International Journal of Immunopathology and Pharmacology最新文献

We aimed to investigate the potential pro-oncogenic properties of GREM1 by Pan-cancer multi-omics analysis. Accumulating evidence has highlighted that GREM1 (Gremlin 1), serves as an inhibitor of BMP (Bone Morphogenetic Protein) family, involve in bone related diseases, carcinogenesis, cell stemness, and cell differentiation. However, the effect and underlying mechanism of GREM1 on the cancer biology remain largely elusive. The mRNA expression of GREM1 were extracted from GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) database. Analysis of OS (Overall Survival), PFI (Progression Free Interval), DSS (Disease-Specific Survival), and ROC (Receiver Operating Characteristic) were performed to predicted prognostic value of GREM1 in various cancers. The TIMER (Tumor Immune Estimation Resource) online tool was used to investigate the relationship between GREM1 transcriptional level and infiltration of immune cells. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis and GO (Gene Ontology) analysis were used to investigate the GREM1 related molecular events, and then constructed a PPI (Protein-Protein Interaction) network via the STRING (Search Tool for the Retrieval of Interaction Genes/Proteins) online tool. Western blot was performed to investigate the indicated protein expression. In the present study, our results showed that GREM1 tended to be upregulated in various cancers, which would correlate with the poor prognosis. Mechanistically, our results showed that GREM1 involve in regulating the ECM-receptor interaction pathway, upregulation of MMP activity, angiogenesis, and immune cell infiltration. In vitro studies, our results further showed that BMP agonist significantly decreased the protein level of GREM1 in GES-1 cells and BGC cells, which accompanied by inhibiting migration and proliferation in GES-1 cells and BGC cells. BMP inhibitor significantly promoted GREM1 expression and migration in BGC cells, but not GES-1 cells. GREM1 might serve as a potential and promising prognostic biomarker for drug development and cancer treatment.

Objective: This study aims to develop a prognostic model for HCC based on TME-related factors.

Introduction: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis, largely due to the complex and heterogeneous interactions between stromal and immune cells within the tumor microenvironment (TME).

Methods: Genome and transcriptome data, as well as clinical information of HCC patients, were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The TME score was evaluated using the "ESTIMATE" R package. Differentially expressed genes (DEGs) associated with TME phenotype were analyzed using the LIMMA R-package. Survival outcomes were compared using Kaplan-Meier curves with log-rank test and Cox proportional hazards model. Protein-Protein Interaction (PPI) networks integrated with multivariate survival and LASSO analyses were utilized to identify TME-related hub genes for a risk score model. A nomogram predicting prognosis of HCC patients was developed through four independent cohorts.

Results: The TME scores showed a negative correlation with tumor progression and survival in HCC patients. We identified 50 core genes with high connectivity in the PPI network, as along with 33 key DEGs associated with survival in HCC. Intersection analysis revealed six hub genes -CXCL8, CXCL1, CCR7, IL7R, MMP9, and CD69. The risk score based on these six TME-related hub genes was significantly associated with overall survival and clinicopathological characteristics of HCC patients. Furthermore, the nomogram demonstrated its ability to discriminate HCC patients from healthy individuals using peripheral blood mononuclear cells.

Conclusion: We have developed a TME-related risk scoring model for HCC patients and identified six hub gene panel that serve as a potential biomarker for personalized prognosis of immunotherapy and non-invasive diagnostics of HCC.

Explore the causal relationship of risk between type 1 diabetes and primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). A causal association between type 1 diabetes and autoimmune liver disease remains ambiguous. This study explored potential causality between different autoimmune conditions, indicating that caution should be taken of the occurrence of autoimmune liver diseases in daily management of T1D patients. Genetic variants were extracted as instrumental variables from the genome-wide association study (GWAS) of PBC, PSC, type 1 diabetes (T1D), and type 2 diabetes (T2D). Associations between four primary liver enzymes, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transferase (ALT), and glutamyl transaminase (GGT), and blood glucose-related indicators such as 2h-glucose post-challenge (2hGlu), fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (HbA1c) were also evaluated (GWAS p-value < 5 × 10^-8). A bi-directional two-sample Mendelian randomization (MR) design was used to assess causality between type 1 diabetes and autoimmune cholestasis. Genetic susceptibility to T1D increased the risk of PSC and PBC. Genetic susceptibility to T2D reduced the risk of PSC and showed no correlation with PBC. Genetically susceptibility to PBC increased the risk of T1D and showed no correlation with T2D. Genetically susceptibility to PSC did not impact the risk of T1D and T2D. T1D patients have an increased risk of PBC/PSC, but such causation is not mediated or explained by the altered blood glucose levels. A bi-directional causal association was identified between type 1 diabetes and autoimmune cholestasis. The findings provide new insight into the management of patients with these conditions.

Immune Checkpoint Inhibitors (ICIs) are monoclonal antibodies that block inhibitory immune targets, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L). Pembrolizumab targets the PD-1 receptor of lymphocytes in lung cancer treatment. ICI checkpoint blockade enhances immunity against cancer cells. However, loss of immunoregulatory control can cause autoimmune reactions in various organs, leading to immune-related adverse events (irAEs). The most common irAE is ICIs-induced colitis, which usually develops 6-8 weeks after ICI initiation and can involve any part of the gastrointestinal system. Herein, we report a presentation of pembrolizumab-induced colitis in a female patient with metastatic lung cancer and review the most recent findings in the model of checkpoint-induced colitis. It was interesting to learn that the colon mucosa may show normal macroscopic findings, but microscopically, immunotherapy-induced autoimmune colitis could be present. Additionally, patients with grade 2 or higher symptoms should have a colonoscopy, receive systemic corticosteroids as treatment, and, based on their response, receive biologic therapy. Here, we present a case report of in a 45-year-old female who has been a smoker for 25 years, without comorbidities, and with metastatic lung cancer who developed colitis after the seventh cycle of pembrolizumab. This case presentation highlights the importance of early recognition and appropriate intervention in order to prevent permanent interruption of treatment with checkpoint inhibitors, as well as prevention of colitis complications.

Cell-free DNA (cfDNA) has emerged as a potential biomarker for assessing disease activity and prognosis in rheumatoid arthritis (RA). However, the association between cfDNA levels and the established RA markers of inflammation and disease severity remains unclear. The current study aimed to detect plasma levels of cfDNA in patients with RA and to investigate their association with RA activity indicators (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score-28 (DAS28)), prognostic markers (rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA)), and the musculoskeletal ultrasonographic (US7) scores. This controlled cross-sectional study included 108 RA patients and 108 healthy controls. Plasma levels of cfDNA were quantified by real-time PCR using ALU repeats. Levels of ESR, CRP, RF, and ACPA were measured using routine laboratory assays. Synovial inflammation and joint damage evaluation was performed using the US7 scoring system. Plasma levels of cfDNA were higher in RA patients than controls (P < 0.001) and significantly increased with higher DAS28 scores among all RA activity groups. Also, cfDNA levels were significantly positively correlated with ESR, CRP, RF, and ACPA levels (P-values <0.001). Regarding US7, cfDNA was significantly positively correlated with synovitis and erosion scores (P-values <0.05) but did not correlate significantly with tenosynovitis scores (P-values >0.05). In addition, plasma cfDNA was significantly higher in seropositive RA patients than in seronegative patients (P = 0.007). The odds ratio for cfDNA as a risk factor for erosions was 2.254. This study revealed that cfDNA levels are elevated in RA patients and positively associated with disease activity indicators and prognosis markers. Further research is warranted to validate these findings in larger cohorts and explore the clinical implications of cfDNA measurement in RA management.

Objective: To study the role and underlying mechanisms of dihydromyricetin on the myocardial function in mice induced by CCl₄.

Methods: Eighteen C57BL/6 mice (6-8 W, female) were randomly divided into the following three groups: control group, CCl₄-induced positive group (CCl₄ group), dihydromyricetin group, six mice/group. NLRP3-deficient (NLRP3^-/-) C57BL/6 mice used the same age, gender, and modeling method. The HL-1 cells were used for in vitro experiments. The HL-1 cells were treated with PBS, CCl₄, and CCl₄ + DMY respectively.

Results: The RT-qPCR results showed that compared to the mice induced by CCl₄, the dihydromyricetin increased the Arg-1 mRNA level in the mouse myocardial tissues. The mRNA expressions of the iNOS, IL-33, and ST2 were reduced by the dihydromyricetin. The results of immunohistochemistry showed that dihydromyricetin decreased IL-33 protein expressions in the myocardial tissues. Western blot results also showed that compared with the control group, the activation of NLRP3 inflammasomes in the myocardial tissues of mice injured by CCl₄ was increased, and dihydromyricetin can reduce NLRP3 inflammasomes activation in the myocardial tissues induced by CCl₄. The results of ELISA showed that dihydromyricetin could reduce the IL-1β level in the serum of the mice induced by CCl_4. Consistent with the in vivo results, compared with the control group, the NLRP3 inflammasome activation and IL-33/ST2 expression were increased in the CCl₄-treated HL-1 cells, while DMY significantly weakened this effect. Interestingly, NLRP3 deficiency enhanced the protective effect of DMY on myocardial function in mice.

Conclusions: IL-33/ST2 signaling pathways and NLRP3 inflammasome activation may be involved in dihydromyricetin improving the myocardial function of the mice induced by CCl₄.

Objective: The aim of this study was to investigate the effects of halofuginone (HF) on gastric cancer cells and whether the combination of HF and trametinib has synergistic effects.

Introduction: Halofuginone, a natural small molecule isolated from the plant Dichroa febrifuga, has been found to have anticancer activity in a variety of cancers, but few studies on HF in gastric cancer.

Methods: cell viability was performed using the CellTiterGlo assay and apoptosis and cell cycle analysis was performed by Annexin V-FITC staining and PI staining. We also analyzed RNA sequencing and differentially expressed genes was shown using the heatmap. Western blot and qPCR were carried out to determine the expression of pro-apoptotic and anti-apoptotic proteins.

Results: HF inhibited proliferation and induced apoptosis in gastric cancer cells in a dose-dependent manner. HF induced the expression of p-ERK in gastric cancer cells. HF and trametinib synergistically inhibited the gastric cancer cell proliferation. Trametinib inhibited HF-induced p-ERK expression. HF reduced anti-apoptotic protein Mcl-1 expression and reduced trametinib-induced upregulation of Mcl-1 expression.

Conclusion: HF exerts its anti-cancer effects in gastric cancer and has a synergistic inhibition with trametinib, which may provide a novel therapeutic strategy for gastric cancer.

Excess iron has been associated with cardiovascular diseases. Flavonoids are antioxidants and cardioprotectants. Therefore, the goal of the current study is to evaluate the anti-apoptotic, antioxidant, and iron-chelating qualities of two flavonoids, rutin (R) and hesperidin (H), as well as their potential to prevent induced ferroptosis in rats. It is an in vivo cross-sectional study, in which rats were divided into 12 groups; control, H, R, H + R, Fe, Fe + IR, Fe + IR + Ref, Fe + H, Fe + IR + H, Fe + R, Fe + IR + R and Fe + IR + H + R. Cardiac and serum iron levels, serum troponin I, creatine kinase-MB (CK-MB), total iron binding capacity (TIBC), transferrin, ferritin, and hepicidin were determined. Moreover, the levels of malondialdehyde (MDA), nitric oxide (NO) and glutathione (GSH) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), were also determined. The expression levels of DMT1, ACSL4, GPX4, Nrf2, and caspase-3 genes were evaluated by RT-qPCR. Lastly, a histological analysis of the heart tissues from several groups of rats was conducted. After hesperidin and/or rutin treatment, our results revealed that cardiac markers (serum troponin I and CK-MB), iron metabolism markers (serum and cardiac iron, TIBC, ferritin, transferrin, hepicidin and DMT1 expression levels) and oxidative stress markers (MDA, NO and ACSL4 expression levels) were significantly (P ⩽ 0.05) reduced, while the antioxidant markers (GSH level, GPx and SOD activities and GPX4 and Nrf2 expression levels) were significantly (P ⩽ 0.05) increased. Also, hesperidin and rutin exerted its protective anti-apoptotic role by significantly (P ⩽ 0.05) decreasing caspase-3 expression levels. Hesperidin and/or rutin treatment can be proposed as a therapeutic candidate to attenuate ferroptosis.

Objective: This study aimed to elucidate the anti-inflammatory mechanisms of asiatic acid (AA) by focusing on its modulation of the nuclear factor-κB (NF-κB) signaling pathway and to evaluate its therapeutic effects in murine models of both acute and chronic colitis.

Introduction: AA, a naturally occurring triterpenoid compound derived from Centella asiatica, is known for its anti-inflammatory activity. However, its comprehensive effects on both acute and chronic intestinal inflammation, particularly through detailed modulation of the NF-κB pathway, have not been fully elucidated.

Methods: Human intestinal epithelial cells COLO 205 and murine macrophage cells RAW 264.7 were pretreated with AA, followed by stimulation with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), respectively. The mRNA expression of pro-inflammatory cytokines, including interleukin (IL)-8, TNF-α, and IL-6, was quantified using real-time RT-PCR. Western blotting was performed to assess the phosphorylation and degradation of the NF-κB inhibitor IκBα, and NF-κB DNA-binding activity was assessed via electrophoretic mobility shift assay (EMSA). In vivo, acute colitis was induced using dextran sulfate sodium (DSS) in wild-type mice, and chronic colitis was established by piroxicam administration in IL-10⁻/⁻ mice. Following AA treatment, colon length, body weight, histology (H&E) with histologic scoring, and colonic NF-κB p65 immunohistochemistry (IHC) were evaluated.

Results: AA significantly downregulated cytokine expression in both cell lines. It inhibited IκBα phosphorylation and degradation, and EMSA demonstrated a marked reduction in NF-κB DNA-binding activity. In mice, AA attenuated body weight loss, colonic shortening, and histologic inflammation in both DSS and IL-10⁻/⁻ models. Concomitantly, colonic IHC showed reduced nuclear NF-κB p65.

Conclusions: AA alleviates intestinal inflammation by suppressing NF-κB signaling in vitro and exhibits therapeutic efficacy in both acute and chronic colitis models, suggesting its potential as a therapeutic candidate for inflammatory bowel disease.