narrowband Ultraviolet B Phototherapy.

Porokeratosis is a rare epidermal disorder characterized by annular or linear hyperkeratotic plaques with slightly raised thread-like borders, and in most cases, atrophic centers. Disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis (DSAP), which primarily involve sun-exposed areas, are common types of porokeratoses. Histologically, a column of parakeratotic cells, a so-called cornoid lamella, is a hallmark of porokeratosis. Porokeratosis is considered to result from the inability to eliminate an abnormal keratinocyte clone induced by genetic factors and various stimuli, including sunlight, artificial ultraviolet light, viral infections, immunosuppressive conditions (hematologic malignancies, organ transplants, or autoimmune disease), and immunosuppressive therapies. Here, we report a 59-year-old Korean woman with DSAP that developed after narrowband ultraviolet B (NB-UVB) therapy for psoriasis. Our case emphasizes the occurrence of DSAP due to NB-UVB that is able to induce local immunosuppression at the irradiated site; the pathogenesis of DSAP remains unclear.

Comparison of the Efficacy of Azithromycin Versus Doxycycline in Acne Vulgaris: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Acne vulgaris is one of the most common disorders of the pilosebaceous unit. Although doxycycline is considered to be a first-line anti-acne antibiotic, various other antibiotics have been tried due to its adverse effects and contraindications. We performed a meta-analysis of randomized controlled trials (RCTs) that compared the efficacy of oral azithromycin pulse therapy with that of oral daily doxycycline in the management of moderate to severe acne vulgaris. METHODS: Five scientific databases (MEDLINE, EMBASE, Cochrane Library, SCOPUS, and Web of Science) were searched to identify relevant studies. A review of 1,341 publications produced six RCTs that met our predefined inclusion criteria. The clinical outcome measures were remaining acne lesion counts, patients' self-assessment of treatment, and the investigators' assessment of treatment after 12 weeks. RESULTS: We included six studies assessing 906 patients with moderate to severe acne vulgaris. Meta-analyses of clinical outcome measures revealed no significant difference between the two groups regarding remaining acne lesion counts (p=0.27), patients' self-assessment of treatment (p=0.67), and the investigators' assessment of treatment (p=0.32). The incidence of severe adverse events leading to the discontinuation of therapy was higher in the doxycycline daily therapy group when compared with the azithromycin pulse therapy group. CONCLUSION: This study indicates that azithromycin pulse therapy is equivalent to doxycycline at 12 weeks in the efficacy of the treatment for moderate to severe acne vulgaris Therefore, oral azithromycin pulse therapy may be a good alternative to doxycycline in the management of acne for those unable to tolerate doxycycline.

Clinical Features and Awareness of Hand Eczema in Korea.

BACKGROUND: Hand eczema is one of the most common skin disorders and negatively affects quality of life. However, a large-scale multicenter study investigating the clinical features of patients with hand eczema has not yet been conducted in Korea. OBJECTIVE: To identify the prevalence of various hand diseases, which is defined as all cutaneous disease occurring in hands, and to investigate the clinical features of patients with hand eczema and the awareness about hand eczema in the general population and to compare the prevalence of hand eczema between health care providers and non-health care providers. METHODS: To estimate the prevalence of hand diseases, we analyzed the medical records of patients from 24 medical centers. Patients were assessed by online and offline questionnaires. A 1,000 from general population and 913 hand eczema patients answered the questionnaire, for a total of 1,913 subjects. RESULTS: The most common hand disease was irritant contact dermatitis. In an online survey, the lifetime prevalence of hand eczema was 31.2%. Hand eczema was more likely to occur in females (66.0%) and younger (20~39 years, 53.9%). Health care providers and housewives were the occupations most frequently associated with hand eczema. Winter (33.6%) was the most common season which people experienced aggravation. The 63.0% and 67.0% answered that hand eczema hinders their personal relationship and negatively affects daily living activities, respectively. CONCLUSION: Hand eczema is a very common disease and hinders the quality of life. The appropriate identification of hand eczema is necessary to implement effective and efficient treatment.