International Journal of Immunopathology and Pharmacology最新文献

Objective: Cannabidiol (CBD) administration (5 mg/kg) in healthy rats has been shown to significantly decrease lymphocyte subset numbers in peripheral blood without involvement of natural killer cells. The aim was to evaluate whether lymphocyte numbers also decrease in the spleen.

Introduction: CBD, the major non-psychotropic compound of Cannabis sp., is an effective treatment for inflammatory and autoimmune diseases with various anti-tumor effects, but the mechanisms of its long-term actions in vivo remain unclear.

Methods: To examine the effects of CBD on lymphocyte subsets in the spleen and NK cellular cytotoxicity (NKCC), adult male Wistar rats (n = 63) were administered intraperitoneal injections of CBD (2.5 or 5 mg/kg/day) for 14 consecutive days, and lymphocyte counts were obtained using flow cytometry. NKCC in the peripheral blood and spleen was quantified using a Chromium-51 release assay. Furthermore, the effect was similar to a decrease in lymphocytes caused by treatment with the selective receptor antagonist AM630 (1 mg/kg).

Results: The results indicate that repeated administration of CBD at a dose of 5 mg/kg/day decreased splenic lymphocyte numbers, involving T and non-T/NK CD45RA+ lymphocytes but not NK cells. The effects of CB₂ receptor antagonist were not significant, but it had a significant interaction with CBD. No changes in NKCC were observed following CBD administration.

Conclusion: These results reveal that in healthy rats, CBD produces similar lymphopenic effects in the spleen as it does in peripheral blood without affecting NK cell counts or cytotoxicity.

The oral epithelium is a dynamic interface between host and environment, where keratinocytes not only serve as structural components but also actively modulate immune responses. Emerging research identifies IRF6 as a pivotal regulator of epithelial differentiation and immune signaling within chronic inflammatory contexts. This narrative review explores the role of IRF6 and its downstream effects in oral keratinocytes, particularly in relation to Toll-like receptor (TLR) activation, CCL5-mediated inflammation, hypoxic signaling, and the epithelial-mesenchymal transition (EMT). It proposes a mechanistic framework for understanding the progression from chronic inflammation to epithelial disruption and malignant transformation in oral mucosal disorders. Modulation of IRF6 signaling represents a promising therapeutic target for restoring epithelial integrity and halting disease progression in chronic inflammatory oral diseases. This model lays groundwork for future research integrating molecular biomarkers and immune modulation strategies in oral pathology.

Objective: This study aims to comprehensively investigate the expression profiles of interleukins in prostate adenocarcinoma (PRAD) and their relationship with immune cell infiltration, tumor progression, and patient prognosis. By establishing an interleukin-related risk score, we seek to enhance the understanding of the tumor immune microenvironment and facilitate the development of tailored immunotherapeutic strategies for PRAD patients.

Introduction: Interleukins can nurture a tumor promoting environment and simultaneously regulate immune cell infiltration. However, the potential roles of interleukins in the prostate adenocarcinoma immune landscape remain abstruse.

Methods: We comprehensively investigated the interleukin expression patterns and tumor immune landscape of prostate adenocarcinoma patients. And explored the interleukin expression patterns with immune infiltration landscape. The interleukin score was established using LASSO cox regression analysis. Multivariate Cox regression analysis was employed to assess the prognostic value of the interleukin score.

Results: We identified two distinct interleukin clusters, characterized by different immune cell infiltration, tumor promoting signaling pathways activation and prognosis. The interleukin score was established to estimate the prognosis of individual prostate adenocarcinoma (PRAD) patient. Further analysis demonstrated that the interleukin score was an independent prognostic factor of PRAD. Finally, we investigated the predictive value of interleukin score in the programmed cell death protein (PD-1) blockade therapy of patients with prostate adenocarcinoma. At the same time, the differences in related genes among different prostate cell lines were also identified.

Conclusions: This study demonstrated the correlation between interleukin and tumor immune landscape in prostate adenocarcinoma. The comprehensive evaluation of interleukin expression patterns in individual prostate patients contribute to our understanding of the immune landscape and helps clinicians selecting proper immunotherapy strategies for prostate patients.

Systemic lupus erythematosus (SLE) patients are at greater risk of developing osteoporosis (OP) than the general population. This study aimed to identify crosstalk genes between SLE and OP and to validate their diagnostic accuracy as biomarkers. Data analysis based on Gene Expression Omnibus (GEO) datasets was conducted. We utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and differential expression analysis to identify crosstalk genes (CGs). Machine learning algorithms and consensus clustering were applied to screen shared diagnostic biomarkers and construct two predictive models featuring key genes. We also investigated potential subgroups, immune infiltration across different subtypes, and validated hub mRNAs using quantitative real-time PCR (qPCR). Molecular docking was performed to simulate the interaction of a small molecule compound with its target. We identified 19 CGs and developed two predictive models: the IL1R2-GADD45B and CHI3L1-IL1R2-SPTLC2 diagnostic score thresholds. The CHI3L1-IL1R2-SPTLC2 model showed improved predictive accuracy for lupus-associated osteoporosis. The C2 subtype was found to potentially regulate bone metabolism in SLE patients. Immune infiltration analysis indicated a strong association between CGs and multiple immunocytes, with IL1R2 being a common element in both models. Molecular docking suggests that Anakinra's therapeutic effect may involve IL1R2. Our study introduces novel diagnostic biomarkers and predictive models for lupus-associated osteoporosis, with a particular focus on IL1R2 as an innovative biomarker and therapeutic target. These are anticipated to aid early screening and risk assessment in SLE patients, pending large-scale clinical validation.

Objective: This study aimed to investigate the effect of rapamycin on inflammatory pain in rats.

Introduction: Inflammatory pain is a kind of pathological pain caused by inflammatory mediators or factors such as TNF-α (Tumor Necrosis Factor-α), IL-1β (Interleukin-1β), and IL-6 (Interleukin-6). NSAIDs and opioid analgesics are commonly used for relieving inflammatory pain, but the side effects limit their clinical application. New drugs based on new mechanisms for inflammatory pain are urgently needed. Autophagy is an evolutionarily conserved homeostatic process for lysosomal degradation of intracellular components. Recent reports indicate the involvement of autophagy in the development and maintenance of neuropathic pain, but the role of autophagy in inflammatory pain still needs to be explored.

Methods: The pain-related behaviors of rats were studied by paw withdrawal threshold and paw withdrawal latency. The autophagy level of the rat spinal cord was detected by western blots. The concentrations of TNF-α, IL-1β, and IL-6 were detected by ELISA.

Results: We found that the paw withdrawal threshold and paw withdrawal latency were both significantly decreased after CFA (Complete Freund's Adjuvant) injection, accompanied by the activation of mTOR signaling pathway and the inhibited autophagy flux in the spinal cord. And inflammatory cytokines were increased in the spinal cord after CFA injection. Then, we studied the effect of rapamycin on CFA-induced inflammatory pain in rats, and found that rapamycin restored the autophagy flux and significantly reduced mechanical allodynia and thermal hyperalgesia. In addition, rapamycin significantly decreased the levels of TNF-α, IL-1β, and IL-6 after CFA injection in the spinal cord.

Conclusion: Our results suggested that rapamycin might be a promising candidate for the treatment of inflammatory pain by restoring the autophagy flux in the spinal cord.

Objective: The effect of the cGAS/STING pathway on antitumor immunity and its connection to senescence in vivo necessitates further investigation.

Introduction: Cellular senescence and its secretory phenotype (the SASP) are implicated in modulating the immune microenvironment of cancer possibly through the cGAS/STING pathway.

Methods: Gene expression data from paired colon cancer and adjacent non-malignant mucosa (98 patients, n = 196 samples; 65 patients, n = 130 samples) were analyzed for cGAS/STING and a senescence signature. Immunohistochemistry assessed cGAS/STING protein expression in 124 colorectal samples.

Results: Approximately one-quarter of patients displayed senescence profiles in both gene sets, yet without significantly correlating with cGAS/STING expression. Notably, cGAS expression was higher than STING in tumor tissue compared to non-malignant colonic mucosa. Protein analysis showed 83% positive cGAS expression and 39% positive STING expression, with discrepancies in expression patterns. Additionally, 15% of samples lacked both markers, while 35% exhibited positive staining for both. No significant correlations were found between cGAS/STING status and tumor stage, patient age, lymphovascular invasion, or lymph node involvement.

Conclusions: Our findings demonstrate significant senescence marker expression in colorectal cancer samples but with no correlation with cGAS/STING.

Background: The programmed cell death-ligand 1 (PD-L1) combined positive score is used as a patient selection tool and predictive factor for anti-programmed cell death-1 (PD-1)/PD-L1 therapy in gastric cancer. However, the expression of PD-L1 and major histocompatibility complex class I (MHC-I) can be affected by conventional treatment approaches.

Objective: In this study, we examined the effects of chemotherapy on surface PD-L1 and surface MHC-I expression in living and apoptotic gastric cancer cells. AGS (moderately differentiated) and SNU-1 (poorly differentiated) cells were treated 5-Fluorouracil (5-Fu), cisplatin, mitomycin c (MMC), and FOLFOX (5-Fu, leucovorin, and oxaliplatin).

Methods: To quantify the expression levels of surface PD-L1 or surface MHC-I on living and apoptotic cells, the cells were co-stained with annexin V and PD-L1 or MHC-I antibodies. The percentages of single positive (annexin V-negative, PD-L1-positive; annexin V-negative, MHC-I-positive) and double positive (annexin V-positive, PD-L1-positive; annexin V-positive, MHC-I-positive) cells were analyzed by flow cytometry.

Results: Every tested chemotherapeutic agent increased the levels of surface PD-L1 and surface MHC-I, although the extents of increase differed in AGS and SNU-1 cells. In AGS cells, 5-Fu caused the largest increases in surface PD-L1 and surface MHC-I. However, 5-Fu caused the weakest increases in surface PD-L1 and surface MHC-I in SNU-1 cells. Notably, chemotherapy-mediated increases in surface PD-L1 and surface MHC-I mostly occurred on apoptotic cells.

Conclusion: Our findings reveal that chemotherapy mainly increases surface PD-L1 and surface MHC-I on apoptotic gastric cancer cells.

Objective: This study aims to analyze MRSA isolates from pediatric cancer patients, determine the prevalence of PVL genes and assess their clinical implications.

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant challenges in pediatric oncology settings. Understanding the prevalence, genotypic characteristics, and antibiotic resistance patterns of MRSA aids in improving patients' outcomes.

Methods: A total of 120 S. aureus isolates from patients receiving chemotherapy for treatment of malignant diseases and developing BSIs during febrile episodes were examined. Isolates were identified using Gram staining, biochemical tests, and VITEK 2-Compact 15. Antimicrobial susceptibility was tested using the Kirby-Bauer disk diffusion method. Molecular characterization included PCR assays for 16S rDNA, multiplex PCR for femA, mecA, and PVL genes, and SCC_mec type.

Results: Out of 120 isolates of Staphylococcus aureus, 97 (80%) isolate possessed mecA gene and were identified as MRSA, MRSA bacteremia harboring PVL gene was detected in cancer patients in Egypt at 26.8% of MRSA isolates. The study identified a higher fatality rate in patients aged 6-10 years (26.7%) compared to other age groups (p < 0.044). Deceased patients exhibited higher leukocyte counts and lower platelet counts. Solid tumor patients had significantly higher neutrophil and monocyte counts. Type II of SCC_mec correlated with survival and mortality, with the PVL gene being a significant factor. Type III showed a higher prevalence of femA and mecA among survivors, while Type IVb was associated with better outcomes. Antibiotic susceptibility revealed high resistance to cefoxitin, cefepime, and Tazocin, but better sensitivity to ciprofloxacin and gentamicin, particularly in Types IV and V.

Conclusion: The study highlights the age-related fatality differences and the impact of HCV infection on survival rates. Hematologic parameters and SCC_mec types play a crucial role in patient outcomes. The observed antibiotic resistance patterns necessitate the need for targeted therapies based on MRSA SCC_mec types.

Objective: The current study aimed to investigate the role of β and α1-adrenoceptors in pancreatic regulation of glucose homeostasis, apoptosis, and fibrosis in a rat model of dexamethasone-induced insulin resistance.

Introduction: Insulin resistance is a hallmark of metabolic syndrome and is often linked to glucocorticoid excess. β- and α1-adrenoceptors are key modulators of glucose metabolism and tissue remodeling, yet their roles in pancreatic dysfunction under metabolic stress remain incompletely understood. Emerging evidence highlights β-arrestin2 as a key mediator of apoptosis and fibrosis beyond classical G protein signaling.

Methods: Insulin resistance was induced in rats by subcutaneous dexamethasone (10 mg/kg/day) for 7 days. The therapeutic effects of carvedilol, phenylephrine, phenylephrine + carvedilol, propranolol, doxazosin, and doxazosin + propranolol were evaluated in relation to glucose homeostasis and pancreatic apoptotic/fibrotic signaling.

Results and conclusion: Dexamethasone impaired glucose homeostasis, expanded islet mass, and triggered pancreatic cell apoptosis and fibrosis via upregulated BAX/Bcl-2 expression ratio, downregulated cAMP, upregulated PKA, ERK1/2, and CREB expression with elevated PKB activity and reduced FOXO1 expression. % Level of β-arrestin2 was reduced in pancreatic islets and elevated in exocrine pancreas in relation to the aforementioned modulations. Blockade of β- or α1-adrenoceptors significantly ameliorated these effects, with combined blockade yielding superior benefits. Carvedilol's effects were largely β-mediated, with minor α1 involvement. Low-dose phenylephrine yielded modest improvement, supporting a context-dependent, protective role of α1-adrenoceptor activation during metabolic stress. The dependence of drugs' effects on β-arrestin2 highlights its potential as a central regulator of pancreatic remodeling and a promising target in IR-linked pathologies.

Objective: This study aimed to evaluate whether EDTA-based targeted chelation therapy can act as senomorphic in chronic kidney disease (CKD)-induced vascular calcification.

Introduction: Vascular calcification, a significant complication of CKD, is induced due to osteogenic trans-differentiation and senescence of vascular smooth muscle cells (VSMCs). Senescent VSMCs contribute to inflammation and calcification via the senescence-associated secretory phenotype (SASP). Recent evidence implicates the NLRP3 inflammasome as a key mediator of inflammation and senescence in vascular calcification. We previously demonstrated that EDTA chelation therapy removes calcium deposits from arteries in the CKD model. In this study, we investigated whether EDTA also exerts senomorphic effects by reducing NLRP3 expression and vascular cell senescence in calcified aortic tissue.

Methods: We used an adenine diet-based rodent model of late-stage CKD and an ex vivo aortic ring culture model to evaluate the senotherapeutic potential of EDTA-loaded human serum albumin nanoparticles tagged with anti-elastin antibody-Flexibzumab (EDTA NPs). For validation, we performed a comparative proteomics analysis on the total proteins harvested from the abdominal aortas of the EDTA-treated and untreated animals.

Results: Our results show that targeted chelation therapy with EDTA NPs decreases the percentage of SA-β-gal positive senescent cells in the calcified aorta and acts as senomorphic by decreasing NLRP3 inflammasome formation, which is a primary intracellular source of senescence-associated secretory phenotype (SASP).

Conclusion: For the first time, the current study provides proof of concept on the senotherapeutic potential of a targeted chelation therapy and its capacity to modulate SASP from the senescent cells accumulated in calcified aorta.