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关键词： Allergen immunotherapy   allergic   PLGA   mites   rhinitis  

摘要： Subcutaneous immunotherapy has several limitations, including the long dose escalation period, frequent injections and risk of adverse reactions. Crude extracts used for immunotherapy can contain unrecognized immunostimulatory components or induce neosensitization. Therefore, in this study, we aimed to develop a new efficient method to induce allergen-specific immune tolerance using Dermatophagoides pteronyssinus (Der p) 1-containing nanoparticles. We developed two different types of allergen-containing poly(lactic-co-glycolic) [PLGA] nanoparticle vaccines: Der p 1-encapsulated and Der p 1-conjugated vaccines. House dust mite (HDM)-sensitized mice were administered positive control (PC), PLGA (vehicle control), encapsulated vaccine (EV), and conjugated vaccine (CV) via intravenous injections one week after sensitization. Subcutaneous immunotherapy group received three subcutaneous HDM extract injections at two-day intervals. After challenge, we compared the rhinitis symptoms, immunoglobulin (Ig) levels, and histopathology of the nasal mucosa and analyzed splenocyte cultures for cytokine production and regulatory T cell activation. EV and CV groups exhibited improved nasal symptoms and lower ear swelling and inflammation in the nasopharyngeal lavage and nasal tissues than PC group. Serum HDM-specific IgG1 levels were higher in EV and CV groups than in PC group. No changes were observed in the total and HDM-specific IgE levels in EV group. EV group exhibited lower interleukin-4, -5, -13, and -17 levels and higher interleukin-10 and interferon-gamma levels than PC group. The two vaccinated groups exhibited significantly higher regulatory T cell activation than PC group. Overall, intravenously administered Der p 1-containing nanoparticles alleviated the allergic responses and induced tolerance in a murine allergic rhinitis model.

关键词： Xijiaqi Formula   chronic heart failure   myocardial fibrosis   extracellular matrix remodeling   TGF-beta 1  

摘要： ContextChronic heart failure (CHF) is the common concern following myocardial infarction. Xijiaqi Formula (XJQ) effectively treats CHF clinically while the underlying mechanism remains *** study was designed to investigate the effect and mechanism of XJQ on CHF in rats following *** and methodsUHPLC-Q-TOF-MS/MS was utilized to analyze the constituents of XJQ. Post-MI CHF was induced in rats by permanent ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiogram and hemodynamic. Myocardial morphology, fibrosis, and ultrastructure were evaluated through HE staining, Masson staining, and transmission electron microscopy, respectively. Myocardial transcriptomics were employed to identify genes that may be altered in response to XJQ treatment. Consistently, XJQ inhibited TGF-beta 1-induced myofibroblast activation in *** significantly improved cardiac function and structure, mitigating fibrosis, edema, and mitochondrial damage, while reducing key biomarkers (BNP, NT-proBNP, cTnT, Ang II). Transcriptomic analysis indicated that the differentially expressed genes influenced by XJQ were predominantly associated with extracellular matrix (ECM) remodeling. Notably, XJQ inhibited the upregulation of ECM proteins, including Adamts2, Fbln1, Itgbl1, and Ltbp3 mRNAs, as well as the proteins TGF-beta 1, P-Smad2/3, and MMP2. Additionally, in vitro experiments revealed that XJQ significantly suppressed the activation of myofibroblasts induced by TGF-beta *** significantly attenuated the progression from MI to CHF by inhibiting fibroblast activation mediated by TGF-beta 1/Smads signaling. The molecular mechanisms underlying this effect appear to be intricately linked to its regulation of ECM remodeling proteins, specifically Adamts2, Itgbl1, Fbln1, and Ltbp3.

关键词： Diabetes   islet   non-coding RNA   apoptosis   extracellular vesicles  

摘要： Small non-coding RNAs, such as microRNAs and tRNA-derived fragments, are key regulators of cellular processes, but the functions of small intronic RNAs (sinRNAs), a recently identified RNA class, remain largely unknown. Here, we report that two sinRNAs, sinR-D and sinR-T, are upregulated in pancreatic beta-cells of NOD mice, a well-established model of type 1 diabetes. Using in vivo RNA-tagging, we demonstrate that these sinRNAs are packaged into extracellular vesicles released by infiltrating CD4+ T lymphocytes and subsequently delivered to beta-cells during the early stages of autoimmune attack. Functional analyses revealed that overexpression of sinR-T has little effect on beta-cell viability, whereas sinR-D markedly increases beta-cell apoptosis. This finding suggests that the transfer of sinR-D contributes to beta-cell destruction and the onset of type 1 diabetes. Furthermore, pull-down experiments with biotinylated sinRNAs identified Ago2, a core component of the RNA-induced silencing complex (RISC), as a binding partner of sinR-D, indicating mechanistic parallels with microRNA-mediated regulation. Collectively, our data uncover a novel role for sinRNAs as extracellularly transferred regulators of beta-cell fate, expanding the repertoire of small RNAs implicated in the initiation of type 1 diabetes.

关键词： Fowl adenovirus   whole genome   coinfection   pathogenicity   differential transcriptomics  

摘要： Fowl adenoviruses (FAdVs) are widely distributed in poultry populations around the world, and many diseases are associated with FAdV infection in chickens. This study documented the first characterization of coinfection with fowl adenovirus serotypes 1 and 4 (FAdV-1 and -4) associated with hydropericardium hepatitis syndrome (HHS) in Chinese layer flocks, revealing a novel viral cooperation mechanism. Two novel strains (CH/SX/201805-1 and -4) were identified and isolated, with whole-genome sequencing showing CH/SX/201805-1 clustering with FAdV-1 (99.7% identity to FAdV-A-61/11z), whereas CH/SX/201805-4 displayed characteristic ORF19/27/29 deletions mirroring emergent Chinese FAdV-4 variants. Experimental coinfection in SPF chickens resulted in 87.5% mortality, which was 16.7% greater than that resulting from infection alone, with exacerbated pathology. In vitro coinfection experiments demonstrated concurrent viral replication within same LMH cells, a previously unreported phenomenon, where FAdV-1 increased FAdV-4 replication efficiency 21-fold (p < 0.001). Transcriptomic profiling revealed heat shock protein A2 (HSPA2) as the most differentially expressed gene, which was upregulated 2.8-fold during coinfection compared with infection with FAdV-4 alone. Functional validation through HSPA2 knockdown reduced FAdV-4 replication, establishing that FAdV-1 potentiates FAdV-4 through HSPA2-mediated host modulation. These findings provide the first evidence of HSPA2-dependent interserotype synergy in FAdV and can be used to develop a cellular model for FAdV coinfection studies. These insights redefine the understanding of FAdV pathogenesis and create new avenues for targeted intervention strategies against emerging FAdV coinfections.

关键词： Benign prostatic hyperplasia   alpha-1 blockers   5 alpha-reductase inhibitors   PDE5 inhibitors   FDA adverse event reporting system  

摘要： ObjectiveTo compare the real-world safety profiles of alpha 1-adrenoceptor antagonists (alpha 1-blockers), 5 alpha-reductase inhibitors (5ARIs), and phosphodiesterase type 5 inhibitor (PDE5I) used in the treatment of benign prostatic hyperplasia (BPH).MethodsThis retrospective pharmacovigilance study analyzed FDA Adverse Event Reporting System (FAERS) from Q1 of 2004 to Q2 of 2025. Reports of adverse events (AEs) in male BPH patients receiving AUA guideline-recommended drugs including alpha-1 blockers (tamsulosin, silodosin, doxazosin, and alfuzosin), 5ARIs (finasteride and dutasteride), and tadalafil were extracted. Disproportionality analysis was performed to detect significant safety signals. AEs were classified using MedDRA *** 9,540 unique reports and 25,796 AEs entries, patients aged 65-80 years accounted for the majority of the reports. Most AEs occurred within 30 days of treatment initiation. Hospitalization was the most common serious outcome. Sixteen significant AEs were detected, including pollakiuria, gynecomastia, breast pain and so on, with distinct reporting patterns across drug *** large-scale pharmacovigilance analysis identified distinct post-marketing safety signals among guideline-recommended pharmacotherapies for BPH, confirming known risks and suggesting potential novel adverse-event signals warranting further investigation.

关键词： Hypertension   circadian blood pressure   dipper hypertension   non-dipper hypertension   endothelin-1   endothelin-2   endothelial dysfunction  

摘要： Objective: The aim of this study was to evaluate serum endothelin-1 (ET-1) and endothelin-2 (ET-2) levels in patients with dipper and non-dipper hypertension compared to normotensive controls and to investigate the potential diagnostic value of these biomarkers in distinguishing circadian blood pressure phenotypes. Methods: This prospective case-control study included 163 participants classified into three groups based on 24-hour ambulatory blood pressure monitoring (ABPM): normotensive controls (n = 60), dipper hypertensive (n = 61), and non-dipper hypertensive (n = 42) patients. Dipper status was defined as a 10% nocturnal reduction in both systolic and diastolic blood pressure. Individuals with diabetes, established cardiovascular disease, or secondary hypertension were excluded. Serum endothelin-1 (ET-1) ET-1 and endothelin-2 (ET-2) ET-2 levels were analyzed using double-antibody sandwich ELISA kits. Results: ET-1 levels were significantly lower in dipper hypertensive patients (p < 0.001) compared to other groups. Conversely, ET-2 levels did not significantly differ between hypertensive phenotypes. ET-1 proved to be a strong diagnostic marker for distinguishing non-dipper hypertension (AUC = 0.830, sensitivity 83.3%, specificity 75.4%). While advanced age independently predicted the non-dipper pattern (OR = 1.101, p = 0.002), BMI and D-dimer were associated with the dipper phenotype. Conclusion: This study identifies serum endothelin-1 is a strong, independent marker of the non-dipper hypertensive phenotype, which is associated with increased cardiovascular risk. The preservation of low endothelin-1 levels in dipper hypertension patients reflects intact endothelial and circadian regulation, whereas the absence of this response in non-dipper patients indicates impaired vascular adaptation. The inverse association of endothelin-2 with non-dipper status further suggests a protective buffering role that may be attenuated by increasing metabolic burden.

关键词： Self-management   diabetes education   youth health   health services accessibility   scoping review methodology  

摘要： This scoping review aims to systematically explore the extent, nature, and gaps in the existing literature on self-care practices among adolescents and young adults aged 10-24 years living with type 1 diabetes mellitus (T1D) in Sub-Saharan Africa. The review will examine self-care knowledge, attitudes, practices, perceived barriers and facilitators, and interventions developed to support self-care. Type 1 diabetes mellitus accounts for approximately 5-10% of all diabetes cases globally and disproportionately affects children and young people in low- and middle-income countries. Adolescence and young adulthood are critical developmental periods during which self-care behaviours are established and may influence long-term health outcomes. In Sub-Saharan Africa, adolescents and young adults with T1D face challenges including limited healthcare infrastructure, inadequate disease awareness, restricted access to insulin and diabetes supplies, and high out-of-pocket costs. This scoping review will include quantitative and qualitative studies, systematic reviews, and grey literature published in English from January 2004 onwards. The review will follow the Joanna Briggs Institute methodology for scoping reviews. A three-step search strategy will be applied across PubMed, MEDLINE, Web of Science, CINAHL, and Embase. Two independent reviewers will screen titles, abstracts, and full texts. Data will be extracted using a structured tool and synthesised using narrative, tabular, graphical, and thematic approaches.

关键词： mRNA vaccine   influenza   adverse events   hemagglutination inhibition titers   cell-mediated immunity  

摘要： This first-in-human, randomized, controlled, phase 1 proof-of-principle study evaluated the safety, reactogenicity, and immunogenicity of an investigational mRNA-based monovalent influenza vaccine encoding influenza A/H1N1 hemagglutinin (FLUmHA). Younger adults (YA) aged 18-45 y received one dose of FLUmHA at one of 10 dose levels (0.5-100 & micro;g, n = 24/25 per group) or licensed Flu Dresden-quadrivalent seasonal influenza vaccine (Flu D-QIV, n = 35) on day (D)1. Older adults (OA) aged 60-80 y received FLUmHA (18 & micro;g, n = 32) or Flu D-QIV (n = 16). Reporting rates for solicited adverse events (AEs) occurring within 7 d post-vaccination generally increased with increasing FLUmHA dose levels, and were 62.5%-100% (severe: 0.0%-20.8%) in YA across FLUmHA dose levels versus 88.6% (severe: 2.9%) in Flu D-QIV-vaccinated YA, and 62.5% (severe: 0.0%) (FLUmHA) versus 56.3% (severe: 0.0%) (Flu D-QIV) in OA. Unsolicited AEs within 28 d post-vaccination were reported by 50.0%-70.8% of YA across FLUmHA dose levels versus 68.6% of Flu D-QIV-vaccinated YA, and by 43.8% (FLUmHA) versus 50.0% (Flu D-QIV) of OA. No safety concerns were identified. A/H1N1 hemagglutination inhibition titers increased from pre-vaccination to D22, with adjusted geometric mean increases (GMIs) of 6.2-36.7 across YA and OA groups;the observed response was dose-dependent and higher in FLUmHA (for doses > 1 & micro;g) versus Flu D-QIV recipients. Titers decreased but remained above pre-vaccination levels at D183 (GMI: 2.9-14.0). Additionally, FLUmHA elicited a numerically higher hemagglutinin-specific CD4+ T-cell response (predominantly Th1 profile) than Flu D-QIV, both in YA and OA. These results support the progression to clinical development of a multivalent mRNA Flu vaccine candidate.

关键词： Gout   macrophage polarization   CA72-4   Siglec-15   TIGIT/SHP-1 signaling  

摘要： Excessive M1 polarization of macrophages is a key driver of inflammatory processes in gout, while the regulatory mechanisms involved remain unclear. Herein, the role of carbohydrate antigen 72-4 (CA72-4), derived from human synovial cells (HFLS), in regulating macrophage M1 polarization during gout progression was investigated. PMA was used to induce differentiation of THP-1 cells into macrophages, and the macrophages were then treated with a conventional medium (CM), the CM was from Non-treated HFLS (NCM), or the CM from MSU-treated HFLS (MCM), and then incubated with MSU treatment for 24 h. Cell viability was assessed by CCK-8 assay. IL-1 beta, TGF-beta 1, and CA72-4 levels in the supernatant of macrophages were detected by ELISA. The interaction between CA72-4 and sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was analyzed by Co-IP assay. MSU-induced HFLS to secrete CA72-4, and CA72-4 derived from HFLS inhibited MSU-induced macrophage M1 polarization. Mechanistically, CA72-4 activated the TIGIT/SHP-1 signaling in macrophages by binding to Siglec-15 on macrophages. As expected, Siglec-15 knockdown weakened the activation effect of MCM on TIGIT/SHP-1 signaling and the inhibitory effect on macrophage M1 polarization. MSU stimulated HFLS to secrete CA72-4, and CA72-4 derived from HFLS suppressed MSU-induced macrophage M1 polarization by activating TIGIT/SHP-1 signaling through targeting Siglec-15.