Paxbp1 is indispensable for the maintenance of peripheral CD4 T cell homeostasis.

The size and condition of the peripheral CD4 T cell population determine the capacity of the immune response. Under homeostatic conditions, the size of the peripheral CD4 T cell population is maintained through turnover and survival. However, the underlying mechanisms remain inadequately understood. Here, we observed a significant decrease in the percentage of CD4 T cells in the periphery following the targeted deletion of the Paxbp1 gene in mouse T cells. In the absence of Paxbp1, naïve CD4 T cells displayed reduced surface interleukin-7 receptor levels and a decreased capacity to respond to survival signals mediated by interleukin-7. In addition, naïve CD4 T cells deficient in Paxbp1 demonstrated impaired T cell antigen receptor signalling, compromised cell cycle entry, decreased proliferation, and increased apoptosis following stimulation, all of which contributed to the reduction in the number of peripheral CD4 T cells. Therefore, our study highlights the indispensable role of Paxbp1 in maintaining peripheral CD4 T cell homeostasis.

Corrigendum: OPN promotes pro-inflammatory cytokine expression via ERK/JNK pathway and M1 macrophage polarization in Rosacea.

[This corrects the article DOI: 10.3389/fimmu.2023.1285951.].

Clinical and histopathological characteristics, diagnosis and treatment, and comorbidities of Bowen's disease: a retrospective study.

Background: Bowen's disease (BD) is a slow-growing precancerous skin condition, often concurrent with other diseases, with a high misdiagnosis rate. Previous studies show that patients with BD in different populations have differentiated characteristics. Materials and methods: A retrospective study was conducted in a tertiary hospital in Shenzhen, China. Data about demographic information, diagnosis and treatment, clinical and pathological characteristics, and comorbidities of 50 patients with BD were collected and analyzed. Results: Clinical data of onset age and disease course of 43 patients with BD were available, the average onset age of male and female patients are 55.1 (standard deviation (SD) = 15.29) and 58.2 (SD = 15.59) years old, respectively; the average disease course of male and female patients are 25.3 (SD = 28.63) and 33.9 (SD = 49.65) months, respectively. The onset age (p = 0.52) and disease course (p = 0.49) between male and female patients are not significantly different. Interestingly, there is a negative correlation between onset age and disease course (r = -0.245, p = 0.11). The correct rate of clinical diagnosis is relatively low (54.00%); Some patients with BD are misdiagnosed as Bowenoid papulosis (10.00%), actinic keratosis (8.00%), basal cell carcinoma (8.00%), seborrheic keratosis (6.00%), and pigmented naevus (4.00%). Trunk and limbs are the most common distribution sites of BD lesions, and 94.00% patients with BD are treated with surgical resection; 66.00% patients with BD had comorbidities, including skin diseases (48.48%), cardiovascular diseases (39.39%), gastrointestinal diseases (30.30%), respiratory diseases (27.27%), and tumors (18.18%). The most commonly observed histopathological characteristics of BD are squamous-cell hyperplasia (86.00%), disordered maturation with atypical keratinocytes (74.00%), atypical mitoses (60.00%), hyperkeratosis with hypokeratosis (48.00%), dermal inflammatory cell infiltration (36.00%), and koilocytosis (22.00%). Conclusion: BD often occurs in middle-aged and elderly people and is easily misdiagnosed. The onset age and disease course of patients with BD are not significantly different between males and females, whereas there is a negative correlation between the onset age and disease course. BD is more likely to occur in trunk and limbs in the Chinese population, and most patients with BD are concurrent with comorbidities.

The crucial roles of m6A RNA modifications in cutaneous cancers: Implications in pathogenesis, metastasis, drug resistance, and targeted therapies.

N6-methyladenosine (m6A) is the most abundant internal modification on RNA. It is a dynamical and reversible process, which is regulated by m6A methyltransferase and m6A demethylase. The m6A modified RNA can be specifically recognized by the m6A reader, leading to RNA splicing, maturation, degradation or translation. The abnormality of m6A RNA modification is closely related to a variety of biological processes, especially the occurrence and development of tumors. Recent studies have shown that m6A RNA modification is involved in the pathogenesis of skin cancers. However, the precise molecular mechanisms of m6A-mediated cutaneous tumorigenesis have not been fully elucidated. Therefore, this review will summarize the biological characteristics of m6A modification, its regulatory role and mechanism in skin cancers, and the recent research progress of m6A-related molecular drugs, aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.

National situation, trends, and predictions of disease burden of atopic dermatitis in Chinese children and adolescents.

Background: Atopic dermatitis (AD) is an important global health problem affecting children and adolescents and detailed national information of disease burden in China is lacking. We aimed to evaluate the national disease burden of AD in Chinese children and adolescent, to provide the temporal trends over the past 30 years and to predict the burden for the next 10 years. Methods: The data of AD in China, including incidence, prevalence, and DALY, and population data were obtained from the Global Burden of Disease Study 2019 (GBD study 2019), which were estimated using the DisMod-MR 2.1. We analyzed the three measures by age and sex; the age groups were <5 years, 5-9 years, 10-14 years, and 15-19 years. The joinpoint regression analyses was conducted to assess the temporal trends from 1990 to 2019. The Bayesian age-period cohort (BAPC) model was used to predict measures from 2020 to 2030. Results: In 2019, the highest incidence case and rate were observed in <5 years group; for prevalence and disability adjusted life year (DALY), the groups of <5 years and 5-9 years showed similar higher levels and the groups of 10-14 years and 15-19 years had similar relatively lower levels. Overall, the male-to-female ratios were >1 in <5 years group and <1 in 10-14 and 15-19 age groups. The trend analyses found an overall trend of decrease in cases of the three measures; in recent about 3 years, slight increase trends were shown in cases and rates of the three measures in <5 years group. The prediction analyses found a slight decreasing trend for cases of these measures and a slight increasing trend for rates of these measures in the <5 years group in the next 10 years; the 5-9 years group was predicted to increase slightly in rates of the three measures. Conclusion: In conclusion, the groups of <5 years and 5-9 years are two important populations that need targeted measures to reduce disease burden of AD in China. Regarding sex disparity, we should pay more attention to males in <5 years group and to females in 10-19 years group.

The updates and implications of cutaneous microbiota in acne.

Acne is a chronic inflammatory skin disorder that profoundly impacts the quality of life of patients worldwide. While it is predominantly observed in adolescents, it can affect individuals across all age groups. Acne pathogenesis is believed to be a result of various endogenous and exogenous factors, but the precise mechanisms remain elusive. Recent studies suggest that dysbiosis of the skin microbiota significantly contributes to acne development. Specifically, Cutibacterium acnes, the dominant resident bacterial species implicated in acne, plays a critical role in disease progression. Various treatments, including topical benzoyl peroxide, systemic antibiotics, and photodynamic therapy, have demonstrated beneficial effects on the skin microbiota composition in acne patients. Of particular interest is the therapeutic potential of probiotics in acne, given its direct influence on the skin microbiota. This review summarizes the alterations in skin microbiota associated with acne, provides insight into its pathogenic role in acne, and emphasizes the potential of therapeutic interventions aimed at restoring microbial homeostasis for acne management.

The Crucial Roles and Research Advances of cGAS-STING Pathway in Cutaneous Disorders.

The cGAS-STING signaling pathway senses the presence of cytosolic DNA, induces strong type I interferon responses, and enhances inflammatory cytokine production, placing it as an important axis in infection, autoimmunity, and tumor immunity. Recent studies have shown that the abnormalities and/or dysfunctions of cGAS-STING signaling are closely related to the pathogenesis of skin diseases and/or cancers. Additionally, a variety of new therapeutics targeting the cGAS-STING signaling are in development for the treatment of skin disorders. However, the precise molecular mechanisms of cGAS-STING-mediated cutaneous disorders have not been fully elucidated. In this review, we will summarize the regulatory roles and mechanisms of cGAS-STING signaling in skin disorders and recent progresses of cGAS-STING-related drugs as well as their potential clinical applications.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Psoriasis Through TNF-α/NF-κB/MMP13 Pathway.

Psoriasis is a chronic, immune-mediated disease that affects 2-3% of the global population. Recently, mesenchymal stem cells (MSCs) have been used to alleviate psoriasis. However, the therapeutic mechanisms of MSCs remain unclear. Matrix metalloproteinase-13 (MMP13), a member of the MMPs family, is the key enzyme in the cleavage of type II collagen and plays a pivotal role in extracellular matrix (ECM) remodeling. Here, it was found that Mmp13 was upregulated in the skin lesions of an imiquimod-induced mouse model, which was downregulated after intravenous infusion of human umbilical cord MSCs (hUC-MSCs). Knockdown of MMP13 inhibited the proliferation of keratinocytes and arrested the cell cycle in G1 stage. In addition, hUC-MSCs were co-cultured with THP-1 or PMA-stimulated THP-1 directly in vitro to simulate the fate of systematically infused hUC-MSCs. The level of TNF-α was decreased in the supernatant of co-cultured hUC-MSCs and THP-1 or PMA-stimulated THP-1. Moreover, it was identified that TNF-α upregulated MMP13 through the NF-κB pathway in keratinocytes. In conclusion, we propose that systematically infused hUC-MSCs exert a therapeutic effect on psoriasis through the TNF-α/NF-κB/MMP13 pathway.

OPN promotes pro-inflammatory cytokine expression via ERK/JNK pathway and M1 macrophage polarization in Rosacea.

Rosacea is a chronic inflammatory dermatosis that involves dysregulation of innate and adaptive immune systems. Osteopontin (OPN) is a phosphorylated glycoprotein produced by a broad range of immune cells such as macrophages, keratinocytes, and T cells. However, the role of OPN in rosacea remains to be elucidated. In this study, it was found that OPN expression was significantly upregulated in rosacea patients and LL37-induced rosacea-like skin inflammation. Transcriptome sequencing results indicated that OPN regulated pro-inflammatory cytokines and promoted macrophage polarization towards M1 phenotype in rosacea-like skin inflammation. In vitro, it was demonstrated that intracellular OPN (iOPN) promoted LL37-induced IL1B production through ERK1/2 and JNK pathways in keratinocytes. Moreover, secreted OPN (sOPN) played an important role in keratinocyte-macrophage crosstalk. In conclusion, sOPN and iOPN were identified as key regulators of the innate immune system and played different roles in the pathogenesis of rosacea.

circPLIN2 promotes clear cell renal cell carcinoma progression by binding IGF2BP proteins and miR-199a-3p.

Recent evidence has indicated that circular RNAs (circRNAs), a novel type of regulatory RNA, play important roles in the development and progression of various cancers. However, the potential regulatory roles and molecular mechanisms of circRNAs in clear cell renal cell carcinoma (ccRCC) remain largely unclear. Here, we explored circRNA expression profiles in 10 paired samples of RCC (including cancer tissues and surrounding tissues) from the Gene Expression Omnibus (GEO) datasets GSE124453 and GSE108735. We initially identified hsa_circ_0086457, designated circPLIN2, derived from exons 4 to 5 of the PLIN2 gene. We observed that circPLIN2 was preferentially located in the cytoplasm and was more stable than its linear counterpart PLIN2. circPLIN2 was significantly upregulated in ccRCC cells and tissues, and its overexpression was correlated with higher clinical stage and worse prognosis for ccRCC patients. Moreover, gain- and loss-of-function assays indicated that circPLIN2 promoted ccRCC cell proliferation, migration, and invasion in vitro and ccRCC tumor growth and metastasis in vivo. Mechanistically, circPLIN2 not only increased the stability of the c-Myc and MARCKSL1 mRNAs by binding to the KH domains of IGF2BP proteins but also competitively sponged miR-199a-3p to abolish the repressive effect of miR-199a-3p on ZEB1 expression, which ultimately resulted in ccRCC tumorigenesis and progression. Collectively, our results suggest that circPLIN2 may represent a promising diagnostic and prognostic biomarker and a potential therapeutic target for ccRCC patients.

iTRAQ-Based Proteomics Analysis of Rat Cerebral Cortex Exposed to Valproic Acid before Delivery.

Autism spectrum disorder (ASD) is a neurological and developmental disorder characterized by social and communication difficulties. Valproic acid (VPA) injection during pregnancy elicits autism-like behavior in the offspring, making it a classic animal model of ASD. However, the mechanisms involved have not yet been determined. In this study, we used iTRAQ (isobaric tags for relative and absolute quantification) proteomics analysis of the cerebral cortex of a VPA rat model (VPA group) and controls (CON group). The results showed that 79 differentially expressed proteins (DEPs) were identified between the VPA group and the CON group. Based on bioinformatics analysis, the DEPs were mainly enriched at synapses, especially glutamatergic synapses and GABAergic synapses. Some DEPs were involved in energy metabolism, thyroid hormone synthesis pathway, and Na+-K+-ATPase. Cytoskeleton and endoplasmic reticulum (ER) stress-related proteins were also involved. Some DEPs matched either the ASD gene database or previous reports on cerebral cortical transcriptome studies in VPA rat models. Dysregulation of these DEPs in the cerebral cortex of VPA rats may be responsible for autism-like behavior in rats. We also found that some DEPs were associated with neuropsychiatric disorders, implying that these diseases share common signaling pathways and mechanisms. Moreover, increased expression of DEPs was associated with energy metabolism in the cerebral cortex of VPA rats, implying that ASD may be a distinct type of mitochondrial dysfunction that requires further investigation.

Effect of treatments on skin microbiota in patients with atopic dermatitis: a protocol for systematic review.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease and skin microbiota dysbiosis shows an important role in the pathogenesis of AD. Effects of treatment on skin microbiota for patients with AD have been evaluated in recent years; however, the results remained controversial across studies. This systematic review will summarise studies evaluating the effect of treatments on skin microbiota among patients with AD. METHODS AND ANALYSIS: We will search PubMed, EMBASE, Web of Science, ClinicalTrials.gov and Chinese Clinical Trial Registry in November 2021; other data sources will also be considered, including searching specific authors and screening references cited in the enrolled articles. Interventional studies, which enrolled patients with AD receiving treatments and reported treatment-related skin microbiota changes, will be included. Our primary outcomes include skin microbiota diversity and treatment-related differential microbes; the secondary outcomes include microbiota functions and microbial interactions. Risk of bias assessment will be performed using Cochrane risk-of-bias tool for randomised trials, risk of bias in non-randomised studies of interventions and methodological index for non-randomised studies. Two researchers will independently perform study selection, data extraction and risk of bias assessment, with disagreements resolved by group discussions. Subgroup analyses will be performed according to different types of treatment for AD. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review. Findings will be disseminated via peer-reviewed publication or conference proceedings. PROSPERO REGISTRATION NUMBER: CRD42021246566.

Proteomic Profiling of Cerebrum Mitochondria, Myelin Sheath, and Synaptosome Revealed Mitochondrial Damage and Synaptic Impairments in Association with 3 × Tg-AD Mice Model.

Alzheimer's disease (AD) is the most common age-associated dementia with complex pathological hallmarks. Mitochondrion, synaptosome, and myelin sheath appear to be vulnerable and play a key role in the pathogenesis of AD. To clarify the early mechanism associated with AD, followed by subcellular components separation, we performed iTRAQ (isobaric tags for relative and absolute quantification)-based proteomics analysis to simultaneously investigate the differentially expressed proteins (DEPs) within the mitochondria, synaptosome, and myelin sheath in the cerebrum of the 6-month-old triple transgenic AD (3 × Tg-AD) and 6-month-old wild-type (WT) mice. A large number of DEPs between the AD and WT mice were identified. Most of them are related to mitochondria and synaptic dysfunction and cytoskeletal protein change. Differential expressions of Lrpprc, Nefl, and Sirpa were verified by Western blot analysis. The results suggest that decreased energy metabolism, impaired amino acid metabolism and neurotransmitter synthesis, increase compensatory fatty acid metabolism, up-regulated cytoskeletal protein expression, and oxidative stress are the early events of AD. Among these, mitochondrial damage, synaptic dysfunction, decreased energy metabolism, and abnormal amino acid metabolism are the most significant events. The results indicate that it is feasible to separate and simultaneously perform proteomics analysis on the three subcellular components.

Hsa-miR-372-5p regulates the NIMA related kinase 7 and IL-1ß release in NK/T-cell lymphoma.

Epstein-Barr virus (EBV) infection is prevalent and associated with distinct diseases including infectious mononucleosis (IM), chronic active EBV infection (CAEBV) and NK/T-cell lymphoma (NKTL). However, the specific roles of EBV in these diseases remain unclear. Here, the whole miRNA expression datasets derived from 7 IM, 6 CAEBV, and 3 NKTL biopsies were obtained. Homo sapiens microRNA-372-5p (Hsa-miR-372-5p) was upregulated in both CAEBV and NKTL patients. Overexpression of hsa-miR-372-5p altered the expression of over 100 proteins. In addition, hsa-miR-372-5p may target NIMA related kinase 7 to regulate NLRP3 inflammasome activation in host cell. Taken together, we reported different miRNA expression profiles in distinct EBV associated diseases, which provided novel insights to understand how host miRNAs contribute to the mechanism of EBV associated diseases. Hsa-miR-372-5p, as well as other differential expressed miRNA, might serve as potential targets in the therapy of various EBV associated diseases.

Protein Biomarkers of Autism Spectrum Disorder Identified by Computational and Experimental Methods.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects millions of people worldwide. However, there are currently no reliable biomarkers for ASD diagnosis. Materials and Methods: The strategy of computational prediction combined with experimental verification was used to identify blood protein biomarkers for ASD. First, brain tissue-based transcriptome data of ASD were collected from Gene Expression Omnibus database and analyzed to find ASD-related genes by bioinformatics method of significance analysis of microarrays. Then, a prediction program of blood-secretory proteins was applied on these genes to predict ASD-related proteins in blood. Furthermore, ELISA was used to verify these proteins in plasma samples of ASD patients. Results: A total of 364 genes were identified differentially expressed in brain tissue of ASD, among which 59 genes were predicted to encode ASD-related blood-secretory proteins. After functional analysis and literature survey, six proteins were chosen for experimental verification and five were successfully validated. Receiver operating characteristic curve analyses showed that the area under the curve of SLC25A12, LIMK1, and RARS was larger than 0.85, indicating that they are more powerful in discriminating ASD cases from controls. Conclusion: SLC25A12, LIMK1, and RARS might serve as new potential blood protein biomarkers for ASD. Our findings provide new insights into the pathogenesis and diagnosis of ASD.

CRM197-Coupled Der p 2 Peptides Suppress Allergic Airway Inflammation in a Der p 2-Induced Asthma Mouse Model.

Allergic diseases affect more than 25% of the global population. Der p 2 is the major allergen of the house dust mite (HDM) Dermatophagoides pteronyssinus. Allergen-specific immunotherapy is the only treatment to change the course of allergic diseases. In this study, two synthesized Der p 2 peptides coupled to cross-reacting material 197 (CRM197) showed reduced IgE reactivity and allergenic activity. CRM197-coupled Der p 2 peptides induced rDer p 2-specific IgG1 antibodies in mice, which could inhibit HDM-allergic patients' IgE binding to rDer p 2. The immunity effects of CRM197-coupled Der p 2 peptides were studied in an rDer p 2-induced asthma mouse model. CRM197-coupled Der p 2 peptides can suppress asthmatic airway inflammation in this model. Analysis of IL-4, IL-5, and IFN-γ levels in bronchoalveolar lavage fluid revealed that the suppression was associated with a shift from a Th2 to a Th1 response. Thus, CRM197-bound Der p 2 peptides exhibited less allergenic activity than the rDer p 2 allergen, which preserved immunogenicity and may be candidates for mite allergy vaccines.

Comparative Proteomics Analysis of Serum Proteins in Gestational Diabetes during Early and Middle Stages of Pregnancy.

PURPOSE: This study is designed to screen serum proteins that may serve as biomarkers for gestational diabetes mellitus (GDM), and clarify the mechanisms of disease. EXPERIMENTAL DESIGN: By using isobaric tags for relative and absolute quantitation proteomics analysis, serum proteins levels were quantified in pregnant women who subsequently developed GDM (12-16 weeks), GDM patients (24-28 weeks), and their corresponding controls. The strategy of mixing samples is used in proteomic analysis. RESULTS: Thirty-one and 27 differentially expressed proteins are identified in the serum of pregnant women with developed GDM at 12-16 weeks and GDM patients during 24-28 weeks, respectively. Thirty eight and 28 proteins are identified in 24-28 weeks versus 12-16 weeks controls (24/12 CTR group), and 24-28 weeks GDM patients versus 12-16 weeks women with subsequently developed GDM (24/12 GDM group), respectively. Most of these proteins in the case and control subjects are associated with diabetes and maternal and perinatal short- and long-term complications. CONCLUSIONS AND CLINICAL RELEVANCE: The results highlight the roles of complement system and the blood clotting cascade in the pathogenesis of GDM. Differentially expressed proteins may serve as potential biomarkers for GDM prediction and diagnosis in the future.

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children.

Autism is one of the most common neurological developmental disorder associated with social isolation and restricted interests in children. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. To search for biomarkers for early detection and exploration of the disease mechanisms, here, we investigated the protein expression signatures of peripheral blood mononuclear cells (PBMCs) in autistic children compared with healthy controls by using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach. The results showed a total of 41 proteins as differentially expressed in autistic group as compared to control. These proteins are found associated with metabolic pathways, endoplasmic reticulum (ER) stress and protein folding, endocytosis, immune and inflammatory response, plasma lipoprotein particle organization, and cell adhesion. Among these, 17 proteins (13 up-regulated and four down-regulated) are found to be linked with mitochondria. Eight proteins including three already reported proteins in our previous studies were selected to be verified. Five already reported autism associated pro-inflammatory cytokines [interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-6, IL-12, and tumor necrosis factor-α (TNF-α)] were detected in plasma by enzyme-linked immunosorbent assay (ELISA) analysis. The results were consistent with proteomic results and reports from previous literature. These results proposed that PBMCs from autistic children might be activated, and ER stress, unfolded protein response (UPR), acute-phase response (APR), inflammatory response, and endocytosis may be involved in autism occurrence. These reported proteins may serve as potential biomarkers for early diagnosis of autism. More specifically, simultaneous detection of three proteins [complement C3 (C3), calreticulin (CALR), and SERPINA1] in the plasma and PBMCs could increase the authenticity of detection.

Alzheimer's Disease Is Responsible for Progressive Age-Dependent Differential Expression of Various Protein Cascades in Retina of Mice.

Alzheimer's disease (AD) is a devastating neurodegenerative disease associated with cognitive impairments and memory loss usually in aged people. In the past few years, it has been detected in the eye retina, manifesting the systematic spread of the disease. This might be used for biomarker discovery for early detection and treatment of the disease. Here, we have described the proteomic alterations in retina of 2, 4, and 6 months old 3×Tg-AD mice by using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. Out of the total identified proteins, 121 (71 up- and 50 down-regulated), 79 (51 up- and 28 down-regulated), and 153 (37 up- and 116 down-regulated) significantly differentially expressed proteins (DEPs) are found in 2, 4, and 6 month's mice retina (2, 4, and 6 M), respectively. Seventeen DEPs are found common in these three groups with consistent expression behavior or opposite expression in the three groups. Bioinformatics analysis of these DEPs highlighted their involvement in vital AD-related biological phenomenon. To further prompt the results, four proteins from 2 M group, three from 4 M, and four from 6 M age groups are successfully validated with Western blot analysis. This study confirms the retinal involvement of AD in the form of proteomic differences and further explains the protein-based molecular mechanisms, which might be a step toward biomarker discovery for early detection and treatment of the disease.