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关键词： TNF-alpha   fibroblasts   PMM2-CDG   inflammation   transcriptomics   glycomics  

摘要： Introduction Glycosylation is a post-translational modification that plays a crucial role in immune system activity. Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disease affecting glycosylation with a multi-systemic impact. PMM2-CDG patients commonly show immune disfunction and elevated pro-inflammatory cytokine levels that may link to other symptoms. However, the underlying immune mechanisms remain unclear. Given Tumour Necrosis Factor (TNF)'s key role in inflammation, this study proposes that defective glycosylation of its receptors disrupts intracellular signalling, leading to changes in the immune response of PMM2-CDG *** To address this, we applied an integrative approach, combining transcriptomics, glycomics, and immune-related assays to investigate the impact of TNF-a stimulation via TNF receptor 1 (TNFR1) in a cohort of PMM2-CDG patients' skin *** Our results reveal a multifaceted disruption of TNF-a signalling in PMM2-CDG fibroblasts. We observed structural abnormalities in TNFR1, including altered receptor shedding. PMM2-CDG cells also showed an altered N-glycosylation profile, affecting particularly, high mannose N-glycans. At transcriptional level, PMM2-CDG cells, especially those bearing the R141H heterozygous variant, exhibited a distinct gene expression profile, after stimulation, characterized by dysregulation of immune and signalling pathways. Functionally, these molecular alterations translated into a diminished secretion of key inflammation and infection mediators, such as interleukin-6 (IL-6) and C-C Motif chemokine ligand 5 (CCL5) upon TNF-a stimulation. Similarly, essential signalling kinases including extracellular-signal-regulated kinase (ERK) 1/2, p38 and c-Jun N- terminal kinase (JNK) 2 showed reduced expression in PMM2-CDG cells, and their expression did not alter following TNF-a stimulation, unlike control *** Our findings point to TNFR1 signalling dysregu

关键词： Cognitive function   Flexi-bar exercise   BDNF   TNF-alpha   mircoRNAs  

摘要： PurposeAppropriate physical exercise could prevent, delay, or reverse cognitive decline in aging people, which could improve their quality of life. However, the underlying mechanisms are still elusive. The present study aimed to explore the effects of 8-week Flexi-bar vibration exercise (FE) on the cognitive function in middle-aged and elderly women and uncover the underlying *** middle-aged and elderly women were randomly assigned to the FE group or the control group (n = 15 in each group). Executive function and real-time oxyhemoglobin concentration (oxy-Hb) changes in different cerebral regions were evaluated through the Color-Word Stroop Test and functional near-infrared spectroscopy, respectively. Circulating levels of Brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay. The expression levels of microRNAs were determined using microRNA sequencing and real-time PCR approaches, followed by an integrated bioinformatics/biostatistics *** data showed that 8 weeks of FE had a positive effect on preventing cognitive decline, with improved blood oxygen content in the dorsolateral prefrontal cortex (DLPFC), up-regulated BDNF level, and down-regulated level of TNF-alpha in serum. Besides, our data showed that 14 microRNAs, which are related to the cognitive function, were up/down-regulated in the FE *** study revealed that 8-week FE could regulate the expression levels of microRNAs related to cognitive function, elevate BDNF level, and decrease TNF-alpha level, and thus improve cognitive performance in middle-aged and elderly women.

关键词： IL-9 signaling   Obesity   Inflammasome   Helminths   Inflammation   insulin resistance  

摘要： Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELM alpha+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1 beta and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.

关键词： ischaemic stroke   interleukin-1 beta (IL-1 beta)   interleukin-1 receptor antagonist (IL-1Ra)   inflammation   eicosanoids   neuroinflammation  

摘要： Ischemic stroke is a leading cause of mortality and disability in adults. The inflammatory cascade is driven by various inflammatory molecules, such as interleukin-1 beta (IL-1 beta), and counteracted by its antagonist, interleukin-1 receptor antagonist (IL-1Ra). Eicosanoids are inflammatory derivatives of free fatty acids. Arachidonic acid (AA) derivatives exhibit pro-inflammatory activity, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives, known as specialized pro-resolving mediators, have anti-inflammatory properties. This study aimed to analyze potential associations between eicosanoids and key inflammatory molecules, including IL-1 beta and its antagonist IL-1Ra. In this prospective study, we investigated inflammatory molecules in 73 ischemic stroke patients. We analyzed interactions between IL-1 beta, IL-1Ra, and eicosanoids as follows: resolvin E1, prostaglandin E2, resolvin D1, lipoxin A4 (5S, 6R, 15R), protectin DX, maresin 1, leukotriene B4, 18RS-HEPE, 13S-HODE, 9S-HODE, 15S-HETE, 17 HDHA, 12S-HETE, 5-oxo-ETE, and 5-HETE. In 73 ischemic stroke patients, mean IL-1 beta was 1.31 +/- 1.54 pg/mL and IL-1Ra 810.8 +/- 691.0 pg/mL. Spearman correlations showed positive associations between IL-1 beta and protectin DX (rho = 0.56, p < 0.001), and 17 HDHA (rho = 0.26, p < 0.05) and 5-oxo-ETE (rho = 0.27, p < 0.05). IL-1Ra correlated negatively with protectin DX (rho = -0.58, p < 0.001) and 17 HDHA (rho = -0.29, p < 0.05), and positively with leukotriene B4 (rho = 0.34, p < 0.005). After multivariable adjustment, associations with IL-1 beta lost statistical significance, whereas the inverse relationships between IL-1Ra and protectin DX/17 HDHA remained significant (p < 0.005). Despite the known anti-inflammatory roles of protectin DX and 17 HDHA, and the pro-inflammatory role of leukotriene B4, their activity in the early subacute phase of ischemic stroke appears to be influenced by complex interplays, possibly mediated by IL-1 beta and IL-

摘要： Patients requiring recurrent platelet transfusions are subject to platelet transfusion refractoriness (PTR), a therapeutic failure due to rapid clearance of transfused platelets from the circulation. One major cause of PTR is the presence in the recipient of multiple IgG directed against allogeneic HLA Class-I (HLA-I) molecules expressed by the donor platelets. Strikingly, the presence of anti-HLA-I IgG does not necessarily correlate with PTR, thus questioning the role of the antibody properties themselves. Using blood of HLA-I alloimmunized patients with or without PTR, we identified the subclasses of their anti-HLA-I IgG. We found the distribution of these subclasses to be different according to patients, with IgG1 being predominant in non-PTR patients while IgG1 in combination with IgG2 or IgG3 were detected in PTR patients. To understand the mechanisms associated with PTR, we used human chimeric pan-HLA-I IgG1, IgG2, or IgG3 antibodies and assessed the functional implications of these human IgG subclasses on platelet activation. We showed that each subclass led to platelet aggregation, P-selectin exposure and Annexin V binding. However, we found that the mechanisms of platelet activation differed between subclasses. Specifically, we discovered that pan-HLA-I hIgG2-induced platelet activation was CD32a dependent, while hIgG1- and hIgG3-induced platelet activation relied on complement recruitment. Hence, this study may have direct implications for hierarchizing pathogenic anti-HLA-I alloantibodies in highly polyimmunized patients and be a valuable aid in selecting suitable treatments, particularly by streamlining the search for functionally compatible platelet components.

关键词： DR-18   IL-18   MT: Regular Issue   anti-CTLA-4 antibody   cytokine   immune checkpoint inhibitor   immunotherapy   oncolytic virus   systemic toxicity   tumor microenvironment   vaccinia virus  

摘要： Cytokines are promising for cancer treatment but face challenges like short half-lives, high-dose requirements, and systemic toxicity. Oncolytic viruses provide an ideal platform to overcome these limitations by delivering cytokines directly to tumor sites, enabling high local concentrations within the tumor microenvironment (TME). This study utilized an oncolytic vaccinia virus (oVV) to deliver interleukin-18 (IL-18) and its variants and assessed their antitumor effects across different tumor models. The non-secreted mature IL-18 mutein (nsmDR-18)-expressing oVV demonstrated potent antitumor efficacy with reduced systemic toxicity. It increased the expression of antitumor factors, including IL-2, interferon gamma (IFN-gamma), granzyme B, and perforin, while expanding tumor-reactive CD39+CD103+CD8+ T cells and reducing severely exhausted PD-1+TIM-3+CD8+ T cells, thereby transforming immunologically "cold" tumors into "hot" tumors. However, nsmDR-18-expressing oVV treatment also elevated regulatory T cells (Tregs) and upregulated immune checkpoint molecules (PD-1, PD-L1, and CTLA-4). Combining nsmDR-18-expressing oVV with anti-CTLA-4 antibody significantly improved overall survival and induced systemic, tumor-specific antitumor immunity. These results highlight the potential of nsmDR-18-expressing oVV as a therapeutic strategy, supporting further exploration in clinical trials.

关键词： Psoriasis   Psoriatic arthritis   Therapy   Ultrasonography with high-frequency probes  

摘要： PurposeTo evaluate the effectiveness of IL-17 and IL-23 inhibitors in psoriatic nail and enthesis involvement by ultrasonography with the use of high-frequency probes (HFUS). To correlate the obtained HFUS findings with disease activity of patients with psoriatic arthritis (PsA).Material and MethodsConsecutive early na & iuml;ve patients with PsA underwent HFUS on nails and entheses before and after 24 weeks of treatment with IL-17 or IL-23 inhibitor. The Brown University Nail Enthesis Scale (BUNES), considering morphometry and Power Doppler (PD), and the Madrid Sonography Enthesitis Index (MASEI) score were used to evaluate these features. HFUS findings were correlated with the extension of the disease on skin by Psoriasis Area and Severity Index (PASI) and joints by Disease Activity Index for Psoriatic Arthritis (DAPSA).ResultsTwenty early na & iuml;ve patients with PsA were treated for 24 weeks with an IL-17 or IL-23 inhibitor. A significant reduction of BUNES PD was observed considering the whole cohort of patients receiving these drugs (p = 0.044), whereas, despite a trend, no significant difference was reported comparing BUNES morphometry. The BUNES PD correlated with PASI (r = 0.466, p = 0.030) and with DAPSA (r = 0.444, p = 0.032), whereas BUNES morphometry did not. A significant reduction of MASEI was observed considering the whole assessed cohort of patients treated with these drugs (p = 0.045). The MASEI correlated with both PASI (r = 0.429, p = 0.037) and DAPSA (r = 0.499, p = 0.017).ConclusionsThis proof-of-concept study demonstrated that the assessment by HFUS may provide additional accurate information about the effectiveness of IL-17 and IL-23 inhibitors in psoriatic nail and enthesis involvement.

摘要： Immune checkpoint inhibitors (ICI) have shown impressive performance in treating several types of solid tumors. However, they have been ineffective in glioblastoma (GBM), in part due to the immunosuppressive tumor microenvironment (TME) created by GBM-associated macrophages (GAMs). To uncover MHC-I peptide antigens for targeted immunotherapy, we performed cell type specific immunopeptidome analysis on primary macrophages and GBM tumor cells in a co-culture system to profile MHC-I associated antigen presentation at the tumor-macrophage interface. Co-culturing tumor cells and macrophages induced increased presentation of peptides derived from proteins associated with cytokine signaling pathways on macrophages and from proteins associated with the Rho GTPase pathway on GBM tumor cells. In vivo expression was validated for a cohort of co-culture-induced GAM or GBM associated peptides selected as potential immunotherapy targets, and an mRNA vaccine was developed encoding six peptides from GAMs and GBM tumor cells. Two doses of vaccination generated an antigen specific immune response, significantly delayed GBM tumor growth, and in some cases eradicated tumors. These results demonstrate the translational potential of co-culture induced MHC peptide antigens as therapeutic targets for GBM/GAM targeting vaccines.

关键词： computational biology   gastrointestinal   immunology   inflammation   mechanism-based pharmacokinetics-pharmacodynamics   multiscale modeling  

摘要： Interleukin 6 (IL-6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal-transducing element gp130 through ligation of either the membrane-bound or soluble IL-6 receptor (termed classic and trans-signaling respectively). It has been proposed that selective inhibition of trans-IL-6 signaling could ameliorate the deleterious, pro-inflammatory effects of IL-6, while preserving the homeostatic activity of classic IL-6 signaling. We developed an in silico, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans-IL-6 signaling. In the first stage, we developed a limited-scope model of IL-6 signaling to establish the quantitative properties of classic and trans-signaling pathways on a short timescale following stimulation with IL-6. The model included both a pan-inhibitor of IL-6 classic and trans-signaling and a soluble gp130-Fc that selectively inhibited trans-signaling. In the second stage, we developed a multi-scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL-6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi-scale model, we identified a dose-response relationship between selective inhibition of trans-IL-6 signaling and tissue regeneration. Moreover, selective inhibition of trans-IL-6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL-6 suppression. These findings suggest that global suppression of IL-6 signaling could negatively affect IL-6-induced regeneration activity, whereas this effect is less likely for selective inhibition.

关键词： Energy transfer  

摘要： Hyperthyroidism, a multifaceted endocrine disorder, is strongly associated with specific human leukocyte antigen (HLA) alleles, which also play a critical role in drug-induced complications such as agranulocytosis. Conventional HLA genotyping methods often face limitations in simultaneously achieving high accuracy, rapidity, and operational simplicity. To address these challenges, we developed a multimodal biosensing platform for the highly sensitive detection of alleles. This platform synergistically integrates three modalities. After molecular recognition, Electrochemiluminescence resonance energy transfer (ECL-RET) was employed using nanomaterials to generate ECL signals, Hybridization chain reaction (HCR) was incorporated to produce fluorescence signals, while nanozyme-mediated colorimetric reactions were coupled to generate visual signals. The combination of these strategies ensures exceptional sensitivity, specificity, and assay stability. Furthermore, spatial separation of the recognition and signal generation domains was implemented to minimize matrix interference from complex biological samples, significantly enhancing clinical applicability. This innovative approach establishes a novel paradigm for the precise analysis of HLA alleles, offering transformative potential for clinical diagnostics and advancing the frontiers of biosensing technologies.