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关键词： Mechanical stress   Cytokines   Focal adhesion kinase   Ion channels   Gingival epithelial cells  

摘要： Objectives: Mechanical stress on the teeth and alveolar bone caused by bruxism, orthodontics, and implants affects the periodontal tissues, causing gingival recession and alveolar bone resorption, and entire body, including the heart and vascular system. Although the same forces exerted on the alveolar bone and teeth are exerted on gingival epithelial cells, little is known about the effects of mechanical stress on these cells. This study investigated the effects of mechanical stress on gingival epithelial cells. Methods: Ca9-22 cells (human gingival epithelial cells) were used. They were seeded onto the silicone and stretched cyclically. Mechanical stress-stimulated Ca9-22 cells were evaluated for pro-inflammatory interleukin (pro-IL)-1(3 production using Western blotting and analyzed to assess the phosphorylation level of intracellular signaling molecules. Results: Mechanical stress induced pro-IL-1(3 upregulation in Ca9-22 cells, which was significantly inhibited by ruthenium red. Ruthenium red significantly inhibited mechanical stress-induced phosphorylation of focal adhesion kinase (FAK), P130cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2) induced by mechanical stress. Additionally, Y15 significantly inhibited the upregulation of pro-IL-1(3 expression and phosphorylation of FAK, P130cas, and ERK1/2 stimulated by mechanical stress. Conclusions: In Ca9-22 cells, mechanical stress may increase pro-IL-1(3 production via mechanosensitive ion channels and FAK. These findings revealed the mechanisms of inflammation in mechanically-stressed Ca9-22 cells and may aid in the development of therapeutic approaches to prevent bone resorption.

关键词： CD8(+) T-lymphocytes   dendritic cells   epitopes   HCC   T-lymphocyte   tumor-associated antigen  

摘要： Background: HCC is the most common form of primary liver cancer, and despite recent advances in cancer treatment, it remains associated with poor prognosis and a lack of response to conventional therapies. Immunotherapies have emerged as a promising approach for cancer treatment, especially through the identification of tumor-specific immunogenic epitopes that can trigger a targeted immune response. This study aimed to identify immunogenic epitopes associated with HCC for the development of specific immunotherapies. Methods: We used high-throughput data screening and bioinformatics tools for antigens and epitope selection. The immunogenicity of the selected epitopes was studied after coculture of peripheral blood mononuclear cells obtained from healthy donors or HCC patients with a plasmacytoid dendritic cell line loaded with the selected peptides. Specific CD8(+) T cell amplification and functionality were determined by labeling with tetramers and by IFN-gamma and CD107a expression (flow cytometry and ELISpot). Results: We analyzed the transcriptional gene expression landscape of HCC to screen for a set of 16 ectopically expressed genes in a majority of HCC samples. Epitopes predicted to bind to HLA-A*02:01 with high affinity were further validated for their immunogenicity using the previously described plasmacytoid dendritic cell line in ex vivo CD8(+) activation assays using patient immune cells. Three out of the 30 tested epitopes, namely FLWGPRALV (MAGE-A3), FMNKFIYEI (AFP), and KMFHTLDEL (LRRC46), elicited a strong T-cell response, in activation assays, degranulation assays, and IFN-gamma secretion assays. Conclusions: These results highlight the potential of these peptides to be considered as targets for immunotherapies. The discovery of such immunogenic epitopes should improve immune-based treatments for liver cancer in combination with the current treatment approach.

关键词： HLA   HLA-DPA1*01:03:61   novel allele   sequencing-based typing  

摘要： HLA-DPA1*01:03:61 differs from HLA-DPA1*01:03:01:02 by one nucleotide substitution in codon 81 in exon 2.

关键词： TB   tuberculosis   TNF   tumor necrosis factor  

关键词： AVL9   Chemoresistance   NF-κB   KPC   PDAC   AG   gemcitabine combined with albumin-paclitaxel (Abraxane)   AUC   area under the curve   ChIP   chromatin immunoprecipitation   dCDA   dCyd deaminase   dCK   dCyd kinase   DEGs   differentially expressed genes   FNA   fine-needle aspiration   GEM   gemcitabine   HRE   hypoxia response element   IC50   half maximal inhibitory concentration   IFN   interferon   IHC   immunohistochemistry   IKK   inhibitor of kappa B kinase   IκB   inhibitory-κB   KPC   Kras G12D Trp53 R172H Pdx1-Cre   KPCA   Kras G12D Trp53 R172H Pdx1-Cre AVL9 fl/fl   mRNA   messenger RNA   NF-κB   nuclear factor–κB   p-   phosphorylated   PCA   principal components analysis   PDAC   pancreatic ductal adenocarcinoma   PDO   patient-derived organoid   PDX   patient-derived xenograft   scRNA-seq   single cell transcriptomic sequencing   SKP1   S-Phase Kinase Associated Protein 1   TCGA   The Cancer Genome Atlas   tSNE   t-distributed stochastic neighbor embedding  

摘要： BACKGROUND & AIMS: Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen. METHODS: We used organoid models, patient-derived xenografts, and genetically engineered mouse models in our study. Chromatin immunoprecipitat ion, double luciferase assay, coimmunoprecipitation, and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in patient-derived xenografts, patient-derived organoids-based xenograft, and KPC models. RESULTS: Through multistrategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1a, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IkBa to SKP1, leading to enhanced ubiquitination and degradation of IkBa, which further activates the nuclear factor-kB pathway. The potential AVL9targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC. CONCLUSION: AVL9 expression is driven by HIF-1a in PDAC. The physical interaction of AVL9, IkBa, and SKP1 provides a novel molecular mechanism for the abnormal activation of the nuclear factor-kB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.

关键词： Clear aligner   Cytokines   Gingival crevicular fluid   Interleukin-8   Interleukin-6  

摘要： Objectives: To compare short-term changes in the levels of interleukin-8 (IL-8) and interleukin-6 (IL-6) in the gingival crevicular fluid (GCF) of individuals undergoing orthodontic treatment with clear aligners. Materials and Methods: This study included 15 individuals. Each patient used clear aligners designed not to cause tooth movement in the GCF sampled teeth, to be changed every 10 days. GCF samples were collected from teeth 16 (upper right first molar) and 31 (lower left central incisor) at baseline and after the procedure at the first hour, third, seventh, 14th, and 21st days. In addition, clinical periodontal parameters for the full mouth and the teeth from which GCF was collected were recorded initially and on the 21st day. Results: A statistically significant difference was observed between the levels of IL-8 before the procedure, on the third and seventh days, and on the 21st day (P < .01). The increase in IL-6 levels on the 14th and 21st days was significantly different compared to the levels before the procedure (P < .01). A positive correlation was detected between IL-8 and IL-6 levels at the first hour, a negative correlation on the third day, and a lower level of positive correlation on the seventh, 14th, and 21st days. Conclusions: Within 21 days, the levels of IL-8 and IL-6 significantly increased in individuals undergoing orthodontic treatment with clear aligners. Within the limits of this study, the clear aligner material may affect the levels of IL-8 and IL-6 in the GCF.

关键词： AML   GAL-9   Inflammation   IL-1 beta   NF-kappa B  

摘要： Background and purpose:T-cell immunoglobulin and mucin-domain containing protein-3 (TIM-3)/ galectin-9 (Gal-9)/ autocrine loop in myeloid leukemia stem cells provokes inflammation through the NF-kappa B signaling pathway, which is influential in the expression of inflammatory factors. Interleukin 1 beta (IL-1 beta) is a vital inflammatory cytokine that plays an important role in the proliferation and therapy resistance of acute myeloid leukemia (AML) cells. This study aimed to assess the effect of Gal-9 on IL-1 beta in the human leukemic U937 cell *** approach:The U937 cells were cultured in different concentrations of Gal-9. Cell counting kit-8 was used to assess the effect of Gal-9 on human leukemic U937 cell proliferation. Also, its impact on the expression of TIM-3, Gal-9, IL-1 beta, IL-1 beta R, IL-1 beta RAP, and NLRP3 genes and IL-1 beta protein was studied by RT-PCR and ELISA, respectively. Moreover, the effect of Gal-9 on the NF-kappa B signaling pathway was evaluated by western ***/Results:U937 cells were expanded in the presence of Gal-9 in a concentration-dependent manner. Following treatment of U937 cells with Gal-9, the gene expression of Gal-9, IL-1B, IL-1BR, and IL-1BRAP were significantly upregulated compared to the control group. The IL-1 beta concentration increased following Gal-9 treatment in a concentration-dependent manner, while following time-pass its level significantly decreased. Furthermore, Gal-9 slightly increased NF-kappa B *** and implications:Gal-9 increased IL-1 beta level as a critical inflammatory cytokine in the proliferation and resistance of AML cells to therapy. According to this finding, targeting and blocking the TIM-3/Gal-9 autocrine loop can suppress IL-1 beta production and facilitate AML treatment.

关键词： Transmembrane TNF-alpha   Reverse signaling   LPS/TLR4 signaling pathway   MCPIP1   SIRT1  

摘要： Background: Studies have demonstrated that transmembrane tumor necrosis factor-alpha (tmTNF-alpha) plays an anti-inflammatory role. tmTNF-alpha has a dual function, acting as both a signaling ligand and a receptor that transmits reverse signaling to cells expressing tmTNF-alpha. However, the role and mechanisms of tmTNF-alpha reverse signaling in sepsis are not fully understood. Objective: To explore the potential role and mechanisms of tmTNF-alpha reverse signaling in lipopolysaccharide (LPS)-induced inflammation. Methods: The expression levels of tmTNF-alpha and TNF-alpha mRNA were evaluated using flow cytometry and real-time PCR, respectively. We employed the anti-TNF-alpha drug infliximab to stimulate tmTNF-alpha reverse signaling and measured interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP)-1 production through real-time PCR and ELISA in THP-1-derived macrophages. The location of p65 was determined through immunofluorescence assay. The phosphorylation and acetylation of p65, as well as the expression levels of MCP-induced protein 1 (MCPIP1) and Sirtuin 1 (SIRT1), were evaluated using western blotting. Results: Our findings revealed that tmTNF-alpha reverse signaling reduced the expression of IL-6 and MCP-1 triggered by LPS. tmTNF-alpha reverse signaling inhibited the nucleartranslocation of p65, suppressed p65 phosphorylation and acetylation, and upregulated the expression of negative regulatory molecules MCPIP1 and SIRT1 in the LPS/ toll-like receptor 4 (TLR4) signaling pathway . Conclusion: This study demonstrates that tmTNF-alpha reverse signaling plays a negative regulatory role in inflammation triggered by LPS by inhibiting the TLR4/ nuclear factor kappa B (NF-kappa B) signaling pathway. This study helps to further understand the function of tmTNF-alpha reverse signaling and offers new therapeutic possibilities for sepsis and other inflammatory diseasesconditions.

关键词： HLA-B*18:01:56   NGS HLA typing novel   novel HLA-B allele  

摘要： HLA-B*18:01:56 showed two synonymous nucleotide differences compared to the HLA-B*18:01:01:01 allele in codons 224 and 225.

关键词： l-DOPA-induced dyskinesia   neuroinflammation   NF-kappa B signalling pathway   TNF-alpha  

摘要： Levodopa-induced dyskinesia (LID) is a common and debilitating complication of long-term Parkinson's disease treatment. This review explores the roles of NF-kappa B and TNF-alpha signalling pathways in LID pathophysiology and potential therapeutic approaches targeting these mechanisms. Chronic levodopa treatment leads to aberrant neuroplasticity and neuroinflammation, involving activation of NF-kappa B and increased production of pro-inflammatory cytokines like TNF-alpha. NF-kappa B activation in glial cells contributes to sustained neuroinflammation and exacerbates dopaminergic neuron loss. TNF-alpha levels are elevated in brain regions affected by LID and correlate with dyskinesia severity. Several compounds are involved in mitigating LID by modulating these pathways. Agmatine reduces NF-kappa B activation and NMDA receptor expression while protecting dopaminergic neurons. Resveratrol and doxycycline demonstrate antidyskinetic effects by attenuating neuroinflammation and TNF-alpha production. The Rho-kinase (ROCK) inhibitor fasudil and cannabinoid receptor 2 (CB2) receptor agonists also show efficacy in reducing LID severity and neuroinflammation. Hydrogen gas inhalation decreases pro-inflammatory cytokine levels associated with LID. These findings highlight the complex interplay between NF-kappa B, TNF-alpha and other neurotransmitter systems in LID pathogenesis. Targeting neuroinflammation and glial activation through these pathways represents a promising strategy for developing novel LID treatments. Further research is needed to fully elucidate the mechanisms and optimize therapeutic approaches targeting NF-kappa B and TNF-alpha signalling in LID.