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关键词： Macrophages  

摘要： Asian sand dust (ASD), a significant desert sand dust, contains sub-2.5 µm fine particles and adversely affects human health, particularly exacerbating respiratory diseases. Despite this, the intricate physiological responses triggered by inhaled ASD particles remain incompletely understood. This study aimed to comprehensively examine the respiratory effects of ASD, focusing on the spatial distribution of inhaled ASD fine particles within the lungs and the immediate physiological responses they incite. Intratracheal administration of ASD fine particles in mice resulted in efficient phagocytosis by alveolar macrophages (AMs), leading to subsequent neutrophilic inflammation. A subset of ASD-phagocytosed AMs underwent necroptosis, releasing interleukin-1α (IL-1α), causing an increase in chemokines and neutrophils. These responses occurred rapidly within hours of exposure, with endotoxin in ASD particles contributing to the process. Despite variations in desert sand dust composition based on collection locale and timing, this study's findings provide a foundational basis for understanding the biological effects of desert sand dust. Insights gained into the biological responses to desert sand dust hold promise for developing preventive measures such as air purifiers, and therapeutic agents such as IL-1α neutralizing antibodies, antibacterial agents and cell death inhibitors for human diseases associated with such environmental exposures. © 2024 The Author(s)

关键词： Tea polyphenol   Lung injury   Inflammation   Silica particles   Silicosis   Pulmonary disease  

摘要： Background: Silicosis, an interstitial lung disease caused by inhalation of silica particles, poses a significant health concern globally. Green tea polyphenol (TP) stands out as a promising therapeutic candidate, yet its specific protective effects and in-depth mechanisms against silicosis have not been thoroughly investigated. Purpose: This study aimed to systematically assess the protective potential of TP against silicosis and to elucidate the underlying mechanisms of its action. Methods: A combination of physiological, transcriptomic, molecular, and computational techniques was employed. HPLC was used to identify the components of TP, and its antioxidant properties were tested with DPPH and ABTS assays. The effects of TP on lung injury were assessed in silicosis mice using histopathology, qRT-PCR, and western blot. Transcriptomic analysis was applied to explore the differentially expressed genes and pathways in response to TP intervention. In vitro studies with mouse alveolar macrophages (MH-S) examined TP's effects on cell viability, proliferation, apoptosis, and inflammation responses. Integrated qRT-PCR, western blot, immunohistochemistry, and molecular docking were performed to confirm the molecular mechanism underlying the protective effects of TP against silicosis. Results: TP effectively attenuated pulmonary inflammation and fibrosis in silicosis mice, as evidenced by significant reductions in inflammation and fibrotic markers. Moreover, TP's therapeutic benefits were linked to its cytoprotective effects on alveolar macrophages, notably its ability to protect MH-S cells from silica particle- induced apoptosis, inhibition of proliferation, and inflammatory response, underscoring its targeted protective effects at the cellular level. Mechanistically, TP exerted its anti-silicosis activity by targeting key pathways implicated in inflammatory responses, notably through the inhibition of the IL-17/NF-kappa B p65 signaling cascade. Molecular docking simulation

关键词： Chemerin   IL-6   TNF-alpha   OSCC   Metastasis  

摘要： Aims Elevated levels of adipokine chemerin have been identified in oral squamous cell carcinoma (OSCC) and found to be associated with metastasis to the cervical lymph nodes. The underlying mechanism through which chemerin affects OSCC progression is unclear. The aims of this study were firstly to determine chemerin levels and cytokine concentrations in serum from patients with OSCC and in OSCC cell cultures, and secondly to observe chemerin effects on OSCC cell cytokine secretion, migration, and invasion in vitro. Methods Serum samples were collected from 20 patients diagnosed with OSCC, including groups with (LN+) and without (LN-) cervical lymph node metastasis. A Luminex liquid suspension assay was used to quantify serum concentrations of 27 types of cytokines. Correlations between chemerin and cytokines (i.e., IL-6, IL-15, GM-CSF, RANTES, TNF-alpha, and VEGF) were analyzed. ELISAs (enzyme-linked immunosorbent assays) were used to determine concentrations of chemerin and selected cytokines in serum and in supernatants of OSCC cell cultures (SCC9 and SCC25 cell lines). OSCC cells were stimulated with human recombinant chemerin, STAT3 inhibitor, or IL-6 together with TNF-alpha neutralizing antibodies. Phosphorylated STAT3 protein levels were measured with western blot analysis. OSCC cell migration and invasion were investigated with Transwell assays. Results Compared to the LN- group, OSCC patients with cervical lymph node metastasis had higher levels of IL-6 (P = 0.006), IL-15 (P = 0.020), GM-CSF (P = 0.036), RANTES (P = 0.032), TNF-alpha (P = 0.005), VEGF (P = 0.006), and chemerin (P = 0.001). Patients' serum chemerin levels correlated directly with IL-6, GM-CSF, TNF-alpha, and VEGF levels in OSCC patients. Exogenous recombinant chemerin treatment promoted secretion of IL-6 and TNF-alpha via activation of STAT3 in OSCC cells. Chemerin induced OSCC-cell migration and invasion, and these effects were reduced by IL-6 and TNF-alpha neutralizing antibodies. Conclusio

关键词： Atopic dermatitis   dendritic cells   IL-4   TH2 polariza- tion   cutaneous sensitization   allergic skin inflammation  

摘要： Background: Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigenObjective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. Methods: DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD41 T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. Results: Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVAsensitized skin of Il4-/- mice and CD11c-CreIl4rflox/-mice, which lack IL-4Ra expression in DCs (DC degrees/degrees ll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC degrees/degrees ll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. Conclusions: Mechanical skin injury causes basophildependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.

关键词： Anti-inflammatory effect   Antioxidant enzyme   Cardamonin   Periodontal ligament cells   Signal transduction  

摘要： BackgroundCardamonin is classified as a natural chalcone, and has been reported to possess various bioactive effects. However, there have been limited attempts to utilize cardamonin in the treatment of periodontitis. This study aimed to investigate whether cardamonin has anti-inflammatory effects on human periodontal ligament cells (HPDLCs), which are a component cell of periodontal tissue. Specifically, the study seeks to determine whether cardamonin affects the expression of inflammatory mediators, such as cytokines and adhesion molecules, induced by interleukin-1 beta (IL-1 beta) in HPDLCs, as well as the signaling pathways activated by IL-1 *** and chemokine levels in supernatants of HPDLCs were measured by ELISA. Western blot analysis was used to measure protein expression and signal transduction pathway activation in *** found that IL-1 beta-induced CC chemokine ligand (CCL)2, CCL5, CCL20, CXC-chemokine ligand (CXCL)10, and interleukin (IL)-6 production and intercellular adhesion molecule (ICAM)-1 and cyclooxygenase (COX)-2 expression in HPDLCs were suppressed by cardamonin treatment. We also found that cardamonin suppressed IL-1 beta-activated nuclear factor (NF)-kappa B pathway, and the phosphorylation of signal transducer and activator of transcription (STAT)3. Furthermore, cardamonin treatment enhanced the expression of the antioxidant enzymes, heme oxygenase (HO)-1 and NAD(P)H dehydrogenase [quinone] 1 (NQO1), in *** this study, we found that cardamonin could suppress the production of inflammatory mediators in HPDLCs as well as the activation of several signaling pathways induced by IL-1 beta treatment.

关键词： IL-21   Combination therapy   Immune checkpoint inhibitors   Solid tumors  

摘要： Solid tumors significantly impact global health, necessitating enhanced prevention, early diagnosis, and treatment approaches. Tumor immunotherapy, notably through programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1), offers new hope to patients with advanced tumors, although many still do not benefit. Interleukin-21 (IL-21), a cytokine produced by certain immune cells, performs various biological functions by activating the JAK/STAT signaling pathway. Currently, recombinant IL-21 demonstrates promising antitumor activity and acceptable toxicity in several clinical trials. However, challenges such as side effects, offtarget reactions, and a short half-life limit the effectiveness of cytokine-based immunotherapies. Therefore, researching enhanced IL-21 treatment strategies in solid tumors is crucial. Integrating IL-21 with various treatment modalities, including immune checkpoint inhibitors, additional cytokines, vaccines, or radiotherapy, is essential for improving response rates and prolonging patient survival. This review explores the specific mechanisms of IL-21 in prevalent high-incidence tumors, examines improved strategies for IL-21 in solid tumors, and aims to provide a theoretical basis for developing targeted treatment strategies.

关键词： cost-effectiveness   DQ-genotype   Saudi Arabia  

摘要： Objectives: The data on the usefulness of DQ-typing in screening for celiac disease (CD) among type 1 diabetic (T1D) patients came from the West. We conducted this study among T1D patients to: (1) determine the frequency of DQ-genotypes, (2) assess the risk associated with human leukocyte antigen (HLA)-DQ genotypes, and (3) identify the cost-effective screening strategy. Methods: HLA-DQ genotyping was performed on 67 T1D patients with CD (cases) (mean age 15 years) and 224 T1D patients without CD (controls) (mean age 18.29 years) (2021-2023). The entry criterion for the control group was duration of T1D >= 5 years and negative annual celiac serology assay. Results: On comparison of the cases versus controls, T1D patients carrying homozygous DQ2.5 genotype (30% vs. 13.8%) or DR3-DQ2.5 haplotype (81.3% vs. 65.7%) showed significantly "higher risk" (odds ratio [OR] = 2.64, p = 0.002;OR = 2.3, p = 0.008, respectively) to develop CD. Only 4% do not harbor any of the CD-at risk genotypes (DQ2.5, DQ8, or DQ2.2) and none developed CD. Heterozygous DQ8 was associated with a significantly lower risk of developing CD with OR of 0.123 (1.5% in cases vs. 10.3% in controls, p = 0.022). Conclusion: Only 4% of Saudi patients with T1D carry DQ-genotypes at no risk to develop CD, which supports the European guidelines that recommend celiac serology test as the most cost-effective screening method. We identified the risk gradient associated with DQ-genotypes to develop CD in our population which could help in counseling patients for the risk to develop CD and planning follow-up serology tests.

关键词： Escherichia coli  

摘要： Endometritis, an inflammatory disease affecting dairy cattle, causes substantial economic losses in the dairy industry. Conventional treatment using uterine infusion of antibiotics often results in bacterial resistance and antibiotic residues in milk. Thus, identifying novel, effective therapeutic targets for endometritis in dairy cows is necessary. Nuclear receptor subfamily 1 group D member 1 (NR1D1) activation attenuates inflammatory responses in various diseases through transcriptional repression;however, its role in treating bovine endometritis remains unclear. This study investigated the role and underlying mechanisms of NR1D1 in endometritis using a bovine endometrial epithelial cell line (BENDs) and primary bovine endometrial epithelial cells, both induced with Escherichia coli lipopolysaccharide (LPS). Immunofluorescence staining revealed the predominant nuclear localization of NR1D1 in endometrial epithelial cells. LPS treatment (1 μg/mL for 12 h) significantly increased the expression levels of NR1D1 and proinflammatory cytokines (IL-6, IL-1β, IL-8, and CCL5) in BENDs. Immunohistochemical staining showed elevated NR1D1 expression in uterine tissues of cows with endometritis. Deletion of NR1D1 significantly increased IL-6 mRNA expression;NR1D1 overexpression substantially repressed IL-6 expression in BENDs. NR1D1 agonist SR9009 attenuated LPS-induced mRNA expression of proinflammatory cytokines (IL-6, IL-1β, CCL5) in both BENDs and primary endometrial epithelial cells. Additionally, SR9009 treatment attenuated LPS-induced inflammatory responses in the endometrium of mice. Dual-luciferase reporter assays and real-time monitoring via luminescence assays showed that NR1D1 overexpression significantly repressed luciferase activity driven by the IL-6 promoter region, which was abolished by deletion of the retinoic acid receptor-related orphan receptor-responsive element (−473 to −479) within the IL-6 promoter fragment. In summary, NR1D1 activation alleviates th

关键词： CWF19L1   splicing   splicing factor   alternative splicing   spliceosome   snRNP   t cell   cytotoxicity   cytokine   antitumor immunity   cDNA   complementary DNA   CTL   cytotoxic lymphocyte   GO   Gene Ontology   IgG   immunoglobulin G   KEGG   Kyoto Encyclopedia of Genes and Genomes   NK   natural killer   PQBP1   polyglutamine binding protein 1   PRPF19   pre-mRNA processing factor 19   RI   retained intron   RT   room temperature   SE   skipped exon   shRNA   short-hairpin RNA   snRNP   small nuclear ribonucleoprotein   TCR   T cell receptor   TNF   tumor necrosis factor   TNFRSF   TNF receptor superfamily  

摘要： Effective cancer immunotherapy relies on enhancing the host's immune response, particularly by boosting T cell-mediated cytotoxicity against tumor cells. In this study, we identify CWF19-like cell cycle control factor 1 (CWF19L1) as a novel splicing regulator that enhances T cell-mediated cytotoxicity. CWF19L1 interacts prominently with key splicing factors within the nucleus, including components of the U5 small nuclear ribonucleoprotein and the pre-mRNA processing factor 19 (PRPF19) complex. Deficiency of CWF19L1 disrupts alternative splicing of immune-related genes, resulting in diminished expression of cytotoxic molecules. Furthermore, CWF19L1 plays a critical role in promoting T cell-mediated antitumor responses by upregulating the expression of effector cytokines. Our findings unveil previously undocumented functions of CWF19L1 in alternative splicing and its involvement in the regulation of antitumor immunity, highlighting its potential as a therapeutic target for novel cancer immunotherapies.