Immunopharmacology and Immunotoxicology最新文献

The aim of this study was to evaluate the potential nephroprotective effects of telmisartan (TMS) and nicorandil (NIC) in rats treated with polymyxin B (PMB).

Rats were randomly allocated into four groups. Normal control; PMB (12 mg/kg/day, S.C. for one week); TMS + PMB (10 mg/kg/day TMS orally (p.o.) for two weeks); and NIC + PMB (3 mg/kg/day NIC, i.p. for two weeks). Both drugs were administered one hour prior to PMB for one week and continued for an additional week. At the end of the treatment period, animals were anesthetized, and blood and kidney tissue samples were collected for histological and immunohistochemical analyses, as well as assessments of renal function, oxidative stress markers, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptotic biomarkers.

The findings demonstrated that both telmisartan and nicorandil significantly improved renal function and attenuated oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis-related markers. Histopathological findings supported these results.

The renoprotective effects of telmisartan and nicorandil were mediated through modulation of the Nrf2/NQO1 antioxidant pathway and FAS/FASL apoptotic signaling, along with downregulation of renal expression of p53, cytochrome c, and caspase-3. These observations clearly indicate the protective role of both agents against PMB-induced nephrotoxicity.

ObjectiveDendritic cells (DCs) play a pivotal role in the progression of atherosclerosis by modifying cell surface markers and cytokine secretion. While vitamin D is recognized for its ability to suppress the maturation of DCs, its effects on fatty acid metabolism in DCs remain unclear. This study investigated the effects of vitamin D on fatty acid metabolism and maturation in bone marrow-derived dendritic cells (BMDCs) from control (CON) and Ldlr^-/- (ATH) mice.Materials and methodsSix-week-old male C57BL/6J mice were fed a control diet containing 1000 or 10,000 International Units (IU) of vitamin D₃/kg diet (CON-vDC or CON-vDS), while Ldlr^-/- mice were fed a Western diet containing 1000 or 10,000 IU of vitamin D₃/kg diet (ATH-vDC or ATH-vDS) for 16 weeks. BMDCs were differentiated from bone marrow cells for 7 days and treated with 1α,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) (0 or 10 nM) during the culture period. On day 6, BMDCs were stimulated with lipopolysaccharide (LPS) for 24 h to induce maturation.ResultsIn vitro 1,25(OH)₂D₃ treatment reduced surface marker expression including major histocompatibility complex class II (MHC II), cluster of differentiation (CD)80, CD86, CD40, and interleukin (IL)-12p70 production. AMP-activated protein kinase (AMPK) expression was higher in the vitamin D supplemented group. Moreover, in vitro 1,25(OH)₂D₃ treatment downregulated expression of fatty acid synthesis-related genes (Srebp1c, Acaca, and Fasn) in immature BMDCs. Fatty acid oxidation-related gene expression (Cpt1α and Pparg) increased in the CON group but decreased in the ATH group with in vitro 1,25(OH)₂D₃ treatment.ConclusionThese findings suggest that vitamin D may inhibit the mature BMDC phenotype by regulating fatty acid metabolism in BMDCs.

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.

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.

Objective: This mini review aims to synthesize current evidence on signaling mechanisms particularly classical and trans-signaling pathways, and also to evaluate the therapeutic potential of targeting IL-6 in thrombotic disorders.

Methods: The research design is to provide a focused and systematic literature survey of peer-reviewed studies focusing on the role of IL-6 signaling in DVT. Databases including PubMed, Scopus, and Web of Science were utilized using relevant keywords like "interleukin-6", "gp-130̎", "endothelial dysfunction", "IL-6 inhibitors", "deep vein thrombosis", and "IL-6 trans-signaling". The shortlisted articles were critically evaluated to integrate current knowledge on IL-6-mediated thrombo-inflammation, especially focusing on emerging therapeutic strategies such as monoclonal IL-6 receptor inhibitors and selective blockade of IL-6 trans signaling using sgp130Fc.

Results: Evidences demonstrated that sustained IL-6 trans-signaling contributes to endothelial dysfunction, hypercoagulability and thrombus formation. Pre-clinical and clinical studies indicate that IL-6 pathway inhibition can reduce thrombus burden, improve endothelial function and attenuate inflammatory and pro-coagulant states. Selective inhibition of IL-6 trans-signaling via sgp130Fc appears particularly promising, as it suppresses pathological inflammation while preserving the protective effects of classical IL-6 signaling.

Conclusions: Although IL-6 inhibitors are not currently approved for clinical management of DVT, growing evidence supports IL-6 as a key therapeutic target in thrombo-inflammatory disorders. Balancing the pleiotropic effects of IL-6 remains a challenge, however, selective modulation of IL-6 signaling, and synergy with anticoagulants, represent a promising strategy for improving DVT treatment outcomes. Further translation and clinical studies are required to optimize therapeutic approaches and patient selection.

Objective: Pharmaceuticals are emerging pollutants that have received great interest because of their discharge into aquatic ecosystems through wastewater worldwide. However, studies on the effects of these pollutants on aquatic animals are limited. Dexamethasone is a potent synthetic glucocorticoid with anti-inflammatory and immunosuppressive effects. Understanding how this medicine affects the immune response of fish was the topic of interest in the present study. The present study investigated the effects of dexamethasone on the innate immune response of the spleen and head kidney cells of Acanthopagrus arabicus in vitro.

Materials: Cultured spleen and head kidney cells were exposed to dexamethasone with various concentrations in vitro. After 48 h, the toxic effects of dexamethasone on innate immune factors were assessed.

Results: Based on the results, the sensitivity of cultured spleen and head kidney cells to dexamethasone increased in a concentration-dependent manner. Dexamethasone significantly decreased the number of IgM-secreting cells and IgM secretion. It also significantly reduced the C3 content of the cultivated cells but did not significantly alter the C4 and ACH50 contents or lysozyme activity of the cultivated cells. Furthermore, dexamethasone significantly suppressed respiratory burst activity and nitric oxide production in the spleen and head kidney cells.

Conclusions: In conclusion, the immunosuppressive effect of dexamethasone was due mainly to its suppressive effects on IgM-secreting cells and IgM production, C3 content, burst activity and nitric oxide production in the spleen and head kidney cells.

Background: After acute myocardial infarction (AMI), reperfusion therapy can help restore blood flow and nutritional support to the ischemic myocardium, thereby limiting ongoing myocardial injury. However, its effectiveness is increasingly challenged by myocardial ischemia-reperfusion (I/R) injury. In this regard, micheliolide (MCL) has been reported to exert beneficial effects in cardiovascular disease. Herein, we aimed to determine the mechanism underlying the cardioprotective effects of MCL in a rat I/R model.

Method: Rats were randomly divided into a control group, an I/R group, and an I/R + MCL group. After a two-week intervention, their serum and heart tissues were collected. Myocardial histopathology was assessed using Hematoxylin-Eosin (HE) staining, and cardiomyocyte apoptosis was evaluated by TUNEL staining. Levels of CK-MB, cTnI, BNP, TNF-α, IL-1β, and IL-6 in serum and cardiac tissue were measured using the enzyme-linked immunosorbent assay (ELISA). Commercial kits were used to measure cardiac MDA, SOD, GSH-Px, and ROS. Western blotting was performed to detect KEAP1, NRF2, and apoptosis-related proteins in the rats' cardiac tissues.

Result: MCL treatment reduced KEAP1 expression and increased NRF2 expression in myocardial tissue, decreased cardiomyocyte apoptosis, improved cardiac function, alleviated myocardial tissue damage, and lowered inflammatory and oxidative stress levels in I/R rats.

Conclusion: MCL regulates the KEAP1/NRF2 signaling pathway to reduce oxidative stress and inflammation, producing a cardioprotective effect in rats with acute myocardial infarction undergoing ischemia-reperfusion injury.

Context: Influenza is a viral infection with pandemic potential that affects individuals of all ages. The immune response is key to resolving the disease; however, immune deregulation, such as cytokine storm, can cause tissue damage and death. Diethylcarbamazine (DEC), a drug with immunomodulatory effects, has demonstrated anti-inflammatory and antifibrotic properties. However, DEC's activity in viral respiratory infections remains unknown.

Objective: This study aimed to analyze the effect of DEC in a model of respiratory epithelial cells infected with Influenza A (H1N1)pdm09 virus (IAV) to evaluate its action on antiviral immune effectors and viral titer.

Materials and methods: A549 cells were cultured, infected with IAV, and treated with DEC. Viral load was quantified at 24 h and 48 h. Subsequently, Cytokine levels (IL-1β, IL-6, IL-8, IL-10, IL-15, and RANTES) were analyzed from supernatants at both timepoints using a Bio-Plex Pro-Human Proinflammatory Cytokine kit. RNA was obtained from cells, and RT-qPCR was performed to evaluate the expression of genes encoding MYD88, NLRP3, NF-κB, IFN-β, and IFN-λ.

Results and discussion: Results showed that IFN-λ1 expression was consistent across all groups (p > .05). IFN-β expression increased at 24 h in DEC-treated infected groups (p < .05) but returned to baseline at 48h (p > .05). IL-8 secretion was significantly higher in the IAV + DEC20 group at 24h compared to the MOCK (p ≤ .05), but no differences were found at 48 h (p > .05). Infected cells treated with the lowest DEC dose showed a lower viral titer compared to IAV-infected (p ≤ .05).

Conclusion: DEC maintained IFN-λ1 expression, regulated levels of IFN-β and IL-8, and reduced viral load in IAV-infected epithelial cells.

Objective: Glucocorticoids (GCs) represent a vital group of steroid hormones naturally occurring in humans, with the ability to be synthesized artificially as well. They are essential in facilitating the normal physiological functions of mammals. Within typical physiological ranges, GCs chiefly contribute to the regulation of metabolism and the maintenance of homeostasis. When given in elevated pharmacological doses, GCs offer anti-inflammatory and immunosuppressive advantages, making them key treatments for various inflammatory conditions and immune-related disorders. By improving our understanding of glucocorticoid receptor (GR) biology and the molecular processes that underpin GC actions, we seek to clarify the influence of GCs on the immune system and their role in facilitating anti-inflammatory responses, ultimately offering insights for creating novel therapeutic approaches to enhance the beneficial effects of GCs.

Methods: This review conducts a thorough analysis of GR, elaborating on its structure, function, and involvement in inflammation by investigating the molecular processes that might enhance the efficacy of GCs in addressing both inflammatory and infectious disorders.

Results: The interaction between GCs and GR is crucial for regulating the expression of various inflammatory genes. This regulation occurs primarily through two mechanisms: transrepression and transactivation.

Conclusions: Both intracellular and extracellular signals modulate GR activity at various stages, underscoring the importance of understanding GR structure, activation processes, and the interplay of pathways to create innovative therapies that target GR signaling, either independently or in combination with other treatments.

Objective: This study developed triptolide-loaded liposomes (TPL) for intranasal delivery to mitigate systemic toxicity of free triptolide (TP) while enhancing therapeutic efficacy in neuroinflammatory and Alzheimer's disease (AD) models.

Methods: Biodistribution of luciferin liposomes was compared across oral, intravenous, and nasal routes using in vivo imaging. TPL was prepared via thin-film hydration with optimized phospholipid/cholesterol ratios. Safety profiles of intranasal TPL and TP were evaluated in wild-type mice. Efficacy was assessed in LPS-induced neuroinflammation and APP/PS1 AD models through behavioral tests, histopathology, and molecular analyses.

Results: Nasal administration demonstrated superior brain accumulation of luciferin liposomes compared to oral and intravenous routes. Optimized TPL exhibited spherical morphology with appropriate particle size, high drug encapsulation efficiency, and sustained release characteristics. Intranasal TPL showed reduced systemic toxicity relative to free TP. In disease models, TPL significantly improved behavioral and cognitive performance in both LPS-treated and APP/PS1 mice. Histopathological analysis revealed attenuated neuronal damage, reduced Aβ plaque deposition, and suppressed glial activation (IBA-1 and GFAP expression). Molecular studies demonstrated downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, COX-2, IL-6) and apoptosis markers (Bax, Caspase-3), accompanied by increased expression of survival-related proteins (p-Akt, Bcl-2).

Conclusions: The nasal TPL delivery system effectively enhances brain targeting of TP while reducing systemic exposure. Its multimodal mechanisms-including anti-inflammatory effects, amyloid pathology modulation, and apoptosis regulation-support therapeutic potential for neurodegenerative disorders.