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关键词： Stem cells  

摘要： Background: rotator cuff injury (RCI) is a common shoulder injury that is difficult to completely repair with surgery. Therefore, new strategies are needed to promote tendon-bone healing. The purpose of this study was to explore the possible mechanism of the protective effect of a porous hydrogel loaded with BMSCs overexpressing IL-4 on tendon-bone healing. Methods: the cell counting kit-8 assay was used to evaluate the cytotoxicity of the porous hydrogel and the protective effects of bone marrow mesenchymal stem cells (BMSCs) overexpressing IL-4. Green fluorescence was detected through immunofluorescence analysis after the porous hydrogel loaded with BMSCs was transfected with the IL-4 adenovirus. The expression of M1 and M2 polarization-related proteins was detected using an immunofluorescence assay. Additionally, apoptosis-associated proteins and TGF-beta/Smad2/3 signaling pathway-related proteins were evaluated through immunofluorescence, immunoblotting and PCR analyses. ECMs were evaluated via RT-PCR and immunofluorescence analyses. In vivo CT and histological analyses were performed to evaluate the protective effects of the BMSC-overexpressing IL-4 porous hydrogel. Results: BMSCs were isolated and cultured and met the criteria for the identification of mesenchymal stem cells. Immunofluorescence detection was performed after the transfection of adeno-associated viruses overexpressing IL-4, and it was found that fluorescence intensity was strongest with an MOI value of 80. More importantly, after loading the porous hydrogel, the resulting hydrogel complex could further promote the polarization of M2 cells and inhibit the polarization of M1 cells in vitro. After treatment with the BMSC-overexpressing IL-4 porous hydrogel, the TGF-beta pathway was significantly activated in the IL-4/BMSC group, while the protective effect was significantly weakened after SB431542 treatment. The results of in vivo CT and histological analyses showed that therapy with IL-4/BMSCs cou

关键词： Juvenile idiopathic arthritis   Rheumatoid factor   TNF inhibitor  

摘要： Objectives Rheumatoid factor (RF) binds to the immunoglobulin Fc portion, which might influence the efficacy of Fc-carrying TNF inhibitors (TNFi). This has been shown in studies in adults with RF-positive RA, but not yet in children. The aim of this study was to determine efficacy of TNFi in children with seropositive polyarthritis according to rheumatoid factor levels. Methods Two databases were searched for patients with JIA/seropositive polyarthritis, admitted between November 2009 and March 2023. Data collected were demographic data, treatment with antirheumatic medications and JADAS27 and cJADAS27 prior to and after start of TNFi treatment. Changes in JADAS27 and cJADAS27 on TNFi were compared between patients with highly elevated RF (> 160 U/ml) and low titre RF (< 160 U/ml) using repeated measures ANOVA. Results 28 patients were included, 16 with RF < 160 U/ml at diagnosis, and 12 with RF >= 160 U/ml. 21 patients (75%) were treated with etanercept, three (11%) with adalimumab and four (14%) with golimumab, 23 patients additionally received methotrexate. Mean JADAS27 (cJADAS27) at treatment start was 23.0 +/- 14.7 (21.0 +/- 12.1), and 4.8 +/- 5.0 (4.8 +/- 4.7) at assessment after starting TNFi. Independent-samples t-test comparing percentage improvement as well as an ANCOVA determined that mean JADAS27 and cJADAS27 scores did not differ significantly across the two time points. Conclusions Unlike in adults, efficacy of TNFi was not diminished by elevated levels of RF in this cohort of pediatric patients with seropositive polyarthritis. Further studies are necessary to confirm these findings.

关键词： glutamine   HSC70   LDHA   signal transduction   IFN-β   immunogenic cell death  

摘要： Glutamine plays a role in cell signaling that regulates gene expression and impacts tumorigenesis. However, it is still unclear how glutamine transduces signals in cells. Here, we show that glutamine binds to heat shock cognate protein 70 (HSC70) to stimulate the deubiquitinase otubain domain containing protein (OTUD4) independently of known glutamine metabolic or signaling pathways, resulting in lactate dehydrogenase A (LDHA) stabilization via the microautophagy-lysosome pathway, increased lactate production and decreased expression of interferon (IFN)-b and its targets, hallmarks of immunogenic cell death (ICD). In cancer cell lines and patient-derived organoids and xenografts, glutamine depletion or glutamine transport inhibition combined with ICD-inducing chemotherapeutic drugs synergistically activates IFN-b, promotes CD8+ T cell recruitment, and inhibits cancer cell growth via the OTUD4/LDHA axis. CD8 expression is negatively correlated with expression of the glutamine transporter alanine/serine/cysteine transporter 2 (ASCT2), OTUD4, and LDHA in cancer patients. Thus, we identify an intracellular glutamine signaling pathway, and targeting this pathway is a promising strategy for cancer treatment.

摘要： Group 2 innate lymphoid cells (ILC2s) are critical players during type 2 inflammation present in most forms of asthma. ILC2s are tissue-resident cells that produce cytokines IL-5 and IL-13 critical to eosinophilic airway inflammation, mucus production, remodeling, and hyperresponsiveness. Though each ILC subset (ILC1s, ILC2s, ILC3s) is identified by specific transcription factors, cell surface receptors and cytokine profiles, functional plasticity between ILC subtypes occurs in various contexts. IL-18/IL-18R loci SNPs are linked to asthma in multiple genome-wide association studies and IL-18 has been shown to promote plasticity in ILC2s. Despite this, little is known about the role of IL-18/IL-18R on ILC2 responses in the lung. Within hours after mice were exposed to the fungal allergy , airway levels of IL-18 and IL-18 receptor expression increased on ST2+ ILCs. Single-cell RNA sequencing of lung cells from Alternaria-challenged mice showed that was largely expressed by alveolar macrophages, while IL-18R was highly expressed in IL-13+ILC2s. Utilizing IL-18 receptor knock-out mice (IL- 18R-/-), we observed increases in IL-17A production from both ST2+ and ST2-negative ILCs compared to control mice. We further observed an early increase in dual production of IL-5 and IL-17A in ST2+ ILCs followed by enhanced lung eosinophilia in the absence of IL-18R. Together, our findings suggest that IL-18 signaling prevents IL-17A production from ILC2s and subsequent eosinophilia . A further understanding of the regulation of ILC plasticity may lead to novel therapeutic targets in the treatment of ILC-driven asthma.

关键词： 肾综合征出血热   汉坦病毒   细胞因子   发病机制  

摘要： 肾综合征出血热是汉坦病毒感染引起的人兽共患性疾病，炎症细胞因子风暴与肾综合出血热的病情发展密切相关。本文通过对肾综合征出血热患者临床进展过程中的抗炎、促炎细胞因子研究进展进行综述，以期全面了解其与肾综合征出血热病程进展的相关性，为临床诊疗与评估病情提供参考。

关键词： autoimmunity   migration   myocarditis   IL-23   T cell  

摘要： Th1 and Th17 cell-mediated autoimmunity is critical for myocarditis induction. Antigen-presenting cell (APCs)-released interleukin (IL)-12 and IL-23 are implicated in the differentiation of Th1 and Th17 lineages. In this study, we utilized cardiac self-antigen myosin heavy chain alpha (alpha-MyHC)-pulsed bone marrow-derived dendritic cells (bmDCs) and wild-type, IL-12p35-/-, and IL-23p19-/- mice to investigate the influence of IL-12 and IL-23 on CD4+ T cells in experimental autoimmune myocarditis (EAM). All mice (Mus musculus) receiving alpha-MyHC-pulsed bmDCs developed acute myocarditis and accumulated interferon (IFN)-gamma-positive and IL-17A-positive CD4+ T cells in cardiac tissue. Compared to immunization with wild-type bmDCs, adoptive transfer of alpha-MyHC-pulsed IL-23p19-/- bmDCs resulted in decreased numbers of IL-17A+CD4+ T cells and in a twofold reduction of infiltrating T lymphocytes in the hearts of recipient mice, despite unaffected infiltration count of CD45+ leukocytes. In contrast, IL-12p35-/- bmDCs induced fewer IFN-gamma-producing CD4+ T cells but did not affect T lymphocyte infiltration. Furthermore, IL-23p19-/- recipient mice showed reduced heart-infiltrating CD3+ T cells, but not total CD45+, compared to wild-type mice after adoptive transfer of alpha-MyHC-pulsed IL-23p19-/- bmDCs. Likewise, in the transgenic TCRM model of EAM, TCRMxIL-23p19-/- mice showed reduced myocarditis severity and fewer T lymphocytes in their hearts pointing to impaired T cell trafficking in absence of IL-23. We validated the pro-migratory effect of IL-23 on activated CD4+ T cells in vitro and demonstrated an essential role of Rho GTPases in this process. Our findings provide new insights into the pro-inflammatory activity of IL-23 in autoimmune myocarditis, highlighting its unique role in promoting T cell migration.

摘要： Diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge and requires the development of new therapeutic approaches. The identification of cuproptosis, a newly defined form of copper-induced cell death, has provided innovative insights for cancer therapy. Here, we report that loss of the mitochondrial matrix reductase FDX1 in DLBCL cells impairs the antitumor effect of elesclomol (ES), which performs its function by transporting excess copper into cells. Overexpressing (OE) FDX1 significantly sensitized DLBCL cells to ES-induced cell death in vitro and enhanced the anticancer activity of ES in vivo. Furthermore, treatment with ES in FDX1-high expression patient-derived xenograft (PDX) showed a significantly greater inhibitory effect than in FDX1-low expression PDX. Mechanistically, FDX1 promotes the induction of IFN-beta-dependent PANoptosis by increasing IRF3 phosphorylation in DLBCL cells upon ES treatment. Consistent with this finding, patient cohort analysis revealed that FDX1 expression correlated positively with enhanced IRF3 phosphorylation. Together, our findings are the first to identify the central role of FDX1 in synergizing with ES to activate IFN-beta signaling and induce PANoptosis. This study enables us to re-explore the clinical anticancer potential of ES as a novel therapeutic strategy for DLBCL.

关键词： IFN gamma   miRNA   miR-1291   SOCS3   JAK/STAT pathway  

摘要： Liver cancer represents the third leading cause of cancer-related mortality globally, with hepatocellular carcinoma (HCC) accounting for the majority of cases. Despite a range of treatment options, the prognosis for advanced HCC remains poor, underscoring the need for further investigation into its pathogenic mechanisms and identification of potential therapeutic targets. Interferon gamma (IFN gamma) plays a crucial and multifaceted role in the occurrence and development of tumors. During tumorigenesis, alterations in miRNA expression occur, leading to subsequent changes in the expression of downstream target genes. However, the precise mechanism through which IFN gamma exerts its effect via miRNA remains incompletely understood. In this study, high-throughput sequencing was employed to explore the miRNAs regulated by IFN gamma in an HCC cell line. The results revealed that IFN gamma regulates 17 uncharacterized miRNAs and 30 named miRNAs identified in the miRNA database. Among the miRNAs regulated by IFN gamma, miR-1291 emerged as a prominent candidate. This study observed that miR-1291, along with KANSL2 mRNA and protein, is significantly upregulated in HepG2 and Huh7 cells. To investigate the role of miR-1291, HepG2 cells with both overexpression and inhibition of miR-1291 were established. High-throughput sequencing was then performed to examine the functional impact of miR-1291. The sequencing results revealed that genes regulated by miR-1291 are involved in cell cycle regulation and DNA replication. These findings were validated through qRT-PCR, cell proliferation assays, and colony formation assays, all of which confirmed that miR-1291 promotes HepG2 cell proliferation. Further analysis using a luciferase reporter assay and Western blot confirmed that SOCS3 is a direct target of miR-1291. Additionally, Western blot experiments demonstrated that miR-1291 promotes phosphorylation of the JAK/STAT signaling pathway by targeting SOCS3. These observations provide c

关键词： IL-37   APAP   Liver injury   Sterile inflammation   Oxidative stress  

摘要： Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI), which can lead to sterile inflammation and progress to acute liver failure and even death. However, there are currently limited therapeutic options available. Iinterleukin-37 (IL-37) is considered as an anti-inflammatory cytokine. The role and novel mechanism of IL-37 on DILI are still unknown. Male C57BL/6 mice were pretreated with IL-37 for 2 h prior to intraperitoneal injection of acetaminophen (APAP). Hepatic function was assessed by measuring serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Liver tissue damage was evaluated via hematoxylin and eosin (H&E) staining. The inflammatory response was characterized by immunohistochemical (IHC) analysis of myeloperoxidase (MPO) and lymphocyte antigen 6 complex locus G (Ly6G), and the levels of interleukin-6 (IL-6), IL-10, transforming growth factor-beta 1 (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) in liver tissue. Oxidative stress status was determined by measuring superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels. CYP2E1 mRNA expression was analyzed using qPCR. Protein expression of phosphorylated p38 (pP38), phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), and phosphorylated p65 (pP65) was evaluated by Western blotting. Compared to the model group without recombinant human IL-37 treatment, the model + IL-37 group exhibited significantly attenuated liver injury, characterized by reduced neutrophil infiltration, decreased levels of pro-inflammatory mediators IL-6 and TNF-alpha, and elevated levels of the anti-inflammatory cytokines IL-10 and TGF-beta 1. The levels of pp38, pERK1/2, and pp65 in liver tissue were significantly suppressed in the Model + IL-37 group compared to the Model group at 24 h. Furthermore, MDA levels were significantly lower in the IL-37-treated group relative to the model group, while