Immunopharmacology and Immunotoxicology最新文献

Objective: This study aimed to assess the effect of chronic administration of Monosodium Glutamate (MSG) on blood cells, thymus, spleen, and inflammatory indicators through interleukin (IL)-17 and interleukin (IL)-10 gene expression levels in blood and in thymic and spleen tissues in male Wistar rats.

Methods: Rats were treated with MSG orally once daily for 90 days at two different doses with and without probiotic supplementation (Bacillus Subtilis and Bacillus Pumilus). Blood samples were collected for CBC, IL-10, and IL-17 gene expression in blood. The spleen and thymus were taken for histological and immunohistochemical studies.

Results: WBC results showed no significant difference among groups. A statistically significant higher mean IL-10 was observed among the low dose with probiotic (group 4) compared to other groups. There was a significantly higher mean of IL17 among low dose without probiotic (group 2). The mean level of IL-17 was high among group 4. Sections from thymus and spleen of MSG groups showed histological derangement. Immunohistochemical staining in tissues supported the observed gene expression levels in blood. Groups with higher cytokine gene expression generally showed stronger tissue staining, confirming consistency between transcription and protein levels and this strengthens interpretation of MSG-induced immune alterations.

Conclusion: High-dose MSG was associated with a decreased level of IL-10 with various degrees of tissue inflammation. Adding probiotics to low-dose MSG resulted in increased levels of IL-10 in blood. The low serum level of IL-17 in the high-dose MSG groups was associated with high degrees of inflammation with little improvement with probiotic.

Objective: Sepsis-induced cardiotoxicity (SIC) is a critical complication characterized by inflammation, oxidative stress, and apoptosis, leading to myocardial dysfunction. The short-acting opioid analgesic remifentanil (REMI) possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the cardioprotective effects of REMI on lipopolysaccharide (LPS)-induced SIC by examining inflammation, oxidative stress, apoptosis, and mitochondrial function.

Materials and methods: Thirty-two female Wistar albino rats were divided into four groups: control, lipopolysaccharide (LPS), LPS+REMI, and REMI. Myocardial and aortic tissues were analyzed for histopathology, immunoexpression of Caspase-3 (Cas-3), nuclear factor kappa beta (NF-κB), and tumor necrosis factor alpha (TNF-α). Oxidative stress markers, including total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), were measured. Mitochondrial apoptosis-related gene expression of AMP-activated protein kinase (AMPK), BCL2 Associated X (BAX), B-cell lymphoma 2 (BCL-2), Sirtuin 1 (SIRT1), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was assessed.

Results: LPS administration induced severe histopathological damage, increased oxidative stress (elevated TOS and OSI), and upregulated apoptotic (Cas-3, BAX/BCL-2 imbalance) and inflammatory (NF-κB, TNF-α) markers. REMI treatment significantly alleviated myocardial and aortic injury, reducing the histopathological score. It markedly decreased Cas-3, NF-κB, and TNF-α expression, lowered TOS and OSI levels, and modulated the BAX/BCL-2. Furthermore, REMI restored the expression of AMPK, SIRT1, and PGC-1α genes, indicating a protective effect on mitochondrial biogenesis and energy metabolism.

Conclusions: REMI exhibits significant cardioprotective effects in LPS-induced SIC by attenuating inflammation, oxidative stress, and apoptosis while preserving mitochondrial homeostasis.

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.

Objectives: Recently, cancer rates have increased among women of reproductive age. As a result, chemotherapy exposure is a common cause of premature ovarian failure (POF). The present study evaluated Losartan's protective effects against cyclophosphamide (CP)-induced POF.

Methods and results: Forty female nuligravid Sprague-Dawley rats were used. Rats were randomly placed in four groups: Group I (control group); Group II (losartan group); received Losartan 100 mg/kg daily by gavage oraly for 30 days; Group III (POF group): POF was induced by intraperitoneal injection of 50 mg/kg of CP on day one of the experiment and then 8 mg/kg/day for fifteen serial days; Group IV (Losartan + POF group): received losartan 100 mg/kg daily for thirty days one hour before CP intraperitoneal dosage of 50 mg/kg on the first day of the experiment and then CP has given in a dose of 8 mg/kg/day for fifteen successive days. Physiological sera of blood and tissue samples were evaluated biochemically, hormonally, and histopathologically at the end of the experiment. Losartan treatment improved E2, FSH, LH, and oxidative stress biomarkers. Furthermore, coadministration of Losartan to the POF group exhibited a significant lessening in systolic blood pressure, a significant improvement in ovarian blood flow velocity, and a significant decline in ovarian vascular resistance related to the POF group. Furthermore, Losartan reduced the histopathological and immunohistochemical alterations, enhanced SIRT1 gene expression, and decreased NF-κB gene expression.

Discussion: Our findings suggest that Losartan protects rats from cyclophosphamide-induced ovarian toxicity.

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.