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关键词： endocannabinoids   graft-versus-host disease   inflammation  

摘要： Graft-versus-host disease (GVHD), a secondary complication of bone marrow transplantation, leads to the development of a systemic inflammatory illness in the host, resulting in high mortality and morbidity. Current therapies lack prophylactic effectiveness and often fail to achieve an optimal immunological balance between inflammation and immunosuppression. In this study, we investigated the effects of palmitoylethanolamide (PEA), an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory, and neuroprotective effects, on the complex pathology of GVHD. Treatment with PEA reduced clinical disease severity in GVHD mice, leading to an 80% increase in survival rates. Additionally, PEA created an immunoregulatory environment in the spleen by reducing the activation of CD3+CD4+ cells. In the intestine, PEA protected against damage, reduced the number of CD3+CD4+ and CD3+CD8+ cells, and suppressed the activation of CD3+CD8+ cells. PEA also decreased the levels of TNF-alpha in the intestine and increased IL-10 production. Furthermore, in the liver, PEA treatment reduced the number of CD8+ cells, the activation of CD3+CD4+ and CD3+CD8+ cells, and TNF-alpha levels. The effect of PEA on survival was dependent on Peroxisome Proliferator-activated receptor gamma (PPAR-gamma) activation but did not rely on cannabinoid (CB) receptors activation. In addition to GVHD protection, PEA treatment did not interfere in the graft-versus-tumour response. These results demonstrate the therapeutic potential of PEA as a promising option for the treatment of GVHD, balancing inflammation and immunosuppression, and improving both survival and clinical outcomes.

摘要： [This corrects the article DOI: 10.1093/jbmrpl/ziaf056.].

关键词： recurrent aphthous stomatitis   macrophage   IL-17a   IFN-gamma   mucosa immunity   CD4+T cell   anti-Ly6G  

摘要： Recurrent aphthous stomatitis (RAS) is a common chronic oral disease with unclear pathogenesis. Chronic inflammation associated with RAS has been linked to the dysregulation of local immune responses. We used a murine model of acetic acid-induced chemical stomatitis (CS) to assess changes in the systemic and local immune environments of CS mice relative to healthy mice. Flow cytometry revealed a significant increase in neutrophil infiltration and elevated proportions of Th1 (CD4+IFN-gamma+) and Th17 (CD4+IL-17a+) cells in the lingual mucosa of CS mice 7 d after CS induction, indicating an active inflammatory response in the CS immune microenvironment. Given that Th17 cells indirectly recruit neutrophils, we used Rorc-/- mice to evaluate the effects of Th17 cell depletion. Neutrophil infiltration was markedly reduced, and decreased tissue damage was observed in the lingual mucosa of Rorc-/- mice, as confirmed by hematoxylin and eosin staining. To further investigate the mechanism underlying Th17 cell generation in stomatitis, we induced CS in Il6ra-/- mice, which exhibited significantly reduced inflammatory cell infiltration and ulcer severity in the lingual mucosa. Treatment with an anti-Ly6G antibody treatment, which can directly target and deplete neutrophils, also significantly reduced local inflammation in the CS mouse immune microenvironment and diminished Th1 and Th17 cell infiltration, indicating a positive feedback loop between Th17 cells and neutrophils in stomatitis. In conclusion, the IL-6-Th17-neutrophil axis plays a critical role in stomatitis pathogenesis, suggesting that targeting this axis could present a novel immunotherapeutic strategy for alleviating mucosal damage in patients with RAS.

关键词： checkpoint blockades   immunotherapy   response prediction   MHC-I pathway   tumor mutational burden   TMB  

摘要： Immune checkpoint inhibitors produce durable antitumor effects in various cancers, but not all patients respond. High tumor mutational burden (TMB) is a known predictor of clinical benefit. In this study, we focused on the MHC-I-dependent neoantigen presentation pathway to enhance predictive capabilities beyond TMB. Using pan-cancer immunogenomic analyses of somatic mutation data from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we analyzed 33 cancer types. Objective response rates (ORRs) to PD-1/PD-L1 inhibitors were evaluated in relation to immune characteristics, including TMB, neoantigen load, MHC-I gene expression, and CD8+ T cell fraction. Spearman's rank correlation was used to assess these relationships. TMB s howed the strongest correlation with ORR (r=0.783, P=2.17x10-5). However, integrating TMB, HLA-A expression, and CD8+ T cell fraction significantly improved predictive accuracy (r=0.865, P=1.80x10-6). Validation in external cohorts confirmed these findings, revealing notable differences in MHC-I pathway activity between responders and non-responders to immunotherapy. Our results demonstrate that the MHC-I antigen presentation pathway is strongly associated with response to PD-1/PD-L1 inhibitors. Importantly, combining antigen expression, processing, presentation, and recognition features provides superior predictive power compared to TMB alone. This integrated approach could improve treatment outcome predictions and advance personalized immunotherapy strategies.

关键词： interleukin-33   hepatocellular carcinoma   programmed death ligand 1   regorafenib   sorafenib  

摘要： Hepatocellular carcinoma (HCC) is a highly lethal cancer with increasing incidence rates worldwide. The recommended treatments for advanced-stage HCC are sorafenib and regorafenib;however, developing resistance to these medications significantly limits their effectiveness, and the underlying mechanisms are poorly understood. The present study demonstrated that interleukin-33 (IL-33) promotes sorafenib resistance via immune regulation. In vitro, western blotting and reverse transcription-quantitative PCR showed that both sorafenib and regorafenib treatments led to an increase in the upregulation and secretion of IL-33 through a positive feedback loop involving the IL-33/transmembrane suppression of tumorigenicity 2 (ST2L) pathway. Senescence-associated beta-galactosidase staining and western blotting revealed that sorafenib and regorafenib treatments induce cell senescence in HCC cells. Flow cytometric analysis indicated that he secreted IL-33 enhanced programmed cell death ligand 1 (PD-L1) expression in HCC cells by activating NF-kappa B pathways in response to the treatments. In vivo, a HCC-bearing subcutaneous mouse model revealed that blocking the IL-33 signaling pathway with anti-IL-33 or anti-ST2L neutralizing antibodies, combined with sorafenib, significantly reduced tumor size, growth rate, and weight. Additionally, there was a notable decrease in tumor PD-L1 expression and an increase in intra-tumor CD8+ T cells infiltration. Importantly, the enhanced therapeutic efficacy of the anti-IL-33 treatment in sorafenib-treated HCC-bearing mice was lost in immunocompromised mice. This indicates that the anti-IL-33 neutralizing antibody enhances the antitumor activity of sorafenib by modulating the immune response rather than directly affecting HCC cell proliferation. The findings of the present study suggested that IL-33 plays a role in decreasing the therapeutic effectiveness of sorafenib and regorafenib in HCC cells. The present study highlights the potential of t

关键词： Atherosclerosis   C1q/TNF-related protein-1   Mendelian randomization   Coronary artery disease   Ischemic stroke   Multivariate  

摘要： Aims: To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease. Methods: Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors. Results: Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR =1.31, CI:1.04-1.66;FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19;FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11;FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18;FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis. Conclusion: CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

关键词： Gynecology   Interleukin 10   Neopterin   Nutritional risk index   Oncology  

摘要： Introduction: We aimed to investigate the relationship between preoperative nutritional status with postoperative interleukin-10 (IL-10) and neopterin in gynecologic oncology cases. Materials and methods: This prospective study included cases hospitalized in our clinic. Preoperative cases were divided into two groups as low and high risk according to Nutritional risk score (NSR-2002). Demographic and clinical characteristics and questionnaires including the NSR-2002 form were recorded. IL-10 and neopterin levels were analyzed 1 week postoperatively. Results: Forty-five low-risk and 43 high-risk cases were evaluated. The mean ages of the cases were 56.7 +/- 7.8 and 57.2 +/- 14.3 years, respectively, and no significant difference was found between them (P = 0.854). There was a statistically significant difference between the two groups in terms of upper arm circumference (P = 0.043), triceps skinfold thickness (P = 0.010), shorter wound healing time (P = 0.009), neopterin (P = 0.037), IL-10 (P = 0.043), preoperative ferritin (P = 0.001), hemoglobulin (P = 0.026), albumin (P = 0.047), postoperative ferritin (P = 0.015), hemoglobulin (P = 0.044), and albumin (P = 0.042) levels in favor of the low-risk group. Among the significant factors, only wound healing time had positive correlation (P = 0.006, r = +0.290). Conclusions: Nutritional status is closely related to case recovery in the postoperative period. Postoperative changes to high interleukin-10 and neopterin levels in cases with low nutritional index show the importance of nutrition in the postoperative period. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： All-trans retinoic acid   Keratinocytes   Apoptosis   Inflammatory responses   Stevens-Johnson syndrome   Toxic epidermal necrolysis  

摘要： Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe hypersensitivity reactions characterized by extensive epidermal necrosis, often induced by medications. This research aims to investigate the involvement of all-trans retinoic acid (ATRA), a derivative of vitamin A known to induce dermatological toxicity resembling SJS/TEN, in the development of these conditions. Utilizing network toxicology methodologies, molecular docking technology, and experimental validation, we identified 159 common targets between ATRA and SJS, 38 with TEN, and 27 shared among all three conditions through databases such as SwissTargetPrediction and GeneCards. Protein-protein interaction (PPI) network analyses highlighted key targets like TNF, MAPK1, and IL6, associated with apoptosis, inflammation, and immune regulation. Enrichment analyses identified significant pathways, particularly TNF, MAPK, and JAK-STAT signaling pathways. Molecular docking studies confirmed strong binding interactions between ATRA and these central targets. Experimental results demonstrated that ATRA treatment reduced keratinocyte viability, increased apoptosis, raised lactate dehydrogenase (LDH) release, and upregulated pro-inflammatory cytokines such as TNF-alpha, IL1B, IL6, and PTGS2 in human keratinocyte cell lines (HaCaT) and primary keratinocytes (NHEK).Western blot analysis revealed ATRAinduced upregulation of cleaved caspase-3 and phosphorylated NF-kappa B p65, alongside increased COX-2 and TNF-alpha protein levels, confirming activation of apoptotic and inflammatory pathways downstream of TNF signaling. These findings suggest that ATRA may exacerbate SJS/TEN pathogenesis by influencing apoptotic pathways and inflammatory responses via TNF-related mechanisms, offering insights for exploring therapeutic targets and enhancing drug safety in clinical settings.

关键词： Lymphocyte-specific protein-1 (LSP1)   Experimental Sjogren's syndrome (ESS   Th17 cells   Primary Sjogren's syndrome (pSS  

摘要： Lymphocyte-specific protein-1 (LSP1) is known to negatively regulate T cell migration in autoimmune diseases. However, its role in the development of T cell-dependent Sjogren's syndrome remains unknown. In this study, we found that LSP1 expression was decreased in T cells in salivary glands (SGs) of mice with experimental Sjogren's syndrome, accompanied by enhanced infiltration of leukocytes into SGs. Moreover, Lsp1- /- mice had higher frequency of IL-17A-expressing T cells in cervical lymph nodes as well as increased severity in SGs than WT mice. Concurrently, LSP1 expression was reduced in human T cells of primary Sjogren's syndrome (pSS) patient. Particularly, pSS patients showed an increased Th17 cells, which inversely correlated with LSP1 expression. Taken together, these findings suggest that LSP1 deficiency promote Th17 cell development and exacerbation of pSS. LSP1 might be a potential therapeutic target to regulate Th17 response and to treat autoimmune diseases like pSS.

关键词： PMBCL   TNF-alpha   IFN-gamma   PD-L1  

摘要： Objectives: Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that shares features with diffuse large B-cell lymphoma (DLBCL), but also with classical Hodgkin lymphoma (cHL). PMBCL often contains aberrations of genes involved in the immune response such as cREL and PD-L1, whose expression is also influenced by cytokines TNF-alpha and IFN-gamma. Methods: In this study, cell lines Farage, U2940, MedB-1 and Karpas1106p were used as PMBCL models and treated with different concentrations of TNF-alpha and IFN-gamma over 24 and 48 h, followed by the quantification of cREL, CXCL10 and PD-L1 expression. Additionally, the expression of TNF-alpha, IFN-gamma, cREL, CXCL10, CXCR3, PD-L1 and PD-1 genes was compared between PMBCL tissue samples and B-cell and T-cell rich zones of non-tumour tonsils. Results: Prolonged exposure to TNF-alpha increased cREL expression, while IFN-gamma strongly induced CXCL10 expression. The change in the expression of PD-L1 in response to the treatments differed across various cell lines. There was no statistically significant difference in the expression of the target genes between tumour and non-tumour patient tissue samples. Conclusions: the obtained results suggest that the immune checkpoints in PMBCL cells are affected by both their genetic profile and tumour microenvironment.