Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)–knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.
Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.
Background Mycobacterium farcinogenes–senegalense group mostly cause bovine farcy, which rarely infect human beings. We reported one case of cutaneous Mycobacterium farcinogenes–senegalense group infection in an immunocompetent victim. Case presentation A 66-year-old Taiwanese woman with hypertension developed tender nodules on her left dorsal foot for 2 months. Tissue culture identified Mycobacterium farcinogenes–senegalense group. The lesion was treated successfully with clarithromycin and sulfamethoxazole/trimethoprim, followed by surgical excision. Conclusions Mycobacterium farcinogenes–senegalense group infection should be considered as a potential pathogen of skin infection in immunocompetent patients.
Background: The rising incidence of implantation mycoses and invasive fungal infections prompts the need for studies describing the latest trends of these diseases; however, the literature remains scarce from tropical Asia in recent years. We shared our 11-year clinical experience at a tertiary center in Southern Taiwan to improve physicians’ understanding of the diseases, which could help them assume appropriate management strategies. Patients and methods: Forty cases of pathology-proven cases of implantation mycoses and invasive fungal infections with cutaneous involvement were retrospectively reviewed. The epidemiology, patients’ characteristics, initial clinical impressions, fungal species, management, and outcomes were compared and reported. Results: Fonsecaea sp. was the most commonly (14%) involved species in implantation mycoses. The percentages of immunocompromised patients with implantation mycoses and invasive fungal infections were 26% and 60%, respectively. Additionally, 46% of patients with implantation mycoses had type 2 diabetes mellitus. The lesions were commonly mistaken for skin appendage tumors, skin cancers, and hyperkeratotic dermatoses. The prognosis was favorable for the implantation mycoses (83% showed clinical improvement) but bleak for the invasive fungal infections (100% mortality). Conclusions: Presentations of implantation mycoses and invasive fungal infections vary widely, and immunocompromised status and diabetes mellitus are important associated factors.
Background Nickel, the fifth most common element on Earth, is the leading inducer of contact allergies in humans, with potent immunological effects. Nickel‐induced contact allergies predominantly affect females. Maternal exposure to nickel has been associated with several developmental abnormalities. However, how a maternal nickel exposure affects the development of atopic diathesis and immune abnormalities in children has never been addressed. Objectives We aimed to determine whether maternal nickel exposure affects the development of atopic dermatitis and immune abnormalities in their children. Methods Using a birth cohort study, we analysed 140 mother–child pairs recruited in 2012–2015 from central Taiwan. Maternal exposure to nickel was estimated using urinary nickel levels measured by inductively coupled plasma mass spectrometry (ICP‐MS). The serum levels of 65 analytes and IgE in 3‐year‐old children were profiled with a multiplex ELISA. The correlation between the maternal urinary nickel concentration and serum analyte levels was assessed using Spearmen's correlation. Multivariant regression analysis was performed to evaluate the association between maternal urinary nickel levels and serum analyte concentrations in their children. Results The geometric means of the maternal urinary nickel and the children's serum IgE levels were 2.27 μg/L and 69.71 IU/mL, respectively. The maternal nickel exposure was associated with increased serum levels of IL‐1β, IL‐2, TNF‐α, and leukaemia inhibitory factor (LIF) but with decreased serum levels of matrix metalloproteinase‐1 (MMP‐1), IL‐2R, and eotaxin‐1 in the children. In addition, the development of childhood atopic dermatitis at 3 years old was significantly associated with the child's serum levels of IgE and IL‐2R, but it was negatively associated with the maternal nickel exposure. Conclusions This is the first study showing the potential immunological effects of maternal nickel exposure in their children at an early developmental stage.
Sebaceous carcinoma (SC) is a rare malignant neoplasm with sebaceous differentiation.SC is classified into eyelid and extraocular SC clinically. Most studies have focused on the eyelid SC in terms of pathogenesis, treatment, and prognosis. In skin, Wnt/beta-catenin and hedgehog signaling are two major pathways in sebaceous differentiation. We aimed to characterize the clinical and histopathological features of extraocular SC and to measure the expression of beta-catenin, lymphoid enhancer-binding factor 1 (LEF1), sonic hedgehog (Shh), and protein patched homolog 1 (PTCH) in extraocular SC. Ten cases of extraocular SC were identified from 2007 to 2020. The clinical features, microscopic findings, and prognosis were analyzed. Immunohistochemical stain for beta-catenin, LEF1, Shh, and PTCH were performed in extraocular SC and other benign sebaceous tumors including sebaceous hyperplasia, sebaceous adenoma, and sebaceoma. The male:female ratio was 4:6. The median onset age was 73.5 years (range, 43-88). Seven patients out of 10 were diagnosed after 60 years. Most extraocular SC were located on the head and neck with indurated plaque. Two patients had concurrent internal cancers and three patients showed lymph node metastasis at time of presentation. Five-year overall-survival was 40%. Beta-catenin was expressed membranously in all sebaceous hyperplasia, but was expressed variably in extraocular SC (1/5). While LEF1 was unequivocally expressed in normal hair follicles, LEF1 expression was absent in all extraocular SC and benign sebaceous tumors. Regarding the sonic hedgehog signaling, Shh and PTCH were all expressed in the cytoplasm of sebaceous hyperplasia, sebaceous adenoma, and sebaceoma. In contrast, PTCH was absent in all cases of extraocular SC and only 50% of the extraocular SC expressed cytoplasmic Shh. To conclude, extraocular SC commonly affects facial skin in the elderly. Inactivated Wnt/beta-catenin and aberrant hedgehog pathway may contribute to the carcinogenesis of extraocular SC. Further studies may be required to elucidate the causative mechanism of these pathways in extraocular SC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.