AMPK activation modulates IL-36-induced inflammatory responses by regulating IκBζ expression in the skin.

BACKGROUND AND PURPOSE: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin. EXPERIMENTAL APPROACH: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators. KEY RESULTS: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression. CONCLUSION AND IMPLICATIONS: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders.

Diagnosis and Treatment of Leprosy in Taiwan during the COVID-19 Pandemic: A Retrospective Study in a Tertiaty Center.

Currently, over 200,000 new cases of leprosy are reported annually worldwide. Although leprosy was thought to have been eradicated in Taiwan, a few new cases still occur annually. Protean clinical manifestations of leprosy and immunological reactions result in delayed diagnoses. In addition, drug-resistant leprosy is emerging and poses treatment challenges. In this retrospective study, we collected and analyzed the clinicopathological features, leprosy type, treatment response, and relapse rate of patients with leprosy in our hospital between January 2009 and November 2022. We found that 54% of patients were Indonesian, and borderline lepromatous leprosy was predominant (39%); moreover, histoid leprosy and the Lucio phenomenon were also reported. Polymerase chain reaction analysis identified four positive cases, including a dapsone-resistant (4%) case. Our findings indicated good control of leprosy and a lower rate of dapsone resistance than that reported by the World Health Organization (4% vs. 13%) from 2009 to 2015. We found that the patient profile in terms of the treatment duration, recurrence rate, systemic symptoms, and neurological symptoms did not differ between before and during the pandemic. We report the recent advances in leprosy diagnosis, drug-resistant gene mutations, post-exposure prophylaxis, vaccination, and the effect of coronavirus disease 2019 on leprosy to facilitate updated leprosy diagnosis and management.

A Case Series With Acquired Dermal Melanocytosis: A Retrospective Study From 2001 to 2018.

ABSTRACT: Acquired dermal melanocytosis (ADM) is a pigmented lesion caused by melanocytes in the dermis, and it is most often observed on the face of young and middle-aged Asian women. ADM development may be associated with melanin synthesis alterations, but little evidence of its molecular and histological alteration has yet been reported. This study aimed to evaluate ADM in different body locations using different immunohistochemical and chemical staining techniques. This retrospective case series includes consecutive patients confirmed as ADM by biopsy between 2001 and 2018. Patient data and archival images were used to determine the pattern and duration of skin lesions, as confirmed by data analysis of immunohistopathological staining of skin biopsy specimens. A total of 22 ADM patients were included with mean age at diagnosis of 47 years, and 63.6% were female. The most common site was limbs (36.4%), followed by face (27.3%), trunk (22.7%), and scalp (13.6%). Melanin levels were highest in the face and upper extremities and lowest in the trunk. All participants had perivascular distribution of dermal melanocytes, particularly on the face and limbs. The perineural distribution of dermal melanocytes was observed in the lower limbs, with prominent inflammation and fibrosis on the scalp. Dermal melanocytes expressed most markers recognizing melanocytes except for CD117. Analysis of this ADM case series has confirmed that melanin is activated by dermal melanocytes that may aggregate along blood vessels. CD117 may be a useful biomarker by which to identify the migration of epidermal melanocytes.

Thioredoxin-interacting protein regulates keratinocyte differentiation: Implication of its role in psoriasis.

Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D3  suppressed but TGF-α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12-myristate 13-acetate (PMA), also diminished TXNIP expression, which was reversed by PKC-δ knockdown. TXNIP knockdown reduced PMA-induced involucrin and transglutaminse-1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H2 O2 -induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA-induced PKC-δ phosphorylation, TGF-α, and EGF-triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross-regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis.

Taiwanese dermatological association consensus for the definition, classification, diagnosis, and management of urticaria: A 2021 update.

Urticaria is a prevalent disease with substantial physical, psychological, and economic impacts. With the advent of understandings of the disease and the emerging evidence of treatments, the international guidelines for treating urticaria have been updated in recent years. In order to update the 2014 edition of the Taiwanese Dermatological Association (TDA) consensus of urticaria, a total of 17 dermatologists with extensive experience in urticaria management were invited to and attended the TDA consensus meetings. All the specific aspects of the content were approved by at least 75% of the experts in attendance. Comparing to the former edition, several substantial modifications were made. For diagnosis, D-dimer was added as the recommended routine test in patients with chronic spontaneous urticaria. For pharmacological management, treatment suggestions were simplified. The approved-dosed, the up-dosed second-generation antihistamines, omalizumab, and cyclosporine were listed as the first-line to the fourth-line treatment, respectively. In addition, the management for patients of special considerations, such as the elderly, children, and pregnant women, were all discussed and mentioned in the consensus. We hope the updated TDA consensus can serve as a reference for all physicians and can help the physicians providing up-to-dated managements for these patients.

Critical roles of irradiance in the regulation of UVB-induced inflammasome activation and skin inflammation in human skin keratinocytes.

UVB dosage is generally regarded as the most critical factor that determines the severity of UVB-induced skin erythema. However, recent studies have demonstrated that different UV irradiances induce varying biological responses in mouse skin even at constant UV doses. UVB-induced inflammasome activation is particularly observed in human skin keratinocytes, which are classified as immunocompetent cells, but not in mouse skin keratinocytes, which do not express sufficient inflammasome complex components. In human skin UVB-induced sunburn reactions, NLRP1 inflammasome activation critically mediates the inflammatory responses. Here, we employed primary human skin keratinocytes to explore the impact of different irradiances of a constant UVB dosage on inflammasome activation and related inflammatory responses. Our findings indicated that low-irradiance UVB induced relatively stronger NLRP1 inflammasome activation, which manifested as more active IL-1ß, IL-18 release, and enhanced procaspase-1 cleavage compared to high-irradiance UVB at the same dose. Irradiance did not influence cell lysis or the expression of inflammasome complex proteins including NLRP1, proIL-1ß, proIL-18, procaspase-1, and ASC. The UVB-induced TNF-α and cyclooxygenase-2 expression was also relatively higher in keratinocytes exposed to low-irradiance UVB. Low-irradiance UVB also increased reactive oxygen species production. UVB-triggered signaling analysis revealed that low-irradiance UVB resulted in more prominent p38 and JNK activation. Therefore, our findings indicated that, in addition to the role of total dosage, irradiance crucially modulates UVB-elicited inflammation in human skin keratinocytes, thus providing novel insights into human skin photobiology.

Fabrication of electroactive polypyrrole-tungsten disulfide nanocomposite for enhanced in vivo drug release in mice skin.

The present study focused on the development of electric stimuli drug release carrier based on transition metal dicgalcogenides. First, tungsten disulfide (WS2) was exfoliated and functionalized using thiol chemistry with various thiol-terminated ligands such as thioglycolic acid (TGA), mercaptosuccinic acid (MSA), and 2-ethanethiol (2ET). The exfoliated WS2 underwent non-covalent coating with an electrically conductive polypyrrole (PPy) for functionalization, of which MSA-WS2-PPy achieved the highest 5-FU (anticancer drug) loading. An electrically-stimulated drug release experiment showed that TGA-WS2-PPy achieved a higher drug release (90%) than MSA-WS2-PPy (70%) and 2ET-WS2-Ppy (35%). The TGA-WS2-PPy exhibited swelling/recombination between PPY and MSA-WS2 substrate under electrical stimulation, resulting in the highest 5-FU release. From the MTT assay result, there was no significant toxicity observed for TGA-WS2-PPy-FU on HaCaT cells, indicating the biocompatibility of TGA-WS2-PPy-FU in the absence of electrical stimulation. However, HaCaT cells died when incubated with TGA-WS2-PPy-FU under electrical stimulation. Finally, Raman mapping studies for TGA-WS2-PPy drug release in the skin of nude mice demonstrated that the carrier penetrated deeper into the skin of the mice while other systems failed to exhibit significant effects under electrical stimulation. The present study offers a novel approach in developing a non-invasive electrically-stimulated drug release system based on WS2 and an externally-controlled delivery model.

Lucio phenomenon mimicking antiphospholipid syndrome: The occurrence of antiphospholipid antibodies in a leprosy patient.

Lucio phenomenon is an atypical reaction of leprosy, characterized by vasculitic lesions that can mimic antiphospholipid syndrome (APS) clinically. Distinguishing the two can be difficult as antiphospholipid autoantibodies may be present in patients with leprosy. We report on a 32-year-old female patient presenting with a sudden onset of fever, hemorrhagic bullae, and skin necrosis on her lower legs. She was treated for APS due to the presence of antiphospholipid antibodies but had an inadequate response. A skin biopsy revealed thrombotic vasculopathy and necrotizing vasculitis associated with aggregation of foam cells in the perivascular area and subcutis, with acid-fast bacilli in the histiocytes and blood vessel walls. Direct immunofluorescence showed IgM, C3, and fibrinogen deposition in the superficial and deep dermal blood vessels. The pathology confirmed the diagnosis of Lucio phenomenon, and appropriate therapy was given. It is essential to evaluate the patient comprehensively, including clinical, serological, and pathological aspects, to obtain the correct diagnosis.

Neutrophilic Figurate Erythema.

Neutrophilic figurate erythema (NFE) has been rarely reported. This study aimed to identify the clinical and pathological features of NFE. We retrospectively reviewed the information from diagnostic cases from 2000 to 2013. The diagnosis of NFE includes clinically annular rash, histopathologically predominant neutrophilic perivascular and interstitial infiltrate in the dermis without evidence of vasculitis, and exclusion of other known specific entities. Fifteen cases of NFE were identified, including 11 women and 4 men. The age distribution was 18-66 years (average 41). The major characteristic patterns in NFE were blistering annular erythema (5/15 patients), purpuric annular erythema with vesicles (4/15 patients), and multiple annular rash with central ring-shaped scales (4/15 patients). There was no specific predicted location and no association with a major systemic disease. Papillary dermal edema and mild-to-moderate leukocytoclasis in the upper dermis are the main histopathological features. Ten of the 15 patients had recurrent episodes. Two patients who had single episode were associated with drug reaction. Antineutrophil therapy was required to control the symptoms in 3 patients. NFE has a similar clinical course as erythema annulare centrifugum but has distinct features that can be recognized clinically. The pathologists should be aware of the entity when making the diagnosis of neutrophil-mediated inflammatory disorders. The treatment regimen for neutrophilic dermatoses may be needed to manage the skin lesions.

Spectrum and clinical variants of giant cell elastolytic granuloma.

BACKGROUND: Giant cell elastolytic granuloma, also known as annular elastolytic giant cell granuloma or actinic granuloma, is histologically characterized by elastophagocytosis. Recent studies have revealed various clinical presentations in both sun-exposed and non-sun-exposed areas. OBJECTIVES: To clarify clinical characteristics based on case series observation. METHODS: We retrospectively reviewed patients who fulfilled the pathological diagnosis criteria for giant cell elastolytic granuloma seen at Mackay Memorial Hospital from 2000 to 2014. Patient characteristics, clinical presentation, duration, associated diseases, treatment, and prognosis were analyzed. RESULTS: A total of 22 patients were analyzed and categorized into three major variants. Eight patients with the "annular form" showed large annular lesions, which were usually associated with sun exposure. Six patients with the "papular form" presented with small papules. Eight patients in the "mixed form" group exhibited both papules and smaller annular plaques. The papular form had the youngest age of onset and shortest disease duration. The known consequences in 19 patients were resolved in seven, improved in three, recurred in four, and persisted in five patients. CONCLUSIONS: The term "giant cell elastolytic granuloma" is more appropriate because these were not completely related to actinic changes and may be nonannular. The papular form is not easily recognizable without a biopsy.

Anatomical distribution and outcome of surgical excision of fibrokeratoma - a clinical analysis of 124 cases.

BACKGROUND: Fibrokeratoma is a benign, cutaneous, fibrous tumor usually occurring on the digits. There is little data about their occurrence on nondigital areas and their surgical outcomes. OBJECTIVES: We sought to retrospectively characterize the distribution and surgical outcome of fibrokeratoma. METHODS: We retrospectively reviewed the clinical information of patients with a histopathological diagnosis of fibrokeratoma, including age, gender, lesion site, number of lesions, symptoms and signs, history of trauma, and any recurrence. RESULTS: We identified 124 patients diagnosed with fibrokeratoma in a 13-year period. The mean age was 42 years. There was a male predilection (2 : 1), and all lesions were solitary. Twenty patients (16%) had symptoms, and 13 patients (10%) had a history of trauma. Thirty patients (24%) had lesions on nondigital areas, including the upper and lower extremities and buttocks. The overall recurrence rate was 4% (five cases). Among them, three recurrent lesions were located on the periungual area of the toe. Nine patients (7%) had giant fibrokeratoma (>1 cm) but none recurred. CONCLUSION: Although most fibrokeratomas appeared on the digits, a certain number of cases (24%) were located on nondigital areas. The periungual area of the toe was the most common local recurrent site.

Folliculitis in prurigo pigmentosa: a proposed pathogenesis based on clinical and pathological observation.

BACKGROUND: Prurigo pigmentosa is a rare inflammatory dermatosis whose exact etiology is not understood yet. The purpose of this study was to provide evidence of hair follicle involvement in the pathogenesis by analyzing its clinicopathologic features. METHODS: Patients who fulfilled both the clinical and histological diagnostic criteria of prurigo pigmentosa were recruited. Their histopathologic findings, clinical features and medical histories were analyzed. RESULTS: A total of 32 confirmed patients were enrolled from 2002 to 2013. Their ages ranged from 11 to 79 years with a female predominance. Patient lesions were primarily reddish-brown and located on the back. A total of 25 patients (78%) had pathological involvement of hair follicles, either bacterial colonies in the hair follicles (21/32, 66%), folliculitis (8/32, 25%) or perifolliculitis (15/32, 47%). There was a significantly higher proportion of patients with hair follicle involvement compared with control groups with either noninflammatory (5/43, 12%, p < 0.001) or inflammatory skin diseases (12/32, 38%, p = 0.002) on the back. Minocycline was an effective antibiotic treatment either singly or in combination with steroids. CONCLUSIONS: The frequent presence of bacterial colonies along with sequelae of inflammatory changes on biopsy provides new evidence to support the theory that prurigo pigmentosa is a reactive inflammation associated with bacterial folliculitis.

Enhancing the in vivo transdermal delivery of gold nanoparticles using poly(ethylene glycol) and its oleylamine conjugate.

In this study, we investigated the effect of (ethylene glycol) (PEG) and PEG-oleylamine (OAm) functionalization on the skin permeation property of gold nanoparticles (GNS) in vivo. Chemisorption of polymers onto GNS was verified by a red shift in the ultraviolet-visible spectrum as well as by a change in the nanoparticle surface charge. The physicochemical properties of pristine and functionalized nanoparticles were analyzed by ultraviolet-visible spectroscopy, zeta potential analyzer, and transmission electron microscopy. Transmission electron microscopy revealed that the interparticle distance between nanoparticles increased after GNS functionalization. Comparing the skin permeation profile of pristine and functionalized GNS, the follicular deposition of GNS increased twofold after PEG-OAm functionalization. Moreover, PEG- and PEG-OAm-functionalized nanoparticles were able to overcome the skin barrier and deposit in the deeper subcutaneous adipose tissue. These findings demonstrate the potential of PEG- and PEG-OAm-functionalized GNS in serving a multitude of applications in transdermal pharmaceuticals.

Characterization of Cutaneous Plasmacytosis at Different Disease Stages.

BACKGROUND/AIMS: Cutaneous plasmacytosis is rare and still not well understood. A retrospective study was made of 9 Chinese patients with 1- to 15-year histories of biopsy-proven cutaneous plasmacytosis diagnosed between 2003 and 2015. METHODS: Patient records and archival photographs helped establish the pattern and duration of skin lesions, and skin biopsy specimens provided additional data. RESULTS: The mean age at diagnosis was 46.4 years. Two patients had lesions within 1 year of developing the disease, and 4 had lesions lasting longer than 5 years. One patient had lymphadenopathy of the neck that was later determined to be Castleman disease. Three patients had elevated IgG4 levels; only 2 had increased IgG4+ cells in skin tissues. Flexural accentuation was prominent. Four patients had elevated IgG levels, and 1, with an IgG level >5,000 mg/dL, developed systemic plasmacytosis (later confirmed as Castleman disease). The level of IgG4 subclass was related to disease duration, whereas IgG4+ plasma cells in tissues seemed irrelevant. CONCLUSION: Routine laboratory tests, especially measurement of IgG4 levels, may be useful for following patients with cutaneous plasmacytosis. Because of the retrospective nature of our study, we could only evaluate the results of a single IgG4 test for each patient, but the results pointed to cutaneous plasmacytosis in all 9 patients, who had different stages of the disease. Serial skin biopsies may also be helpful for gauging disease progress. Although IgG4-related disease was not established in any of these patients, long-term follow-up is warranted for all patients.

Seborrheic keratosis with bowenoid transformation: the immunohistochemical features and its association with human papillomavirus infection.

The bowenoid transformation of seborrheic keratosis (SK) has rarely been reported. The purpose of this study is to identify their diagnostic immunohistochemical features and association with human papillomavirus (HPV) infection. Skin biopsy specimens of the phenomenon were retrieved from 2001 to 2010. Benign SK, Bowen disease, bowenoid papulosis, and squamous cell carcinoma were included as controls. All specimens were stained for hematoxylin and eosin, Ki-67, p21, p16, p53, and cyclin D1. Polymerase chain reaction-amplified HPV DNA was analyzed. Seventeen cases of SK with bowenoid transformation were identified. The immunohistochemical pattern of bowenoid transformation was similar to that of Bowen disease and bowenoid papulosis. The malignant cells exhibited increased expressions of p16, p21, and ki-67 and a decreased expression of cyclin D1 (P < 0.01). HPV DNA was detected in 5 cases of bowenoid transformation. In conclusion, a portion of the cases of SK with bowenoid transformation were associated with HPV infection. Selective immunohistochemical stains were helpful in the diagnosis of malignant change in these cases.

Angioplasmocellular hyperplasia: a clinicopathologic study of 10 patients.

BACKGROUND: Angioplasmocellular hyperplasia is rarely reported. OBJECTIVE: The purpose of this study is to describe and analyze the clinicopathologic features of angioplasmocellular hyperplasia. METHODS: The records of 10 patients (mean age, 45 years; range, 17 to 71 years) with characteristic histologic features of angioplasmocellular hyperplasia were reviewed and the histopathologic findings, clinical features, and medical histories analyzed. Formalin-fixed, paraffin-embedded specimens were examined by immunohistochemical staining. RESULTS: The most common clinical appearance was a single nodule with an erythematous rim. Histologically, the inflammatory infiltrate comprised mainly polyclonal plasma cells. There was vascular proliferation of capillaries and venules with varying numbers of plump endothelial cells. There were no definite predisposing factors. LIMITATIONS: The number of cases was limited and all patients were Asian. CONCLUSIONS: Angioplasmocellular hyperplasia had a distinct clinical appearance characterized by its inflammatory rim. The nature of the infiltrating cells and distribution of blood vessels indicates that it is a form of reactive plasmocytic inflammatory vascular hyperplasia.