课程文献中心 更多>>

关键词： Psoriasis   Protocatechuic aldehyde   Inflammation   STAT3   Ttranscription   Keratinocyte  

摘要： Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from Salvia miltiorrhiza (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions. Further molecular mechanism studies demonstrated that PA inactivated STAT3 and inhibited STAT3-mediated transactivation of interleukin-1 alpha (IL-1 alpha) and C-X-C motif chemokine ligand 9 (CXCL9) in epidermal keratinocyte both in vivo and in vitro. Knockdown of STAT3 attenuated the repression effect on IL-1 alpha and CXCL9 by PA. Our results suggested that PA repressed the transactivation of IL-1 alpha and CXCL9 through inhibiting STAT3 in keratinocyte. PA could be potentially used for psoriasis topical treatment or be as a lead compound for drug development.

关键词： IL-33   Intercellular interaction   Periodontal ligament fibroblasts   Immunomodulation   Macrophages   Diabetes-associated periodontitis  

摘要： Tissue-resident fibroblasts with immunomodulatory properties have recently been identified as key players in inflammation. However, their roles within the periodontal niche in diabetes-associated periodontitis remain unclear. Interleukin (IL)-33, known as an "alarmin" in inflammatory responses, has recently emerged as a potential contributor to periodontitis. Herein, we show that IL-33 levels are reduced in periodontal ligament fibroblasts (PDLFs) in the in vivo models of diabetes-associated periodontitis and in vitro models of diabetic inflammation. In the in vitro co-culture model, overexpression of IL-33 in PDLFs promotes M2 macrophage polarization, while knockdown of IL-33 in PDLFs instigates M1 macrophage polarization. Notably, supplementation with IL-33 in vivo significantly alleviates periodontal tissue destruction and enhances M2 macrophage infiltration, whereas targeting the IL-33/ST2 axis exacerbates tissue damage and promotes M1 macrophage polarization in diabetes-associated periodontitis. Additionally, the CUT&RUN assay confirms the direct regulation of IL-33 by Yes-associated protein (YAP). These findings demonstrate that IL-33 deficiency in PDLFs favors M1 macrophage polarization, thereby exacerbating the pathogenesis of diabetes-associated periodontitis. Our study underscores the essential immunomodulatory role of PDLFs in creating an inflammatory niche and unveils a novel interaction axis between PDLFs and macrophages in diabetes-associated periodontitis.

关键词： copolymer/ionic liquid membrane   morphology   nanoconfinement   mesoscopic dynamics simulation   grand canonical Monte Carlo-molecular dynamics simulation   gas transport   gas separation  

摘要： The phenomenon of ionic liquid (IL) nanoconfinement within a copolymer/IL membrane reportedly enhances membrane selectivity, solubility, and transport in gas separations. Also, the copolymer/IL membrane morphology has been found to affect IL stability at high transmembrane pressures. In this work, a combined mesoscopic dynamics simulation and hybrid grand canonical Monte Carlo/molecular dynamics (GCMC-MD) simulations were carried out to investigate the morphologies, as well as CO2/CH4 gas diffusivities, solubilities, and selectivities of polystyrene-b-poly(ethylene oxide) (PS-b-PEO)/1-Ethyl-3-methylimidazolium thiocyanate ([EMIM][SCN]) and PS-b-PEO/1-Ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][Tf2N]) membranes. The latter simulations focused on nanoconfined ILs in the copolymer/IL phase boundaries at 2.5 and 5 nm confinement lengths. The investigated systems were four nanoconfined ILs, i.e., PS/[EMIM][SCN]/PEO (the IL forming a separate microphase, denoted IL-Micro), PS/[EMIM][Tf2N]/PEO, PS/[EMIM][SCN]-PEO/PS (the IL distributed in the PEO phase, denoted IL-PEO), and PS/[EMIM][Tf2N]-PEO/PS, and five control systems, i.e., PS/PEO/PS, bulk PS, bulk PEO, bulk [EMIM][SCN], and bulk [EMIM][Tf2N]. Based on the mesoscopic dynamics simulation results, the dominant membrane morphologies at IL loadings of <50 vol % were lamellar or cylindrical (favorable for both IL stability at high transmembrane pressures if the bedding planes are horizontal, i.e. at 90 degrees to the nominal direction of the transmembrane pressure gradient) with the IL-PEO or IL-Micro phases. Also, there was an overall 50% match between the observed PS-b-PEO/[EMIM][SCN] and PS-b-PEO/[EMIM][Tf2N] membrane morphologies. Based on the MD simulation results, both CO2 and CH4 diffusivities were the smallest in the bulk PS (control) and highest in the PS/[EMIM][Tf2N]/PEO system (IL-Micro between the PS and PEO phases) at both confinement lengths. The CO2 diffusivities were, on average, lar

关键词： antigen presentation   MHC class-II   HLA-DM   HLA-DM susceptibility   mathematical model   immunopeptidome prediction  

摘要： Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function;we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.

关键词： Neutrophil extracellular traps   IL-18   IFN-gamma   Cardiac conduction abnormalities   Cx43 gap junction  

摘要： Doxorubicin-induced cardiotoxicity (DIC) is one of the most severe side effects of doxorubicin, yet the underlying mechanisms remain incompletely understood. Our results showed that Neutrophil extracellular traps (NETs) accumulated in plasma and cardiac tissue after doxorubicin treatment. The inhibition of NETs formation by Pad4 gene ablation significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of Troponin T (cTnT) and creatine kinase MB (CK-MB) in mice. In addition, reductions in left ventricular fractional shortening and ejection fraction induced by doxorubicin were more severe in WT mice than in Pad4-/- mice. Immunostaining and qPCR analyses revealed that NETs activated macrophages to release pro-inflammatory cytokines such as IL-18, IL-1 beta, and TNF-alpha. IL-18, in turn, activated T cells to produce IFN-gamma, which, along with TNF-alpha, downregulated the expression of Cx43, thereby inducing cardiac conduction abnormalities. We identify that IL-18-IFN-gamma-Cx43-induced cardiac conduction abnormalities triggered by neutrophil extracellular traps is the key molecular and cellular determinants of DIC. Furthermore, targeting NETs formation using ozone therapy significantly alleviated DIC. This study highlights the critical role of NETs in the development of DIC and proposes ozone therapy as a potential therapeutic strategy for treating DIC.

摘要： A patient with longstanding multicentric Castleman’s disease that had progressed after multiple therapies was entering hospice care. Inhibition of tumor necrosis factor will have led to remission for 24 months as of the publication of this letter.

关键词： Rheumatoid arthritis   Pyroptosis   IL-17 pathway  

摘要： Background: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 ( SLC7A11 ) influences RA development. Methods: Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-18 and IL-1 beta), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-alpha. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro. Results: CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-alpha-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL- 17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of

摘要： Inflammation stimulation regulates the activity of hematopoietic stem cells (HSCs) through direct-sensing and cytokine-mediation. It is known that HSCs directly sense lipopolysaccharide (LPS), a classical infection-related inflammatory signal, via toll like receptor 4 (TLR4) and subsequently become active. However, the mechanism underlying the activity change of HSCs induced by LPS remains incompletely disclosed. Here we explored that under LPS stimulation, the activation of interferon alpha (IFN alpha) signal pathway resulted in the activation and exhaustion of HSCs in vitro, indicating HSCs directly responded to LPS through the downstream IFN alpha signal pathway. We also discovered the increased production of IFN alpha in mice bone marrow and expression of interferon-alpha/(3 receptor (IFNAR) on mice HSCs after LPS stimulation. Creatine, an IFN alpha inhibitor, could reverse the activation and prevent the exhaustion of HSCs caused by LPS by suppressing the expressions of genes associated with the IFN alpha signal pathway both in vitro and in vivo. Furthermore, we found that the IFNAR deficiency in mice effectively protected HSCs from activation, elevated apoptosis and impaired reconstitution ability under LPS stimulation in vivo. This finding further supports the notion that LPS activates and injures HSCs indirectly via promoting IFN alpha secretion in the bone marrow environment. Overall, our findings reveal that LPS causes the injury to HSCs either through direct or cytokine-mediated indirect activation of the IFN alpha signal pathway.

关键词： IL-18   Endometriosis   Recurrent spontaneous abortion   Polycystic ovary syndrome   Infertility  

摘要： Interleukin (IL)-18 is one of the members of IL-1 family cytokines, it was originally named as interferon gamma (IFN-gamma) inducing factor. IL-18 is a pleiotropic immune regulator and has a bidirectional regulatory effect on immunity. It exerts a potent pro-inflammatory effect by inducing the expression of IFN-gamma, also has an important anti-inflammatory role. In recent years, IL-18 has received widespread attention and become a research hotspot. Previous studies have described the roles of IL-18 in the pathogenesis of many diseases. However, the biologic activities of IL-18 and its role in the reproductive endocrine and reproductive immune related diseases are still not well understood, such as endometriosis (EMS), recurrent spontaneous abortion (RSA), polycystic ovary syndrome (PCOS), and infertility, which are closely related to inflammation and immunity. Here, we reviewed the research progress of IL-18 in these diseases in the past few years. This article provides an overview of the latest knowledge about the roles of IL-18 in these diseases, with a view to providing new possibilities for the diagnosis and treatment of reproductive endocrine and reproductive immune related disorders.

关键词： Chronic apical periodontitis   Hepcidin   Liver   IL-6/STAT3 signaling   Iron metabolism   Porphyromonas gingivalis  

摘要： Background and Aims: Chronic apical periodontitis (CAP), an inflammatory disease of the oral cavity caused by bacterial infections with Porphyromonas gingivalis (P. gingivalis) as a key pathogen, has been associated with systemic effects, potentially influencing distant organs including liver. The liver plays a key role in iron metabolism and immunity by hepcidin. This study aims to investigate the impact of P. gingivalis-induced CAP on liver and systemic iron metabolism, focusing on the role of the IL-6/STAT3 signaling pathway in hepatic hepcidin synthesis. Methods: A murine model of CAP was established by pulp chamber infection with P. gingivalis. Serum levels of IL6, ferritin, and hepcidin were measured via ELISA. High-throughput sequencing was used to analyze hepatic gene expression, and immunohistochemistry with fluorescent staining was performed to validate protein expression in liver tissues. Results: CAP led to significant changes in serum iron, ferritin, and IL-6. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed enrichment in pathways like JAK/STAT signaling and acute-phase responses, and gene set enrichment analysis (GSEA) also indicated activation of IL-6/ JAK/STAT3 signaling pathway. Iimmunofluorescence confirmed increased IL-6, p-STAT3, and hepcidin expression. These levels were alleviated by stattic treatment, mitigating CAP-induced inflammatory and ironregulatory effects. Conclusion: P. gingivalis-induced CAP triggered systemic inflammation and disrupts iron metabolism via the IL-6/ STAT3 signaling pathway, potentially affecting liver function. Targeting this pathway may offer therapeutic strategies for managing iron dysregulation in chronic inflammatory diseases like CAP.