International immunopharmacology最新文献

Background: Neuroinflammation and programmed cell death are two key pathogenic processes that contribute to poor patient outcomes in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Neuronal pyroptosis in SAH has been explored in connection to berberine (BBR), a naturally occurring isoquinoline alkaloid having neuroprotective properties. However, its precise role and molecular mechanisms in this case remain unknown.

Objective: To investigate the protective effects of BBR on EBI following SAH and elucidate its potential molecular mechanisms.

Methods: Network pharmacology and molecular docking techniques were employed to identify core targets and pathways of BBR. In vivo experiments: A mouse SAH model was established via intravascular puncture. Groups included sham surgery, SAH model, BBR treatment, and BBR combined with GSK3β overexpression. Neurological function, cerebral edema, blood-brain barrier permeability, and key molecules in the pyroptosis pathway were assessed using neurological function scoring, brain water content measurement, immunofluorescence, and Western Blot techniques. In vitro experiments simulated SAH injury by exposing HT22 hippocampal neurons to oxygenated hemoglobin (OxyHb). BBR's effects were validated using CCK-8 assays, fluorescence analysis, qPCR, and Western Blot. Mechanistic rescue experiments employed GSK3β agonists.

Results: Network pharmacology predicted GSK3β as a key target of BBR, enriched in the pyroptosis pathway. In vivo experiments demonstrated that BBR significantly improved neurological deficits in SAH mice and reduced cerebral edema and blood-brain barrier disruption while simultaneously inhibiting GSK3β activation in cortical neurons and downstream Caspase-1 cleavage, GSDMD-N fragment generation, and IL-1β maturation. However, intracerebroventricular overexpression of GSK3β reversed these protective effects of BBR. In vitro experiments further confirmed that BBR concentration-dependently inhibits OxyHb-induced pyroptosis and inflammatory responses in HT22 neurons, while GSK3β overexpression significantly antagonizes its protective effects.

Conclusion: BBR alleviates EBI following SAH by targeting GSK3β inhibition, thereby blocking the caspase-1/GSDMD-dependent neuronal pyroptosis pathway.

Kidney tubular cell death caused by elevated blood sugar levels plays a significant role in the progression of diabetic nephropathy (DN). Recent studies have highlighted ferroptosis, a form of regulated cell death, as a critical mechanism underlying tubular cell death in DN. Ubiquitin-specific protease 38 (USP38) has been identified as a key modulator of the ferroptosis process; however, its role in renal tubular cell ferroptosis and DN progression remains unexplored. This study aimed to investigate whether USP38 adjusts ferroptosis in renal tubular cells and its impact on DN progression, elucidating the underlying mechanisms involved. USP38 levels were markedly increased in HK-2 cells stimulated with high glucose (HG) and in the kidneys of diabetic mice. Knockdown of USP38 mitigated HG-induced damage and fibrosis while inhibiting ferroptosis in HK-2 cells; conversely, overexpression of USP38 exacerbated these effects. Further investigations revealed that USP38 modulated the expression of iron metabolism-related proteins, including responsive element binding protein 2 (IREB2), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), and transferrin receptor protein 1 (TfR1). Mechanistically, USP38 was found to directly interact with IREB2 and regulate both its ubiquitination and stability. Moreover, overexpression of IREB2 significantly reversed the inhibitory effect of USP38 silencing on ferroptosis. In vivo experiments demonstrated that USP38 knockdown alleviated renal damage, fibrosis, and inflammation while suppressing iron overload and ferroptosis in DN mice. In conclusion, USP38 mediates renal tubular cell ferroptosis under HG conditions through IREB2-mediated iron overload. Targeting USP38 to prevent tubular epithelial cell ferroptosis may effectively mitigate DN progression, providing a novel regulatory mechanism and potential therapeutic target for this disease.

Chronic obstructive pulmonary disease (COPD) is a global public-health concern due to its currently high morbidity and mortality. Cigarette smoke (CS) exposure, the primary inducer of COPD, can provoke ferroptosis in lung epithelial cells. Melatonin, a neurohormone, has potential anti-inflammatory and anti-oxidative capacities. In this study, we investigated the protective effects of melatonin on CS exposure-induced COPD mice, and its underlying mechanisms of actions. The results showed that CS exposure caused obvious lipid peroxidation and the accumulation of ferrous (Fe²⁺) with the decreased expression of melatonin receptor (MT), thus triggered ferroptosis of lung epithelial cells in vitro and in vivo. In vitro, melatonin upregulated xCT, GPX4 and ferritin (FTH1/FTL) expression, reversed the CSE-induced ferroptosis depending on activated MT with the elevated phosphorylation of cAMP response element-binding protein (CREB^ser133). CREB knockdown (KD) caused melatonin failure to upregulate GPX4 and FTH1/FTL expression, thus did not inhibit CSE-induced ferroptosis of airway epithelial cells. Moreover, after suppressing the transcriptional regulation of p-CREB, melatonin again failed to promote GPX4 and FTH1/FTL expression and inhibit CSE-induced ferroptosis. The mechanistic dissection showed that melatonin led to the nuclear translocation of p-CREB which in turn bound to the promoter regions of GPX4 and FTH1/FTL genes, promoted their expression. In CS-induced COPD mice, melatonin alleviated pulmonary inflammation, emphysema and airway remodeling, improved lung function via activating the CREB-GPX4/ferritin signaling axis and inhibiting ferroptosis of pulmonary epithelial cells. Taken together, our findings indicates that melatonin inhibits CS-induced ferroptosis via activating CREB-GPX4/ferritin axis depending on activated MT. These findings can help lead to promising protective strategies for COPD.

Osteoarthritis (OA) is a common degenerative joint disease, mainly characterized by cartilage extracellular matrix (ECM) degradation, inflammatory response and chondrocyte apoptosis, with mitochondrial dysfunction as its key pathogenic factor. Melittin (Mel), the main active component of bee venom, has been confirmed to possess anti-inflammatory, antioxidant and anti-apoptotic effects, but its therapeutic effect and specific mechanism on OA have not been fully elucidated. This study explored the therapeutic effect and mechanism of Mel on OA through in vitro and in vivo experiments. In vitro experiments showed that Mel could dose-dependently reverse IL-1β-induced OA-like changes in rat chondrocytes: it not only upregulated ECM anabolic markers such as type II collagen (COL2) and aggrecan (ACAN), downregulated ECM catabolic markers such as matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5), but also inhibited inflammatory markers such as IL-1β, IL-18, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), while restoring PINK1/Parkin-mediated mitophagy. Mechanistically, Mel exerted a protective effect against the pathological progression of OA induced by destabilization of the medial meniscus (DMM). In conclusion, Mel is expected to be a potential candidate for OA treatment.

Background: Acute lung injury (ALI) is a highly fatal inflammatory disease, lacking of safe and effective therapeutic drugs. Anti-inflammatory treatment is an effective strategy of ALI.

Purpose: This study aimed to identify compound 24, a novel dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) inhibitor, as an anti-inflammatory agent for ALI.

Methods: We established the LPS-induced RAW 264.7 cell inflammation model and the mouse ALI model. ELISA and real time-PCR (RT-PCR) were used to detect the levels of inflammatory factors in supernatant and lung. Reactive oxygen species (ROS) production was measured by flow cytometry using DCFH-DA. HE was used to determine the pathological damage of lung. Immunohistochemistry was applied to detect inflammatory biomarkers in lung. The infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF) was determine by flow cytometry. Molecular docking, cellular thermal shift assay (CETSA), and western blot (WB) were conducted to measure the drug-target interaction and inflammatory signaling.

Results: Pretreatment with compound 24 significantly reduced the levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitric oxide (NO), and ROS in vitro, and alleviated the release of inflammatory factors, infiltration of inflammatory cells, and tissue damage in the lung. Mechanistic studies indicated that compound 24 might exert its anti-inflammatory effect by targeting DYRK1A and inhibiting the TLR4/NF-κB signaling pathway.

Conclusions: In summary, compound 24 exerted anti-inflammation effect with potential value for further development into a therapeutic drug for ALI treatment.

Immune checkpoint blockade has revolutionized clear cell renal cell carcinoma (ccRCC) treatment, yet therapeutic resistance remains a significant clinical challenge. Aberrant glycosylation contributes to tumor progression and immunotherapy resistance. However, the specific glycans and corresponding immunomodulatory receptors involved in ccRCC remain poorly understood. Here, we identify polysialylated CD56 (PSA-CD56) as a key glycan-mediated immune regulator that drives immunosuppression in ccRCC through engagement of Siglec-7. Elevated PSA-CD56 expression was inversely correlated with CD8⁺ T cell infiltration and predicted inferior responses to immunotherapy. Genetic ablation of NCAM1 (encoding CD56) in renal epithelial cells suppressed tumor growth and enhanced CD4⁺ and CD8⁺ T cell infiltration in vivo. Mechanistically, PSA-CD56, but not its non-polysialylated form, directly bound to Siglec-7 on CD8⁺ T cells, suppressing the production of IFN-γ and TNF-α and promoting T cell apoptosis. Importantly, blocking the PSA-CD56/Siglec-7 interaction with specific antibodies restored T cell effector functions and triggered apoptosis of ccRCC cells. Our study unveils the PSA-CD56/Siglec-7 axis as a novel glyco-immune checkpoint, which represents a promising target for therapeutic interventions in ccRCC.

Exosomes, extracellular vesicles secreted by various cell types, encapsulate specific microRNAs that play a critical role in biological processes, particularly intercellular communication. Exosomal microRNAs play a significant role in health and disease, as they regulate gene expression, modulate immune responses, and influence various signaling pathways. In healthy individuals, exosomal microRNAs contribute to homeostasis by facilitating tissue repair, regulating metabolic processes, and maintaining effective cellular communication. However, dysfunction in their activity may result in various health concerns, including cardiovascular disorders, neurological diseases, and cancer. This review will explore biogenesis, mechanisms of action, and roles of exosomal microRNAs in health and disease. A comprehensive understanding of these biomarkers highlights their potential as diagnostic tools and therapeutic targets, thereby paving the way for innovative disease management strategies and the advancement of personalized medicine. Notably, most therapeutic applications of exosomal miRNAs remain at the preclinical or early translational stage, and further standardization and clinical validation are required before widespread implementation.

Sepsis, a systemic inflammatory response syndrome caused by infection, can lead to life-threatening multi-organ dysfunction. Among its complications, sepsis-induced cardiomyopathy (SIC) represents one of the most severe conditions with poor prognosis. Currently, pharmacological options for clinical management of SIC are limited and often yield suboptimal outcomes, necessitating the urgent exploration of novel therapeutic strategies. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, possesses a variety of biological properties. Importantly, recent studies have highlighted the crucial protective role of GDF11 in various cardiovascular diseases. However, to date, there have been no reports on the alterations and effects of GDF11 in SIC. In this study, we initially observed a significant downregulation of GDF11 expression in both myocardium and serum of C57BL/6 J mice treated with lipopolysaccharide (LPS). Subsequently, through endogenous overexpression of GDF11 or exogenous supplementation with recombinant GDF11, we found that GDF11 mitigated lipid peroxidation-dependent ferroptosis by inhibiting iron accumulation and ameliorating mitochondrial dysfunction, thereby alleviating cardiac dysfunction and myocardial injury in septic mice. Additionally, our cellular experiments demonstrated that GDF11 could also inhibit LPS-induced ferroptosis in neonatal mouse cardiomyocytes. Nevertheless, blocking the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway using ML385 in vivo or Nrf2 siRNA in vitro abrogated the above protective effects of GDF11 against SIC. Taken together, our findings show that GDF11 may alleviate SIC by inhibiting cardiomyocyte ferroptosis through activation of the Nrf2 signaling pathway, suggesting GDF11 as a potential therapeutic target for treating patients with sepsis.