International Journal of Immunopathology and Pharmacology最新文献

The skin serves as the primary defensive barrier of the human body against external stimuli and damage. Keratinocytes, which are the predominant cell type in the human epidermis, undergo a differentiation process that is crucial for the formation of the skin barrier. Myricetin, a dietary flavonoid present in various fruits and vegetables, is known to play a significant role in maintaining intestinal barrier function; however, its impact on the skin barrier remains inadequately understood. Consequently, this study investigates the effects of myricetin on the differentiation of epidermal keratinocytes and the integrity of the skin barrier. Differentiation of primary mouse keratinocytes was induced using 1.8 mM CaCl₂. tudy demonstrated that myricetin effectively suppresses cell proliferation and induces both cell cycle arrest and calcium ion (Ca²⁺) influx, without influencing apoptosis. Concurrently, myricetin enhances the expression of differentiation markers, including K10, TGase1, Filaggrin, and Involucrin, and facilitates the formation of tight junctions. Upon examining the underlying mechanisms, we discovered that myricetin activates the TRPV4 channel, and the promotion of keratinocyte differentiation by myricetin is contingent upon the activation of this channel. In summary, these findings suggested that myricetin could promote keratinocytes differentiation and have well-established skin barrier protective function.

Objective: Acute respiratory distress syndrome (ARDS) is a severe pulmonary condition characterized by inflammation and lung damage, frequently resulting in poor clinical outcomes. Recent studies suggest that the gut-lung axis, mediated by gut microbiota, is critical in ARDS progression. This study investigates the therapeutic potential of fecal microbiota transplantation (FMT) in an ARDS rat model (n = 6).

Introduction: The pathogenesis of ARDS involves complex interactions between the lungs and gut, with microbiota playing a key role. Understanding the effects of FMT on lung function and gut microbiota may provide new therapeutic strategies for ARDS management.

Methods: Sprague-Dawley rats were pre-treated with a broad-spectrum antibiotic cocktail to create a germ-free state and subsequently exposed to intranasal lipopolysaccharide to induce ARDS. The rats then received FMT treatment. Lung samples were analyzed using histopathology and transcriptomics. Fecal samples were analyzed using 16S rRNA sequencing and metabolomics.

Results: FMT treatment significantly reduced lung injury and improved pulmonary function, as evidenced by increased partial pressure of arterial oxygen (PaO₂) and decreased partial pressure of arterial carbon dioxide (PaCO₂). FMT also significantly altered in gut microbiota composition by regulating the gut microbiota composition of Akkermansia and Lactobacillus, restoring the abundance of genera such as Muribaculaceae, Clostridia_UCG-014, Prevotella, and Adlercreutzia, while reducing Romboutsia. FMT restored key metabolic pathways involved in lipid metabolism, amino acid biosynthesis, and immune regulation, including the modulation of immune pathways like mTOR signaling. These alterations contribute to reduced lung injury and improved pulmonary function.

Conclusion: These findings indicate that FMT may exert its beneficial effects in ARDS by modulating the gut microbiota and enhancing metabolic and immune responses. However, given that this study remains in the preclinical stage, further validation in clinical studies is necessary before considering clinical application.

Objective: To investigate the comprehensive landscape of hepatotoxic adverse events (AEs) associated with immune checkpoint inhibitors (ICIs), with a special focus on evaluating the potential risk of lethal hepatotoxic AEs.

Introduction: The widespread adoption of ICIs has markedly improved the prognosis for patients with advanced cancer. However, this therapeutic advance is accompanied by the risk of immune-related adverse events (irAEs), especially hepatotoxic AEs, which particularly affect patients with pre-existing liver diseases or hepatobiliary cancers.

Methods: Reports in the FAERS database from Q1 2014 to Q3 2024 were collected. The characteristics of ICI-related hepatotoxic AEs were summarized. Disproportionality analysis was conducted to calculate reported odds ratios for assessing signals of hepatotoxic AEs. Additionally, logistic regression was employed to evaluate patient-related factors contributing to an increased risk of these AEs.

Results: Hepatotoxic AEs increased yearly and occurred primarily in patients with hepatobiliary tumors. CTLA-4 inhibitors exhibited the highest incidence of AEs. In contrast, PD-1 inhibitors had the shortest median time to AE onset. Abnormal hepatic function was a common AE, whereas Stauffer's syndrome was identified as a rare AE. The risk of hepatotoxic AEs was notably elevated by combination immunotherapy and the concurrent use of specific drugs. Despite variations in the safety profiles of different ICI regimens, these differences did not significantly influence the risk of fatal hepatotoxicity. Furthermore, older men who experienced other AEs were found to be at higher risk for developing fatal hepatotoxicity.

Conclusion: The safety profiles of different ICIs vary widely, necessitating individualized drug selection based on patient-specific factors.

The objective of this study was to identify the prognostic biomarkers for hepatocellular carcinoma (HCC) by analyzing the N6-methyladenosine (m6A) RNA modification. HCC is a complex malignant tumor induced by various pathogenic factors. m6A RNA modification and its regulators influence the tumorigenesis and advancement of HCC. RNA sequencing and clinical data were extracted from the TCGA-LIHC and ICGC-LIRI-JP database. Single-cell RNA sequencing data were processed using Seurat and Harmony packages. ConsensusClusterPlus identified molecular subtypes, and ssGSEA quantified m6A regulator-related gene sets. Differentially expressed genes were analyzed, followed by the establishment of a risk model. qRT-PCR validated mRNA expression in Huh7, Hep 3B, and Hep G2 cells and normal hepatocytes. Four molecular subtypes based on m6A regulator transcriptional profiles of m6A regulators were identified, each exhibiting unique clinical, prognostic, and pathway characteristics. A robust risk model distinguished the high- and low-risk groups, revealing obvious differences in immune cells infiltration and chemotherapeutic drug sensitivity. qRT-PCR confirmed significant differential expression of key genes (TRNP1, KIF20A, and CFRHR3) in HCC cell lines and normal hepatocytes. In conclusion, the established risk model may serve as a perspective tool for prognostic prediction, and provide insights into the functions of m6A involved in HCC.

This study aimed to characterize micronutrient deficiencies, including iron, ferritin, folic acid, vitamin D, zinc (Zn), vitamin B₁₂, and copper, in patients with celiac disease, and evaluated the effects of these deficiencies on selected hematological parameters, including hemoglobin and mean corpuscular volume (MCV). Celiac disease (CeD), an immune-mediated disorder affecting the small bowel, is associated with genetic factors and micronutrient deficiencies. This meta-analysis was performed in accordance with the PRISMA guidelines. Literature searches of multiple databases retrieved 4140 studies, of which 45 were selected. Risk of Bias was performed in accordance with the STROBE checklist. Meta-analysis revealed a significant difference in hemoglobin levels between patients with CeD and controls (standardized mean difference (SMD) -0.59 (95% confidence interval (CI) -0.8459 to -0.3382); P = 0.0003). Iron levels were lower in patients with CeD (SMD ≈ -0.4 (95% CI -0.7385 to -0.0407); P = 0.0334), as were ferritin (SMD -0.6358 (95% CI -0.8962 to -0.3755); P = 0.0002), folic acid (SMD -0.5446 (95% CI -0.9749 to -0.1142); P = 0.0187), and vitamin D (SMD -0.4011 (95% CI -0.8020 to -0.0001); P = 0.0499) levels, while Zn levels were significantly reduced (SMD -1.1398 (95% CI -2.0712 to -0.2084); P = 0.0242). No significant differences were found in MCV, or copper or vitamin B₁₂ levels between patients with CeD and controls. This study highlighted significantly higher micronutrient deficiencies in patients diagnosed with CeD than in controls, underscoring the importance of systematic nutritional assessment and multidisciplinary management to address micronutrient deficiencies and minimize negative health impact(s).

SOT patients require immunosuppressors to avoid graft rejection. Therapeutic drug monitoring is insufficient to find the optimal balance with immunosuppression. The evaluation of cell-mediated immunity by enzyme-linked immunospot (ELISpot) assay enumerating interferon-gamma (IFN-γ) is increasingly use. ELISpot assays are performed on peripheral blood mononuclear cells (PBMC) isolated from blood and brought into contact with specific peptides in an immunosuppressor-free environment. This study aims to determine the in vitro diffusion of tacrolimus in PBMC and to assess whether prior in vitro incubation of PBMC with tacrolimus modifies the IFN-γ ELISpot results when assessing the T-cell immune response. PBMC from healthy volunteers were obtained. Tacrolimus was added to the ELISpot wells at increasing concentration and quantification was obtained using liquid chromatography mass spectrometry. Results showed that the in vitro PBMC diffusion rate of tacrolimus was measured at 32%. A decrease in T-cell reactivity occurred with increasing tacrolimus concentration. The intra-PBMC concentration of tacrolimus able to inhibit 50% of T-cell reactivity was 163 pg/10⁶ PBMC, which is in the range of the in vivo intra-PBMC concentration in SOT recipients. T-cell functional assessment using ELISpot in patients treated with immunosuppressors may require the addition of immunosuppressors in vitro to better reflect the in vivo situation.

The aim of this study was to evaluate the country-specific reporting status profile of immunomodulatory drugs (IMiDs)-related adverse events (ImrAEs) in real-world clinical practice, using data from the Japanese Adverse Drug Event Report (JADER) and Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) databases. Immunomodulatory drugs, including thalidomide and its derivatives, are a new class of anticancer and anti-inflammatory drugs. IMiD risk management programs have instituted sufficient measures to prevent fetal effects but do not address adverse effects experienced by patients themselves. To date, no study has compared ImrAE profiles across countries. Adverse events were defined using the preferred terms in the Medical Dictionary for Regulatory Activities. The number of reported adverse events related to IMiDs in each country (the United States and Japan) was investigated. In both Japan and the United States, myelosuppression, pneumonia, and neuropathy peripheral have been reported as adverse events suspected to be associated with IMiDs. Adverse event profiles differed between the countries. The number of adverse event reports for thalidomide increased transiently in the United States in 2008 following the multiple myeloma indication, and then exhibited a downward trend. The number of adverse event reports for lenalidomide and pomalidomide has increased in the United States since their launch. The number of transient reports increased in Japan in 2015, when pomalidomide was launched. In this study, the profile of ImrAEs was revealed using the FAERS and JADER databases. Our comparative safety study indicated the importance of comparing the safety profiles of IMiDs using post-marketing real-world data. It is important to focus on the adverse events experienced by patients taking IMiDs, as well as the effects of IMiDs on fetuses.

Objective: This study aimed to investigate the relationship between fibroblast growth factor 19 (FGF19) and the prognosis and immune infiltration of colorectal cancer (CRC) and identify the related genes and pathways influencing the onset and progression of CRC.

Introduction: The potential of FGF19 to guide the prognosis of CRC and inform immunotherapeutic strategies warrants further investigation.

Methods: We performed Quantitative Real-Time PCR to assess the expression of FGF19 and conducted a bioinformatics analysis to evaluate the impact of FGF19 expression on the clinical prognosis of CRC. We also analyzed the association between FGF19 expression and immune cell infiltration in CRC, and explored the related genes and pathways through which FGF19 influences CRC development.

Results: CRC patients with higher FGF19 expression exhibited a poorer prognosis. In terms of the Receiver Operating Characteristic (ROC), FGF19 achieved an area under the curve (AUC) of 0.904. FGF19 expression correlated with the N stage, M stage, and pathological stage in patients with CRC. Functional enrichment analysis revealed significant enrichment of FGF19 in pathways associated with tumor development. ssGSEA and Spearman correlation analysis demonstrated that FGF19 expression was linked to tumor immune cells. We discovered that FGF19 is closely related to neutrophil extracellular traps (NETs), which play a significant role in the immune microenvironment.

Conclusion: FGF19 is a key gene associated with immunity and prognosis in CRC patients. Our findings suggest that FGF19 may influence CRC progression by promoting NETs expression, which leads to suppression of immune cells.

Objective: This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma.

Methods: Bioinformatics tools and drug sensitivity assays were used to investigate the association between Aurora-A expression level and lenvatinib resistance in hepatocellular carcinoma cell lines. Cell function experiments had performed after treatment with lenvatinib and/or a selective Aurora-A inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, and dual-luciferace reporter assay were performed to identify the downstream molecular mechanism of Aurora-A dysregulation.

Results: Aurora-A expression was positively correlated with lenvatinib resistance in hepatocellular carcinoma cells. The Aurora-A selective inhibitor MLN-8237, in combination with lenvatinib, synergistically inhibited hepatocellular carcinoma cell proliferation in vitro and vivo, suggesting the Aurora-A might be a potential therapeutic target for lenvatinib resistance. Mechanistically, Aurora-A induced FGFR1 expression through the hsa-circ-0058046/miR-424-5p/FGFR1 axis. Aurora-A promotes lenvatinib resistance through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma cells. The simultaneous inhibition of FGFR1 by the Aurora-A inhibitor MLN-8237 and lenvatinib overcame lenvatinib resistance in hepatocellular carcinoma cells.

Conclusion: Collectively, our findings indicate that Aurora-A promotes lenvatinib resistance through the hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma (HCC) cells. These results suggest that Aurora-A may serve as a therapeutic target for HCC patients exhibiting lenvatinib resistance. Furthermore, the combination of lenvatinib and MLN-8237 shows potential for clinical trials aimed at overcoming lenvatinib resistance.