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摘要： Interleukin (IL)-18 functions primarily through its 18-kDa mature form produced from caspase-1 cleavage. However, IL-18 can also be processed by other proteases, leading to the generation of different fragments with less recognized functions. Here, we discover that, in cancer cells, caspase-3 cleavage of IL-18 generates a 15-kDa form of IL-18, referred to as short IL-18. Unlike mature IL-18, short IL-18 is not secreted, and does not bind IL-18R alpha;instead, it translocates into the nucleus, facilitating STAT1 phosphorylation at Ser727 via CDK8, and enhancing the expression and secretion of ISG15. This signaling cascade in cancer cells mobilizes natural killer cells with increased cytotoxicity to eliminate various syngeneic tumors and colitis-associated colorectal cancer in mice. Moreover, patients with colorectal cancer who have an abundance of short IL-18 in the nucleus have a better prognosis. This work highlights a distinct anti-tumor pathway driven by short IL-18.

关键词： Catalpol   Collagen-induced arthritis   NF-kappa B signaling pathway   Rheumatoid arthritis   Synovial inflammation  

摘要： Background/rationale Rheumatoid Arthritis (RA) is a prolonged autoimmune condition marked by persistent inflammation, causing joint damage and bone erosion. Catalpol (CAT), an iridoid glycoside, offers anti-inflammatory benefits, warranting its study in RA models. Objective To investigate the anti-inflammatory effects of CAT in RA by evaluating its impact on cellular and animal RA models. Methods In vitro biological actions of CAT were investigated by the methods of cell viability, proliferation, migration, invasion, apoptosis, ROS generation, double luciferase reporter assay for NF-kappa B-p65 activity, Nitrite release detection, and RT-qPCR for gene expression in Tumor Necrosis Factor-alpha (TNF-alpha)-induced Human Fibroblast-Like Synoviocytes from RA patients (HFLS-RA) (cellular RA model). Arthritis severity, joint cellular structure, gene expression, inflammatory factors, and joint inflammation studies were investigated in mice with collagen-induced arthritis (CIA) (animal RA model). Key results CAT treatment groups showed significant improvements (P < 0.001) in cell viability, migration, invasion, and apoptosis compared to the TNF-alpha-induced group. ROS generation and the activity of NF-kappa B-p65 were significantly reduced (P < 0.001). Nitrite release was decreased (P < 0.01, P < 0.001) in CAT-treatment groups. Pro-inflammatory and bone- metabolizing cytokine gene expression was markedly downregulated (P <0.05, P < 0.001) in the cellular RA model. CIA mice treated with CAT exhibited significantly reduced arthritis severity, paw edema, and arthritis index (P < 0.05, P < 0.01). Joint pathology scores showed improvement (P < 0.001) in CAT-treatment groups. In the animal RA model, bone-metabolizing and inflammatory cytokine gene expression was significantly reduced in CAT-treatment groups (P < 0.01, P < 0.001). Conclusion CAT effectively reduces RA's inflammation and bone metabolism issues, suggesting its potential as a therapeutic agent for RA treatments.

关键词： HLA   HLA-DPA1*02:01:34   new allele   synonymous mutation  

摘要： HLA-DPA1*02:01:34 differs by a single synonymous mutation compared to HLA-DPA1*02:01:01:02 in codon 212 in Exon 4.

关键词： neuroinflammation   circadian rhythms   depression-like behavior   mitochondria   RNA-seq  

摘要： Neuroinflammation is involved in the development of depression and may induce depression-like behaviors by affecting metabolism through interactions with circadian rhythms. As the hub of metabolism, mitochondria are regulated by various types of metabolism and release signals that regulate cellular functions. In this study, we performed transcriptomic analysis of the hippocampus of IL-33-overexpressing mice to provide new ideas to explore the pathogenesis of inflammation-mediated depression at the transcriptional level. Male C57BL/6J mice and IL-33-overexpressing mice were subjected to behavioral tests. The hippocampus was extracted during the light or dark period, and differential gene expression analysis was conducted using RNA sequencing. Differential gene enrichment analysis was performed, as well as multilayered analysis of mitochondrial transcriptional rhythms by integrating the regulatory networks and Mito 3.0 database. The results were further verified using RT-qPCR. IL-33-overexpressing mice exhibited depressive behaviors associated with rhythmic disorders and shortened circadian cycles. Differential KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that the top 20 pathways with the lowest p-values included mood-related, immune-related, and circadian rhythm-related pathways. Differential gene GO (Gene Ontology) enrichment analysis showed that 20 of the top 30 pathways with the lowest p-values were related to metabolism. Transcriptome data from IL-33-overexpressing mice showed that the mitochondrial-encoded subunit of the oxidative respiratory complex showed predominantly increased expression during the light period. Metabolic disorders and disrupted mitochondrial transcriptional rhythm were also observed. Weighted gene correlation network analysis showed that the circadian cycle is associated with depression-like behavior disorders. Network analysis showed that circadian-related genes were enriched in mitochondrial pathways related t

关键词： Erythema Nodosum Leprosum (ENL)   Thalidomide   Immune response   Polymorphisms   Cytokines  

摘要： Erythema nodosum leprosum (ENL), an inflammatory reaction in leprosy, causes painful nodules, fever, and malaise due to immune system activation. Thalidomide is an effective treatment, although associated with important adverse effects. We aimed to evaluate the association of genetic variants in genes encoding tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) with the response to treatment of ENL with thalidomide. 148 patients from the South and Northeast regions of Brazil were included. Genomic DNA was isolated from blood and/or saliva samples using commercial kits, and genetic variants in TNF, IL6, IL1/3, and IFN gamma genes were genotyped by TaqMan system. We identified an association between polymorphisms in TNF (rs1799964C, rs1800630A, rs1799724T and rs1800629A) IL1/3 (rs4848306G, rs1143623G, rs16944A, and rs1143627A), IL6 (rs2069840C and rs2069845G) and IFN gamma (rs2430561T) with thalidomide dose variation in a time-dependent manner. Associations of IL6 and TNF haplotypes with thalidomide dosage variation over the time of treatment were also observed. Polymorphisms in TNF, IL6, IL1/3, and IFN gamma genes may modulate their expression levels, potentially impacting the required dosage of thalidomide in the treatment of ENL. Our findings should be confirmed in further studies to estimate the size effect of these polymorphisms on ENL treatment with thalidomide.

关键词： bimekizumab   biologics   Il-17 inhibitors   intraclass switch   psoriasis  

关键词： HLA-C*03:702   NGS HLA typing novel   novel HLA-C allele  

摘要： The new HLA-C*03:702 allele showed one non-synonymous nucleotide difference compared to the HLA-C*03:04:01:01 allele in codon 258.

关键词： LCN2   IL-6   Traumatic brain injury   Neuroinflammation   Biomarker  

摘要： Clinical biomarkers are crucial for diagnosing and predicting outcomes in patients with traumatic brain injury (TBI). In this study, we performed an unbiased analysis of plasma proteins in acute TBI patients using bead-based multiplex assays and identified a strong positive correlation between LCN2 and IL-6 levels. Based on these findings, we hypothesized that LCN2 and IL-6 are closely related circulating biomarkers for TBI. Our previous and current studies demonstrate that the expression of LCN2, IL-6, and its receptors is upregulated in patients with chronic traumatic encephalopathy, in mouse models of traumatic and ischemic injury, and in an in vitro scratch injury model. Lcn2-deficiency reduced the injury-induced expression of IL-6 and its receptors in both animal and scratch injury models. These results suggest an augmented LCN2-dependent IL-6 signaling in the injured brain. As both LCN2 and IL-6 are secreted proinflammatory mediators, we further explored the possibility of cross-regulation between LCN2 and IL-6. In cultured glial cells, treatment with recombinant LCN2 protein enhanced the microglial expression of IL-6, while IL-6 protein treatment increased astrocytic LCN2 expression. Moreover, IL-6 expression and release were elevated in LCN2-overexpressing transgenic mice. Mechanistically, IL-6 enhanced astrocytic LCN2 expression through STAT3 signaling, while LCN2 upregulated microglial IL-6 expression through the NF-kappa B pathway. Taken together, our results suggest an important role of the LCN2-IL6 axis in amplifying neuroinflammation through a positive feedback loop in secondary brain injury conditions. Finally, this study implies the utility of LCN2 and IL-6 as closely related biomarkers for TBI diagnosis and prognosis.

关键词： cancer-associated fibroblast   interferon-licenced fibroblast   non-small cell lung cancer   secretome   tumour microenvironment  

摘要： Cancer-associated fibroblasts (CAFs) are the dominant nonmalignant component of the tumour microenvironment (TME). CAFs demonstrate a high level of inter- and intra-tumour heterogeneity in solid tumours, though the drivers of CAF subpopulations are not fully understood. Here, we demonstrate that non-small cell lung cancer (NSCLC) patient-derived CAFs upregulate the secretion of inflammatory cytokines (IL6, LIF, IL33, GM-CSF, IL1ra) and chemokines (CCL2, CCL3, CCL4, CCL20, CXCL8, CXCL9, CXCL10, CXCL11) in response to in vitro co-culture with anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs) via IFN gamma and TNF alpha. Furthermore, T-cell-derived IFN gamma inhibits CXCL12 secretion by CAFs in vitro. Our results highlight the ability of T-cell effector cytokines to modulate the CAF secretome in NSCLC.

关键词： Extracorporeal shock wave   Temporomandibular joint disorder syndrome   IGF-1   TNF-alpha   IL-1 beta  

摘要： As a new therapeutic method, extracorporeal shock wave (ESW) has shown remarkable efficacy in the treatment of temporomandibular joint disorder syndrome. Numerous studies have shown that it has the advantages of noninvasiveness, short treatment time, etc. It can effectively relieve pain and improve symptoms such as joint mobility and opening degree. In clinical practice, through accurate diagnosis and positioning of different patients, appropriate treatment parameters such as therapeutic transducer, frequency and pressure can be selected to significantly improve the efficacy. At the same time, follow-up evaluation after treatment, including temporomandibular joint disorder index and visual analogue score, is also helpful to fully understand the rehabilitation of patients. Extracorporeal shock wave therapy (ESWT) brings new hope to patients with temporomandibular joint disorder syndrome and has a broad application prospect.