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关键词： APG777   pharmacokinetics   IL-13   anti-IL-13 mAb   biologic therapy   human mAbs   atopic dermatitis   type 2 diseases   lebrikizumab   YTE   half-life extension   interleukin-13   type-2 inflammation  

摘要： Background: IL-13 plays a key role in the induction and perpetuation of type 2 immune responses associated with the development of atopic dermatitis and other chronic inflammatory diseases. mAbs targeting IL-13 have demonstrated efficacy in IL-13-driven diseases;however, current therapeutics require dosing every 2 to 4 weeks, resulting in significant injection burden for patients. APG777 is a humanized, IgG1 IL-13-targeting mAb that has been engineered to have an optimized pharmacokinetic profile, allowing for less frequent dosing. Objective: We sought to investigate the in vitro potency and in vivo pharmacokinetics of APG777. Methods: The affinity of APG777 was characterized using surface plasmon resonance;the half-maximal inhibitory concentration (IC50) of APG777 was determined in various in vitro assays measuring inhibition of IL-13 signaling via signal transducer and activator of transcription 6 phosphorylation and chemokine release in relevant cell lines. Pharmacokinetics of APG777 were evaluated in nonhuman primates following a single intravenous or subcutaneous infusion. All studies included lebrikizumab produced based on the publicly available sequence as key comparator. Results: APG777 demonstrated a similar in vitro potency across numerous assays compared with lebrikizumab and a 2-fold longer serum half-life following subcutaneous injection in nonhuman primates. Conclusions: These data provide evidence in support of the clinical potential of APG777 in diseases where IL-13 signaling is a main driver of the inflammatory response. The prolonged halflife of APG777 may enable less frequent dosing compared with current treatments, which could reduce injection burden and increase compliance. APG777 is currently being investigated in a phase 2 randomized, controlled trial in patients with atopic dermatitis. (J Allergy Clin Immunol Global 2025;4:100545.)

关键词： Terahertz waves   Metasurface   Immunosensing   Single-stranded DNA aptamer   TNF-alpha  

摘要： In this study, we present a terahertz metasurface biosensor modified with single-stranded DNA aptamers for the specific detection of tumor necrosis factor-alpha (TNF-alpha). We employed micro-nano fabrication techniques to construct the biosensor, which was subsequently characterized using terahertz frequency-domain spectroscopy. The system demonstrated a theoretical sensitivity reaching 124.71 GHz/RIU. To achieve specific detection of TNF-alpha, the sensor surface was functionalized with a nucleic acid aptamer. The experimental results show that the frequency shift of the resonance peak is linearly correlated with the concentration of tumor necrosis factor-alpha. The method achieves a detection limit of 0.1 ng/ml and a sensitivity of 13.9 GHz/lg(ng/ml). Most notably, the sensor exhibits greater sensitivity to TNF-alpha compared to ovalbumin and whey protein, confirming its highly specific detection capabilities. This study presents a novel approach for the real-time, efficient, and label-free detection of TNF-alpha, offering significant implications for the diagnosis of cancer and other associated diseases.

关键词： Cytokine   Cytomegalovirus   C -X-C chemokine receptor type 4   Immunology   Interleukin-10 (IL-10)   Macrophage Inhibitory Factor (MIF)   Trefoil factor 2 protein (TFF2)   Receptor crosstalk   Ubiquitin   Virus  

摘要： Human cytomegalovirus (HCMV) is a widespread beta-herpesvirus that establishes lifelong latent infection in host cells. The HCMV UL111A gene encodes cmvIL-10, a viral homolog of the anti-inflammatory cytokine IL-10 (hIL-10). Like hIL-10, cmvIL-10 binds to the human cellular IL-10 receptor (IL-10R) and activates the JAK/STAT3 pathway, promoting transcription of immunosuppressive genes. Notably, cmvIL-10 binds to the IL-10R with higher affinity than hIL-10 and retains most of its functions, including enhancing CXCR4 signaling triggered by its primary ligand, CXCL12. The CXL12/CXCR4 axis regulates key cellular processes such as gene expression, cell migration, proliferation, and apoptosis. CXCR4 also interacts with alternative ligands including macrophage inhibitory factor (MIF), trefoil factor 2 protein (TFF2), and extracellular ubiquitin (UB). Here, we show that cmvIL-10 enhances CXCR4-mediated cell proliferation and migration induced by MIF and TFF2 but not by UB. We also found that hIL-10 enhances MIF-mediated cell proliferation yet has no effect on TFF2-mediated cell proliferation. The CXCR4 antagonist AMD3100 effectively blocks cell migration driven by TFF2, while only partially inhibiting MIF-mediated cell migration. These results suggest that cmvIL-10 promotes crosstalk between IL-10R and CXCR4, underscoring its role in modulating immune responses during HCMV infection. Our findings provide insight into how cmvIL-10 contributes to immune evasion and pathogenesis in HCMV.

关键词： Nervous necrosis virus   Oral immunization   IFN-gamma   DNA vaccine   Immune effect  

摘要： Viral nervous necrosis (VNN), caused by nervous necrosis virus (NNV), poses a major threat to global aquaculture, causing severe mortality and economic losses in high-value species like grouper. Oral vaccination offers a practical approach for large-scale prevention but faces challenges including gastrointestinal antigen degradation and inadequate mucosal immunity. To overcome these, we developed an oral DNA vaccine by encapsulating a plasmid encoding the NNV capsid protein (CP) and IFN-gamma within PLGA microparticles (CPIF@PLGA). Synthesized via double emulsion-solvent evaporation, these spherical microparticles (ca. 8 mu m in diameter) exhibited high encapsulation efficiency (84.3 %). In vivo immunization of grouper demonstrated that CPIF@PLGA significantly increased survival to 82.2 % post-NNV challenge versus controls, reduced viral loads in brain and eyes, and enhanced systemic and mucosal immunity. This was evidenced by elevated serum IgM, IgT, lysozyme, SOD, and complement activity, alongside upregulated expression of immune-related genes (IL-1 beta, TNF-alpha, CD4, CD8 alpha, MHCI alpha, IgM) in spleen and hindgut. Our findings establish PLGA microparticles as an effective oral delivery platform and IFN-gamma as a potent adjuvant, eliciting robust and durable protection. This study provides a promising strategy for developing effective and scalable oral vaccines against NNV in aquaculture.

关键词： IL-33   Ror2   Wnt/beta-catenin   Organoid   Intrauterine adhesion   Endometrial injury  

摘要： Background: Intrauterine adhesions (IUA) are a major cause of secondary infertility, yet existing treatments have limited efficacy. This study explores the potential of targeting Ror2, a key mediator in the IL-33/Wnt/(3-catenin signaling pathway for IUA treatment. Methods: First, we established an IL-33-induced intrauterine adhesion (IUA) mouse endometrial organoid (EMOs) model. Using parallel reaction monitoring (PRM) technology, we identified Ror2 as the target protein linking IL-33 to the Wnt/(3-catenin signaling pathway in mouse uterine tissue. Subsequently, we constructed lentiviral vectors for Ror2 knockdown (Lv-shRor2) and overexpression (Lv-Ror2) to evaluate the role of Ror2 in endometrial fibrosis and stem cell proliferation. Finally, we assessed murine fertility via in situ injection of Ror2-overexpressing adenoviral particles (Ad-Ror2) into the uterine cavity. Results: The results showed that IL-33 at 100 ng/ml for 24 h had the strongest effect on the model. Lv-shRor2 promoted endometrial fibrosis by activating the Wnt/(3-catenin pathway, while Lv-Ror2 inhibited this pathway, enhancing endometrial stem cell proliferation and improving fertility in IUA mice. Conclusions: These findings suggest that Ror2 could be a promising target for regulating the Wnt/(3-catenin pathway in IUA treatment.

关键词： systemic inflammation   cognition   inflammaging  

摘要： Objectives Elevated peripheral inflammatory markers among older adults are associated with cognitive decline, particularly for women, for whom cognitive decline is more prevalent and rapid. Few prospective studies have examined gender-specific associations between inflammation and cognitive decline or examined stable, mean differences (i.e., between-person effects) versus fluctuations (i.e., within-person effects) in *** Participants (N = 235) were older adults (Mage= 75.1, range = 60-92) from a longitudinal study that included neuropsychological assessments and blood draws every six months for up to 12 years. Systemic inflammation was operationalized as serum interleukin-6 (IL-6). The Trail Making Test measured psychomotor processing speed (TMT-A), task-switching (TMT-B), and executive functioning (TMT-B-TMT-A). Multilevel models tested associations between cognition and inflammation and moderation by gender. Models controlled for relevant covariates (e.g., age, gender, education, body mass index, cardiovascular medication count).Results Higher mean IL-6 was associated with slower TMT-A performance for women (gamma = .036, p = .04) but not men (gamma = -.01, p = .45). Higher mean IL-6 was associated with slower TMT-B performance (gamma = .036, p = .02), but not after covariate adjustment (gamma = .016, p = .28) and there was no significant moderation by gender. There were no significant associations between within-person IL-6 and any outcome, between- or within-person IL-6 and TMT B-A performance, or any 3-way interactions between gender, IL-6, and study wave on any *** Psychomotor speed, but not executive function, was sensitive to changes in systemic inflammation in a gender-specific way. Gender-specific differences in neurological aging remain a fruitful direction and critical target for future intervention research aimed at addressing preclinical Alzheimer's disease and accelerated aging.

关键词： Osteoarthritis   IL-6 trans-signaling   sgp130Fc   Chondrocytes   Lipid metabolism   Inflammation  

摘要： Background: Interleukin-6 (IL-6) trans-signaling plays a pivotal role in the pathogenesis and progression of osteoarthritis (OA), contributing to chronic intra-articular inflammation and cartilage degradation. Soluble gp130-Fc (sgp130Fc) is a selective inhibitor of IL-6 trans-signaling that spares classical signaling. This study aimed to elucidate the role of IL-6 trans-signaling in knee OA and evaluate the therapeutic potential of sgp130Fc. Methods: Synovial fluid from OA patients at different disease stages was analyzed for IL-6, soluble IL-6 receptor (sIL-6R), and sgp130 levels by ELISA. Primary rat chondrocytes were treated with Hyper-IL-6 to activate IL-6 trans-signaling and co-treated with sgp130Fc to assess cell viability, gene expression, and lipid metabolism alterations. A rat OA model was established via the Hulth method, followed by intra-articular administration of sgp130Fc. Histological, immunohistochemical, and lipidomic analyses were performed to evaluate cartilage integrity and inflammatory responses. Results: Levels of IL-6, sIL-6R, and sgp130 in synovial fluid increased with OA progression. Hyper-IL-6 impaired chondrocyte viability, activated JAK1-STAT3 signaling, promoted inflammatory and catabolic gene expression, and disrupted lipid metabolism, all of which were reversed by sgp130Fc treatment. In vivo, sgp130Fc injections alleviated cartilage degradation, reduced synovitis, suppressed inflammatory mediators, and restored lipid homeostasis. Conclusions: Targeted inhibition of IL-6 trans-signaling with sgp130Fc effectively mitigates cartilage degeneration and inflammation in OA, highlighting its potential as a novel disease-modifying therapeutic strategy for knee osteoarthritis.

关键词： Neuroimmunology   Pediatric Demyelinating Disease   Early Stage Investigator  

关键词： anti-IL monoclonal antibodies   biological therapy   psoriasis   safety   skin cancer  

摘要： Our study aimed to investigate the correlation between skin cancer and anti-interleukin (IL) therapy in patients with moderate-to-severe psoriasis. This was an observational monocentric study in which we enrolled a total of 235 patients in which 127 patients were affected by moderate-to-severe psoriasis and treated with anti-IL monoclonal antibodies (mAbs) for at least 6 months, whereas 108 patients affected by mild psoriasis were treated with topical therapies. Afterward, we performed a dermatologic visit to all the subjects, collecting anamnestic information including risk factors for skin cancer. We examined the skin lesions on their entire body by polarized and nonpolarized dermoscopy. A total of 21 suspicious lesions in the first group and 17 in the second one were removed and histologically analyzed. Twelve (9.4%) cancerous or precancerous lesions were found in the first group: seven (5.5%) basal cell carcinoma (BCC) and five actinic keratosis. The mean time to cancer onset was identified as 22 months after the start of four therapy, with an SD of 18 months, suggesting an earlier onset with respect to the start of therapy in our population. On univariate analysis, age (P = 0.001) and age of psoriasis onset (0.009) were statistically significant. Nine of 17 were skin cancers in the second group. Our study provided real-life evidence of the percentage of patients with skin cancers during therapy with anti-IL mAbs, demonstrating a good safety profile of the investigated drugs.

关键词： Bruceine A   Ulcerative colitis   Barrier integrity   Macrophages   HSP90   IL-17/NF-kappa B pathway  

摘要： Background: Bruceine A (BA), a natural quassinoid compound derived from the fruit of Brucea javanica, has demonstrated diverse pharmacological activities. However, the treatment effectiveness of BA against ulcerative colitis (UC) and its underlying mechanisms of action are yet to be fully elucidated. Purpose: To explore the effects of BA against UC and uncover its underlying mechanisms, with a particular focus on its influence on inhibiting macrophage M1 polarization via the IL-17/NF-kappa B pathway. Methods: A murine UC model was constructed using 3 % dextran sulfate sodium (DSS) and treated with BA. Colon length, histopathological damage, inflammatory mediators, and epithelial barrier integrity were assessed to evaluate BA's therapeutic efficacy. In vitro, cell viability and macrophage polarization biomarkers (e.g., iNOS and TNF-alpha) were quantified to evaluate the cytoprotective effects of BA. The potential mechanisms of BA in combating UC were investigated using network pharmacology, with direct targets validated through biophysical approaches. Furthermore, western blot analysis was employed to confirm BA's regulatory effect on the protein expression of the IL-17/NF-kappa B pathway in both UC mice and macrophages. Results: BA treatment effectively restored colon length, attenuated histopathological inflammation, and repaired epithelial barrier via upregulating tight junction proteins (e.g., ZO-1 and Occludin) in UC mice. Although BA failed to enhance cell viability in DSS-injured IEC-6 cells, it potently inhibited M1 macrophage polarization in THP-1 cells, as evidenced by downregulated iNOS and TNF-alpha. Mechanistically, BA bound to heat shock protein 90 (HSP90), leading to a significant reduction in the expression of IL-17/NF-kappa B pathway-related proteins, thereby suppressing the IL-17 pathway and the NF-kappa B cascade activation. Notably, overexpression of HSP90 abrogated BA's inhibition of the IL-17/NF-kappa B pathway and M1 macrophage polarization. Co