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关键词： Hepatocellular carcinoma   Aflatoxin B1   M2-like macrophages   IL-6-mediated immunosuppression   Immunotherapy  

摘要： BackgroundThe development of liver cancer in China is mainly caused by HBV, HCV infection, and exposure to aflatoxin. Especially in warm and humid southern regions, aflatoxin pollution poses a threat to health, emphasizing the urgency of research on related liver ***, through in vivo experiments, the important role of AFB1 in mediating changes in the immune microenvironment of liver cancer has been preliminarily validated. In addition, statistical and mIHC analysis were conducted on clinical specimens collected from patients exposed and non-exposed to aflatoxin. Transcriptome sequencing technology enabled us to further explore the specific molecular mechanisms underlying the occurrence of HCC caused by AFB1 exposure. Finally, the synergistic effect of targeting IL-6 on PD1 therapy was validated through an in vivo animal tumor *** found that AFB1 indirectly influences M2-like macrophage polarization by upregulating IL-6 expression in tumor cells through the NF-kappa B signaling pathway. To address this challenge, we evaluated the efficacy of targeting IL-6 in combination with PD1 antibody therapy in a subcutaneous tumor model. Our results demonstrate that the combination treatment significantly reduces tumor growth, decreases the number of M2-like macrophages, and enhances CD8 + T cell infiltration compared to monotherapy with PD1 antibody ***, our study highlights the potential of targeting IL-6 as a therapeutic strategy and suggests avenues for further research and clinical studies to validate and translate these findings into clinical applications, ultimately leading to improved outcomes for patients with AFB1-associated hepatocellular carcinoma.

关键词： HLA-DQB1*06:483   HLA-genotyping   Illumina  

摘要： The HLA-DQB1*06:483 allele differs from HLA-DQB1*06:10 by a single nucleotide substitution in exon 3.

关键词： Celiac disease   Gluten-Free Diet   immune modulation   scRNA-seq   regulatory T cells   APCs   antigen-presenting cells   CD   celiac disease   DE   differential expression   DEGs   differentially expressed genes   GFD   Gluten-Free Diet   GIP   gluten immunogenic peptides   HLA   human leukocyte antigen   IEL   intraepithelial lymphocytes   PBMCs   peripheral blood mononuclear cells   QC   quality control   scRNA-seq   single-cell RNA sequencing   Th   T helper cell   Treg   regulatory T cell   UMAP   uniform manifold approximation and projection for dimension reduction  

摘要： Celiac disease (CD) is an autoimmune disorder with a strong genetic component, triggered by gluten ingestion. Although a Gluten-Free Diet (GFD) is the standard treatment, its short-term effects on immune cell modulation in pediatric CD remain largely unexplored. This study aimed to investigate transcriptional changes in peripheral blood mononuclear cells (PBMCs) of pediatric CD patients following a strict GFD for 9–10 months, using single-cell RNA sequencing (scRNA-seq). An observational longitudinal study was conducted on five pediatric CD patients pre-GFD and post-GFD (confirmed by gluten immunogenic peptide determination in feces). PBMCs were analyzed using droplet-based scRNA-seq to identify cluster markers and differentially expressed genes (DEGs) between pre-GFD and post-GFD cells. Nineteen immune cell clusters encompassing a variety of classical immune cell subtypes were identified. Key findings included the downregulation of pro-inflammatory genes and the upregulation of immune-regulatory genes after a GFD in different immune cell subsets. Changes in macrophages and monocytes suggested improved immune balance, while T cells demonstrated a shift towards reduced effector activity. Notably, post-GFD regulatory T cells transitioned into a trajectory towards enhanced immunosuppressive profiles, as evidenced by increased HLA-G and decreased DDX5 expression. A strict short-term GFD induced significant immune modulation in pediatric CD patients, highlighting potential biomarkers for disease monitoring. Nevertheless, due to the small sample size, results should be interpreted with caution, and larger cohort studies are needed for further confirmation and validation. These findings provide insights into the immunological mechanisms of GFD and suggest avenues for non-invasive diagnostic strategies to enhance patient management.

关键词： Inflammation   Interleukin-6   Neonatal Mortality   Non-competitive Modulator   Preterm Birth  

摘要： Preterm birth (PTB) is a major cause of neonatal mortality and morbidity. Evidence supports a determinant role for interleukin-6 (IL-6) in the pathophysiology of PTB. Our group developed a small peptide, HSJ633, that antagonizes the interleukin-6 receptor (IL-6R). Binding assays performed on HEK-Blue IL-6 cells reveal that HSJ633 appears to bind to IL-6R on a site remote from the IL-6 binding domain. Concordantly, HSJ633 selectively inhibits STAT3 phosphorylation while preserving the activation of cytoprotective AKT, p38, and ERK 1/2. In vivo, in a murine model of LPS-induced PTB, HSJ633 reduces inflammation in gestational and fetal tissues, preserves the integrity of fetal organs, and improves the survival of neonatal progeny when administered before and after the induction of labor by an inflammatory stimulus. Relevantly, the pharmacological inhibition of STAT3 in mice is sufficient to prevent PTB. Findings reveal first-in-class efficacy of a small peptide inhibitor of IL-6R, namely HSJ633, in impeding the inflammatory cascade associated with PTB and mitigating adverse neonatal outcomes.

关键词： Dendritic cells   Interleukin-12p70   Mycobacterium tuberculosis   NADPH oxidase 4   Type 1 T helper cells  

摘要： Background Mycobacterium tuberculosis (Mtb) infection triggers oxidative stress, necessitating host mechanisms to maintain redox balance. The NADPH oxidase (NOX) family, which produces reactive oxygen species, plays an integral part in this process. While the protective role of NOX2 in Mtb infection is well-studied, the function of NOX4 remains unclear. Methods To investigate the impact of NOX4, we infected C57BL/6 wild-type (WT) and NOX4-deficient ( Nox4 -/- ) mice with the Mtb K strain, assessing bacterial burdens, lung pathology, and immune responses. Then, we analyzed cytokine production and signaling pathways to explore the interaction between dendritic cells (DCs) and T cells. Results Nox4 -/- mice exhibited reduced bacterial burden and milder lung pathology compared to WT mice, accompanied by increased DC infiltration and a higher frequency of CD4 + T cells of the Th1 subset that secrete interferon-gamma (IFN-γ) in the lungs . Interestingly, ex vivo experiments showed no significant difference in IFN-γ production by T cells from WT and Nox4 -/- mice when activated using antibody-coated beads. However, Mtb-infected bone marrow-derived DCs (BMDCs) from Nox4 -/- mice markedly enhanced IFN-γ production in WT T cells. Further investigation into the role of NOX4 in DCs revealed that BMDCs from Nox4 -/- mice infected with Mtb produced significantly higher levels of IL-12. This elevation was attributed to enhanced activation of IRF1, mediated by the AKT/GSK-3β signaling pathway. Conclusion NOX4 negatively regulates IL-12 production in Mtb-infected DCs, suppressing Th1-mediated immunity. Its absence enhances Th1 responses, improves immune control of Mtb. Targeting NOX4 may improve tuberculosis outcomes by strengthening host immunity.

关键词： HLA-DRA   CcRCC   Prognosis   Tumour microenvironment   Single-cell sequencing  

摘要： Recombinant human leukocyte antigen class II histocompatibility antigen (HLA-DRA) has been implicated in the development of various cancers, but its specific role in clear cell renal cell carcinoma (ccRCC) remains *** samples and clinicopathological data from 78 ccRCC patients were collected. Immunohistochemical staining and H-Score analysis were performed to evaluate HLA-DRA expression and its association with clinicopathological features and prognosis. A survival prediction model incorporating multiple clinical and pathological variables was developed. Immune infiltration analysis explored HLA-DRA's role in the tumor microenvironment at the single-cell level, while pathway enrichment analyses identified chemicals, genes, and co-expressed genes associated with HLA-DRA. HLA-DRA expression was significantly higher in ccRCC tissues compared to adjacent normal tissues. Elevated HLA-DRA expression correlated with the Fuhrman nuclear grade and was associated with poor prognosis, as demonstrated by Kaplan-Meier and Cox regression analyses. Diagnostic and prognostic models, including ROC curve and nomogram analyses, highlighted HLA-DRA's predictive value. Immune infiltration analysis revealed strong associations between HLA-DRA expression and the infiltration of lymphocytes, chemokines, and chemokine receptors, with single-cell studies pinpointing monocyte macrophages as the primary source of HLA-DRA expression. Co-expression and pathway enrichment analyses suggested that HLA-DRA contributes to ccRCC pathogenesis and progression through diverse pathways. Additionally, several chemicals were identified as modulators of HLA-DRA ***-DRA plays a pivotal role in ccRCC diagnosis, prognosis, and immune regulation, highlighting its potential as a biomarker and therapeutic target.

关键词： fibro-adipogenic progenitor cells (FAPs)   heme oxygenase-1 (HO-1)   interleukin-6 (IL-6)   muscle satellite cells (MuSCs)   myogenic differentiation   oxidative stress  

摘要： Fibro-adipogenic progenitor cells (FAPs) support muscle tissue homeostasis, regulate muscle growth, injury repair, and fibrosis, and activate muscle progenitor cell differentiation to promote regeneration. We aimed to investigate the effects of co-culturing FAPs with muscle satellite cells (MuSCs) on myogenic differentiation. Proteomic profiling of co-culture supernatants identified significant DCX, IMP2A, NUDT16L1, SLC38A2, and IL-6 upregulation. Comparative transcriptomics of mono-cultured versus co-cultured MuSCs revealed differential expression of oxidative stress-related genes (, , , , , and ). Pathway enrichment analyses highlighted cell cycle regulation, TNF signaling, and ferroptosis. Gene ontology analysis of MuSCs indicated significant gene enrichment in myosin-related components. Combined transcriptomic and proteomic analyses demonstrated HO-1 downregulation at the transcriptional and translational levels, with altered pathways being predominantly related to myosin filament, muscle system process, and muscle contraction cellular components. HO-1 knockdown reduced intracellular iron accumulation in MuSCs, suppressing iron-dependent autophagy. This alleviated oxidative stress and promoted myogenic differentiation. Exogenous IL-6 (0.1 ng/mL) downregulated HO-1 expression, initiating an identical regulatory cascade, while HO-1 overexpression reversed the IL-6-mediated reduction in the expression of the autophagy markers LC3 and ATG5, suppressing myogenic enhancement. This establishes the co-culture-induced IL-6/HO-1 axis as a core regulator of iron-dependent oxidative stress and autophagy during myogenic differentiation.

关键词： DRB1*15:03 positive   DRB5 negative   linkage disequilibrium   putative haplotypes  

摘要： The HLA class II region contains nine DRB genes: DRB1, DRB3, DRB4 and DRB5 express functional gene products, whereas DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes. In this study, we assessed the frequency and diversity of two functional genes, DRB1 and DRB5;in particular, HLA-DRB1*15:03 with absence of the associated HLA-DRB5*01:01 allele (DRB1*15:03 positive DRB5*01:01 negative). We aimed to determine the frequency of DRB1*15:03 positive DRB5*01:01 negative in this cohort and to define any putative full or partial haplotypes that may show this genotype pattern. We performed HLA typing by NGS using One Lambda AllType or CareDx AlloSeq Tx17 on 6268 solid organ transplant (SOT) samples using DNA extracted from either buccal swabs or whole blood. The absence of HLA-DRB5 was confirmed by One Lambda LABType rSSOP. Confirmation of DRB1*15 homozygotes was performed by CareDx Copy Number (RUO) tool. In the present cohort, 554 (8.8%) individuals were identified as HLA-DRB1*15:03 positive. Of those, 48 individuals (8.7% of HLA-DRB1*15:03 positive) did not have the associated DRB5*01:01 allele present. We believe that this percentage could be as high as 11.2% when considering DRB1*15:XX homozygotes. Although linkage disequilibrium analysis showed strong LD between DRB1*15:03 and DRB5*01:01 (D ' = 0.89), supporting their co-inheritance on the same haplotype block, a moderate correlation coefficient (r2 = 0.302) implied that DRB5*01:01 is not always present in all DRB1*15:03 carriers. Extended haplotypes associated with this phenomenon were constructed and characterised. Certain HLA-A, B, DRB1 haplotypes were strongly predictive of absent DRB5. To our knowledge, this is the largest cohort ascertaining the diversity and frequency of the HLA-DRB1*15:03 apparent haplotypes. Our results show a considerable proportion of DRB1*15:03 positive individuals lack the DRB5 gene. The results of this study are useful for unrelated donor research, transplantation, anthropological and disease

关键词： TNF-alpha   308 G > A   Migraine risk   Jammu population   Migraine with aura   Migraine without aura   Pro-inflammatory cytokines  

摘要： Migraine is a complex neurological disorder characterized by recurrent unilateral headaches. Its pathophysiology has been associated with inflammatory processes, with TNF-alpha, a pro-inflammatory cytokine, being one such factor implicated in various neurological conditions, including migraine. This study aimed to evaluate the association between the TNF-alpha -308 G > A polymorphism and migraine risk by integrating both a case-control investigation and a meta-analysis to enhance statistical power and reliability. The investigation commenced with a case-control study in the Jammu region of North India, conducted in accordance with STROBE guidelines. To enhance statistical power and reliability, a meta-analysis of independent studies was performed, followed by Trial Sequential Analysis to verify sample size adequacy. First, the case-control study showed that there was no significant association between -308 G > A and overall migraine risk across various genetic models (allele: 0.80 [0.58-1.11], p = 0.193) in the Jammu population. Although the migraine with aura subgroup showed marginal significance in the allelic model (p = 0.02), this association was not supported after adjustment (p = 0.14). Similarly, the meta-analysis revealed no significant association between the polymorphism and overall migraine (allele: 1.21 [0.92-1.58], p = 0.16) or its two clinical subtypes, migraine with aura and without aura. However, when stratified by ethnicity, a significant association was identified in African populations, while no such association was observed in Asian or Caucasian groups. This study underscores the importance of combining case-control data with meta-analysis to strengthen genetic association findings. Future research should focus on larger, multi-ethnic cohorts to validate these findings and improve generalizability.