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关键词： Endothelial cells   Monocytes   Anthocyanins   Phenolic metabolites   Inflammation  

摘要： PurposeIn this study we investigated how anthocyanins and their metabolites exert protection on the vasculature by reducing the inflammation-induced monocyte adhesion to endothelial cells, a fundamental stage in endothelial dysfunction (ED) and *** umbilical vein endothelial cells (HUVECs) were pre-treated with varying concentrations (1,5 and 10 mu M) of cyanidin-3-glucoside or phenolic metabolites, protocatechuic acid (PCA) and vanillic acid (VA), for 24 h, followed by TNF-alpha stimulation for 24 h, with or without the presence of THP-1 monocytes for 1 *** the co-culture model, the adhesion of fluorescent monocytes attached to HUVECs was quantified, as well as pro-inflammatory cytokine IL-6 and MCP-1 in cell supernatant. Expression levels of transcription factors Nrf2 and NF-kappa B-p65, as well as vascular cell adhesion molecule-1 (VCAM-1), intracellular cell adhesion molecule (ICAM-1) and heme oxygenase 1 (HO-1) were measured in HUVECs. All treatments prevented the adhesion of monocytes to endothelial cells, which was associated with reductions in IL-6 and MCP-1. Additionally, phenolic metabolites suppressed adhesion molecules, potentially by their ability to upregulate Nrf2 expression and suppress NF-kappa B p65 phosphorylation. Furthermore, VA caused an upregulation of HO-1 *** findings suggest that pre-exposed physiologically relevant concentrations of phenolic metabolites may hinder ED and inflammation by reducing the adhesion of monocytes to endothelial cells and the inflammatory response via the modulation of NF-kappa B and Nrf2 pathway.

摘要： Background Rheumatoid arthritis is an inflammatory disease frequently treated with TNF inhibitors. Little is known about predictors of response to TNF inhibitors. Because clinical response in rheumatoid arthritis is measured by composite scores containing subjective patient-orientated domains (eg, pain and global disease perception), we hypothesised that patients with high disease representation in the CNS might respond better to TNF inhibitors than patients with less CNS disease representation. Methods We did a phase 3, multicentre, double-blind, placebo-controlled, parallel-group randomised trial in patients with active rheumatoid arthritis at six rheumatology centres across Germany, Portugal, and Serbia. All patients had a functional MRI (fMRI) brain scan at baseline to measure CNS pain activation. Patients (aged >= 18 years) with active rheumatoid arthritis who have active disease despite the use of at least one conventional synthetic disease-modifying antirheumatic drug were stratified according to fMRI (high volume or low volume) and were randomly assigned 2:1 using a randomisation list generated by a study statistician to treatment with the TNF inhibitor certolizumab pegol (400 mg subcutaneously on weeks 0, 2, and 4, and 200 mg once every 2 weeks for maximum 24 weeks) or placebo. Patients and clinicians were masked to allocation. The primary outcome was the proportion of patients reaching low disease activity (Disease Activity Score in 28 joints <= 32) at week 12, analysed in the intention-to-treat population. There was no lived experience involvement in study design. The study was registered with EudraCT (2013-000337-13) and *** (NCT01864265). Findings Between Sept 3, 2013, and Jan 10, 2020, 148 patients with rheumatoid arthritis were screened and 139 (99 [71%] women and 40 [29%] men) were randomly assigned to the high-volume certolizumab pegol group (n=49), the low-volume certolizumab pegol group (n=43), or the placebo group (n=47

关键词： FCGR2A   Macrophages polarization   IL-4/JAK/STAT6 axis   Single-cell sequencing  

摘要： The most common subtype of primary liver cancer is hepatocellular carcinoma (HCC), which accounts for about 90 % of primary liver cancers. Tumor microenvironment (TME) plays important roles in HCC development. TME coexists and interacts with various immune cells. Macrophages are the main components of immune cells in TME. However, the specific mechanism of macrophages in HCC development is not fully understood. We conducted a preliminary study on the gene expression differences between HCC macrophages and paracancer macrophages by single-cell sequencing. Results demonstrated that FCGR2A was highly expressed in liver cancer tissues, and FCGR2A was mainly expressed in M2 macrophages in cancer tissues. The expression level of FCGR2A was correlated with extrahepatic metastasis, maximum tumor diameter, CNLC stage, satellite nodule, and differentiation degree. High FCGR2A expression predicts worse overall survival (OS) and progression-free survival (PFS) in HCC patients. In vivo experiments have verified that both FCGR2A mRNA and protein levels are markedly upregulated in M2 macrophages. Transfection of FCGR2A has been demonstrated to drive the polarization of M2 macrophages through augmenting IL-4 secretion. Further experiments showed that FCGR2A regulated and activated the IL-4/ JAK/STAT6 pathway. Inhibition of JAK/STAT6 signaling pathway is capable of counteracting the promoting influence of FCGR2A-induced M2 macrophages on HCC cell proliferation. What's more,macrophages with high FCGR2A expression showed immunosuppressive influence on NK and T cells viabilities and killing activities on HCC tumor cells. Our findings reveal a crucial FCGR2A /IL-4/JAK/STAT6 axis for M2 polarization and provide a rationale for therapeutics of macrophages targeting HCC.

关键词： COVID-19   cryopreservation   engraftment   graft versus host disease   hematopoietic stem cell transplantation  

摘要： The coronavirus disease 2019 (COVID-19) pandemic created major challenges for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Scientific societies and authorities recommended cryopreserving grafts before starting conditioning regimens, despite limited data on the clinical impact. The Italian Group for Bone Marrow Transplantation (GITMO) conducted a registry-based study involving 3492 patients who underwent allo-HSCT between March 2018 and September 2021. The cryopreserved cohort (n = 976) included patients who received cryopreserved grafts during the pandemic and was compared to the historical cohort (n = 2516). Graft cryopreservation was associated with a lower day 30 incidence of neutrophil and platelet engraftment (adjusted sHR = 0.8 and 0.7, p = 0.031 and p < 0.001, respectively) and delayed hematopoietic recovery. However, primary graft failure rates at day +30 were similar in the cryo and historical cohort (4% vs. 5%, respectively;p = 0.337), also after adjustment (RR = 1.19, p = 0.518). Day 100 incidence of grade II-IV acute GVHD was comparable between the two groups (adjusted sHR = 1.2, p = 0.194). Regarding chronic GVHD incidence, we found that it was higher in patients aged < 18 years in the cryo group (adjusted sHR = 3.9, p = 0.002), but lower in those aged 18-55 years (adjusted sHR = 0.7, p = 0.008). Cumulative incidence of relapse did not differ between historical and cryo cohort (adjusted sHR 1.0. p = 0.943), as well as non-relapse mortality (adjusted sHR 1.1, p = 0.196) and relapse-free survival (adjusted sHR = 1.1, p = 0.197). However, a shorter overall survival was observed in the cryopreserved group (adjusted HR = 1.2, p = 0.038). Transplant centers should carefully balance the benefits and drawbacks of cryopreservation in allo-HSCT.

关键词： Topical administration   Human single-domain antibody   IL-33   Dry eye disease   Asthma   Mucosal Inflammation  

摘要： Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge owing to the limited penetration of biological therapeutics across epithelial barriers. In this study, we explored the potential of human single-domain antibodies (UdAbs) as topical therapeutics for the targeted modulation of interleukin-33 (IL-33) in two mucosal-associated inflammatory disorders. The anti-IL-33 UdAb A12 demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not potently blocking the IL-33 receptor interaction. Compared with the anti-IL-33 control IgG itepekimab, the topical delivery of A12 resulted in significantly elevated corneal concentrations in vivo, which resulted in negligible ocular penetration. Moreover, A12 considerably ameliorated dry eye disease severity by exerting anti-inflammatory effects. Furthermore, in another murine model of allergic asthma, inhaled A12 substantially reduced overall lung inflammation. Our findings revealed the capacity of UdAbs to penetrate mucosal barriers following noninvasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.

关键词： Cadaveric lung transplantation   HLA mismatch   De novo donor-specific antibody   Chronic lung allograft dysfunction  

摘要： ObjectivesGenerally, HLA matching between donors and recipients is not performed in lung transplantation (LTx). Therefore, whether HLA mismatch between donors and recipients (D/R mismatch) influences postoperative outcomes after LTx remains uncertain. In this study, we investigated the influence of D/R mismatch on postoperative outcomes after cadaveric LTx (CLT).MethodsA total of 140 CLT procedures were performed between 2012 and 2020. After excluding 5 recipients with preformed DSA and 1 recipient undergoing re-LTx, 134 recipients were enrolled in this retrospective study. The postoperative outcomes were compared between recipients with higher and lower D/R *** median D/R mismatch (A/B/DR loci) was 4.0 (range, 1-6). When dividing these 134 recipients into two groups (H group [D/R mismatch >= 5, n = 57] and L group [D/R mismatch <= 4, n = 77]), there were no significant differences in the patient backgrounds. The lengths of hospital and intensive care unit stays were similar (p = 0.215 and p = 0.37, respectively). Although the overall survival was not significantly better in the H group than in the L group (p = 0.062), chronic lung allograft dysfunction-free survival was significantly better in the H group than in the L group (p = 0.027). Conversely, there was no significant difference in the cumulative incidence of de novo donor-specific anti-HLA antibodies (dnDSAs) between the two groups (p = 0.716).ConclusionsNo significant difference in dnDSA development was observed between patients with higher and lower D/R HLA mismatches. Given the favorable outcomes in the high HLA mismatch group, CLTs can be performed safely in recipients with high D/R HLA mismatches.

关键词： ROR gamma t   Tc17   Immunotherapy   HCC   CD8+T cells  

摘要： While interferon-alpha (IFN-alpha) demonstrates potent antineoplastic activity against hepatocellular carcinoma (HCC), but many patients have a low response rate and may even develop resistance to it. It is necessary to find new strategies to reduce IFN-alpha resistance and improve its efficacy. RAR-related orphan receptor gamma t (ROR gamma t) agonists exhibit dual immunomodulatory functions, demonstrating both immunosuppression-reducing and immune-activating properties. In this study, we demonstrated that the combination of the ROR gamma t agonist-LYC-55716 and IFN-alpha significantly promoted cytotoxic T cell 17 (Tc17 cell) differentiation and interleukin-17a (I1-17a) expression through activation of the Akt/Stat3 signal pathway. The combination therapy markedly enhanced the tumoricidal activity of differentiated Tc17 cells against hepatoma carcinoma cells. Moreover, this therapeutic strategy showed superior antitumor efficacy in multiple HCC models while maintaining a favorable safety profile compared to single-agent treatment. Importantly, our findings revealed that the combination treatment significantly enhanced CD8+ T cells infiltration into tumor tissues. Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8+ T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)-C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages ROR gamma t agonists to enhance the efficacy of IFN-alpha in HCC therapy.

关键词： Cardiac insulin resistance   Nuclear factor kappa B   Tumor necrosis factor alpha   Suppressor of cytokine signaling 3   Inducible nitric oxide synthase   Sodium-potassium ATPase pump  

摘要： Our previously published results have proven that low-intensity exercise, equivalent to brisk walking, is beneficial in managing cardiac insulin resistance in post-weaning male rats exposed to a fructose-rich diet. Still, its role in protecting against cardiac inflammation is unclear. This experiment was designed to investigate the preventive effect of low-intensity exercise on cardiac inflammation in male post-weaning rats exposed to a fructose-rich diet (10%). Male Wistar rats were randomly assigned to a sedentary control group, a sedentary group with fructose overload, and a fructose overload group subjected to treadmill exercise for nine weeks. Protein expression of cardiac inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9, as well as cellular localization/phosphorylation of nuclear factor kappa B (NF-kappa B), and alpha 1 and alpha 2 subunits of sodium-potassium ATPase pump (Na/K-ATPase) was determined. Additionally, gene expression of tumor necrosis factor alpha (TNF alpha) and suppressor of cytokine signaling 3 (SOCS3) was examined. The results demonstrate that a chronic fructose-rich diet in sedentary rats elevates the expression of key inflammatory markers, including SOCS3, TNF alpha, NF-kappa B, and iNOS, as well as the plasma membrane alpha 1 and alpha 2 subunits. Exercise prevented alterations induced by a fructose-rich diet, except iNOS expression. Additionally, exercise increased the protein expression of the alpha 1 and alpha 2 subunits of Na/K-ATPase in the lysate of fructose-fed rats. These findings suggest that low-intensity exercise is an effective non-invasive strategy for cardioprotection, helping to prevent inflammation by modulating TNF alpha and NF-kappa B expression in insulin-resistant hearts of post-weaning male rats.

关键词： Encephalomyocarditis virus   Linker histone H1.3   MDA5   IRF3   Interferon  

摘要： Multiple core histones play pivotal roles in viral infection process, as evidenced in influenza virus and other viruses. Recent findings indicate that linker histone H1.2 regulates the interferon signaling pathway to modulate influenza and EMCV infections, while H1.3 may also play a role in EMCV infection. In this study, we initially demonstrated that overexpression of H1.3 markedly suppressed the EMCV replication and proliferation. Conversely, knockdown of H1.3 expression led to an upregulation of EMCV replication and proliferation. Additionally, we observed a significant enhancement of EMCV-induced type I IFN production in Myc-H1.3 expressing cells. Our further exploration revealed that H1.3 upregulated the expression of MDA5 and enhanced the phosphorylation of TBK1 and IRF3 during EMCV infection, with opposite effects observed in H1.3 knockdown cells. Subsequently, we confirmed the interaction between H1.3 and MAVS, as well as IRF3, using both endogenous and exogenous Co-IP assays. Furthermore, we demonstrated that H1.3 promoted IRF3 phosphorylation and its nuclear translocation in EMCV-infected A549 cells. Notably, the N-terminal domain of H1.3 may play a crucial role in regulating the IFN-(3 signaling pathway to inhibit EMCV replication. Finally, we observed that EMCV infection upregulated the phosphorylation of H1.3, which may correlate with increased transcriptional expression of genes such as IFN-(3. In summary, our findings address the gap in understanding the involvement of H1.3 in viral infection and elucidate the mechanism by which H1.3 negatively regulates EMCV replication. These findings may provide new insights into potential antiviral targets.

关键词： Avian reovirus   Toll like receptor 3   Autophagy   B16-F10 melanoma cells   IRF3   NF-kappa B   IFN-gamma  

摘要： Oncolytic avian reovirus (ARV) has been identified as a virus capable of selectively infecting and inducing cell death in various cancer cell lines. This study investigates the role of ARV in activating innate immune responses in B16-F10 murine melanoma cells, focusing on the TLR3-IRF3-IFN-gamma-JAK-STAT1 and TLR3-NF-kappa B-IFN-gamma-JAK-STAT1 pathways. Our results revealed that the 6C protein of ARV interacts with toll-like receptor 3 (TLR3) in the cytoplasm, leading to nuclear translocation of IRF3 and NF-kappa B as well as the upregulation of IFN-gamma, as confirmed by quantitative real-time reverse transcription and polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), proximity ligation assay (PLA), and Western blot. Inhibition assays targeting TLR3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B), and interferon regulatory factor 3 (IRF3) further validated the involvement of the TLR3-IRF3 and TLR3-NF-kappa B pathways in IFN-gamma activation. Additionally, cells treated with signal transducer and activator of transcription 1 (STAT1) shRNA and Janus kinase (JAK) inhibitor revealed that ARV promotes autophagy via the IFN-gamma-JAK-STAT1 pathway. Immunofluorescence staining and LC3-mCherry transfection further confirm ARV's role in triggering autophagy via TLR3-IRF3-IFN-gamma-JAK-STAT1 and TLR3-NF-kappa B-IFN-gamma-JAK-STAT1 pathways. Our results revealed that oncolytic ARV induces autophagy and apoptosis in middle to late stages of virus life cycle in murine melanoma cells. These findings highlight the potential of ARV as a novel oncolytic virotherapy through immune pathway activation in cancer cells.