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关键词： GC-C   guanylate cyclase C   KO   knockout   IFN   interferon   scRNA-seq   single-cell RNA-sequencing   WRN   Wnt, R-spondin1 and Noggin  

关键词： IL-1beta   Adenosine 5 '-tetraphosphate   ATP   NLRP3 inflammasome   Human macrophages   Metallothioneins  

摘要： BackgroundThe endogenous nucleotide adenosine 5 '-tetraphosphate (Ap4) is a potent vasoconstrictor. Despite its structural similarity to the danger signal adenosine 5'-triphosphate (ATP), the immunomodulatory effects of Ap4 remain *** of interleukin (IL)-1 beta secretion by Ap4 was studied in both immune cells lines (THP-1, U937) and primary immune cells. Genetic and pharmacological approaches were used to characterize signaling. Cytokine production was measured using ELISA and multiplex assays, while cell viability was determined by MTT and LDH assays. Calcium influx and YO-PRO-1 uptake were assessed via microplate assays and flow cytometry, respectively. RNA sequencing and Western blotting were performed to analyze global gene expression and protein *** demonstrate that Ap4 stimulates IL-1 beta release in primed immune cells without affecting the levels of other cytokines, suggesting specificity in its immunomodulatory actions. Mechanistically, Ap4-induced IL-1 beta release was partially modulated by the P2X7 receptor, a key mediator of inflammation. However, unlike canonical inflammasome activators, this process was independent of potassium efflux, the NLRP3 inflammasome, and caspase-1. Ap4 specifically increased LDH release in macrophages irrespective of priming. Furthermore, Ap4-mediated calcium influx, crucial for immune cell activation, predominantly occurred through P2Y receptors rather than P2X7 receptors. Transcriptomic analysis highlighted Ap4-induced upregulation of metallothioneins, implicating metal ion homeostasis in Ap4-mediated ***, our findings suggest Ap4 as a novel pro-inflammatory mediator capable of inducing IL-1 beta release in innate immune cells through distinct mechanisms from classical NLRP3 inflammasome activators, shedding light on its potential role in inflammatory diseases and vascular disorders.

关键词： biomarkers   gingival crevicular fluid   interleukin-7   interleukin-8   interleukin-13   stabilization splint  

摘要： Background and Objectives: In recent years, numerous studies have investigated and analyzed the levels of molecular biomarkers of temporomandibular disorders (TMD) from various tissue samples and body fluids. However, no study has investigated gingival crevicular fluid (GCF) in TMD patients. The purpose of this study was to determine the concentrations of pro-inflammatory cytokines in GCF before and after stabilization splint (SS) therapy in patients with painful TMD, to investigate whether SS administration causes changes in the concentrations of pro-inflammatory cytokines. An additional aim was to investigate the relationship of GCF cytokine levels with chronic pain intensity and clinical parameters. Materials and Methods: This prospective cohort study included 36 patients who were diagnosed with painful TMD using the Diagnostic Criteria for TMD (DC/TMD). GCF samples were collected at baseline before SS treatment (T0) and at one month (T1) and three months (T2) after the start of therapy. Customized ProcartaPlex Multiplex assays from eBioscience (Invitrogen (TM), Thermo Fisher Scientific, Viena, Austria) were used for the quantitative analysis of pro-inflammatory cytokines (IL-1 beta, IL-6, IL-7, IL-8, IL-13, and TNF-alpha). Patients filled out Croatian versions of questionnaires for self-assessment from Axis II DK/TMP: Graded Chronic Pain Scale (v2) (GCPSv2) and Jaw Function Limitation Scale-20 (JFLS-20). Results: The results showed that the GCF levels of IL-7 (Friedman's test, p = 0.008) and IL-13 (Friedman's test, p = 0.003) were significantly decreased at T2. The GCF level of IL-13 was in negative correlation with chronic pain grade score at T2 (Rho = -0.333), while the GCF level of IL-8 was in positive correlation with mobility limitation (Rho = 0.382) at T1. Conclusions: The results indicate that SS therapy might have a role in reducing inflammation and that the GCF could be a valuable medium for assessing molecular biomarkers.

摘要： Innovations in biologics are transforming the treatment of psoriatic diseases. The ability to target specific levels of immune activation provides a distinct advantage. Interleukin (IL)-17 inhibitors fall into this class of biologics, and they are effectively used to treat a spectrum of psoriatic diseases, such as psoriasis vulgaris and psoriatic arthritis. In recent years, anti-IL-17 agents have been the focus of therapeutic development, with various formulations and routes of administration. In this manuscript, we review pipeline anti-IL-17 therapies for psoriatic diseases identified through a search of *** (January 2019-December 2024) and other databases. Key agents under investigation include netakimab, vunakizumab, xeligekimab, gumokimab, HB0017, CJM 112, JS005, 608, LZM012, ZL-1102, izokibep, sonelokimab, DC-806, DC-853, and LEO 153339. Both preclinical and clinical trial data for each agent are summarized, with an emphasis on their efficacy, adverse effects, immunogenicity, and future outlooks.

关键词： IL-33   ST2   Non-small-cell lung cancer   Apoptosis  

摘要： Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Although targeted therapies have improved treatment outcomes, drug resistance poses a significant challenge, underscoring the need for novel therapeutic strategies. Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions both as a nuclear protein and a cytokine, binding to its receptor, ST2. While IL-33 is known to promote tumour cell migration and metastasis, its role in regulating apoptosis remains incompletely understood. In this study, we focused on endogenous IL-33, employing lentiviral transfection to overexpress both the full-length and mature forms of IL-33 in lung cancer cells. We examined its effects on apoptosis in vitro and investigated the underlying molecular mechanisms. Our findings reveal that endogenous IL-33 inhibits apoptosis in lung cancer cells by modulating the expression of BCL2 and BAX via the ERK1/2 pathway in an autocrine manner. These results uncover a novel mechanism of IL-33-mediated tumour survival and provide a foundation for the development of IL-33/ST2-targeted therapies in NSCLC.

关键词： Active tuberculosis   Burkina Faso   Gene   Genetic susceptibility   IFN-γ  

摘要： Interferon-gamma (IFN-γ) plays a crucial role in resistance to mycobacterial infections, as it is a regulatory cytokine that acts as a pro-inflammatory mediator. Consequently, variants in the gene encoding this cytokine may be associated with a high risk of contracting pulmonary tuberculosis. The present study aimed to investigate the genetic susceptibility of polymorphisms in the gene coding for IFN-γ to infection by Mycobacterium tuberculosis in Burkina Faso. This cross-sectional study was conducted from May 2023 to January 2024. Venous blood was collected from suspected cases. Tuberculosis was confirmed by GeneXpert (CEPHEID). Human genomic DNA was extracted using the salting-out extraction technique, followed by the amplification and genotyping of IFN-γ gene polymorphisms,through the conventional PCR. Statistical analyses were performed using the SPSS and Epi info software. A total of 168 participants were included in the study, with an average age of 38.58 ±14.88, the majority of whom were men (76.19%). In our study population, 73.2% (123/168) were confirmed positive for tuberculosis. Some 46.4% (78/168) of the previous cases were contacts. Of these contact cases, 82.05% (64/78) were GeneXpert positive. The genotypic frequencies of the IFN-γ gene were distributed as follows: 73.3% (AA), 21.8% (AT) and 4.9% (TT), with a frequency of 84.2% for the A allele versus 15.8% for the mutated T allele. No statistically significant association was found between IFN-γ gene polymorphisms and M. tuberculosis infection in Burkina Faso. IFN-γ gene polymorphisms (IFN +874T/A) do not appear to be associated with M. tuberculosis infection in Burkina Faso. © 2025 Cellular and Molecular Biology Association. All rights reserved.

关键词： Chlorpheniramine maleate   Keloid fibroblasts   IL-6   JAK1/STAT3  

摘要： Keloids are abnormal scars formed due to fibroblast dysfunction and excessively deposited extracellular matrix (ECM). Despite the unclear process leading to the occurrence of keloids, several studies have demonstrated that histamine and its H1 receptor can effectively regulate fibroblast functions, contributing to keloid formation. Chlorpheniramine maleate (CPM) as a first-generation H1 antihistamine has been widely applied in symptomatic treatment of allergic conditions but its effects on keloids are unknown. This study holds the objective of exploring its effect on keloids. Cell Counting Kit-8 (CCK-8), apoptosis, cell cycle and migration assays were conducted to determine the effects of CPM on human keloid fibroblasts (KFs), with its therapeutic effect evaluated by constructing a keloid model in nude mice. RNA sequencing analysis, ELISA, western blotting and immunohistochemistry assisted in examining the anti-keloid mechanism of CPM. It was observed that CPM inhibited the proliferation and migration of KFs, promoted apoptosis of KFs, and blocked the G0/G1 phase of KFs. Moreover, local intralesional injection of CPM into nude mice keloid model significantly reduced keloid scars. According to RNA sequencing analysis, the gene expression of IL-6 and JAK-STAT signaling pathway were both negatively related in CPM group versus the control group. According to the in vivo and vitro experiment results, the antikeloid activity of CPM was attributed to its inhibitory effect on the IL-6/JAK1/STAT3 signal pathway. In summary, CPM holds great potential for localized treatment of keloids.

关键词： METTL3   RAC2   Rheumatoid arthritis   M6A methylation modification  

摘要： BackgroundRheumatoid arthritis (RA) is a widely prevalent rheumatic condition causing joint inflammation and damage. RNA methylation plays an important role in RA. Herein, we intended to investigate the function of methyltransferase-like 3 (METTL3) and its N6-methyladenosine (m6A) methylation regulation for ras-related C3 botulinum toxin substrate 2 (RAC2) in ***7A cells were treated with TNF-alpha to establish RA cell model. The expression analysis was performed by RT-qPCR and western blot. Cellular behaviors were examined by CCK-8 assay, flow cytometry, wound healing assay and transwell assay. Oxidative stress was assessed by detecting the associated indicators. Inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA). Interaction between METTL3 and RAC2 was analyzed via RNA immunoprecipitation (RIP) assay and MeRIP ***2 was highly expressed in RA tissues and TNF-alpha-stimulated MH7A cells. Knockdown of RAC2 enhanced apoptosis and reduced proliferation, migration, invasion after TNF-alpha treatment. RAC2 downregulation suppressed oxidative stress and inflammatory response in TNF-alpha-treated MH7A cells. METTL3 promoted RAC2 expression through m6A methylated modification, and METTL3/RAC2 could activate AKT pathway. RAC2 overexpression reversed the effects of METTL3 knockdown on cell proliferation, motility, oxidative stress and *** above results demonstrated that METTL3 facilitated the progression of RA via downregulating RAC2 in an m6A dependent mechanism in TNF-alpha-treated MH7A cells.

摘要： Computational HLA typing has surged as a cost-effective strategy to uncover questions regarding the evolution of the HLA system, enabling immunogenic characterization from ancient DNA (aDNA) data. Nevertheless, it remains to be seen whether these methods are suitable for analyzing aDNA generated without target-enrichment. To investigate this, we evaluated the performance of five HLA typing tools using present-day data with simulated profiles typical of aDNA, as well as from high-coverage aDNA genomes downsampled at different read depths. We found that characterization of Class I genes at the first field resolution is feasible at read depths as low as 2x, where it retains an accuracy of approximate to 80%. Next, we used this insight to characterize HLA evolution in Europe from 154 ancient genomes by detecting allele frequency changes throughout distinct prehistoric European populations. We observed important shifts in alleles associated with infectious and autoimmune diseases, most of which are found by contrasting the HLA landscape of Neolithic Farmers to that of present-day. Interestingly, several of these observations are in line with findings that have been previously reported by target-enrichment-based studies. Our results highlight the feasibility of applying HLA typing on shotgun aDNA data to examine the evolution of this loci during important transitions.

关键词： Allergic rhinitis   type 2 Inflammatory Responses   IL-24   AP-1   Epithelial barrier  

摘要： The epithelial barrier, previously regarded only as a physical defense, is now understood to play a vital role in immune responses and the regulation of inflammation. Allergic rhinitis (AR) is a prevalent chronic inflammatory condition of the nasal mucosa, with House Dust Mite (HDM) identified as a significant inhalant allergen that can impair this barrier. IL-24 has emerged as a key cytokine in allergic diseases, involved in maintaining epithelial cell homeostasis. Nevertheless, the underlying mechanisms of these effects remain inadequately understood. This study explores HDM-induced IL-24 secretion and mucosal barrier impairment using patient and animal tissue samples. Our results confirm that HDM sensitization triggers inflammatory changes in the nasal cavity, with IL24 acting as a key mediator of type 2 inflammation and AR severity. HDM enhances IL-24 secretion via the P38 MAPK pathway and transcription factor AP-1, while IL-24 downregulates occludin and ZO-1 expression through the STAT1/STAT3 signaling pathway, compromising barrier function and increasing permeability. Furthermore, IL-24 promotes IL-33 secretion, further exacerbating the inflammatory response in AR. These findings clarify the mechanisms of epithelial barrier disruption in HDM-sensitized allergic rhinitis and suggest that modulating the IL-24 signaling pathway may serve as a promising therapeutic strategy to restore barrier integrity in AR.