Immunopharmacology and Immunotoxicology最新文献

Background: This study systematically explored the effects of moderate-intensity exercise on tumor immunotherapy efficacy and its mechanisms of action using the MC38 colon cancer mouse model.

Methods: Tumor-bearing mice were randomly assigned to the control group, immunotherapy group, and exercise intervention group. Flow cytometry, Luminex multiplex cytokine assays, and other techniques were employed to assess the regulatory effects of exercise on the tumor immune microenvironment and systemic immune responses.

Results: The results showed that exercise intervention significantly inhibited tumor growth, with a 32.0% reduction in tumor volume and a 34.5% reduction in tumor weight, placing its effect between that of the control and immunotherapy groups (p < 0.05). Exercise training increased CD8+ T cell infiltration in the tumor microenvironment by 83.3%, while decreasing the proportion of Tregs and MDSCs by 26.5% and 28.0%, respectively. Furthermore, exercise significantly enhanced serum IFN-γ levels (+65.6%) and IgG concentrations (+29.4%). Circulating tumor DNA (ctDNA) analysis revealed that the total ctDNA concentration in the exercise group decreased by 66.1% compared to the control group (p < 0.01), with KRAS and TP53 mutation frequencies reduced by 66.4% and 67.8%, respectively. Correlation analysis indicated that the CD8+/Tregs ratio was strongly associated with tumor suppression (r = 0.76), and the IFN-γ/IL-6 ratio increased by 97.4%, showing a significant correlation with efficacy (r = 0.79).

Conclusion: This study confirms that exercise training exerts anti-tumor effects by remodeling the tumor immune microenvironment, activating systemic immune responses, and reducing ctDNA burden. Its unique "immune normalization" effect provides important evidence for the development of "exercise-immunotherapy" combination treatment strategies.

Background: This Summary-data-based Mendelian randomization (SMR) study investigates the genetic basis of Graves' disease (GD) using a multi-omics approach to elucidate biological mechanisms and identify therapeutic candidates.

Methods: SMR and Bayesian colocalization analyzed GD associations with methylation (mQTL), expression (eQTL), and protein quantitative trait loci (pQTL) using FinnGen as the discovery cohort. Top SNPs underwent methylation-gene expression and gene expression-protein interaction analyses. Key findings were validated against an independent GWAS dataset. Functional enrichment characterized pathways for eQTL-SMR-derived loci. The Drug Signatures Database (DsigDB) predicted potential drugs.

Results: Significant multi-omics associations were found. mQTL analysis linked GD to 1,772 methylation sites (294 genes); eQTL identified 157 genes. pQTL signals appeared in two cohorts (4 genes deCODE; 16 genes UKB-PPP). AGER and AIF1 were consistent across omics. AIF1 showed strong GD associations (mQTL OR 1.09; eQTL OR 1.44; deCODE-pQTL OR 3.17; UKB-PPP-pQTL OR 3.46). Integrated analysis revealed a positive correlation between AGER DNA methylation and expression, but negative for AIF1, with colocalization support (PPH3 + PPH4 > 0.8). SMR showed inverse pQTL associations for AGER and positive for AIF1, also colocalized. Independent GWAS validation confirmed GD associations with AGER and AIF1 at pQTL. Enrichment indicated immune/inflammatory pathways. Drug predictions included agents for AGER (Oleanolic Acid, Rutin, Estriol, GW9662) and AIF1 (Quinoline).

Conclusion: This study provides novel insights into GD pathogenesis, highlighting AGER and AIF1 as therapeutically relevant genes. Findings offer valuable insights for GD treatment strategies and potential drug development streamlining, warranting further experimental validation.

Background: Pathological neuroinflammation is a critical factor that disrupts neuronal activity and, when sustained, ultimately contributes to neuronal death. Among the primary mediators of neuroinflammation, microglia play a central role in modulating brain immunity. However, their overactivation is closely associated with neuronal damage and structural remodeling of brain tissue, leading to the onset and progression of various neurodegenerative diseases.

Materials and methods: We investigated the neuroprotective effects of avarol, a marine-derived sesquiterpenoid, focusing on its ability to inhibit lipopolysaccharide (LPS)-induced overactivation of BV2 microglial cells and its subsequent impact on neuronal activity in HT-22 hippocampal neuronal cells.

Results: Pretreatment with avarol significantly attenuated the LPS-induced release of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), as well as oxidative stress markers such as reactive oxygen species (ROS) and nitric oxide (NO). These inhibitory effects were further substantiated by a dose-dependent reduction in nuclear translocation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the inflammatory signaling cascade. Regarding the interaction between microglia and neurons, both conditioned medium and co-culture systems demonstrated that avarol significantly attenuated alterations in neuronal plasticity-related molecules-such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)-induced by activated microglia.

Conclusions: Overall, these findings suggest that avarol exerts neuroprotective effects through the modulation of microglia-mediated neuroinflammation. Importantly, avarol's capacity to traverse the blood-brain barrier highlights its potential as an effective pharmacological agent in mitigating neuroinflammation-associated neurological disorders.

Background: The complex interaction between the adaptive immune system and innate immunological components causes rheumatoid arthritis (RA), a systemic autoimmune disorder that involves synovitis and joint deformity. Brain- spleen axis is a reciprocal cross-communicative circuit serves a crucial role in maintaining immunomodulation and homeostasis. RA complicates extra-articular manifestations in spleen and brain. Exposure to ionizing radiation might exacerbate the severity of RA. Recently, beta- sitosterol (BS), which is a promising phytosterols, has shown efficacy against various inflammatory models.

Objective: Here, we aim at exploring the immunomodulatory effect of BS on the inflammatory responses in arthritic and arthritic-irradiated rats involving articular and extra-articular manifestation implicated in the brain-spleen axis.

Materials and methods: Adjuvant- induced arthritic rats were subjected to fractionated doses of γ-radiation (2 Gy/fraction once per week for 4 successive weeks, up to a total dose of 8 Gy) and either treated with BS (40 mg/kg b.wt./day, p.o.) or the standard anti-RA drug, methotrexate (MTX) (0.5 mg/kg; twice weekly, i.p).

Results: BS ameliorated the arthritic clinical signs, improved histopathological insults, and osteopathological damage as revealed by X- radiography. Moreover, a notable alleviation in key inflammatory culprits was observed in ankle joints. Also, BS modulated apelin-13/APJ and protein kinase C (PKC)/AMP-activated protein kinase (AMPK)/nuclear factor erythroid-2-related factor-2 (Nrf2) signaling pathways in spleen and brain, as well as reduced oxidative stress, augmented antioxidant defenses, and diminished pro-inflammatory cytokines in serum, spleen, and brain that was supported histopathologically.

Conclusion: BS exhibited an immunomodulatory effect involving the brain-spleen axis in arthritic and arthritic-irradiated rats.

Background: Polydatin, a natural component of Polygonum cuspidatum, exhibits potent anti-metabolic properties. The treatment with Poly (10 µm/L) effectively reversed the high glucose (HG)-induced reduction in acetylcholine (ACh)-elicited vasodilation in the aortas of Sprague-Dawley rats.

Methods: Male Sprague-Dawley rats were used to evaluate the effects of polydatin on endothelial function under HG conditions. Endothelium-dependent relaxation (EDR) was assessed in isolated thoracic aortic rings using ACh, with or without L-NAME or tempol. Human umbilical vein endothelial cells (HUVECs) were also treated under normal glucose (NG), HG, or HG + polydatin conditions. Gene expression (NLRP3, VCAM-1, GAPDH) was measured by RT-PCR, while protein levels of eNOS, iNOS, NLRP3, VCAM-1, and GAPDH were analyzed by western blotting.

Results: HG significantly impaired ACh-induced EDR in rat aortic rings, while polydatin (10 µmol/L) restored vascular responsiveness. Mechanistically, polydatin upregulated eNOS and suppressed iNOS expression, and its vasoprotective effects were partially inhibited by L-NAME, indicating nitric oxide (NO) pathway involvement. In both aortic tissues and HUVECs, HG markedly increased NLRP3 and VCAM-1 expression, which was effectively reversed by polydatin, indicating its anti-inflammatory action.

Conclusion: Polydatin counteracts hyperglycemia-induced endothelial dysfunction by enhancing eNOS-dependent NO signaling to restore vasodilatory capacity, while inhibiting NLRP3 inflammasome activation and downstream VCAM-1 expression to attenuate vascular inflammation. These dual mechanisms position polydatin as a therapeutic agent for preserving vascular function in diabeticconditions.

Objectives: Immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy, represent a pivotal approach in the treatment of multiple myeloma (MM). However, the complex immunosuppressive tumor microenvironment (TME) poses significant challenges to their efficacy. Among the immunosuppressive cells in the MM TME, granulocytic myeloid-derived suppressor cells (G-MDSCs) are predominant, yet their functions remain incompletely understood. This study aimed to comprehensively analyze the role of G-MDSCs in MM patients undergoing CAR-T therapy.

Methods: Single-cell transcriptomic data from seven MM patients before and after CAR-T therapy were analyzed to characterize G-MDSCs. Functional enrichment and gene set enrichment analysis (GSEA) were performed to identify signaling pathways. A risk prediction model was constructed using RNA-seq and survival data from 713 MM patients, and validated by Kaplan-Meier analysis. In vitro experiments were conducted to assess the immunosuppressive functions of G-MDSCs.

Results: The findings, though exploratory due to limited sample size and inter-patient heterogeneity, suggested pathological activation and immunosuppressive roles of G-MDSCs potentially linked to patient prognosis. G-MDSCs were identified as key modulators of immune responses within the TME, with GSEA indicating regulation via IFN-α/γ signaling. They may facilitate immune evasion of MM cells by promoting proliferation through the IGF1-IGF1R axis and inhibiting T cells and other immune cells via the SIRPA-CD47 pathway. The risk prediction model based on G-MDSC gene signatures demonstrated high prognostic accuracy (AUC = 0.94). PTGS1 was identified as a key marker associated with high-risk groups, and functional assays confirmed its role in mediating G-MDSC immunosuppressive activity.

Conclusions: This study provides preliminary insights into the functional role of G-MDSCs in the MM TME and highlights their impact on CAR-T therapy outcomes. The findings suggest potential therapeutic strategies, including targeting PTGS1, to enhance CAR-T efficacy. Larger and more diverse cohorts are required to substantiate these observations.

Background: Asthma, a chronic inflammatory disease characterized by inflammation and immunological abnormalities, was the focus of this study, which explored the mechanisms and efficacy of a pediatric anti-cough and asthma sirup in a cigarette smoke extract (CSE)-induced rat asthma model.

Methods: A CSE-induced asthma rat model was treated with a sirup containing roasted ephedra, bitter almond, gypsum, and licorice. Key markers in serum/BALF were measured by ELISA. Inflammatory cells were analyzed by Giemsa staining, pathology by hematoxylin-eosin, and macrophage infiltration by CD68+ immunohistochemistry. Lung tissue apoptosis (TUNEL), and apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3) plus phosphorylated NF-κB (all by Western blot) were evaluated.

Results: The sirup treatment significantly attenuated CSE-induced airway inflammation in asthmatic rats, shown by decreased serum IL-4, IL-5, and IL-13, and reduced inflammatory cell infiltration in BALF. It also restored oxidative balance by reversing MDA elevation and SOD reduction. Histopathologically, it alleviated peribronchial inflammation, cell infiltration, hemolysis, and alveolar septum thickening. Furthermore, it suppressed CSE-induced lung apoptosis, evidenced by fewer TUNEL-positive cells, reduced pro-apoptotic proteins (Bax and cleaved caspase-3), and increased anti-apoptotic Bcl-2, likely via inhibiting NF-κB pathway activation.

Conclusion: The pediatric sirup holds therapeutic potential against CSE-induced asthma by regulating cytokine levels and decreasing pulmonary inflammation/apoptosis.

Background: Leonurine (Leo) has antioxidant and anti-inflammatory activities. In this study, we investigated the effect of Leo in a rat model of lipopolysaccharide (LPS)-induced chronic obstructive pulmonary disease (COPD).

Methods: Rats with COPD were administered Leo, and the pulmonary function parameters, pathological changes, and inflammatory mediators in tissues were evaluated. The expression of IκBa, p65, JAK2, STAT3, p-IκBa, p-p65, p-JAK2 and p-STAT3 was measured using western blotting.

Results: Leo effectively improved the clinical manifestations of COPD by decreasing the pulmonary function parameters including peak expiratory flow and expiratory flow at 50% tidal volume, and improving pathological changes. Leo reduced lung inflammation and oxidative stress by reducing CD68+ cell infiltration, regulating Treg/Th17 cell differentiation, attenuating the production of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-17, increasing IL-10 secretion, and regulating malondialdehyde and glutathione peroxidase levels. In vitro experiments revealed that Leo exhibits similar inhibitory effects on Th17 cell differentiation and macrophage activation. Furthermore, Leo effectively protected against LPS-induced damage to bronchial airway epithelial cells by reducing reactive oxygen species production. Mechanistic investigations revealed Leo inhibits NF-κB transcriptional activity, downregulates the levels of p-p65, p-JAK2, and p-STAT3 without affecting their total protein levels.

Conclusion: Our results suggest that Leo exerts therapeutic effect against COPD. Leo inhibited tissue inflammation and oxidative stress in COPD rat models via inhibition of the NF-κB and JAK2/STAT3 signaling pathways.

Background: Successful pregnancy relies on the healthy completion of implantation, decidualization, and placentation. Additionally, the balance of the inflammatory response is crucial in processes such as trophoblast invasion, tissue, and vascular remodeling.

Objective: Our study aimed to assess the involvement of the NLRP3 inflammasome pathway during the peri-implantation period in mice treated with and without the NLRP3 inhibitor MCC950.

Materials and methods: Uteri during the estrous phase and uteri and implantation sites on days 1, 4, 5, 6, and 8 of pregnancy from mice with/without MCC950 treatment were collected. Serum was obtained from blood samples. The localization and expression of NLRP3 inflammasome pathway members NLRP3 and Gasdermin D were determined using immunohistochemistry. Additionally, protein levels of NLRP3, Caspase-1, Gasdermin D, IL-1β, and IL-18 were assessed using Western blot, while serum levels of IL-1β and IL-18 were measured using ELISA.

Results: The number of implantation sites in the MCC950-treated mice was lower than in untreated mice. The members of NLRP3 inflammasome pathway were observed to be intensely expressed at the implantation sites. NLRP3 was observed predominantly cytoplasmic on days 5, 6, and 8, while in the MCC950-treated mice, NLRP3 was translocated to the nucleus. Gasdermin D expression in subepithelial stroma cells during embryo implantation and invasion was decreased in the MCC950-treated mice. Serum IL-1β and IL-18 levels were high when embryo implantation began in peri-implantation period.

Conclusions: Our findings suggest that NLRP3 inflammasome pathway and inflammasome-dependent programmed cell death pyroptosis may play role during embryo implantation and decidualization.