International Journal of Immunopathology and Pharmacology最新文献

Objective: Given the global high incidence of colorectal cancer (CRC) and the need for subtype-specific molecular targets, this study aims to investigate the role and therapeutic potential of EIF4A1 in colon and rectal cancers.

Introduction: The potential of Eukaryotic translation initiation factor 4A1(EIF4A1) to guide prognosis and inform immunotherapeutic strategies in colon and rectal cancers warrants further investigation.

Methods: EIF4A1 expression levels were measured by quantitative real-time PCR (qRT-PCR), and EIF4A1 protein expression was evaluated via immunohistochemistry (IHC). Additionally, multi-dimensional database analyses were performed to characterize the biological functions of EIF4A1 and explore its heterogeneity in CRC.

Results: EIF4A1 expression was upregulated in both colon and rectal cancers, with significant associations with poor survival outcomes. Functional enrichment analyses indicated that EIF4A1 was predominantly associated with the neutrophil extracellular trap (NET) network in colon cancer. Strong positive correlations between EIF4A1 expression and neutrophil infiltration were observed in both cancer subtypes. Notably, EIF4A1 exhibited divergent immune infiltration patterns: a strong positive correlation with CD8⁺ T cells in colon cancer, versus a negative correlation with CD4⁺ T cells in rectal cancer. EIF4A1 also showed strong positive correlations with immune checkpoint molecules (PD-1, PD-L1, CTLA4, and LAG-3) in colon cancer, whereas these correlations were weaker in rectal cancer.

Conclusion: The heterogeneity of EIF4A1 and its differential roles in driving cancer progression between colon and rectal cancers highlight the need for subtype-specific immunotherapeutic strategies for these malignancies.

Objective: This meta-analysis aims to systematically evaluate the associations of four specific Single Nucleotide Polymorphisms (SNPs)-rs712829, rs712830, rs11568315, and rs884225-located in the promoter, intronic, and 3' untranslated regions (3'UTR) of the EGFR gene, with lung cancer risk.

Introduction: The associations between EGFR gene polymorphisms and lung cancer risk is a topic of ongoing debate, which is still deemed controversial. Despite numerous studies, results are inconsistent.

Methods: We conducted a comprehensive literature search across the PubMed, Science Direct, and Web of Science databases to identify relevant case-control studies examining the association between EGFR gene polymorphisms and lung cancer risk.

Results: From an initial pool of 26,959 articles, 10 case-control studies were included, involving 2471 lung cancer patients and 4489 controls. A significant association between rs712829 and increased lung cancer risk was found across multiple genetic models. Under the allelic contrast model (G vs T), the OR was 1.31 (95% CI = [1.02; 1.68], p < 0.05), the dominant model (GG + GT vs TT) showed an OR of 1.69 (95% CI = [1.07; 2.67], p < 0.05), the homozygote model (GG vs TT) yielded an OR of 1.70 (95% CI = [1.00; 2.88], p < 0.05), and the heterozygote model (GT vs TT) had an OR of 1.64 (95% CI = [1.01; 2.66], p < 0.05). No significant associations were found for rs11568315, rs712830, and rs884225.

Conclusion: The findings from the current meta-analysis confirm that rs712829 within the EGFR gene is significantly associated with lung cancer risk according to the allele, dominant, homozygote and heterozygote models.

Background: Spinal cord injury (SCI) results in a multitude of cellular and pathological changes including neuronal loss, axonal damage, gliosis, and loss of motor and sensory function. In 40%-70% of patients, SCI can also trigger the development of neuropathic pain. Our previous study demonstrated that SCI patients who developed autoantibodies to glial fibrillary acidic protein (GFAP) were at increased risk for the subsequent development of neuropathic pain. However, whether GFAP autoantibodies (GFAPab) contribute to the development of neuropathic pain after SCI had yet to be examined.

Objective: Using a mid-thoracic contusion model of SCI in male Sprague-Dawley rats, we examined the effect of exogenous anti-GFAP antibodies on SCI pathology, pain-associated molecular changes, and behavior.

Methods: Anti-GFAP or IgG was administered at 7- and 14-days post-injury. Immunohistochemistry was performed to measure the relative levels of calcitonin gene-related peptide (CGRP), and inflammatory proteins in dorsal horn tissue. To assess the development of neuropathic pain, the von Frey test and the Mechanical Conflict-Avoidance Paradigm (MCAP) were performed.

Results: CGRP immunoreactivity was significantly higher in the anti-GFAP-treated injured rats compared to control SCI IgG-treated rats. As anticipated, SCI rats had a lower pain threshold at 1- and 2-months post-injury compared to laminectomy-only controls. However, pain withdrawal threshold was not significantly affected by post-injury administration of the anti-GFAP. Operant testing revealed that SCI rats treated with the anti-GFAP had a trending increase in pain sensitivity.

Conclusion: Taken together, these data suggest that autoantibodies to GFAP following SCI may contribute to developing pain states following SCI.

Background: Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory abilities, particularly in a milieu of hyperactive immune system, through secreting a number of cytokines, growth factors, bioactive compounds and peptides, and by cell-cell contact. During viral infection, failure of immuno-neutralization of the viral particles, recruits T-lymphocytes (T-cells) that clear the virally-infected cells. MSCs greatly potentiate T-cells anti-viral activity.

Objective: The objective of this study is to assess the ability of the cytokine-primed MSCs to activated T-cells, towards an antiviral application.

Method: Human umbilical cord MSCs (UC-MSCs) were isolated from Wharton Jelly of a consented donor. UC-MSCs were primed with interferon (INF)-γ and transforming growth factor (TGF)-β1. Peripheral blood T-cells were isolated using mini-max and CD3+ population was purified using anti-CD3 immuno-magnetic beads. Naïve or primed MSCs were co-cultured with naïve and phytohemagglutinin (PHA)-activated CD3+ T-cells. T-cell activation was evaluated by changes in their rate of proliferation by cell count, flowcytometric immuno-phenotyping for CD25 expression, and IL-6 secretion in the conditioned medium.

Results: The findings revealed that CD3+ T-cells count nonsignificant differed comparing the five experimental groups; Naïve MSCs, Naïve T cells, coculture with naïve MSCs, coculture with primed MSCs, and upon phytohemagglutinin-activation, despite a nonsignificant reduction of proliferation in the last two groups' coculture. Only the coculture with the primed MSCs showed significant activation of T-cells assessed as CD25 expression compared to the other groups (p < 0.001 and p = 0.002, respectively). The undetectable levels of IL-6 in the conditioned medium of naïve MSCs, turned markedly high after their cytokine-priming (p < 0.001), reaching nonsignificant difference compared to naïve T-cells. Compared to naïve MSCs, naïve T-cells secreted considerable amounts of IL-6 (p < 0.001). Incubation of naïve MSCs with phytohemagglutinin-activated T-cells further the secretion of IL-6, to a level significantly higher than all of the aforementioned three groups; naïve MSCs, naïve T-cells and primed MSCs (p < 0.001, p = 0.0194, and p < 0.001, respectively). However, coculture of the cytokine-primed MSCs with phytohemagglutinin-activated T-cells dampened IL-6 secretion to a level that was significantly lower than that observed with naïve MSCs-phytohemagglutinin-activated T-cells coculture (p < 0.001).

Conclusion: The cytokine-primed UC-MSCs significantly upregulated CD25+ expression on T-cells, while hindering IL-6, without affecting their proliferation rate. This may point to potentially stronger antiviral effects, while alleviating the viral infection-induced cytokine storm.

Crohn's disease (CD) involves immune system interactions with intestinal tissue, driven by pro-inflammatory cytokines like Tumor Necrosis Factor (TNF-α). Adalimumab, targeting TNF-α, regulates associated inflammatory responses. Despite being humanized, it may induce immunogenic processes, affecting treatment effectiveness. Thus, monitoring serum adalimumab and anti-drug antibody (ADA) levels can optimize therapy. Understanding genetic factors influencing adalimumab response can enhance personalized treatment and improve patient quality of life. We aimed to quantify adalimumab serum levels, assess test interchangeability, detect ADA, examine immune complex formation, and investigate genetic phenotypes related to immunogenicity in CD patients. Seventy CD patients in the maintenance phase with adalimumab were classified into active (CDA) and remission (CDR) groups. Adalimumab concentration was determined via enzyme-linked immunosorbent assay (ELISA-Promonitor) and lateral flow assay (Quantum Blue), with assay interchangeability assessed statistically. ADA and immune complex formation were quantified using ELISA assays. DNA was genotyped for the genes ATG16L1, CD96, and CD155. No significant differences in adalimumab serum concentrations were observed between groups, regardless of the assay. However, a statistical difference between the tests indicated measurement disparity (P = 0.003), with moderate agreement (Lin's correlation of 0.247). ADA was detected in 4 of 27 of the patients with infratherapeutic levels, 3 in the CDA group and 1 in the CDR group. Analysis of immune complexes revealed significantly higher concentrations in the CDA group (P = 0.0125). The genotypic evaluation revealed significant associations for the CD96 CC (wild-type) genotype with higher CRP levels, colonic involvement, and infratherapeutic levels of adalimumab. ATG16L1 CC genotype was associated with higher CDEIS and fecal calprotectin values, while the variant (TT) genotype had lower platelet counts. The effectiveness of treatment with adalimumab was not directly related to higher medication levels in this cohort. The disparity between tests indicates the need to use only one test in patient follow-up to ensure accuracy in therapeutic monitoring. Genotypic differences highlight the correlation between the wild genotype for CD96 and ATG16L1 with unfavorable laboratory and endoscopic response to adalimumab. Finally, the more significant levels of immune complexes in the CDA group indicate an association with a worse response to adalimumab.

We aimed to explore the comprehensive cancer landscape of Caspase-10 (CASP10). CASP10, a member of the caspase family, is located at the human chromosome locus 2q33-34. Studies have suggested its potential role in the development of certain cancers. To evaluate CASP10 expression in normal and pan-cancer tissues, we integrated data from The Cancer Genome Atlas (TCGA), GEO, Human Protein Atlas (HPA), and UALCAN databases. The diagnostic and prognostic significance of CASP10 was analyzed using Receiver Operating Characteristic (ROC), Cox regression, and Kaplan-Meier analysis. Correlations of CASP10 with clinical parameters were assessed via the Wilcoxon test, Kruskal-Wallis test, and logistic regression analysis. Genomic variations were explored with cBioPortal, GSCALite database, and UALCAN databases. LinkedOmics database was used to detect the function of CASP10 in pan-cancer. Interactions between CASP10 and the Tumor Immune Microenvironment (TIME) were investigated using TISIDB, TIMER2, and TISCH databases. The GSCALite database was utilized to assess the sensitivity of CASP10 to small-molecule drugs. In addition, Western Blotting (WB) was employed to detect the expression of the CASP10 in our clinical Liver Hepatocellular Carcinoma (LIHC) and Stomach Adenocarcinoma (STAD) cohorts. The transcription and protein expression of CASP10 significantly differ across cancer types, marking it as a biomarker for diagnosis and prognosis. Its expression correlated with certain clinical characteristics such as histological types and Alpha-Fetoprotein (AFP) levels. CASP10 gene exhibited a 2% alteration frequency across pan-cancer patients, with significant SNV and CNV profiles, and decreased methylation levels. CASP10 was closely related to the Nuclear Factor-κappa B (NF-κB), TNF, cell cycle, and JAK-STAT signal pathways. CASP10 showed correlation with immune components in the tumor microenvironment, including lymphocytes, immune stimulators, immune inhibitors, MHC molecules, chemokines, receptors, and Cancer-Associated Fibroblasts (CAFs). Importantly, CASP10 could predict the sensitivity of diverse anti-cancer drugs. Finally, WB analysis validated the overexpression of CASP10 in LIHC and STAD tissues. Our comprehensive bioinformatic analysis reveal the function of CASP10 on the diagnosis, prognosis, and progression of diverse cancer types.

Objective: Sepsis is a life-threatening condition with high global morbidity and mortality. Citrullinated histone H3 (CitH3) has gained recognition as a significant biomarker for early sepsis diagnosis and management. This study aims to investigate the therapeutic potential of targeting both CitH3 and S100A8/A9 to reduce sepsis-induced inflammation and organ damage.

Methods: Using a novel CitH3 antibody distinct from commercial options, we analyzed serum samples from LPS-treated mice through a co-immunoprecipitation assay followed by LC-MS/MS proteomic analysis to explore the interaction between CitH3 and S100A8/A9 proteins in peripheral blood. Additionally, in a Pseudomonas aeruginosa (PA)-induced lung injury model, we assessed CitH3 and S100A8/A9 levels in bronchoalveolar lavage fluid (BALF), alveolar samples, and neutrophils to determine their influence on neutrophil activation and inflammatory responses.

Results: Our study revealed, for the first time, that CitH3 and S100A8/A9 synergistically promoted neutrophil activation, inflammatory responses, and NETosis, which exacerbated lung injury in sepsis. Dual targeting of CitH3 and S100A8/A9 significantly reduced neutrophil recruitment, NETosis, and inflammation in the PA-induced lung injury model. This therapeutic approach improved lung injury and survival rates, accompanied by a shift in cytokine profiles, with reductions in pro-inflammatory cytokines and increases in anti-inflammatory cytokines.

Conclusion: These findings underscore the potential of dual targeting CitH3 and S100A8/A9 as a novel therapeutic approach for sepsis. This combined intervention shows promising effects in reducing inflammation and enhancing survival, offering a groundbreaking strategy for sepsis diagnosis and treatment.

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease with limited treatment options and associated side effects or resistance. This study aims to investigate the therapeutic potential of the natural compound cucurbitacin B (CuB) in RA treatment.

Methods: We utilized a collagen-induced arthritis (CIA) mouse model to evaluate the effects of CuB. Arthritis scores, histological damage, and pro-inflammatory cytokine expression (TNF-α, IL-17A) were assessed. In addition, network pharmacology analysis was performed to explore CuB's molecular mechanisms, focusing on Th17 cell differentiation, IL-17 signaling, and the JAK-STAT pathway.

Results: CuB significantly reduced arthritis severity, decreased histological damage, and lowered the expression of pro-inflammatory cytokines in CIA mice. CuB was found to inhibit STAT3 phosphorylation and reduce the proportion of Th17 cells in the spleen, indicating its potential anti-inflammatory effects.

Conclusion: These findings suggest that cucurbitacin B may serve as a promising novel therapeutic agent for rheumatoid arthritis by targeting key inflammatory pathways.

Objective: Senile pruritus is a specific type of itching that occurs in elderly persons. Previously, we assessed antagonism of the nonselective ligand-gated cation channel transient receptor potential vanilloid 1 (TRPV1; capsaicin receptor or vanilloid receptor 1) and attenuation of atopic dermatitis by the non-steroidal TRPV1 antagonist PAC-14028 in clinical studies. The findings led us to postulate that PAC-14028 may also reduce itching in elderly people by antagonizing the TRPV1 pathway. In this study, we evaluated whether PAC-14028 modulates inflammatory markers present in senile pruritus.

Materials and methods: HaCaT, RAW264.7, and differentiated THP-1 cells under itching-inducing conditions were treated with zymosan or IL-17A and variety of experimental approaches such as molecular modeling simulations, site-directed mutagenesis, overexpression strategies, confocal microscopy, mRNA analyses, and immunoprecipitation/Western blotting analyses were assessed to check changes in inflammatory markers and explore the underlying mechanisms of PAC-14028 activity.

Results: In the bioinformatic analyses, skin inflammation markers were found to be closely related to TRPV1, and the MAPK and NF-κB pathways were upregulated when TRPV1 was activated. In HaCaT cells, PAC-14028 was found to directly bind to TRPV1, inhibiting inflammatory cytokine gene expression and downstream MAPK and NF-κB signaling under various skin inflammatory conditions.

Conclusions: By combining the results of multiple assays, we were able to elucidate the molecular mechanism of PAC-14028 to TRPV1. Taken together, the findings indicate that PAC-14028 as a potential therapeutic agent for elderly people with pruritus.