Immunopharmacology and Immunotoxicology最新文献

Background: Psoriasis and recurrent aphthous ulcers are chronic inflammatory disorders characterized by overlapping immunopathogenic mechanisms, including dysregulation of the interleukin-23/T helper 17 cell (IL-23/Th17) axis, innate immune hyperactivation, and microbial-immune dysbiosis. A shared molecular feature is aberrant phosphodiesterase-4 (PDE4) activity, a central regulator of cyclic adenosine monophosphate (cAMP) signaling and pro-inflammatory mediator production.

Objective: This review aims to synthesize the shared immunopathological landscape between psoriasis and oral aphthous ulcers and to evaluate PDE4 inhibition as a unifying therapeutic strategy based on this common pathophysiology.

Findings/results: The analysis underscores significant mechanistic convergence between the two conditions, positioning PDE4 inhibition as a promising targeted approach. Roflumilast, a potent PDE4 inhibitor, exemplifies this translational potential. Its topical formulation (0.3% cream) is FDA-approved for plaque psoriasis, with phase 3 trials confirming sustained efficacy and a favorable safety profile. In parallel, systemic (oral) roflumilast demonstrates promising clinical activity in oral ulcer management, with studies in Behçet's disease and refractory aphthosis reporting substantial reductions (80-89%) in ulcer frequency and severity.

Conclusion: The shared pathophysiology between psoriasis and recurrent aphthous ulcers provides a strong rationale for repurposing PDE4 inhibitors across these conditions. This review advocates for accelerated translational efforts to evaluate topical roflumilast specifically for oral ulcer management and to broaden its therapeutic application across other chronic inflammatory diseases guided by precision immunomodulation principles.

Background: This study aims to clarify clinical manifestations, diagnostic methods, treatment approaches, and prognostic outcomes of anti-programmed death (PD-1)/programmed death- ligand 1(PD-L1) drugs-induced dermatomyositis (DM).

Methods: This study conducted a retrospective analysis of DM cases induced by anti-PD-1/PD-L1 agents. Through systematic retrieval of relevant databases up to May 7, 2025, case reports were comprehensively collected and comprehensively evaluated.

Results: A total of 49 patients were enrolled, with males accounting for 75.5%. The median age was 66 years (15-85 years). After receiving anti-PD-1/PD-L1 drugs for various tumors, especially lung cancer and melanoma, 35 patients (71.4%) developed de novo dermatomyositis. Notably, compared with patients with a history of dermatomyositis, those with de novo dermatomyositis experienced symptom onset after a longer duration and more treatment cycles of anti-PD-1/PD-L1 drugs. For intervention and treatment strategies, 39 patients (79.6%) discontinued anti-PD-1/PD-L1 drugs, while only 2 patients (4.1%) continued treatment. Following clinical interventions including systemic steroid therapy, immunoglobulin administration, and other immunosuppressive agents, the skin- and muscle-related symptoms of the vast majority of patients improved or completely resolved.

Conclusion: During anti-PD-1/PD-L1 therapy, closely monitor patients' cutaneous and muscular symptoms to detect DM early. For diagnosed DM patients, implement timely interventions according to symptom severity.

Objective: Rheumatoid arthritis (RA) is a chronic inflammatory disease that can cause serious joint destruction if not properly managed. Despite established treatments, many patients struggle to find meaningful relief, emphasizing the need for new treatments. Galantamine (GAL), a naturally occurring alkaloid and acetylcholinesterase inhibitor with anti-inflammatory effects, has showed promise in preclinical RA research.

Methods: This systematic review assessed GAL's potential in RA by searching PubMed, Scopus, ISI Web of Science, and Google Scholar until June 2025, with no language or date restrictions. We omitted review articles, conference abstracts, book chapters, and studies that combined GAL with other substances or diseases. There was no human or in vitro research found, so seven eligible animal studies were analyzed.

Results: Evidence suggests that GAL improves RA outcomes by lowering inflammation and oxidative stress, blocking angiogenesis, and exhibiting anti-arthritic effects. These findings imply that GAL could be an effective treatment for RA. However, the available evidence is limited to animal models, and well-designed clinical trials are required to prove its efficacy and safety in people.

Conclusion: This review emphasizes GAL's therapeutic potential as well as the critical need for translational research to bridge the gap between preclinical and clinical applications.

Objective: Dendritic 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 methods: Six-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.

Results: In 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.

Conclusion: These findings suggest that vitamin D may inhibit the mature BMDC phenotype by regulating fatty acid metabolism in BMDCs.

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.

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.

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.

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.

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.

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.