International Journal of Immunopathology and Pharmacology最新文献

Objectives: Baicalein, a flavonoid derived from the roots of Scutellaria baicalensis Georgi, demonstrates multifarious pharmacological effects due to its high antioxidant activity. However, the latent mechanisms remain insufficiently resolved. In the present research, we evaluated the therapeutic effects of baicalein on isoprenaline (ISO)-induced heart failure and investigated the possible underlying mechanisms.

Methods: Toxicity was analyzed in zebrafish embryos and mouse atrial myocytes HL-1. The MTT assay was used to evaluate the effectiveness of baicalein. DCFH-DA was used as a fluorescence probe to detect intracellular reactive oxygen species (ROS). Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were measured using SOD, MDA and GSH-Px commercial kits. Adult BALB/c mice were randomized into six groups of ten animals each. Cardiac function was analyzed by echocardiographic images. Structural changes were analyzed by hematoxylin & eosin (HE) staining, Masson staining and TUNEL staining. The mechanism of baicalein was investigated by analyzing relative signaling pathways through western blotting.

Results: Our studies show that baicalein both significantly reduces ISO-induced oxidative stress, apoptosis and cardiac fibrosis in vitro and vivo, this phenomenon was related to mitochondrial fusion/fission balance and inhibiting GRP78/CHOP pathway.

Conclusions: Our results suggested that baicalein controls mitochondrial fusion/fission balance and inhibits GRP78/CHOP pathway, thus exerting therapeutic effects in ISO-induced heart failure in HL-1 cells and BALB/c mice. These results suggested that baicalein may be a potential therapeutic agent for heart failure.

Knowledge about total RNA molecules in Parkinson's disease is limited. This gene expression profiling study was conducted with a preclinical experimental design using a mouse model to examine the molecular-biological characteristics and the pathological implication of total RNA gene interaction in Parkinson's disease in silico. In silico analysis of total RNA molecules, the Gene Expression Omnibus database, published results, and preliminary findings of available patient samples apply. The potential signaling network and the effect of the interaction of molecules with total RNA was predicted and confirmed. The research consists of four parts. At first, we analyzed the control and MPTP groups. In the second part, we analyzed FVB-N control and MPTP. In the third part, we analyzed controls. In the fourth part, we analyzed MTPT separately. The constructed network contains total RNA, where the Kyoto Encyclopedia of Genes and Genomes database analysis showed that genes from the signaling pathway are involved in the development and complications of Parkinson's disease in male and female rats. Identified total RNA and genes are involved in altered signaling. There is direct interconnection and interdependence of interactions in the signaling network. Results identified the significant total-RNA molecules of the signaling pathway that connect other molecules. In silico analysis shows upregulated and downregulated genes in Parkinson's disease rats. Preliminary data shows that total RNA molecules interact with other genes, and they are applicable in Parkinson's disease course monitoring, shedding light on how factors impact the expression of genes and offering strategies for management.

Objectives: The objectives of this study were to determine the prevalence of anti-β2glycoprotein-1 antibodies (anti-β2GPI) in Pakistani patients clinically suspected to have antiphospholipid syndrome (APS) and assess their association with clinical manifestations.

Introduction: The antiphospholipid syndrome (APS) is a complex disorder characterized by recurrent thrombotic and obstetric complications.

Methods: An analytical cross-sectional study was conducted at Aga Khan University Hospital from January to June 2022, after obtaining ethical approval (ERC ID: 2021-6404-19580). A total of 133 patients aged 18-60 years, clinically suspected of having APS based on the updated international consensus (Sydney) classification criteria, were recruited. Anti-β2GPI antibodies were tested using the same blood samples provided for aCL testing, with verbal consent. Demographic, clinical, and biochemical data were collected via a structured questionnaire, while information on lupus anticoagulant testing was retrospectively obtained from prior records.

Results: The study included 120 females (90.2%) and 13 males (9.8%) with a mean age of 31.3 ± 8.8 years. Predominant clinical manifestations included unexplained miscarriages at >10 weeks of gestation (n = 77/120 female, 64.2%), while deep venous thrombosis (DVT) was a common non-obstetric clinical feature (n = 18/133, 13.5%). The median level of anti-β2GPI was 2.12 U/ml (1.34-7.04) and 7.5% (n = 10) were positive. Of the 10 positive patients, 2 displayed positive anti-β2GPI while concurrently testing negative for other aPL antibodies. A significant association was identified between the presence of anti-β2GPI and the occurrence of DVT and other venous thromboembolic events (VTE).

Conclusion: This study highlights the prevalence and diagnostic utility of anti-β2GPI in Pakistani patients suspected of APS, identifying cases missed by other aPL tests and showing significant associations with thrombotic manifestations like DVT and VTE. However, the cross-sectional design, lack of confirmatory testing, and absence of locally derived cut-offs limit causal inferences.

Background: Oral mucosal diseases manifest primarily as inflammatory conditions. These diseases affect approximately half a billion people worldwide.

Objective: Novel and effective strategies for treating inflammatory diseases of the oral mucosa have great potential for improving patient outcomes, and warrant study.

Methods: The impact of melatonin on inflammation was investigated using RAW264.7 macrophages and HOEC and HSC-3 oral epithelial cells.

Results: Melatonin decreased macrophage-induced inflammation by acting through the melatonin receptor MTNR1A. Additionally, melatonin mitigated macrophage-induced inflammation in oral epithelial cells. Importantly, the results demonstrated that the effects of melatonin on oral epithelial inflammation were mediated through the KEAP1/Nrf2 signaling pathway.

Conclusion: These findings will contribute to the development of innovative therapies for inflammatory conditions affecting the oral epithelium.

This study aims to identify differentially upregulated ligand-receptor interactions between B-ALL cells and exhausted CD8⁺ T cells and to develop a multivariate Cox regression model for predicting the overall survival of pediatric B-ALL patients based on CCL3/CCL4/CCL5 expression levels. Pediatric B cell-acute lymphoblastic leukemia (B-ALL) is a hematopoietic malignancy. T cell exhaustion has an important impact on the prognosis of leukemia. The interaction between tumor cells and T cells can influence the degree of T cell exhaustion. However, the effects of B-ALL cells on exhausted T cell subpopulations and how the interaction influences the prognosis of B-ALL patients remain unclear. Single-cell RNA sequencing (scRNA-Seq) data from pediatric B-ALL patients were downloaded from GEO. Cell interaction analysis identified ligand-receptor pairs between B-ALL cells and exhausted CD8⁺ T cell. To confirm the function of CCL3/CCL4/CCL5/CCR5 in prognosis prediction, quantitative real-time polymerase chain reaction (qRT-PCR) was employed. We further developed an innovative stratified model that integrates CCL3, CCL4, and CCL5 through multi-Cox regression. Clustering of scRNA-Seq data revealed an increased proportion of exhausted CD8⁺ T cells in relapsed B-ALL, especially terminal exhausted CD8⁺ T cells (CD8_Ex), with increased exhaustion and decreased proliferation scores. Moreover, the CCL3/CCL4/CCL5-CCR5 axis was upregulated in interactions between B-ALL cells and terminal CD8_Ex. Transcriptome data from 221 pediatric B-ALL samples revealed that high CCL3/CCL4/CCL5/CCR5 levels correlate with low overall survival (OS). A multivariate Cox regression model incorporating CCL3/CCL4/CCL5 predicted prognoses. Finally, a model based on the adult B-ALL patients from our center also accurately predicted prognoses. We report for the first time the crucial role of the CCL3/CCL4/CCL5-CCR5 axis in the differentiation of terminal exhausted CD8⁺ T cells in B-ALL. High expression of CCL3, CCL4, CCL5, and CCR5 correlates with poor prognosis in B-ALL, suggesting potential biomarkers and therapeutic targets.

The Coombs test is important in hematology for detecting erythrocyte-bound IgG antibodies or in serm through agglutination methods, but its sensitivity and specificity are limited. Flow cytometry provides a more precise and sensitive alternative for quantitatively assessing RBC-bound IgG antibodies. This assessment is crucial for evaluating the risk of hemolytic reactions and ensuring safe transfusions. This study aimed to explore a new method for the detection of RBC-bound IgG antibodies in rabbits following the injection of human red blood cells. Rabbits serum treated with 2-mercaptoethanol (2-ME) were serially diluted at ratios of 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, 1:512, 1:1024, and 1:2048. These diluted samples were then reacted with O-type red blood cells (RBCs). Serum samples from healthy individuals were used as the control group. The tubes were kept in a water bath at 37°C for 30 min incubation. After incubation, the samples were analyzed using a flow cytometry-based assay. Additionally, the traditional Coombs tube method was used and the strength of IgG antibody and agglutination was graded. The results were analyzed using a flow cytometry-based assay, and the agglutination strength was determined using the Coombs traditional tube method for RBC-bound IgG antibodies. A significant difference was found between the rabbits serum and normal control groups (p < 0.001). IgG titers increased significantly after 1 month of immunization in rabbits compared to the titers observed after 1 week. The serum Anti-D stability test showed a coefficient of variation (CV) of 7.74%, indicating good stability of the test results. In this study, we concluded that the flow cytometry-based assay for detecting RBC-bound IgG antibodies was accurate, sensitive, and had positional value in clinical laboratories and research centers.

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.